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INTEGRATING
NEW PRODUCTS & TECHNOLOGIES INTO PRACTICE NAVIGATING THE Marc E. Gottlieb, MD, FACS Revision 01-b,
January 21, 2011, (Revision 01-a, October 2, 2010), Copyright © 2009 - 2011 |
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This presentation was first given on September 26, 2009 at the
Baptist Health South Florida 4th Annual Wound Symposium. As a new presentation, the organization and
flow may seem a bit disjointed and redundant, but sure to improve if I am
asked to do this topic again.
Nonetheless, the subject is an important one, and hopefully you will
find something useful here to help you work your way through the barrage of
new products that show up every year. This is all about to how identify and analyze useful new
products. Why? Because all of us want to get the best
results for our patients. If your
quintessential psyche is more oriented towards people and patients, then you
want them to have the best, speediest, most expeditious and trouble free
results that they can. If your soul is
more focused on the science and techniques, you want your patient projects
and scientific investigations to have the best results. Either way, we all want the same thing –
the best results – and we are all always looking for the next best thing that
gives us the best results. This
presentation is all about navigating the ocean of new products. |
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Nowadays we seem to live in an environment of phony political
correctness and petty pencil pushers who need to tell everyone else what is
administratively proper and morally righteous. These are the folks who tell you that
accepting a pen or pad of paper from a drug rep is tantamount to the 8th
deadly sin and a violation of the 11th biblical commandment. In a society where form has become far more
valued than substance, it is assumed that you, the educated professional, are
too naive to discriminate legitimate knowledge from hucksterism and
proprietary pitches. A presentation
can totally suck as long as the presenter has signed a waiver that neither he
nor his forebears nor his sire unto the tenth generation has not now nor ever
nor ever will own nary a penny share in the stock of those nefarious
ne’er-do-wells, the inveiglers of immoral, illegal, illicit, and illegitimate
ill-gotten wealth, the fear mongers of medicinal manufactures, the
mind-bending minions of the medical-industrial complex, the conspirators of
commerce and the corrupters of conscience, the Companies. Somebody has to speak up for the truth. So, I start this presentation on a
thoroughly iconoclastic note. I refuse
to make the usual disclaimers. You
judge for yourself if what here is of value.
Instead, I start with an emphatic NON-disclaimer. First,
why am I giving this talk? Because I
was asked to. This is the last subject
in the world I might have thought of giving.
But as I pondered how much I would hate preparing this talk, it
started to make some sense. Having
been through 9 years of surgical residency and 25 years of practice, I have
evaluated and used countless new products.
I have done my fair share of trials (and errors), and some real
science, clinical development, and publication. I guess what I have been good at, and why I
work with a variety of companies, is that I have been able to successfully
take new products and concepts and figure out what to do with them and how to
make them work and integrate them into effective everyday practice. Second, we must
mention the necessity of manufactures.
Without products and the companies of skilled tradesmen who make them,
we would have none of what makes civilization so. It is nice to romanticize about a return to
a simpler aboriginal past. Poets and
philosophers and artists have done it for ever, but even Henry David Thoreau
was able to take Third, we need to
acknowledge products and their proprietary names. The products that keep us out of caves all
have names, not pretentious, sanctimonious, over righteous, politically
correct euphemisms. If I refer to the
facial tissue as Kleenex, or to the pen as a Bic, we all get it. Of course there are other companies with
competing products and trademarks, but in wounds (and medicine in general),
we use a lot of singular tools and products with no competition, no generic
designation, and no pronounceable name other than their well known
proprietary ones. I have a name, you
have a name, we all identify things by their names. So, if I mention a product by name, let the
political correctionists bemoan the fall of civilization and their loss of
petty control. I don’t care. Nor should you. I will do my part and teach. You will do your part and take it all in
and decide if it is meritorious and worth remembering. (And no, I do not own stock nor proprietary interests in any
company I am discussing, but even if I did, you decide . . .) (The image is a
watercolor illustration, one of several painted by artist-illustrator N. C.
Wyeth to illuminate the novel “Arizona Nights” by Stewart Edward White,
1907.) |
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Integrating New
Products and Technologies into Practice #1 New products, why they are important, and why
you should care. Medical arts and sciences evolve, and all practitioners will, in
the course of their careers, be expected to understand the advances that
support better care of the patient – new medical knowledge and also new
products and their usage. Writing home on
an adjustable table. From “Hospital Life
in |
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To illustrate the value of worthy new products, let us start
with a case presentation. This was a
very recent patient, 74 year old woman, with a chondrosarcoma of chest and
abdominal wall. Excision of the tumor
was legacy surgery – just cut it out – but the reconstruction was based on a
combination of new knowledge, new concepts, and new products. The easy efficient uncomplicated good
results of this case were achieved doing an operation that was neither
possible nor conceivable just 25 years ago when I started my surgical practice. The open chest and abdomen needed structurally stable repair
which would endure for years without the need for later hernia surgery. Alloplastic knitted meshes have been with
us for 50 years. Used properly, they
make a structurally sound and long durable abdominal wall substitute. However, we have seen over the years that
they also have a high incidence of late inflammatory complications, bowel
adhesion-obstruction-perforation-fistula.
In the interests of increased biocompatibility, biomatrices of
cadaveric dermis and fascias have come to market. In this case, a layer of cadaveric dermis
was used as the first layer of the reconstruction for its
biocompatibility. A conventional
alloplastic mesh was then used for structural replacement, because this was a
true excised abdominal wall defect, and not just a ventral hernia in which
the native muscles and fascias could have been repaired. The artificial mesh needs living tissue
coverage, and this was done by the simplest trouble free method there is,
using a flap of omentum, transposed on a thin proper-omental pedicle (making
sure that the traverse between matrices and native abdominal wall was
properly overlapped and sealed to avoid late herniation). In the past, simple skin grafts would have
covered the omentum (still a perfectly legitimate thing to do), but in the
interest of avoiding long term scar contractures on this flexor surface, a
regenerative collagen-gag matrix was used for dermal regeneration. Rather than using conventional “tie-over”
compression dressing to splint all of this, a negative pressure wound device
was used for the fixation for the sake of comfort over the next 4 weeks. When the dermal matrix was regenerated, the
final skin graft was placed. Note that
this reconstruction made no further incisions on the body, required no
autogenous flaps (other than the trivial use of omentum), created no
additional pain, created no risk of donor site morbidity nor deficits, had no
risk of flap failure nor dehiscence, has no risk of future herniation,
required almost no hospitalization, and had virtually no risk of failing, all
with predictable and dependable good results that will endure for the
remainder of the patient’s life, all in a short one hour initial case (plus
the later skin graft). Images: top left, an mri showing the
tumor; top right, lines of excision marked around the tumor; mid
left, open lung, liver, bowel after resection; mid
right, insetting the matrices; bottom left, 3 weeks later, the
Integra collagen-gag matrix regenerating and ready for skin grafts; bottom
right, the healed reconstruction about 4 weeks after skin grafts. As a resident in plastic surgery, I was taught to do a
reconstruction like this with large autogenous flaps carved from elsewhere on
the abdominal wall or other nearby structures, or to use fascia lata grafts
and large skin flaps. A good secure
reconstruction could be counted on, but not necessarily with good long term
competence of the abdominal wall, and with a host of acute risks, complications,
and potential failures at the primary site and also the donor sites. Pain, long stay hospitalization, and
various donor site problems could be anticipated. I have done it all ways: legacy operations the way my professors did
it circa 1940-1970, then now-legacy operations that I was taught to do circa
1970-2000, and now this stuff with simple procedures using regenerative
materials, circa 2000 and on. This
“new way” I have had to learn and develop in the real world of everyday
practice as new concepts have evolved and new products have appeared to
support and implement those concepts.
This reconstruction had six distinct elements: alloplastic mesh, omentum flap, and skin
grafts which can be considered traditional surgery in use for 30 years or
more; and cadaveric matrix,
regenerative dermal substitute, and a negative pressure device, all items of
the past 15 years or less. All
surgeons must make their own choices about technique, but for me, I cannot
see any value in doing this the way I learned about it 30 years ago. Good concepts and knowledge are crucial in
all of these advances, but they mean nothing without a company to make the
devices and materials that support those concepts. |
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This and the next two slides are a “gallery of the new”. These are all patients and problems from my
own practice. They represent the
things that I take care of week in and week out, and things that I find
especially interesting and get my own special attention. That is how progress is made – somebody
gets interested enough in a problem to think about it and see a way to get to
a solution or a better method.
Sometimes you will be the innovator with the novel solution. Many times you will be picking up what some
other innovator has discovered, what some other company has made, and figure
out how to make it work for yourself, or to extend the utility and scope of
it beyond what was originally conceived.
The problems illustrated on these three slides have one thing in common
– they are all new concepts of the past 15 years or less, things that I did
not learn as a resident, things that have supplanted legacy practice because
they work so well (easier, safer, fewer complications, more dependable,
better results), things that were wholly contingent on the availability of a
product made by some company. Integra
collagen-gag matrix: This is an artificial
skin and regenerative matrix made from collagen and chondroitin. Originally developed for burn care, it
proved to have remarkable properties, and it is one of the most significant
advances and products in reconstructive surgery in recent memory. It has a duality of effects. Acutely it is a very high quality
artificial skin. When applied to large
wounds (burns, fasciitis, degloving), patients rapidly get systemically
better. When applied to pathological
wounds, inflammation and necrosis immediately cease. Its second role is as the agent of skin
regeneration, but unlike ordinary surgery, it arrests normal wound healing
and instead triggers an embryonic type of tissue formation without scar. It is a new paradigm in surgery that is not
contingent on normal wound healing, and it has found a multitude of uses for
acute wound care, chronic wound care, and plastic surgical
reconstruction. Illustrated is a
patient with a 40 year history of leg ulcers and undiagnosed Sjögren’s. Reconstruction and healing of these chronic
immunopathic ulcers is impossible with anything that depends on normal wound
healing, but is predictable and dependable with Integra, and Integra has become
the standard for closing large immunopathic wounds. Sternal ORIF: Sternal dehiscence after heart surgery was
considered a lethal event in the 1960’s.
By the 1980’s, good plastic surgery with conventional large flaps
solved the mortality problems, but it was still an issue of prolonged care
and morbidity with various acute complications, long hospital stays, and late
sequelae. This is a problem in which
conventional “dictates”, in the truest sense of that word, the “emperor’s new
clothes syndrome”, and a hegemony of misunderstanding of the problem by those
in charge of it have turned a simple issue into death and chaos for countless
people over the past 55 years. Heart
surgeons are not bone surgeons and they are not pus and wound surgeons, so
when they get these problems, it always turns into a freakout that treats
patients like they are ultra sick until that prophecy is fulfilled. The problem is simply one of sternal
mechanics, easy to understand, and easy avoid if you are a bone surgeon, and
easy to manage and fix if you are a wound surgeon. Poor sternal fixation with twist wires (the
non-bone heart surgeon’s traditional and only method of sternal closure)
leads to sternal rupture and pseudarthrosis, nothing more, nothing less. If the problem happens, then you do
conventional wound care until clean enough for reclosure, and then you close
it the way all other bones are fixed, with rigid screw-fixated hardware. The problem can be preempted by plate and
screw fixation as well. By using good
wound care and plate-and-screw hardware, much of this problem can be managed
as an outpatient with little or no morbidity.
The switch from antiquarian no care circa 1960, to what I learned as a
resident, legacy sternectomies and big flaps circa 1985, to simplified safe
effective bone and wound care of the past 15 years is a fundamental change
that was contingent on the products to make it happen, the plates and
screws. You can read more about this
at the Arimedica website, and also in the journal Wound Repair and
Regeneration: - Resolving sternal wounds by hardware fixation, Gottlieb
ME. Wound Repair & Regeneration,
13:A4-A27, March, 2005. - Online DOI:
10.1111/j.1067-1927.2005.130215a.x -
http://onlinelibrary.wiley.com/doi/10.1111/j.1067-1927.2005.130215a.x |
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Apligraf: Apligraf is an engineered living skin
equivalent. It is normal
quintessential skin, dermis and epidermis, grown in culture from donor
foreskin fibroblasts and keratinocytes.
It represents a class of wound treatments, the living cell therapies,
which seem so promising for problem wounds.
It is essentially a pharmaceutical packaged in a living vehicle, and
the biochemistry created by these juvenile cells has a potent effect to
stimulate wound healing. The photos
show a plantar wound following trauma in an otherwise seemingly healthy
person. The wound had become chronic,
and the top image shown was taken many months after the initial events. The two center photos confirm that 8 weeks
of simple adjustments to topical care were not effective. Within 3 weeks of placing the Apligraf, the
wound is nearly healed (and did heal within the next 2 weeks). There will be more about this product on a
later slide, but it is one of those fundamentally different therapies that
solves problems and gets results that has come on the scene in the past 10-15
years, and which has forced
practitioners to rethink what they think they know and how to do things. Botulinum toxin
A: One of my most favorite
operations by far in my career as a surgeon has been the digital
sympathectomy and angiolysis. It is
done for the problem illustrated, digital ischemia and ulceration due to
lupus angiopathy. This is the
fibrostenotic occlusive arteriopathy of the hand and foot that results from
repetitive acute arteritis, most commonly with lupus and
scleroderma-crest. The operation,
usually done at the wrist and in the palm, strips away the arterial
adventitia to eliminate sympathetic nerve fibers (the digital sympathectomy
part), and it can strip away the media in order to correct the fibro-stenosis
(the angiolysis part). This operation
is essentially 100% effective for patients, and nearly 100% effective for
fingers, meaning that all patients have some degree of therapeutic response,
and nearly all ulcerated fingers heal.
For those who are not yet ulcerated or are in early phases of
ulceration and do not need surgery, the same thing can be achieved by
chemical sympathetic blockade, using local anesthetic (bupivicaine) blockade
of the vessels in wrist and hand. I
had many patients who would come in for these blocks, especially during the
cold months. Just like the operation
itself, these blocks would turn the hand warm and pink, relieving pain and
allowing skin lesions to heal. The
drug only lasts several hours, but the effects could last a month, and such
patients would typically come back every month or so during the winter to get
the blocks repeated. Between the
blocks and surgery, I thought we had good dependable treatment for this
problem. And then, all in an instant,
that changed 4 years ago. Some reports
appeared that botulinum toxin A had a variety of neuromuscular effects beyond
just skeletal muscle blockade, and that sustained peri-arterial sympathetic
blockade could be achieved by using the toxin. Favorable results were reported by a couple
of groups at the hand meetings in 2005 and 2006. The technique is the same as I have always
done with anesthetics, but the effects can last for many months. Instantaneously, my practice changed, and I
started using botulinum toxin in lieu of surgery. The results have been amazing. Almost every finger has healed. Every patient gets symptomatic relief for about
4 to 9 months. This is easy to gauge,
because our once-a-month patients now get through the winter on one block and
come back only after these long intervals.
The drug achieves only the sympathectomy effect, not the angiolysis,
so for a rare patient, the surgery is still required. However, having consistently done several
of these operations every year for the prior 10 years, I have now done only 2
operations in the past 4 years. The
clinical results are the same as doing the surgery, and the risks, expense,
and overall utility are much better.
Regardless of treatment, I like taking care of these problems because
it is nice to see scary problems get easy dependable good results. But even when your current practices work
very well, when something better comes along, either better results or less
risk and expense, then it is time to switch practices. The photos show a woman with
scleroderma: an angiogram showing
typical disease; the hand after
surgery; the fingertip ulcer prior to
surgery; and the finger healed a few
weeks after surgery. Nowadays, I would
just use the botulinum toxin. |
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Sometimes what is new is not a new technique or tool, but rather
new concepts and knowledge that guide your overall understanding of disease
and treatment. Immunopathic ulceration
and hypercoagulable disorders and ulceration are major areas of new knowledge
that did not exist when I went through residency, yet they govern the
everyday world of chronic and pathological wound practice. Left upper: Crohn’s disease of skin, ulcers healed
after intralesional steroids, new lesions prevented from ulcerating by prompt
steroid injection. Left lower: lupus-rheumatoid-mixed (mctd) with
ulceration due to synovitis and panniculitis.
Right upper: a 43 year old woman, otherwise healthy, but
with many years of refractory leg ulcers, and a history of multiple venous
thrombosis and pulmonary embolism or thrombosis. The lab confirmed low proteins C&S and
low tcpO2’s around the wounds. She
healed with warfarin therapy and skin reconstruction with a regenerative
matrix. She re-ulcerated after she
stopped taking warfarin, but then rehealed after resuming
anticoagulation. Right lower: a 29 year old
man with long duration refractory leg ulcers.
History and profile were suggestive, and the lab confirmed high
anticardiolipins – an antiphospholipid antibody syndrome – and the patient
healed just by starting warfarin. Much more on
this subject can be found at the Arimedica website. See especially the companion presentation
to this one, given at the same meeting, “(Not) Atypical Ulcers: Autoimmunopathy and Connective Tissue
Disorders: The True Intrinsic Diseases
of Wound Healing”. |
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Integrating New
Products and Technologies into Practice #2 The ever increasing number of new medical
products, and why. There is an ongoing exponential rise in new medical products and
devices. This is attributable to many
factors, including: The general advance of medical knowledge. Advances in micro-level biological science. Advances in materials & electronic technologies. Advances in computer & information technologies. Career track bioengineering and biotechnology. Changes in business finance and investment. A high class
microscope from 1876. |
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Here are some recent statistics concerning the health and wealth
of the medical device market, including estimates of the wound market. The main message is that the medical device
market is big, and getting bigger.
Practitioners will face ever increasing new products that will need
evaluation and a decision about whether to trial them and use them or not. Biotechnology Industry
Organization (BIO) 2006 “The biotech industry has mushroomed since 1992, with Medgadget, June
3, 2008 “Although the top 25 companies represent the lion's share of
sales (almost 60 percent), there are an estimated 20,000 medical devices
companies around the world.” Wound Care
Devices: Growth Amid Uncertainty Medtech
Insight, Executive Summary, January, 2009 “Over the last 15 years, a trend toward evidence-based medicine
has led to a greater understanding of the science behind wound healing. This
knowledge has fueled an explosion of innovation in technology and in the
commercialization of a wide range of new products, generating a worldwide
market estimated at $4.5 billion annually, with double-digit growth projected
over the next three to five years.” American
Medical Student Association http://www.amsa.org/business/King%20Paper%20Medical%20Device%20Spending.pdf Figure 1. US Medical
Device and In Vitro Diagnostic Spending, 1989 to 2004. [Expenditures tripled over 15 years.] Figure 2. Medical Devices
as a Percentage of National Health Expenditures. [Device spending was a relatively steady
percentage of the whole.] |
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Integrating New
Products and Technologies into Practice #3 Historical perspectives and the general
socio-economic framework of modern medical manufacturing and regulation. The deluge of new products is good in principle, but the scene
is muddled by a relaxation of standards, principles, and ethics, in medical
practice, medical education, medical industry, medical finance, business, and
government. Them’s fightin’ words, but let me make my case, and you just
might agree. There’s a good chance
that many of you agree already anyway without further explanation, but read
on . . . An ad for
Lane’s Medicine, a laxative and simple tonic, and who could argue with
feeling better each morning? It is from
The Household, 1892, (a |
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A Diatribe Against a Relaxation of Moral & Professional
Standards 1 Formal medical
education has relaxed its 20th century standards of excellence. Without robust knowledge and analytical
skills, new products and developments can not be critically evaluated. This leaves the door open for hucksterism
and patent medicines. This is
especially problematic for wounds, which is ignored in the schools. No, this is not a matter of the good ol’ days when, “You know
sonny, when I was a kid I had to walk 10 miles in the snow to get to
school.” Standards have relaxed, No one seems to care. What was once the most literate and
educated society on the planet now has some of the most embarrassing
performance when it comes to math and science education, letters and arts,
history and the humanities. The
ultimate spill down is into things like shameful infant mortality and high
school graduation rates. For those of
us who deal with medical students and residents, there are still some stars,
but the average Joe comes nowhere close to the educational and intellectual
standards and expectations of a generation or two or three ago. In my own specialty of plastic surgery, the
noble arts of putting things back together, and the scientific leadership in
wounds and other subjects like peripheral nerves has been subjugated to near
oblivion, the flame kept alive by just a few, while the membership at large
runs retail cosmetology stores, under the guise of a professional office, and
confuses essays on buttock esthetics with real science. Young doctors today seem insufficiently
schooled and skilled in math, physics, chemistry, and basic biosciences, not
enough that they can make learned and insightful judgments about new products
and technologies. And that is not just
their fault. It is the fault of the
enablers, the people who run the schools who are supposed to be guardians of
the curriculum and the morality of education.
Post-graduate educational experiences have been corrupted. CME is trivialized to the point that real
learning is damned in favor of petty certificates that must be paid for. Restricted resident work hours mean
restricted education, learning, maturity, and commitment. In response to a few sensational media
circuses about tired residents, the system was re-engineered so that instead
of incidental mishaps, now everyone is systematically dumbed down and
everybody enjoys a democratically egalitarian dose of mediocrity or worse. American medicine has dumbed down, and it
is getting worse under the self-serving guidance of for-profit stakeholders
and an amoral disengaged dysfunctional government. And it is all the worse for a subject like
wounds which gets insufficient curriculum real estate to begin with. Without well developed minds, charlatans, hucksters,
and pitchmen thrive and profit, and the genuine quality of life declines. 2 Business has
become business for its own sake (and the money), with blatant (and at times
abusive) disregard for science, ethics, customers, patients, &
prescribers. Much of society has been corrupted over the past 20-30 years by
an obsessive quest for money for its own sake. It is manifest in the decimation of
companies and industries, a deterioration of medical practices, priorities, finances,
and moralities, in the corruption of banking and businesses, in the
willingness of overpaid and underperforming executives and their boards to
bankrupt their companies for their own gain, an evaporation of customer
service and concern for users and employees, a disregard for quality and
value, an outsourcing of services and skills that has bankrupted our own
sustainability and self-reliance, the switch from “the customer is always
right” to “whatever our short term day-trading investors want”, chaos and
deterioration of our system of copyrights and patents, fraud in journalism,
fraud in science . . . I could go on, but you already know all of this. There is good news too sometimes, but I
defy you to read the newspaper and conclude otherwise. This has extended to the medical industry,
where big pharma spends a huge budget on direct-to-consumer pitches and
making-of-markets of questionable products, including novel-but-irrelevant
compounds and so-what-slice-of-the-pie-me-too products solely for profits
sake. In recent years, many time
honored basic and categorically necessary drugs, such as autonomic agonists
and antagonists, and urinary antiseptics have disappeared because the profits
are not there on non-patent properties, while at the same time cosmetic
pharma is exploding with drugs to make your penis bigger, your eyelashes
longer, and your orgasms warmer and fuzzier.
Just weeks ago (September 2009), one of the bulwarks of the
traditional “ethical” pharmaceutical industry, Pfizer, was fined $2.3 billion
for deceptive and fraudulent advertising and illegal making-of-markets for a
number of drugs in its portfolio (that’s a big fine). The allegations were not about incidental
oversights or grey-area mistakes subject to interpretation . . . this fine was
levied against a sustained, systematic, and deliberate perversion of ethics
and legality . . . and big companies everywhere seem to think that nowadays
this is all okay. Remember what was
said on slide 2, “Not all companies are angelic, but companies and products
are not intrinsically evil. It is up
to users and prescribers to understand what is of value or not.” It is just that in this day and age, when
moral highroads have been overpaved with overpromises to the land of the
greenback, users need to be a bit more wary, a bit more cynical, a bit less
trusting, and thus a bit more educated and self-responsible for getting and
evaluating information properly. 3 Regulatory
oversight has become overly politicized, arbitrary, bureaucratic, and
inexpert. For wounds, which is ignored
in schools, and the foundational knowledge is not in wide circulation, the
subject is treated perversely and contradictory to science and sense. The United States Food and Drug Administration was established
by the Pure Food and Drug Act of 1906.
That was an example of government at its exemplary best, and it made
our food supply and medical industry the best and safest, most advanced and
productive in the universe. But that
has changed in recent decades.
Personally, I see the FDA as still largely righteous and morally
oriented, still mostly the good guys, but the FDA has also made the news a
lot in recent years for its politicization, inefficiencies, and
mistakes. For wounds, the problem is
that this subject is already ignored and misunderstood by a medical
establishment that is largely 100% uneducated and misinformed about the
subject. Wounds are not heart disease,
diabetes, cancer, nor anything else that gets big funding and expertise – sad
given how important this infrastructure subject is to all of biology. It would be as though the government set up
an agency to resuscitate the automotive industry, and in so doing, hubcaps, vanity
lights, and upholstery got funded, but metallurgy, electronics, and rivets
and welds got ignored, and machinists and engineers were never consulted. For those of us who have observed wound
drugs and devices for many years, or have even had some direct participation
with that agency, it is clear that there is no wound expertise, and a whole
lot of wound naivete. The result (just
speaking about wound products now) is that goofy and irrelevant products come
to market with no valid science behind them, goofy or bad products come to
market with inept and erroneous science behind them, that lame products come
to market with unrestricted indications, that good products come to market
with inane restrictions on use, good products don’t come to market timely or
at all, and that companies are permitted to use false, erroneous, inaccurate,
and misleading marketing materials to promote products good and bad. Wound protocols, study designs, and
endpoints that are expected by the agency are mired in anachronistic
irrelevant concepts that might apply to asthma or hypertension drugs, but not
to wounds. But what the hell, it’s all
about the money anyway . . . 4 There has been
attrition of the principled "ethical drug industry" of the 20th century,
and a resurgence of the
no-claim-is-too-stupid-nefarious-or-disingenuous-to-be-promulgated “patent
medicine era” of unproven remedies that value profit above performance. The Pure Food and Drug Act of 1906 and the FDA put the cabash on
patent medicines 100 years ago, and that was a good thing. Now, hucksters, pitchmen, and anybody with
anything to sell, including once-principled pharmaceutical companies are now
looking for ways to make any claim and get any product in front of your face
to sell it to you. We hear all kinds
of direct-to-consumer advertising for drugs that treat contrived problems
that no one ever heard of. Even good
but exceedingly dangerous drugs, like clopidogrel (Plavix®) get pitched
direct to users. And a lot of it is
predicated on FUD, fear-uncertainty-doubt, scaring people into using your
product, or cajoling them with retail lifestyle products of no legitimate
medical purpose. When big pharma arose
and supplanted patent medicine practices 100 years ago, the industry was designated
“ethical pharmaceuticals” in which sales and marketing were done only to the
physician, not to the patient-user.
The companies now want to do end-runs around the profession, right for
the money shot at the consumer goal line, something which is easy to do when government
ineptitude and behind-doors corruption is blatant, and educational and moral
standards among physicians are mired in who-me?, i-don’t-know, and who-cares. Yes, this is a diatribe.
This is my paper. I have the
soapbox. You could have stopped
reading, but if you are reading this sentence, then you got this far. Agree or disagree, your choice, but unless
you are living in a cave somewhere, you know there is truth in here. Why discuss it? Because it affects the products that are coming
to market and your chances to discern the truth and discriminate good from
bad, wheat from chaff, to “see through” the emperor’s new clothes, to not be
spammed, scammed, and sold, to maintain some principles and morality, to be
someone that your patients can trust to make principled and educated
decisions and recommendations on their behalf. |
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Wound Medicine:
Vulnerary drugs, a brief history # 1 This presentation is obviously about the commercial medicine
trade of today, and in so being it must also reference and allude to the
patent medicine practices of the 19th century. This is a good place to make clear the
distinction between bogus patent medicines, legitimate pharmacy and
therapeutics, and the murky in-between of pseudo-legitimacy that can run
roughshod over the unwary and indiscriminating practitioner. This is best understood by a brief precis
of medicinal and pharmaceutical practices in history. When we talk about the “patent medicine era”, we are referring
to a chapter in the annals of 19th century capitalism. It was a time when an unbridled enthusiasm
to make money allowed any devious entrepreneur a chance to play on people’s
fears and uncertainties about their life and health in order to swindle them
of their hard earned money in exchange for a bottle of magic elixir. (Come to think of it, that sounds an awful
lot like the practices that are re-emerging today – but perhaps I am too
cynical.) This was the era of P.T.
Barnum and the quote, correctly or incorrectly attributed to him, that “there
is a sucker born every minute”. This
was the age of the advent of industrial production, the concept of products
and branding, and the mindset and ability to make markets out of manufactured
goods that could be advertised in nationally distributed publications and
sold by mail, rail, and traveling shows in remote markets. Newspapers and magazines of the latter 19th
century were filled with ads for miraculous cures, medicines packaged in bottles
with fancy labels and pretentious descriptions. People’s anxieties (fud) about their health
will always be the front door to legitimate medicine and pharmacy, but even
more so to disingenuous hucksterism.
No surprise then that some of these 19th century cures were
legitimate products, but many not. Right: for the penultimate salesmen of the era,
there was nothing quite so glamorous as the traveling medicine shows. This is a still from an old silent film,
circa 1920 (I cannot locate the source) portraying the patent medicine shows
as presumably they really happened. Left:
an ad for the Kickapoo Remedies, a prolific print media and medicine
show marketing endeavor to sell patent medicines nominally based on Kickapoo Indian
traditional remedies. |
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Wound Medicine:
Vulnerary drugs, a brief history # 2 A crucial distinction must be made between patent and bogus
medicines versus traditional and historical materia medica. The modern physician, anyone educated after
the mid 20th century, will tend to look down or askance at
traditional remedies. Most modern
doctors will equate the pejorative “folk” and “herbal” remedies with Granny
Clampett and tree-hugging granola crunchers of the hippie commune
persuasion. Any such doctor ought not
be so self-righteous, because (1) most of our important pharmaceuticals come
from plants and other natural sources, and (2) while that doctor may believe
he is the arbiter of what he chooses to prescribe, choosing only proper
modern medicines, the reality is that many prescriptions are a subliminal
hoodwink, a consequence of the manufacturer’s false persuasions and
fud-marketing bolstered by inadequate physician education. To understand the importance of the natural
materia medica, a bit of historical perspective is needed here. Industrial, biological, and pharmaceutical
chemistry had their advent in the mid 19th century, leading to the
first synthetically manufactured drug, aspirin, marketed in 1897. However, aspirin had its origins in natural
plant compounds. In fact many of the
most important drugs in use, now or ever, are gifts from nature. The purely designer-made drugs that are the
focus of modern patent-and-profit marketing are beasts of just the past 30-40
years. The catalogs of the major
pharmaceutical companies of the first half of the 20th century –
the Lilly’s, Merck’s, Abbott’s, Upjohn’s, etc. – list pages of pills that are
distilled, purified, or resynthesized botanicals and biologics. These were the major medicines of most of
the 20th century. The
standard Left: The 14th,
15th, and 16th centuries in Right: Speaking of comfrey, here is an excerpt
from Anthony Askham’s “A little Herbal of the properties of herbes”, 1561 in |
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Wound Medicine:
Vulnerary drugs, a brief history # 3 The mid 16th through the 17th century was the epitome of the
Renaissance, an era of important observational science that paved the way to
the Enlightenment and our principles of scientific thought, investigation,
and education. This was the era of the
Great Herbals, not just the little herbals of the 15th century,
but grand encyclopedic works meant for the professions. Some of these botanical encyclopedias were
written by "naturalists", but most were written by physicians,
because these were the pharmacopoeias and pharmacy textbooks of their
day. One of the greatest of these was
the Gerard-Johnson Herbal. The first
edition appeared in 1597, during the reign of Elizabeth I, written by Dr.
John Gerard, preeminent surgeon and botanist, and herbarist and superintendent
of gardens to colleges and crown.
Gerard’s own first edition copied much from other primary sources, and
it had many errors of his own, making it neither correct nor erudite, but it
became very popular. In 1633 Thomas
Johnson, an apothecary and botanist, was commissioned to undertake a massive
revision of the book, including thorough updates and corrections, more
accurate illustrations, and many new entries.
Scholarly and highly regarded, the 1633 Gerard-Johnson edition, The
Herball or Generall Historie of Plantes, became for generations, well into
the 19th century, the premiere English source of botanical and medicinal
information. (If you love botany,
medical history, or old books, the Gerard-Johnson 1633 herbal is available in
a huge facsimile reprint from Illustrated is the title page from the 1633 Gerard-Johnson
herbal. The plant is one of the entries
in that book, Chapter 389. The engraving
is, titled “Panax Heracleum, Hercules All-heale.” The text quotes “Hercules Wound-wort,
All-heale, Chirons All-heale, Hercules All-heale, Æsculapius All-heale. The leafe or root stamped with honey, and
brought to the forme of an Unguent or Salve, cureth wounds and ulcers of
great difficultie, and covereth bones that are bare or naked without flesh.” In recent centuries, these common names are
applied to the herb Prunella, not Panax species, and nowadays Panax refers to
ginsengs. The engraving illustrates a
plant from the Umbelliferae family, and probably refers to Opoponax
chironium, a plant from the The fact that a surgeon was the botanist and herbarist might
seem peculiar from our modern vantage point, but it was normal and expected
in this era. Here is the title of
another contemporaneous work, published in Paris in 1583 by Esaie le Lièvre
Chirurgien ( a nom de plume?), under the extended title (Englished)
“Pharmacopoeia and Garden of Military Surgery, containing the instruments and
plants most necessary for all Surgeons . . .” Consider another famous contemporary work,
the “Booke of Observations by William Clowes, one of her majesties
Chirurgions, London, 1596”, one of the most important books of surgery from
that era, and the first text to describe treatment for gunshot injuries. Gunshot treatments included elaborate
pharmaceutical recipes using the important vulnerary herbs, such as
plantaginis (plantago, plantain) and prunella. The great French wound surgeon, Ambroise
Paré, a contemporary of Clowes and Gerard, made his greatest observations of
wound care based on herbal vulnerary remedies. Gerard, in his herbal, described sweet
clover, Melilotus officinalis, for its anti-inflammatory and wound healing properties,
“With the juice hereof . . . is made a most soueraigne healing and drawing
emplaster . . . made by a skilfull Surgion.”
(Melilotus officinalis has a modern role as well, as it is the source
of coumarin.) Wound care, surgery, and
herbarism have an important historical and scientifically validated connection. The connection between wounds and pharmaceuticals dropped from
collective knowledge and conscience at the end of the 19th
century. The concept of the
pharmaceutical management of wounds simply evaporated as the pathogenic role
of bacteria in infections was learned.
Wounds are wounds and infections are infections, and the intersection
of those two vast domains of knowledge is limited. However, following the contributions of
Pasteur, Koch, and Lister, the two got inseparably confused. We are now left with a legacy that most
physicians have little or no knowledge whatsoever of wounds, soft tissues, and
surgery (and alas many surgeons likewise have marginal knowledge of wound
science and therapeutics). For most
doctors, a wound is simply an excuse to vent some atavistic aggression under
the guise of a blind obsessive quest to kill germs, rather than a chance to study
the true arts and sciences of wounds, wound pathologies, and wound
therapeutics. And this lapse is not
just a sad but honest misdirection of medical knowledge and curriculum. Make no mistake about it, manufacturers and
advertisers have exploited germophobia to the maximum to get you and your
patients to insist on germ killing products in both the medical and consumer markets. Over the past century, whenever the economy
has gotten rough and society is looking for scapegoats, the germ-fascists
have consistently pulled the fud-trigger to “persuade” you to buy more
antiseptics, antibiotics, and sterility products, and that strategy is a
consistent winner. For the past 140
years we have blinded ourselves to the concept of pharmacological control of
wound biology, and we have ignored the potential tools found in nature. This has been easy enough to do when the
whole subject of wounds has been ignored in the medical curriculum and the
average doctor has zero legitimate knowledge of the subject. It is one of the great ironies of wound and
pharmaceutical science and practice that, just at the moment in history when
we got the knowledge and tools to understand and manipulate biological
chemistry and create potent pharmaceuticals, that the knowledge of germs
occurred concurrently and aborted any interest in the biological and
pharmaceutical chemistry of wounds (and for entirely incorrect, erroneous,
specious, illogical, and fallacious reasons).
Too bad, because the wound is a biological-biochemical system, and
opportunities for the pharmacological control of wounds might be just as rich
as they are for cardiovascular and endocrine and pulmonary therapeutics. Over the past 20 years, modern
bioscientists have started to redevelop the concept of wound
pharmaceuticals. These new or renewed
concepts are based on modern high technologies of genomics, proteomics, and
other sub-cellular biochemistry. Sadly
though, we still have a blind scotoma to the classic aromatic, alkaloid and
other organic phyto-chemicals and pharmaceuticals that might help us heal our
wounds – the wound equivalents of morphine, digitalis, penicillin, atropine,
salicin, curare, quinine, quinidine, reserpine, ephedrine, and other natural
chemicals that just might have genuine vulnerary properties. The collective knowledge of vulnerary drugs
and potential pharmacological control of wounds is archived in the pre-20th
century herbals. It awaits those with
modern knowledge and investigative methods to study these biochemical
resources and rich repositories of potential therapies. It awaits those whose minds have broken the
shackles of blind germophobia and the intellectual anchor of a retarded
medical curriculum, mired in the now anachronistic discoveries of 140 years
ago, that thoroughly ignores the physiology and pathology of one of the
body’s most basic infrastructure systems, wound healing. Reconsider the quote above, “The leafe or root stamped with
honey, and brought to the forme of an Unguent or Salve, cureth wounds and
ulcers of great difficultie, and covereth bones that are bare or naked
without flesh.” Comments like this
have to be taken seriously, but they also raise an issue that is as relevant
today as ever, in fact more so: how do
you discriminate a positive therapeutic effect from a passive effect to
remove injury and inhibition. In an
era when wound care was most likely mostly awful, the use of almost any emollient
or non-irritating botanical was likely to have an effect to control pain,
inflammation, and putrefaction in a wound.
Today, we would just use the terminology “basic wound care” or “wound
hygiene”. This was the great
revelation of Paré, that if you treat living flesh like it was alive, it
stays alive and does well. If you kill
it with “treatment”, it acts dead with all of the adverse effects that that
incurs. Paré was a military surgeon
who was schooled in the medical and surgical culture of his day, a long
lineage from Galen 1400 years prior.
Caught in a situation where he had not enough boiling oil to cauterize
wounds, he treated them with emollients – egg yolk, rose oil, and
turpentine. The improvements in pain
and healing were dramatic, and it revolutionized the practices of surgery
ever since. So, do rose oil and
turpentine have pro-proliferative effects to accelerate wound healing, or is
it just that by treating tissues kindly, they live and do what they should? Paré and his contemporaries understood that
this was just a matter of good hygiene and being kind and gentle to living
things. The traditional materiae
medica have many vulnerary drugs that purportedly accelerate healing, and
there is a time and place for them, but all wounds deserve to get off to a
good start with simple basic hygienic care.
That principle has not changed in 400 years, nor will it ever: phase one of all wound care is to get the
wound under control, healthy, and capable of healing; then phase two are the discretionary
treatments to accelerate healing or promote closure. The remarkable claims of magical healing attributed to magic
potions are a perversion of the 19th century, culminating in the
patent medicine practices just prior to the 20th century. Yet the problem is still with us. As will be demonstrated on later slides,
many products come to market with utterly ridiculous claims of effectiveness
when in fact all that was done was to provide basic wound care. If you provide no care or bad care (which
is what many doctors do), wounds will do poorly. If you provide basic hygiene, using
whatever safe agents appeal to you or your patient, then wounds behave
naturally. Allowing an unimpeded
unfettered uninjured wound to do its natural thing without interference by
bad care will result in normal natural wound healing at natural kinetics or
rates. If the only thing you have ever
witnessed is bad wound healing due to bad care, then seeing normal wound
healing due to basic good care can easily be misinterpreted as accelerated
healing. Sadly, many wound products
that come to market are guilty of this misconduct and misinterpretation. Sadly, many wound products coming to market
are being developed and promoted by people with virtually no knowledge of
wounds, with virtually no clinical experience, who have never seen normal
wound healing with basic proper care.
Sadly, it is all too easy to dupe the potential buyer because it is
easy to baffle people with pseudo-scientific nonsense that purports to show
positive results, regardless of how lame or bogus the product and its
so-called “clinical research” are.
Sadly, the regulatory agencies have such little knowledge of wounds
that the bogus studies get through, opening the door to marketing campaigns
that might be in good faith, but nonetheless show nothing but the effects of
basic good care. And a final note on the pharmacy and botanical practices of this
general era: William Withering.
Working in the latter 18th century, 200 years beyond
Gerard, Paré, and Clowes, he observed the folk practice of using the
foxgloves, Digitalis purpurea, to cure cardiac dropsy, aka congestive heart
failure. His well earned fame does not
come because he simply stumbled on this practice, as though he was a
geographer or explorer or anthropologist on an expedition to some dark jungle
or steamy tropical locale. He was a
physician and botanist of great schooling and learning and experience, and
the foxgloves were a common remedy in his own homeland. He earned his fame because he took this taken-for-granted
traditional remedy, saw it through the filter of contemporaneous scientific
medical knowledge in the Age of Reason, developed an hypothesis about its use
(this era saw the dawn of the “scientific method”), and then tested these
concepts then analyzed the data. Over
the course of a decade, he meticulously studied nearly 200 patients, allowing
him to report on the proper usage and dosing of this drug in the service of
well-reasoned safe and effective medicine.
He is the Father of the Clinical Trial. He applied reason, ration, refinement, and
standardization to the crude drugs in common use for thousands of years. It is seminal events such as this and the
development of aspirin which chart the development of modern pharmacology
from its roots in the traditional materia medica of prior ages, and which
differentiate genuine good pharmaceutical products and practice from the
bogus charlatanism and hucksterism of the 19th century, much of
which is still with us or rapidly returning. |
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Wound Medicine:
Vulnerary drugs, a brief history # 4 As explained above (slide 12), the 19th century saw
numerous changes in transportation, communication, industrial production, branding
and corporatization, and social systems and sensibilities that opened the
door to all things money and melodramatic.
From Barnum’s Circus to Buffalo Bill Cody’s Wild West Show to the
Kickapoo Medicine Shows, it was all a romantic and stirring blend of the real
and the phony, the legitimate and the contrived. At Buffalo Bill’s show, you at least got to
see the real Sitting Bull, and got to watch the real Annie Oakley really
shoot. You got your money’s worth in
entertainment. But the purveyor’s of
magic potions sold you little more than a promise of good health, which you
bought, and bought into, because (1) a fool and his money are soon parted,
(2) there is a sucker born every minute, and (3) fud sells
(fear-uncertainty-doubt). There were
of course some real remedies, but the consumer had no way of knowing what was
real and what was not. There were no
manufacturing standards, no truth in labeling laws, and no guarantee
whatsoever that there was anything more than a bit of alcohol and bitters in
the bottle. The greatest value of the
patent medicine era are the wonderfully whimsical trade cards and labels, and
if you love folk art and ephemera, these are one of the funnest things you
can collect. Shown are a sampling of
some of these cards. Opodeldoc was a generic type of herbal elixir. Gordak’s Highly approved Opodeldoc was an
inestimable remedy for the Rheumatism, and also a long list of other things,
including “. . . it speedily cures violent Bruises . . . and is also a most
excellent Salve for Sores, and is well known to heal the hardest wound in
forty-eight hours.” Alas, if only I
could prescribe such a miracle for my own patients, but forsooth I dream too
much. Dr. Thomas’ Eclectric Oil, made
with electricity, was “capital for burns, bruises, cuts & sprains,” and
just about anything else what ailed you.
Other manufacturers also made “eclectric” [sic] oils, and all manner
of bizarre concoctions, therapeutic claims, and advertising gimmicks are to
be found on similar trade cards.
Notice one of the gimmicks that is at work here: pseudo-legitimate
faddism and buzzword marketing. This
card appeared at the dawn of practical electricity, when the telephone had
been established, electric lighting was coming on line, and electric motors
were starting to revolutionize industry.
Electricity was still a new, novel, and mysterious thing. (Even though the nature of electricity was
still mysterious, its association with biology had been made by the early
1800’s. This only served to heighten
its mystique, so much so that Mary Shelley, who was quite aware of the works
of Galvani and Volta, wrote a novel about the subject, one of the earliest
works of the science fiction genre.
“Frankenstein, or the Modern Prometheus” is a dark gothic insightful
look at the moral dilemmas that might ensue from the then plausibly hypothetical
scientific possibility that electricity might reanimate biological
systems.) Not surprisingly, the
mystery, power, and potential usefulness of electricity were quickly
exploited by those wanting to sell you something for your health. All manner of electrical and magnetic
medical gizmos appeared for all kinds of ridiculous reasons. And just because you can’t put lightening
in a bottle didn’t deter the proprietors from saying just that, that there
was “eclectricity” in that joy juice.
That it was all phony just didn’t matter, because it was all new,
mysterious, romantic, and beguiling, the stuff that every sucker with a
dollar to yield was going to buy, simply because it sounded modern and
scientific, and you literally couldn’t live without it, or so the fud-mongers
sold you. Contrast these patent medicines with the lost waifs of pharmacy,
the traditional materia medica with long histories of vulnerary usage, but
which have not been addressed by modern scientific and clinical methods nor
funding for crude drug research.
Pictured is the common mullein, Verbascum |
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Wound Medicine:
Vulnerary drugs, a brief history # 5 At the turn of the 20th century, the patent medicine
trade gave us some gems such as the one illustrated for Henry’s Carbolic
Salve. In words which Keats, Shelley,
and Byron might have envied, we read an idyl of the poetic and passionate
romance between Alphonso and Imogene: Alphonso
loved dearly the blithe Imogene whose
face was the fairest that ever was seen, but
when he proposed, "alas", Imogene said " I
would gladly accept and with thee would wed but
with ugly eruptions your face is so scarred that
all my life's future, with you would be marred unless
you remove them, so if me you'd have you
must cure them with Henry's Carbolic Salve. Notice Alphonso’s sad countenance, tortured by the ravages of a
great pestilence, and the disgruntled demeanor of deprecation and detestation
on that demoness’s face. Had Alphonso
any good sense, he would have moved on to brighter prospects, but happily or
sadly this tempestuous affair was saved by the greatest invention since warpaint,
Henry’s Carbolic Salve. In a miracle
of industrial era marketing, the trade card was a foldout. When you opened the lower flap, chapter two
of the story literally unfolded before you, a happy and sanguine turn of
events that should make you weep for joy, as undoubtedly it did for our
lovebirds, as can be seen on their coy smiles: Alphonso
this remedy tries – and again pops
the question – nor does so in vain Henry's
Carbolic Salve has swept his face clean of
every unsightly spot that was seen As
a compound for healing it's speedy and sure and
for burns, cuts, and bruises, readiest cure. Thankfully for poor Alphonso he lived at a time when Imogene
knew not of the penis enlargement products that grace the advertising media
in our own enlightened era. The back
of that trade card got down to the gritty technical details about Henry’s
Carbolic Salve, including, “The most powerful healing agent ever discovered .
. . heals burns, cures sores, allays pain, cures eruptions, heals pimples,
heals bruises. Ask for Henry's and
take no other. Beware of
counterfeits.” And here is what you
need to understand . . . This was not quaint and cutesy when it was published
120 years ago. Sure, it was a bit
folksy, meant for a lay rather than a professional audience, but nonetheless
it was au courant, up-to-date in the printing technologies and artistic
styles of the day, hawking a product that was on the forefront of legitimate
practices and progress of that era. No
one then would have laughed at this ad as a quaint antique. Much of what abounds in medicinal marketing
today is just as fake, phony, and bogus, and will be seen as just as
ridiculous and retarded by our descendents in 2130, assuming that society and
culture have not totally imploded. Henry’s Carbolic Salve “was on the forefront of legitimate
practices and progress of that era.”
In understanding how to assess new products and technologies, you need
to understand the pernicious and insidious effects of pseudo-science and pseudo-legitimacy
in marketing, and this is a perfect example.
The germ theory of disease and the principles of antisepsis for wounds
and surgery were established by Pasteur, Lister, and Koch. Joseph Lister was the one who brought these
concepts from the lab and veterinary practice into the clinics, and he
published his first treatise on the subject in 1867. He used carbolic acid, aka phenol, as the
means to disinfect the surgical environment – killing germs on instruments,
supplies, furniture, etc. (as well as using gloves and gowns and other means
of avoiding germ exposure). His
contributions revolutionized safe surgery as much as the advent of anesthesia
in 1847. By about 1890 these concepts
had prevailed, and antisepsis became routine practice in hospitals and
surgery. Carbolic also found its way
into consumer products, such as carbolic soap. Phenol is actually quite toxic, so it has
been supplanted by other antiseptics, but the historical role of this
chemical cannot be overstated.
However, it is easy to see how the use of carbolic, or any antiseptic
could have then been taken to the next step, beyond its well-reasoned use in
surgery, and extrapolated to any problem rightly or wrongly assumed to be
associated with germ-induced disease. When a product such as Henry’s Carbolic Salve appeared, in was a
good-faith product. It fit with
contemporary knowledge. It made sense
at the time that if carbolic could disinfect things, then just kill the germs
and all disease would go away. That
concept is of course incredibly naive and uninformed, but it was in part the
best knowledge of the day, and it was certainly the fad of the day (and for
the past 120 years). Controlling
exposure to germs and avoiding contamination and inoculation are important
(the reasons for using carbolic), but the unspoken assumption after all of
this was that all disease and adverse medical events could be attributed to a
germ . . . just kill all the germs, and human disease will go away. Killing germs thus became the crusade, and
soon enough it was a self-indulgent crusade for its own sake based on
germicidal germophobia and a catechism of sterility. In the case of poor Alphonso, this blind
zeal completely ignores the true pathogenesis of the acnes, and it eschews
all relevant therapy other than killing germs, but the problem was rooted not
in Henry’s product, but in the assumption that germs were really the
issue. And like any great new body of
knowledge that comes to light, as germs and infectious disease did in the
latter 19th century, it is easy for everybody to have an
overzealous vision of the problem as seen through the discolored spectacles
of that latest discovery. If the same
zeal and money went into quality physician and allied professional education
on this subject as goes into the marketing of germ killing products and germ
killing quests at hospitals, then actually morbidity would be dramatically
reduced. (Of course, the problem was
made all the worse when we got internal germ killers – antibiotics.) All of these products have a vital role in
treating genuine infections. But a
huge part of the profit-making sales and use of these products is for
non-infections. When proper germs are
in proper places, they are benign, and oftentimes they serve our own vital
health within the complex ecosystems of our bodies. Nonetheless, all one has to do is
demonstrate that there is a germ in the neighborhood, and doctors have a
Pavlovian response to whip out their antimicrobial artillery. The use of these products is based only
partly on science and legitimate practice, but much more on fallacy, fad, and
fud, born out of inadequate and inept medical education on this subject, and
stoked and cultivated by medicinal manufactures who make large profits through
prescribers’ ignorance, gullibility, and primal fears of these subjects. All of this is a consequence of a 20th
century society that rewards fud-based marketing more than it values proper
medical education and rational doctoring. As we have already stated, wounds are wounds and infections are
infections, and the two domains have only a limited intersection. But combine a lack of good education about
physiology and pathology with a healthy dose of marketing capital and cleverness,
and it is easy to sell you products like Henry’s Carbolic Salve. It was a pseudo-legitimate product. It had some basis in contemporaneous
science. It was conceived of,
manufactured, and sold in good faith, with the naive but fair belief that it
could do the things it espoused. Of
course, that product was never going to clean up acne scars, and no pitchman
with a breath left in his body was going to pass up a chance to overstate and
overplay the product to boost sales, and caveat emptor the buyer had to
beware, but nonetheless it had some perceived basis in reality. And that is the problem with many products,
both then and nowadays. If your
knowledge of a disease or clinical problem is marginal, and some manufacturer
with equally little knowledge is trying to sell you something that fits the
fad and fud of the day, then you can be sold.
Yes, there are products like that, where a company of technologists
has the capacity to make a product and the capital to bring it to market, but
none of the knowledge or expertise of the specialists who will buy it,
prescribe it, use it. In the 1880’s,
it was electromagnetic gizmos made by electrical men who knew nothing about
pathology and clinical medicine. In
our own times, it is bioengineers who manufacture altered genes and proteins,
because they can, to make products that clinicians never asked for, but will
buy for no reason but that it is new. Many
such products are sold in good faith, with buyer and seller, manufacturer and
professional prescriber all on the bandwagon, all bowing to the emperor’s new
clothes, all naively thinking that the product is good. Such products are moral, even if pointless,
erroneous, misleading, and dangerous.
Sadly though there are also the immoral products from deceptive manufacturers
and pitchmen who know that there is no point or value to the product, or who
lie and mislead and tamper with the data about safety and efficacy, with no
moral other than to make money. In the
19th century, there was a lot more deliberate ripoff and
deception. The need to stop that
prompted action by the federal government via the Pure Food and Drug act of
1906. Since then bad products have been more of the good faith naive kind,
but in the past 10 years we have seen a resurgence of the immoral kind. It is up to the prescriber to be
sufficiently educated and sales-resistant in order to properly evaluate new
products, selecting items based on genuine needs and robust knowledge, rather
than falling for glamorous pitches that appeal to your shopping
impulsiveness. To summarize, in the latter 19th century we learned
that germs cause disease. They cause
some of what had been the most fearsome, lethal, refractory diseases of the
day – syphilis, plague, tuberculosis, diphtheria, pertussis, measles,
smallpox, anthrax, and on and on. That
knowledge was not just an epiphany, but a signpost pointing the way to look
for cures for those diseases. Lister
was one of the first to find a weapon against the microbes, in the form of
carbolic antisepsis. In the enthusiasm
and revelation of this new knowledge, everyone’s attention got focused on
germs as the arbiter of not just infectious diseases, but of any and all
disease, and anything that could kill a germ became a selling point for the
whole spectrum between legitimate research and ersatz patent medicines. Henry’s Carbolic Salve was a
pseudo-legitimate product, swept in on this tsunami of contemporaneous
medical knowledge because it fit the romance of killing germs to cure human
illness. But the false pretenses and
true predicates behind Alphonso’s problem were ignored, overlooked, or
misunderstood. Henry’s Carbolic Salve
might actually have been beneficial for Alphonso, serving as a “chemical
peel” that would have helped the scars and epidermal dysplasia, thereby
bolstering the erroneous belief that killing germs was the relevant virtue
(see slide 34 for more about this). We
do the same thing in our own modern times – it is just human nature to try to
explain the unexplained with the latest revelation. In just the past 20 years, wound practice
has seen the same mentality toward collagen, growth factors, and MMP’s
(matrix metalloproteases). As we
elucidated the role of these chemicals in the process of wound healing, there
arose the belief that any of these would be the salvation of all wound problems,
and many companies geared up to produce products based on the chemicals, and to
make marketing campaigns built around the buzzwords. Alas, the wound is a complex system with
diverse pathologies, many of which cannot be affected by these magic bullets,
and the skew between comprehensive reality and the product-of-the moment is
vast – but blessings to those who look for answers, because eventually we do
find things that work. At the turn of the 20th century, there arose in
Europe and the |
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Integrating New
Products and Technologies into Practice #4 The importance of medical products to
advancements in practice. You might think that I am being strictly cynical and
jaundiced. No. Now that that is out of the way, here is
the flip side. While cynicism is valid
because it reflects genuine problems, fortunately the good side of medical
science & development is healthy as well, giving us a dizzying array of
new tools that can safely treat and cure heretofore incurable problems. This is the
famous painting by John Singer Sargent, 1906, of “The Four Doctors” at the |
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This slide lists just a few of the changes in medicine in recent
years that might be considered revolutionary, fundamentally changing the way
we approach problems, changing the safety and efficacy of what we do for the
betterment of our patients. Some of
these changes are hardware and device based, such as orthopedic
implants. Some of these are devices in
the new class of biologics and regenerative medicine and surgery, and some
are cutting edge biologic therapies based on genomics and proteomics. Some represent procedural changes supported
by complex technologies, such as endo-surgery. Some represent logistical improvements,
such as the ability to respond rapidly to coronary and cerebral
thrombosis. Some are diagnostic tools
such as pet and mri, and more importantly, some are the ability to distribute
the results quickly, such as information and network technologies. Some are the integration of the body with
electronic technologies. Some, such as
gene chips and gene therapies, are at the forefront of micro-scale science
being useful for clinical practice.
And surprisingly, something such as the conquest of peptic ulceration
results from the same observational medicine that made great strides in the
18th and 19th centuries, but seen through fresh eyes,
open minds, and a renewed sense of interest in basic pathology. All of these advances depended 50% on new
knowledge, forward thinkers, ardent advocates, and dedicated scientists,
engineers, and clinicians. The other
50% were the devices and technical developments that allowed new and good
ideas to come to tangible realization and functional fruition via for-sale
manufactured products. Without product
concepts and companies to engineer and manufacture them, these advances would
have remained the perpetual dreamscape of some far-in-the-future fantasy
world, while we ourselves would have remained huddled in the cold in our
pre-paleolithic caves. |
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Integrating New
Products and Technologies into Practice #5 Guidelines for assessing new products: general product categories. We have established that the practitioner will be barraged with
new products, good and bad, bogus and legitimate. The purpose of this presentation is to try
to give some guidelines for these questions:
How do you evaluate new products, to decide which ones are theoretically
meritorious or not? If you find
yourself on the front lines of working with new products, how do you decide
which ones you are going to try for yourself, and how do you conclude if they
have a worthwhile role in practice?
How will you recognize good from bad products, good from bad
companies, good from bad effects and results? If a product is proving itself, how will you
integrate it into your own daily practice, and also how will you help others
to understand how to use it? As shown
on the next slide, this starts by sorting out products by type and purpose. An advertising cut
for Quina-Laroche, appearing in Scribner’s Magazine, 1890. This remedy is legitimate. Malaria is a scourge that we still have yet
to conquer. One of our major weapons,
and for a long time our only weapon, was quinine, from the bark of the
cinchona tree, aka Peruvian bark. By
itself it is bitter to the point of utter unpalatability, so it must be compounded with something to make it “go
down”. A strong red Iberian wine was
one good way to mask the flavor, making it, as the label says, “free from the
disagreeable bitterness of other remedies”.
The Brits in tropical climes came up with their own solution, masking
the bitterness by using gin, the popular alcoholic beverage flavored with
juniper and other ingredients, and thus was born the gin-and-tonic. |
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When looking at the broad panoply of wound products, new and
old, they can all be reduced to just a few basic categories. Keeping straight which category a product
goes into is very important to keep expectations about the product in proper
perspective. Good products used for
the wrong purpose will be perceived unfairly and negatively. Once you understand the real value and
purpose of a product, even if it is quite different than what you first
thought about it, you might find an unexpected gem. Most wound products fall within the
following 5 general categories. 1 - Wound and
skin management. These are the basic
products that support wound hygiene, skin health, and the necessities of
daily care. Generic wound care products are dressings and non-specific
topicals that maintain basic wound hygiene, patient comfort, absorption and
moisture, edema control, etc. Purpose specific topicals are those
that serve the purpose of daily hygienic care, but also have some additional
therapeutic or other deliberate purpose.
These include materials that incorporate pharmaceuticals for
controlling bioburden, inflammation, pain, etc. They include agents that have some nominal
(but weak or poorly documented) stimulatory or pro-proliferative effect, such
as those with traditional vulneraries or their purified derivatives such as honey,
allantoin, and acemannan. They also include
those that have some semi-regenerative effect to guide the growth of new
tissue, such as those based on collagens or aminoglycans. Skin
care products are those meant to protect the skin, heal non-ulcerated
dermatoses, treat dermatitis, and care for special problems such as
intertrigo and stoma and fistula problems, including protectants, barriers, moisturizers,
and powders and antifungals. Devices are those that support the
basic essentials of hygienic care, such as chemical products and gizmos for
debridement, and substitutes for conventional dressings such as negative
pressure devices (manufacturers would like to promulgate the notion that
these devices are stimulatory wound accelerants, but first and foremost they
are just another mode of basic hygienic care). 2 - Wound healing. These are products which are meant to
affect the wound healing process by direct pro-proliferative effects on wound
healing cells and their functions. In
general, the wound management products listed in paragraph 1 are those
required for phase one of wound care, getting the wound under control, and
keeping it healthy and capable of healing.
The wound healing products mentioned here in paragraph 2 are the
discretionary items used to promote closure and get the wound healed. These tend to be sophisticated and
technology based, and thus are expensive or have some other major investment
of time, risk, and resources. Hence,
the wound healing products should never be used until the wound has been
controlled and rendered receptive to their effects. Wound healing products can be divided into
two broad groups, stimulatory and regenerative therapies. Stimulatory therapies are those
meant to induce, stimulate, and accelerate wound healing, either returning
retarded wounds to normal kinetics or accelerating wound kinetics beyond
natural rates. They tend to fall into
certain general categories. Platelets
and platelet releasates are meant to concentrate the cytokines or
growth factors which normally trigger or induce the whole wound healing
process. They are available in a
variety of technologies from many vendors.
Purified growth factors are conceptually important, but other
than becaplermin-pdgf (Regranex®), there are no significant products
available. Living cell biologics
have emerged as conceptually more important, in the form of living
re-engineered tissue analogues which put living cells on the wound (usually neonatal
cells from non-specific donors). The
cells do not survive as allogeneic implants or grafts. They live for limited times and then
degenerate, but while there, these young cells express a broad spectrum of
pro-proliferative chemicals which have a stimulatory effect on the
wound. They are best thought of as
pharmaceuticals packaged in living vehicles.
Apligraf® and Dermagraft® are the two common and worthy examples. Acellular biologics are non-living
materials taken from biological sources.
They are mainly fascias or other connective structures stripped of all
cellular and antigenic materials. They
depend on the chemicals or micro-architecture of their matrix to stimulate or
guide host wound cells. Examples are
Oasis® porcine intestinal submucosa (Cook
Biotech and Healthpoint), and
Unite® Biomatrix equine pericardium (Synovis). Dispersed or solubilized biochemicals, such
as collagen and aminoglycan pastes can also be included here. Physical agents are those that
stimulate repair by delivering energy or load to the wound via physical
modalities such as electromagnetics and mechanics. There are devices to deliver radiofrequency
(rf), lasers and other visible light photonics, electrical and
electromagnetics (em), and ultrasound and vibrational energy (us). One of the perversions of medical science
in the 19th and 20th centuries is that everybody got so
focused on biological chemistry and pharma, and made organic chemistry the
acid-test of medical school acceptance, that mostly everybody forgot about
physics in biological systems. The
consequence is that the scientific, clinical development, and regulatory
processes for physics-based devices is not as elaborate or taken as seriously
as anything that has a chemical in it, regardless of the medical subject or
specialty. Wounds are no exception,
and these devices do not get the attention and respect that they deserve, nor
is the data and clinical experience and supportive science there the way they
should be. Nonetheless, many of these
devices seem to be very promising wound stimulants. Old pharmaceuticals are the
vulnerary herbs and traditional remedies that have never made it into well
studied and scientifically developed pharmaceuticals (slides 12 – 16). Too bad, because there is some promise in those
weeds. Certain purpose specific
topicals discussed in the paragraph above, such those with allantoin and
acemannan justifiably fit into this category as well. Novel pharmaceuticals are a variety of items that get
presented at major wound meetings and which are in scientific or commercial
development in labs around the world, but which have yet to appear as
prescription products. Many of these
items sound very promising when presented at meetings, so we will all just
have to wait and see. One of the most
promising of these novel forms of therapy, a biological approach, are the transfectives
in which you “give the wound a cold”, using safe viral vectors to introduce
wound-proliferative genes into wound cells. thereby turning them on to grow
and assemble. The current front lines
of promising wound therapy research seem to be mostly within the realm of wound
healing and wound stimulatory therapies.
These pending products are
biotechnologies based on living cell therapeutics and
genomic-proteomic pharma. How they
will work in clinical practice is yet to be seen. Regenerative
therapies are those which turn off normal post-inflammatory healing and
instead induce embryonic or regenerative processes. Osteoinductive grafts and regenerative bone
healing have been part of the landscape of surgery for many decades, and
similar concepts that apply to tissues and organs in general, including
wounds have become very important in the past 10 – 20 years. With regard to wound healing practice,
there are several available products. They
are mostly (but not all) made of biological chemicals or materials, generally
in the form of a micro-porous scaffold or trellis. They are implants (even when applied on the
surface) that are not alive to start with, but become so as autogenous cells find
the matrix and form the new tissue. Regenerative
skin substitutes are skin analogues that serve as “artificial skin”
when applied to open wounds, getting them healthy, then serving as the
scaffold upon which new dermis or epidermis can form. Integra® collagen-gag matrix is a good
example. Cadaveric skin matrices
are dermis or fascias from allogeneic or xenogeneic sources. They are
stripped of everything but basic connective matrix (collagen, fibronectin,
some gag’s, etc.), and they are non-antigenic when properly processed. Applied to a wound, primitive cells find
the matrix and initiate a process of stromal histogenesis that, entirely
unlike scar, resembles normal embryonic processes resulting in the formation
of new dermis or fascias. They can not
only heal certain refractory wounds, but they can supplant many conventional
wound repair operations, thereby avoiding autogenous donor sites. Many companies make competing products
derived from human, porcine, bovine, and equine sources (Alloderm®, FlexHD®,
Strattice®, Surgimend®, GraftJacket® to name a few). Many of these are promoted as wound healing
or wound stimulatory products as well (e.g. Oasis® and Unite®, mentioned
above) – the nomenclature and effects are not always well characterized, and
these products can have both effects. Miscellaneous
bioparts are the other bric-a-brac of cadaveric harvest, including
miscellaneous skeletal parts for orthopedic reconstruction through whole
organs for transplantation. Most of
these are not intended for wound healing purposes, but understanding their
biology of incorporation, regeneration, and possible atrophy, inflammation,
or rejection is a good starting point to understand the biology of the wound
relevant biologics. The one obvious
cadaveric tissue of wound relevance is skin itself, and cadaveric skin banks
have been in operation for many decades to support burn surgery. The role of allogeneic skin in the
management of wounds is a fundamental in the basic arts and sciences of plastic
surgery, and understanding this modality is important to understanding wound
therapeutics in general. However,
allogeneic skin is more suited to acute wounds, especially large
trauma-burn-fasciitis wounds, whereas modern wound practice focused on chronic
and pathological wounds benefits more from the various other technological
products discussed here. The
conjunction of skin grafts and technology also gives us the opportunity to
grow autologous skin in vitro.
Commercial services to do so have come and gone, limited by the costs
and expenses involved, and these services likewise are mainly suited for
burns. 3 - Patient support
& rehabilitation. These are
the products which assist your care and your patient, oftentimes larger items
involving durable goods, systems and services, and personnel. They can range from crutches and walkers
through splints, braces, and full extremity prosthetics, from wheelchairs and
cushions to pressure relief beds, from colostomy bags to edema pumps to
glucose monitors, from pharmacies to
rehabilitation facilities to home health services. This is obviously a diversified group of
items, and while you might not think of them in the same way as the “wound
healing products”, they are equally important, especially when it comes to
wound prevention and general patient maintenance. Just see how far you can get with the wound
care products if these support products are not there! 4 – Diagnostics. Diagnostic devices are becoming more
relevant in everyday wound practice.
As we become more sophisticated in understanding the chronic wound as
its own disease, biotechnology is bringing us new tools for measuring and
quantifying the wound and the underlying diseases. However, there are few standards or
accepted relevant practices in the wound lab.
Compare wound practice to other specialties and their tests: heart
medicine (ecg, catheterization, pressures and flows, echo), pulmonary
medicine (radiography, pft’s), vascular medicine (angiography, imaging, and
many forms of flow assessment), ophthalmology (ocular pressures, retina
photography, refraction), and so on.
For wounds, there are few tests of the wound per se, wound photography
and linear measurements being the most relevant and prevalent. Even there, many attempts over many years
to develop automated wound measures (area and volume) have failed, and a
nurse with a ruler is still the gold standard. Most “wound diagnostics” are aimed at the
underlying diseases, not the wound itself.
Nonetheless, several of these technologies are quite standard, and you
can expect to see more and more in coming years. There are a few items that can be
considered standard practice at this point, even if not every practitioner or
facility has them: the vascular
laboratory and all of its gizmos, tissue oxygen or tissue perfusion measures
(e.g., TcpO2, laser doppler), pressure mapping (for foot and gait, and for
pelvis-seating-bedding), and the standard clinical lab (auto-immune and
coagulation studies, histology). Young
technologies worth keeping an eye on include wound imaging by multi-spectral
image analysis, and wound proteomics and genomics via gene chips or novel
laboratory panels. 5 - Ancillary therapies. There are many items relevant to wounds,
and the rest can be lumped here. One
example are the surgical devices and wound closure widgets. Surgery is crucial for the final closure
for many wounds (and it has no role or is contraindicated for many others). Going beyond the trivial items (sutures,
staples, glues, instruments, etc.) some surgical principles can be applied to
everyday wound care in the form of mechanical wound closure devices. Meant for office and clinic use, these
gizmos put mechanical forces on the wound, attempting to slowly relax and
advance the skin margins. They are of
mixed utility, especially when dealing with wound-healing-incompetent wounds,
but they are an example of an idea that is sensible at face value. Another example is hyperbaric oxygen therapy,
a modality which is relevant, useful, high profile and expensive, but which
is not explicitly a wound healing technology and which does not fit into the
other categories. Then, there is all
the paraphernalia which supports the management of the underlying diseases
which caused the wound, such as all of the stuff used for vascular surgery
and for pressure relief and management.
If you are in a chronic wound practice, then you will be barraged
regularly with new items, some potentially valuable, some not quite ready for
prime time, and some just simply “not”, and you must make discriminating
choices about which seem meritorious and which are bogus. Competition or cooperation
with other products. Many problems in
medicine require sequential therapies as part of a coordinated program of
care. A diabetic patient in hyperosmolar
ketoacidosis needs certain acute life-and-death treatments. Once that is all stabilized, then he needs
proper diet and insulin therapies. A
Crohn’s patient with acute bowel obstruction or perforation needs life-saving
emergency surgery. Once the acute
phase is resolved, he then needs anti-inflammatory therapies and functional
bowel management. Every problem or
specialty in medicine has its Phase 1 of acute care and stabilization, then
Phase 2 of discretionary care to resolve the disease and its sequelae, then
Phase 3 of preventive care and maintenance.
This is eminently true for wounds, Phase 2 being where discretionary
treatments are applied to heal the wound once it is controlled of its acute
ulcerative phase. However, this is not
what we mean when talking about sequential therapies for wounds. The concept here is all within that
discretionary Phase 2 where you are trying to heal the stabilized wound. The problem is that wounds come in all
sizes and flavors, and they have various logistical problems in their care
related to size, location, number of wounds, resources and personnel
available to assist with the required care, patient disabilities, and
economic resources. Some therapies
work well under some of these constraints, others not, and vice versa. A product or strategy or technique or
modality might work for only so long, inducing a beneficial change in a wound
only up to a point. If it ceases to
work or to get past a certain size of the wound, that must not be seen as a
failure, but rather as the reality that certain products only work within
certain ranges. It is not only
appropriate, but the acknowledged general strategy in wound management that
therapies can and should be used sequentially, one after another, each tactic
being used within its own operating range, then handing off to the next
modality or product as the wound gets smaller. For example, imagine a large pelvic wound following some sort of
trauma or fasciitis. Such wounds
having surface areas of 1000 square centimeters or more are not at all
uncommon. Assume that you have
completely cleaned up all of the acute mess, the patient is now healthy, and
the wound module has proliferated and is receptive to any type of wound
healing or wound closure method you might wish to apply. In principle, skin grafts or other surgery
might resolve much of the problem quickly, but for any number of perfectly
legitimate reasons surgery cannot be done.
However, to expedite closure, you will apply technological products
meant to accelerate wound healing so as to minimize time and costs involved
in restoring the patient to full function.
What can you use?
Becaplermin-PDGF (Regranex®, Systagenix)
is one of the important stimulatory therapies, but it only comes in a 15 Gm
tube, at roughly $1500 per tube. It is
meant to be applied approximately 1 mm thick.
So, 15 Gm is approximately 15 cc (assuming density of the gel is
comparable to water), which sliced into 1 mm wafers gives you 150 sq cm
coverage. So, you need 7 tubes to
cover a 1000 sq cm wound, each day.
You just broke the bank. Sorry,
that option won’t work. Well, what
about Apligraf®, Organogenesis, a
living neonatal cell biologic, another one of our valuable stimulatory
therapies? Each circle of the material
is 42 sq cm, roughly 1/3 or 1/4 of the coverage of a tube of becaplermin, for
roughly the same price, although it only needs to be applied every week or
two. Still, the costs of these
modalities on such a large wound will be comparable – way too much. Even if cost was not an issue, the sheer
physical logistics of applying those materials properly and holding them in
place the requisite time is a challenge.
So, what does work for large wounds like that, easy to use and cost
effective at those scales? We have
products for large scale, starting with the rudiments of good hygiene and
basic cost effective topicals. If we
want to stimulate or otherwise actively affect that big wound, and do so
realistically and economically, we can do so with radio frequency (e.g.
Provant®, Regenesis), or with
negative pressure therapies (e.g. VAC®, KCI
and competing products), or with ultrasound (e.g. Mist®, Celleration), to name a few.
What happens next when the wound has contracted to perhaps only 50 sq
cm, but it has stalled, no further progress for the past few weeks? Time to switch to something else. What now might be a bit more potent and
specific and suitable for the current size?
Apligraf® (Organogenesis) or
Dermgraft®, (Advanced Biohealing) would
be good choices now. And what if after
8 weeks of therapy the wound is now just 5 sq cm, but no more progress is
happening, and these modalities no longer seem to have an effect? Becaplermin-PDGF would now be a good option
at this small size, very cost-effective, yielding 30 days of therapy at
current wound size, but actually 60 days of therapy since the wound will be
getting smaller, enough to carry it across the finish line. (Remember, the use of proprietary names and
products is not to be misconstrued as explicit endorsements, and no one has
paid me anything to put their name in print.
On the other hand, these are the real products we really use because
they really work and let us get our patients fixed up. There are many other products as well, and
you can use the concepts of this section to find the time and place for your
favorite products as well.) Also,
anywhere along the way in this case scenario, surgery could be done to close
the remaining wound if appropriate, and if the above therapies have reduced
wound size leading to smaller grafts or flaps or less post-operative
morbidity or recovery time, that too is valuable. The principle of tandem or sequential
therapies is very important in wound practice, and many products from many of
the categories above may ultimately be used over the duration of care for any
one wound. |
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Integrating New
Products and Technologies into Practice #6 Guidelines for assessing new products: product utility & relevance. There is both wheat and chaff among the endless new products,
and sometimes there comes along a genuinely nutritious and tasty grain that
will fundamentally change they way you and we all do things. All practitioners are obliged to keep an
eye open for them, and hopefully participate as well in the planting and
harvest, i.e. the trials and evaluations, the reporting and education. For any new product or concept, you can choose to wait and hear
the recommendations of other users, or you can take the initiative to be one
of the first to evaluate a new product (and then be the one to communicate
that information to others). Either
way, you will have to discriminate good from bad, real from bogus. The rest of this presentation is meant to
give you some guidelines for separating the wheat from the chaff. |
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The products that support wound practice have a wide range of
relative value and importance. Some
are vital things without which we just as well might be living back in the
trees. Others are strictly
non-essential luxuries, and there are others genuinely valuable but needed just
once in a blue moon. Some are too
expensive or non-pragmatic to be used much, while others are good enough to supplant
whatever else you used to use. When
looking at our supply cabinets and procurement paperwork, products seem to
fall into four general categories, and you can be sure that every new item
will fall into one of these. 1 – Trinkets: baubles & bling in the supply cabinet. These are the items that sounded good when
you decided to try them, but the shine tarnished quickly because they do not
really work. Or else they work well
but have very few eligible patients, or they work well but have all kinds of
administrative headaches that keep them from being practical to use. They may involve some monstrous piece of
equipment that impresses visitors but eats up valuable space. 2 - Toolbox
toys: special items that you
know you will need infrequently, now and then, just in case, but when you
need them you really need them. Any
dude who has a shop, who does woodworking or rebuilds cars knows about this
one, that special wrench or riffler that you know you will use just once in
10 years, but your toolbox would be incomplete without it. 3 – Trailblazers: changing the way we do things. These are the revolutionary things that
change the fundamental ways in which we solve problems and accomplish tasks. Anything that you use daily and take for
granted was once a novel concept or product that had to prove itself in
practice and in the marketplace. Some
advances are overt and obvious and catch on immediately, such as the use of
ether and anesthesia in surgery after its first use in 1846. Others are not so obvious or else meet
resistance to new ways, such as the 30 years it took for Listerian antisepsis
to become normative practice in surgery after its first publication in 1867. 4 – Workhorses: the products you really use everyday. These were once new and novel, and in their
own day they first met acceptance or resistance. Today, you hardly notice them even as you
use them daily. Imagine how your
practices would change if cotton gauze or scissors suddenly disappeared,
narcotics or anti-inflammatory drugs, ecg’s or computers or telephones or
electricity itself. The trailblazers
and workhorses do not announce themselves.
The marketing men behind every new product will make that announcement
for you, but the real value of genuinely valuable products awaits to be
discovered by you. 5 – What if’s
and the wishlist: Yes, we have many wound
products, important or not so, used daily or rarely, highly effective or
so-so, but all real, tangible, and generally easy to procure. But in this business we are always looking
for that other item, the one that works better, the one that gets better
results, the one that is easier to use, the one that solves that special
problem you have right now. In the
quest for new and better, it is worth considering the betas, boneyard items, vaporware,
and other fantasy products of this business, the missing products, what-if’s,
and wishlists, because there are some nuggets to be mined there. First, consider those products that (1) do
not exist, (2) did and died, (3) live in oblivion, (4) could or should be
developed but no one has. As examples
of such products, consider three that incorporate allantoin, acemannan, and hyaluronic
acid. Allantoin (5-ureidohydantoin) is common in nature, the final
water soluble endpoint of purine metabolism in almost all species. Just a very few species, including man,
lack the enzyme to do the final conversion, meaning that our purines degrade
only to marginally soluble urate, giving us the gout. In the classical European materia medica, the
comfrey, Symphytum officianalis, has always been one of the most potent and
preeminent vulnerary herbs. In the
early 20th century, comfrey root was found to have an unusually
high concentration of allantoin. In a
seemingly unrelated thread, many had observed that maggots, fly larvae, which
were commonly found on untreated putrefied wounds seemed to expedite wound
healing. In the 1930’s, those studying
this effect observed that the improvements were greater than could be
attributed to fly “munchies” mechanical debridement. In studying the issue, the benefit was
discovered at the other end of the maggot, with high concentrations of
allantoin in the fly excreta. In 1976
in the Archives of Surgery was a report on a medication compounded of silver
(“A” for Ag, for its anti-microbial properties), zinc (“Z” for Zn, because
its presence in skin was an in vogue topic of the day), allantoin (“A”, for
the threads of evidence just mentioned), all prepared as a cream (“C”, for
topical use). The AZAC paper showed
some nice results healing some chronic wounds. Allantoin is the perfect example of a
classic vulnerary chemical of genuine potential significance that has been
overlooked by serious researchers and corporate development over the past
century. It is easy enough to
hypothesize that as a degradation product at the end of a major metabolic
pathway, that it would have some sort of promotional or inhibitory feedback
on antecedent steps in the chain, thus having useful pharmacological
properties, be they for wounds or otherwise (especially in allantoin-naive
species where the feedback might be strong due to the absence or attrition of
any modulators or dampeners).
Allantoin deserves proper study and development. However, the lack of intense study and
academic rigor did not dissuade at least one company from trying to make a
modern day allantoin-based topical wound product. Carrington Dermal Wound Gel, made by
Carrington Laboratories, has now been on the market about 15-20 years. It is a “second tier” product. It gets little attention. The company does not even seem to have a
website that works. They seem not to
have any reps that visit doctors and hospitals. I do not know what regulatory level it is
subject to with the FDA, but it seems to be sold more as a non-specific
topical, more of a skin care item than a pharmaceutical. Is the lack of a serious market or
marketing effort based on the deliberate strategy of the company about this
product, or a blasé disinterested attitude, or a pragmatic choice based on
regulatory effort versus costs and efficiencies? I don’t know. Twenty years ago, it had some fanfare, now
nada. Is it a good product? I don’t really know, since it is not
available to us in our purchasing contracts for basic everyday products, we
have had prescriptions rejected by pharmacies as non-available or
non-formulary, and any of our patients who want to try traditional
vulneraries can get more potent forms as comfrey extract in health and
natural food stores. The lesson here
is that if there are products which make sense, try to use them and create a
stable supply source. Speak to
manufacturers and get them to give you samples and experiment for yourself
with what works. Ask the pharmacies to
stock it. Have a reliable second
source or backup, which for allantoin is comfrey extract (or modern day
medicinal maggot therapies, which are commercially available if you, your
staff, or patients want to use them).
What if . . . what if somebody had ever properly studied
allantoin? Perhaps we would have a
genuinely potent wound stimulatory therapy in proper concentrations, properly
marketed and available for effective use. Another what if example is acemannan, a polysaccharide that
comes from Aloe species. Aloe vera and
other aloe species have been used as topical burn and wound dressings for a
long time. In the traditional materiae
medica, it is not so much a true vulnerary that makes wounds heal, but more
of an anti-inflammatory that settles the acute phases of acute wounds, especially
useful for burns. Either way, aloe has
received attention off and on for as a potential product for wound care, and
quite a lot of its candidate chemistry has been studied. It has a variety of useful chemicals and
therapeutic properties, including acemannan which, in the early 1990’s, was
focused on for mitogenic and proliferative properties of potential value for
wound healing. It was used by
Carrington to make Carrasyn gel, a topical wound product. I always thought that this company was on
the right track, looking at conventional phyto-chemistry in a search for
vulnerary pharmaceuticals. Remember,
in 1990 “biotechnology” was an incipient industry of high hopes and modern
technologies but uncertain market value and practical utility. But it was the bandwagon that everybody
wanted to ride, and as it has come to fruition, the focus and methods and
market products are generally focused on complex chemicals, recombinant
technologies, genomics and proteomics, and other such cutting edge
technologies that ambitious company execs and scientists learned as grad
students and post-docs, and which are glam and get chi-chi funding. Even in traditional pharma, the focus for
the past 40 years has been on designer drugs culled from giant catalogs of
synthetic organics which can be patented for the patent-and-profit corporate
model. Classic crude drug
pharmaceutical chemicals seem to have become orphaned step children of trivialized
irrelevance. So, any concept or vision
that a Carrington might have is likely never to be fully realized. In part, a company like Carrington has to
fight against the preponderance of time, attention, funding, effort,
personnel, and research that more cutting edge au courant technologies get –
i.e. their failure is not their fault, just bad timing and society. In part, to be successful, their
phyto-vulnerary topicals needed good marketing backed by some compelling
research or data – right-upper on the bogosity matrix – legitimate but with
limited data. As a topical wound
dressing, the regulatory requirements are not so stringent, so good studies
are not so crucial. Thus the allantoin
and acemannan products fall into a trivialized product category, and most
people are unaware of these products.
Do they actually have a legitimate vulnerary effect? Should they be great products in wide use? That is impossible to answer, because
meaningful data never accumulated – but in principle it should have. For products like this, a great study would
incur a rather simple efficient protocol that would make the study
inexpensive (as studies go), and which could be done quickly for hundreds
(even thousands) of patients at multiple centers with several investigators –
a great study that would answer the question, opening the market to these
safe, accessible, inexpensive products if they proved to be useful. Another example, but different, is a product named Hyalofill,
from Convatec. It was on the market
for a few years, but no longer, but possibly returning one of these days
under different proprietorship.
Hyalofill was marketed as a wound dressing. What made it unique was that its active
ingredient was hyaluronic acid. I
cannot recall what if any were the special marketing claims and usp’s (unique
selling points) for this product, but as I recall the claims were somewhat
nebulous “rah rah wound healing”, like so many other products, with some
vague and not-very-technical-erudite-informed-meaningful explanations of why
hyaluronic acid might be important or worth your attention and
prescription. So, the product fizzled,
then died – off the market. It has
since been bought by an investment group that promises to develop and
remarket it. The problem with entrepreneurial
holding companies is that they suck up a portfolio of products, good, bad,
useless, and potential gems, but not being clinical-science-technical people,
they often have no real idea of what the product means, why it is
good-bad-otherwise, and no special plans to do anything with it anytime soon
– good patents and manufacturing processes locked up and wasted in
limbo. I have had discussions with the
new company, with promises that they would speak to use, all enthusiastic
that someone is interested in their shiny new bauble, but they have made no
followup nor further contact. So much
for entrepreneurship and the proverbial “hungry young company”. Why do I want this? Why should this product have remained with
a reputable, experienced, resourceful company like Convatec? Why should you care? Because hyaluronic acid, as one of the
matrix gag’s (glycosaminoglycans) is one of the most profoundly important
chemicals in embryonic histogenesis, control of inflammation, and the healing
of wounds – one of the key agents that governs the execution of the embryogenesis-regeneration
subroutine versus the inflammation-proliferation subroutine. In theory, hyaluronic acid and its sister
chemicals (uronic, chondroitin, heparan, dermatan, etc.) should have a profound
beneficial effect on promoting the healing of the hardest-to-heal
wounds. The problem is that nobody has
really studied it very much as a wound healing entity. For reasons related to history,
happenstance, the hegemony of the pedants and pedagogues running graduate
studies, neanderthal love and other anachronisms, and other reasons related
to lemmings and bandwagons, everybody, from academics to corporate execs to
biotech inventors and investors, everybody has gotten focused on collagen as
a the must-have me-too everyone-else-is-doing-it biochemical wound product. As a wound healing product, pure collagen
makes some but little sense. As a
composite material with fibronectins and other smaller matrix proteins it
makes more sense. As a yet richer material
partnered with gag’s, it makes even more sense. And what about gag’s alone? Who knows, but they probably have a greater
potential role in regulating good wound responses that collagen does, and the
product vector ought to rotate toward the gag axis. Why?
The gag’s are part of the general ground substance. In the embryo, traumatic injury does not
induce inflammation and fibrous healing, just a re-accumulation of ground
substance gag’s and continued embryonic histogenesis. On slide 4 the product Integra was
mentioned (and to be discussed in greater detail on slide 35). A huge amount of information is available
on this product at the arimedica.com website, including a complete discussion
of the histogenesis of the material.
Its ability to eradicate inflammation and then trigger the embryonic
transformation of histo-progenitor cells is largely due to the aminoglycan in
the material (chondroitin). Having a
properly researched, engineered, and manufactured aminoglycan wound cover would
probably be of profound significance for the sake of controlling the effects
of primary disease, the effects and persistence of acute inflammation, and
the ability of regenerative cells, mesenchymal and epithelial alike, to
proliferate, migrate, then reorganize and reassemble a new tissue, i.e. heal”
the wound. Hyalofill never made it to
success because it was conceived of and marketed as a dressing, not as a
wound regulating biologic as it should have been. It failed because the company and all the
lemmings were so focused on collagen and cytokines and silver and alginates
that the product was never properly scrutinized nor reassessed from a science
point of view, nor re-manufactured and re-branded as a properly investigated
wound healing agent. We do not need
more collagen wound products. We
hardly need any at all – topical exogenous collagen by itself just isn’t that
important to wound healing. We really
do need aminoglycan wound products, but now we have none. The company bailed, flipping the “asset”
for cash, instead of holding and rethinking it. If they had held it, they at least had the in-house
resources to re-research this if they chose or could be persuaded. Now, it is in limbo. Too bad.
On the what-if’s and wish list, we also have products pending,
promised to be coming soon to a store near you. So they say. So we have heard. The wound meetings, the big national and
international ones, especially the science-industry-technical ones are where
you will hear the most about items being commercially researched and
developed. There are many lines of
investigation and development. Some
never become tangible. Some get hung
in regulatory purgatory. Some actually
come to fruition. There are many
concepts. The pending products that I
have most been looking forward to are the transfectives – giving your wound
“a cold”. In this approach, safe viral
vectors (e.g. adenovirus), doped with a therapeutic gene such as a wound
proliferative cytokine, are used to inoculate native in situ cells. Preclinical and early clinical work looks
very promising. I am not right now
(2009 -2010) personally aware of where it stands, how close to market
reality, but this is one concept worth looking forward to. What is the message for you, the
discriminating purveyor and prescriber of wound treatment products? Without the products that some company
makes, good concepts do not come to life.
Without a company to sustain a good product, it dies. When end users know something that the
company should but doesn’t, users should speak up for good products, voting
with your emails and phone calls to company reps, or else with your
prescriptions to buy and use the products.
Sometimes good companies with good products just have the wrong idea
about it and need to hear the “real scoop” from YOU (see slide 34). Whatever product you use, do not just use
it blindly. Try to understand what it
does, why, and where it fits in the spectrum of products available, ready to
be used whenever needed, whether that is every day or just once in five
years. |
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Integrating New
Products and Technologies into Practice #7 Guidelines for assessing new products: general framework of evaluation &
adoption. You and your relationship to a new product will depend
individually on you and the product. You
might be on the leading edge of using a new product, or you might wait until
others have established the place for that product. This will depend on your knowledge and
interest in a particular subject, your experience & intimacy with that
subject in daily practice, how much you might have known about or anticipated
the product before it was available, and of course on your overall general
temperament and approach to such things. A street
accident. From “Hospital Life in |
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Here are some points of philosophy to guide your spirit in the
evaluation and use of new products. 1 – Be educated
and resist bogus claims: This is
your primary hedge against disreputable practices by vendors with bogus
products who, solely for their own remuneration, take advantage of you at the
disadvantage of the patients who have entrusted in you. If you want to be a cardiologist, be a good
one. If you want to be an orthopedist,
be a good one. We have a system of
formal specialty education and board certification that has various checks,
balances, performance milestones, and peer examinations to ensure that in the
mature specialties, that graduates can do what is expected of them. For wounds as a specialty, the same rigor
and discipline just is not there yet.
Most people who have voluntarily joined this specialty have the right
morals and motivation, but absent a well defined curriculum and respectable
academic departments, the technical knowledge and skills of wound
practitioners are very variable and oftentimes not very expert. Anybody who cares to be in control of their
own judgments on behalf of their patients, and not be hoodwinked by a company
with a bogus product to sell you, has a few intellectual obligations. You must – must – understand wound science (anatomy,
physiology, pathology) and you must understand the clinical arts of wounds (diagnosis,
therapeutics, management). Even in the
wild and wooly West of Wounds, maintain your equanimity, your intellectual
composure, your professional standards of evaluating and using new
products. Even when you are unfamiliar
with the concepts and background knowledge behind a new product, there is
always time to learn and then make an informed assessment. Don’t let patent medicine practices sway
your thinking. 2 –
Intelligently try new things:
There will be times when promising new products all seem to arrive on
the scene at the same time. You might
decide that you want to try them all.
Perhaps you even try each one one or two times. And then you realize – you cannot possibly
develop expert insights about any one of them if you are using all of
them. They might be similar products,
or they might be very dissimilar (e.g. a topical peptide in a cream versus a
surgical skin substitute) but for the same purpose of getting the wound
closed. For any single wound or patient,
you will get to use one or the other.
Anecdotal use of all such new products is worthwhile to “get a feel
for it”, but not if you want to see which ones really or work or not, nor how
to get the most out of a specific product.
To master a new product, you can only get good with and understand a
few at a time – maybe even just one if it represents a major new change to
your overall practices and strategies.
Ultimately, complete mastery, even complete awareness of all new
products is unrealistic – actually, impossible. Thus your goal must be not to master
everything, but to judiciously pick and choose things that seem most
promising, that most closely fit the needs of yourself and your particular
patients. Like every skilled
craftsman, you must outfit and master YOUR toolbox. What is in your toolbox might differ from
your buddy across the hall, or across town, country, or the whole world, yet
your results might be equally good.
And if anybody’s results are superior, then the value of the relevant
products can be learned at the professional symposia where knowledge and
experience exchange and intermingle.
You must be practical. Give
promising new products an honest safe “test drive”, then focus on those few
that you can make a serious commitment to understanding. Don’t be afraid to “pull the trigger” for potent or risky
therapies. In medicine, we do serious
potentially lethal things to people because we have learned to manage the
risks and complications and get the results.
When we induce cardioplegia on mechanical bypass so we can chop out
and replace a bad mitral valve, we are doing very unnatural things – but we
do it, and successfully. When an
oncologist gives lethal poisons in metered amounts explicitly to destroy your
bone marrow, and thereby put you at risk for deadly infection, so that he can
then replace your cancerous white blood cells, that is serious stuff. But we do it, and we do so
successfully. Most wound therapies
have not quite so much drama, but some do – if I excise all the skin and
fascias for a bad burn or necrotizing fasciitis or primary lymphedema, I do
so because I know I can then rebuild the skin. If I use cyclophosphamide or tacrolimus or
an anti-lymphocyte mab to cure out-of control lymphocytic ulceration of the
skin, I am taking risks, but I know how to manage them, and the good
consequences of careful management are equally important for that patient as
the mitral valve and bone marrow transplants were for their respective
patients. If a new therapy seems
potent, risky, strange, that is the reality of looking for newer better
treatments. No one other than YOU is
going to figure out how to use it and make it work safely and
successfully. If you are a nurse or
physician, then you have the license to prescribe or administer and manage
the product and start figuring it all out.
Unless you invented the product or are involved in pre-market trials,
then if it is on the market it has some safety certification and
“instructions for use”. If your are
the investigator, use your professional skills to figure it out for everyone
else. So, don’t be afraid to use new
products – but use them wisely and carefully. 3 – Share
knowledge: As implied above, real
progress happens when everybody is trying different products, or different angles
on the same product, then they get together and share the news. Share your experience and insights with
others – via discussions, meetings, publications, whatever. Likewise, learn from others who are doing
the same thing with the products they are trying – make a commitment to go
hear them speak, at a dinner meeting or a major symposium or in a journal
article. This issue is addressed more
on slide 47. 4 – Do not
adopt newness for its own sake:
We are all on a quest to find the best tools to do a serious job. Tools – not toys. Toys are beguiling. Toys are fun. But toys do not get the job done. There is always a bit of the “new toy”
mentality in playing with a hyped up new product, even more so when the
product seems categorically different than extant therapies. The companies that invest huge monies in
development and marketing, who have more fealty to their investors than their
clientele are always going to try to “upsell” you to their new, patented,
expensive, high-margin item. Their marketing
staffs get paid to persuade you that new is better, and no strategy, from
boys-with-toys to free pizzas delivered by sexy reps to any other bogus
inducement is necessarily beneath them these days. New can be good – we are all always looking
for something new-better. Sometimes
new is good, sometimes great, and bit by bit we make progress and get better
results with better tools. But new is
not always good, and sometimes new is okay but not ipso facto better, and
often old is better. In fact, many old
products are uncontestable paradigms and foundational therapies. In recent studies, it seems that classic
thiazide diuretics are often just as effective for controlling blood pressure
and edema as the whole bevy of new drug classes that have appeared over the
past 30 years. As the monoclonal
antibody therapies have become accepted and are receiving ever wider
indications and new compounds, we are now seeing a resurgence of interest in
old standby anti-immune drugs, such as azathioprine and especially
6-mercaptopurine, as the very serious toxicities of the newer wonder drugs
become apparent. As antibiotic
resistance becomes an ever increasing cause for media sensationalism and
death-and-doom sayers, it turns out that after three generations of conceptually
different antibiotics, we are now seeing a return to safe and effective use
of classic safe first-round agents, such as the use of tetracyclines and
sulfa to dependably control (even the “resistant”) staphylococcus. Remember, the company is always going to
try to sell you the glitzy new model, because their principles and “morality”
these days is often just the “bottom line”.
Nobody rightly wants clunkers of old products that do not work well,
and nobody expects you to stick with the old when it is inferior. But even when the old is far superior –
safer, more effective, cheaper – the companies are going to sell you what’s
new – because that’s how they make their money and meet investors
expectations – and you have no choice, because you can only buy what they are
selling. And “they” with high profits
to protect are the ones with big budgets to come visit you in your office to
persuade you. The guys with the cheap
dependable old products, the after-market guys, the bulk manufacturers who
sell to the brand label OEM’s, the off-patent generic makers and suppliers,
they do not EVER, never will come and visit you in your office with a nice
looking rep, a warm pizza, and a free imprinted ballpoint pen. There are great new products that you
legitimately buy. Then there are
others where, “baby, you’ve been sold”.
Equanimity – maintain your composure in the face of the sexy sales
pitch. Tools, not toys. Never forget all of the old stuff that
worked, worked well, worked safely, and keep using whatever is best, not
whatever is new. 5 – Remain in
charge of your analysis: The
predicates to this paragraph are the four items above, The conclusion is that you can only buy
what “they” are selling. What “they”
are selling these days often has more to do with recouping big investments
and making profits, more so than serving the public and their clientele. You are not being actively sold on old
products without patents and profitability.
The whole system is rigged towards using what is new, rather than what
works. To reiterate, there are many
great new game-changers, but it remains up to YOU to discern the good from
the bad, to promulgate the good, and to ignore the bad until it goes
away. As an evaluator of new products,
you should never just “jump on the bandwagon” because some pied piper has
promised you a trip to enlightenment, nor because of “popular delusions and
the madness of crowds”. At all times
you must remain in charge of your own psyche and intellect, your own trials
and conclusions. Always beware of
profit motivation and inept misleading marketing materials – because know it
or not, you are being sold. Your own knowledge
and principles must always trump sales pitches and fud. Likewise, you should embrace well reasoned
and effective new items, or at least be open-minded, thoughtful and
analytical, and give them a try. Your
assessments, conclusions, and eventual everyday practices must be based on
all of the virtuous things that you must bring on behalf of your patients who
entrust their lives and well being to you.
New for its own sake is not an inherent virtue. Do not be so enamored of the new that you
forget your old friends. Keep in mind
the total value of the new and old products – cost, utility, effectiveness,
safety – and choose wisely. All good
tools should find a place in your toolbox, ready for service when it is the
best tool for the job. |
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Integrating New
Products and Technologies into Practice #8 The bogosity matrix and individual product
assessment (including case studies). How do you judge the technical merits of a new product? New products involve many details of
chemistry, physics, engineering, materials science, math and statistics,
bio-interface and transduction, computational and human interface
technologies, and analysis and presentation, not to mention the core
biosciences behind it all. In our
complex society with its intricate systems for developing and using products,
one must likewise be familiar with the sociological aspects of how a product
came to market, including some business-finance-marketing, and then the
government-regulatory-legal aspects of it all. Physician education is predicated on the
principle that all physicians have a sufficiently thorough undergraduate then
medical education that they can be conversant on these subjects and cannot be
seduced by the misleading claims of disingenuous salesmen. Even so, these are big subjects, and no one
can be so thoroughly familiar with all of these subjects that every new
product for every purpose can be fully understood and critically evaluated
without some new education or explanation. Practitioners must evaluate new product claims based on several
technical criteria, including: purpose
and need, efficacy; proven or
promising science; safety, risk versus
benefit; utility and cost, comparative
value. Given the reality that no one
can be totally conversant or skilled or expert in the many disciplines
listed, given that you will be asked to assess new technologies and products
that you might have little familiarity with, how can you take the knowledge
you do have, mixed with your plain old common sense, and make an intelligent
evaluation? It can be done. The next few slides should help you decide
when there is a “red flag” warning of a bogus product versus a meritorious
product. We will start with a
checklist of questions and items to be answered for each product, and then we
will learn how to use the “bogosity matrix”. An advertising
cut from The Household, volume XXV, 1892, a nationally distributed women’s
monthly magazine published in |
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So far, we have been talking about general principles and
guidelines for evaluating or working with new products, conceptual premises
and an ethos for good practice. Now,
we will start to focus on the assessment of individual products. Regardless whether you are evaluating a
drug, a device, a new operation, a new therapeutic protocol, or anything
else, the questions you should ask fall into five general categories. 1 – Concept: What is the purpose and rationale? Does it fulfill a need? Does it make sense? Does it solve problems or fulfill needs for
my patients, because current therapies are not good enough? Every product is conceived by its author or
inventor as something useful, but that does not make it so. Unfortunately there are products where the inventor
has a technology or an invention searching for a use, but no direct expertise
or experience in the subject or target audience. In recent years, there have been quite a
few here-today-gone-tomorrow wound products where a naive inventor and his
entrepreneurial investors should have spoken first to a genuine expert and
more accurately assessed the potential utility and technical merits of the
product. There are also products that
go the other way, big winners where the naive or single-minded technologist
stumbled onto something that no one really understood, but once it is on the
market, it has value and applications beyond what anyone might have
guessed. The moral is that you must
keep an open eye and ear to vague and unforeseen possibilities, but still,
the product must have some degree of conceptual utility or necessity before
it gets your serious attention. If the
company representatives cannot themselves explain the value, it will never
win and is not worth your time.
However, if the justification seems sound, even if completely novel,
pay attention. 2 – Proof: Is there valid science, proven or
promising? Does it fit with what is
known? Have satisfactory clinical or
other real world trials and evaluations been made? What were the testing protocols and
analysis? Is it efficacious – does it
work – in the lab, in clinical trials, or anywhere else? Is it safe?
Good ideas are cheap. Getting a
good idea to tangibility, or further yet onto the market, should garner
admiration and respect for anyone who has accomplished it, because it is not
easy and it is not trivial. But that
does not automatically mean that the concept or new product actually does
anything. If you are to take it
seriously, there must be some evidence that it actually does what it claims,
or anything else useful. Recall what
was discussed on slide 14, that many wound products and “trials” or “studies”
confuse simple hygienic care and the restoration of natural wound healing
kinetics with genuine therapeutic effects to accelerate or positively promote
wound healing. Sadly, there are many
wound products that make it to market with good faith but utterly naive and
inept studies that make it past unsophisticated and indiscriminating
eyes. (Until wounds are no longer such
an undervalued subject in the medical curriculum, reviewers, regulators, and
other gatekeepers in the broader arena of medical products will continue to
get duped or make erroneous judgments about what really works or not). Remember, all new products are going to
have limited supporting data, so good proof or data are not make-or-break discriminators. That is why “good concept” is also
important, even more important in the earliest phases of development. Somewhere within the scope of good concept
and good proof, there must be something to win your respect or
attention. If not, then the product
may be bogus. Safety is also a
proof-of-concept issue. Regardless of
how theoretically useful something might be, if it cannot be used safely, it
cannot be used. But, do not
categorically dismiss a nominally dangerous item until you understand more
about it. Crucial tools for medical
practice include cardiac glycosides, cardioplegia, neuromuscular blockers
such as curare and botulinum, and organ transplants and blood transfusion –
all lethal if used improperly, yet all done everyday because we know how to
regulate and manage the risks. 3 – Principals: Who is the company? . . . who is behind the product? . . . are they reputable or credible? Who represents the company? . . . how well? . . . can they adequately answer your questions? How do they do business? . . . how is their customer liaison,
support, feedback, and interaction? Is
this a credible company that you can believe in? Some products come from big experienced
companies that you can trust. Some are
coming from big experienced companies that have gotten some black eyes lately
and deserve your wariness. Many
products are coming from small startup companies that have no track
record. “Good concept” and “good
proof” are thus the important credentials.
Nonetheless you still need to know that you can trust the company to
support your use of the product, to keep you informed, to give you accurate
honest information, and to be around to continue making good products. Ultimately, the most important principal or
stakeholder is you, because if you do not speak up against bogus products, or
if you prescribe and use them for fallacious reasons, then a disservice is
done to your patients and society.
Likewise, if you do not prescribe or properly use worthy products,
then good tools that we might all depend on risk going away. 4 – Principles: Is the product or company driven by
science-biotech, clinical-medical, or business-marketing? Are the marketing materials
meaningful? Who is the target market? Are you dealing with real reps or with
pitchmen? Are the scientists and executives
accessible? Are they dazzling you with
legitimate brilliance, or are they muddling with manure? Every company is going to have some set of
core values and ways of doing business and ways of presenting and
representing themselves. Does it all
seem reputable and dependable to you? You
would think that any self-respecting person or company that wants your
business would pay attention to the details of how they interact with you,
and most do, but some do not, and I find it hard to take them seriously if
they do not take themselves seriously.
Even with great companies and products, you need to understand their
motivation. If the product impetus
comes from clinical-medical people, it is most likely to pass the “good
concept” test. If the impetus comes
from non-clinical biotech inventors, the product might need more time for you
to understand, and it might even be a major game-changer, but it might also
be an irrelevant product with no real utility, even if technically competent. There really is a difference between
products championed by the clinicians who directly appreciate the need versus
those invented by inventors who could and then must seek an indication. Then, there are those products championed
by (overly)-hopeful investment entrepreneurs and company executives where the
motivation is monetary, sometimes with complete disregard for how irrelevant
the product might be. Do the companies
care enough to have the product properly represented? Young companies on shoestring budgets might
have no choice but to use rep companies rather than their own hired staff,
but either way, a good company with a good product should be able to figure
out how to present the product properly with relevant information. I have found that when good reps for good
companies and products cannot answer you questions, they will get you
connected to the scientists, inventors, company executives, or other
clinician users so that you can get the answers you want. Remember, good concept is always crucial,
but in the early phases of any product, even the best products, good proof
and robust information might be scant.
In those cases, good principals and good principles can be equally
important to your assessment and willingness to try a new product. 5 – Value: Is a product efficacious? Is it safe?
Is the risk versus benefit profile favorable? . . . likewise for cost versus
utility? What is the real value of the
item, and what is its comparative value against similar products or options? If a product neither does anything useful
nor is safe, it is of no relevance or consideration. These criteria are so obvious and
fundamental that they are the two paramount criteria for market approval by
the US FDA. Risk-versus-benefit
(bio-medical issues), which includes cost-versus-utility (socio-economic
issues) are relative concepts. The
more morbid or lethal the disease, the more risk we are willing to accept to
get the job done. Does a new item have
value sufficient to make you abandon tried-and-true methods and
products? Are there moral or legal
issues when companies offer inducements to switch that are not based on the
intrinsic merits of the devices or drugs?
(Yes, of course there are.) You,
and only you can make these assessments on behalf of your patients. Here are two examples of net value from the annals of medical manufacturing. Some of the earliest of the modern
patent-and profit pharmaceuticals, in the 1970’s, were the cephalosporins,
then H2-blockers, then non-steroidal anti-inflammatories, then beta-blockers,
etc. Most of these are me-too products
that offer no real advantage over any other in class. In the 1970’s, pepperoni-and-cephalosporin
was the preferred flavor of pizza in doctor offices, clinics, and hospitals
everywhere. All physicians would deny
that they were swayed by such attempts to induce prescriptions or brand
loyalty. Whether they were swayed or
not, the blatant over-the-top abuse of this practice eventuated in some
changes. Make no mistake about . . . if
some company wants to buy you a casual dinner or give you a logo-imprinted
coffee cup in return for your time and attention to hear about a new product,
that is fair. Regardless of what
modern day political correctionists tell you, this has always been fair in
fair-minded society, and it is today’s politically-correct zealots who have
gone overboard in closing the doors of hospitals and medical schools to
company reps, cutting off one of the most valued sources of new information
that is out there. Good information is
good information, and it is not tainted because the words issued past the
lips of a pretty rep with a bag of doughnuts.
But this system did have its abuses, and this is why YOU need to be in
charge of honest and responsible assessments and choices about new
products. It is unlikely that most
me-too cephalosporins or beta-blockers will vary in efficacy or safety or
side-effects. But if one prevails on
better price or less frequent dosing, then those are meaningful differences. All aspects of total value must be
incorporated into your evaluation of new products. Then, in the 1980’s, we had the bed wars. Support Systems International (SSi, now a
part of Hill-Rom) and then Kinetic Concepts, Inc. (now KCI) had a knock-down
drag-out over the hearts and minds and loyalties of hospitals and doctors
buying and specifying pressure relief beds (there were and still are some
smaller players in this field – apologies for not making specific mention of
your names). Today, 20 – 30 years
later, we take the concept of pressure relief so much for granted that it is
easy to forget where we came from.
When these companies offered fluidized sand beds, and then various
types of dynamic airflow beds, these were bizarre products that few could be
persuaded to start using, especially in view of the up front or rental expenses. (Sadly today, there are still hospitals,
insurance plans, and their administrators who still do not understand why
these expenses protect patients and save “millions” in the long run – but
fortunately most do.) These beds were
an example of just a very few visionary doctors working with companies to
bring a concept to fruition. It was a
combination of the clinical, technical, and financial principals, and then
the doctors and nurses like you who prescribed the products, all having an
equal role in the success of not just a company, not just a product, but of a
whole product concept and concepts of care that have made modern hospitals a
much safer place for sick people. But
then something happened. Most
hospitals and insurance companies eventually got the idea, and then the
market changed. Instead of doctors
prescribing specific products, hospitals or payors negotiated comprehensive
service and supply contracts with one company or another. The companies might have duked it out
behind the scenes with the administrators, but from the clinicians point of
view, the bed wars abruptly ended.
With little value to the companies to market directly to the doctors,
the pizza-and-pencil promotions disappeared, but so too did the flow of good
information and support and the direct ear-to-the-market of listening to the
clinicians. And then it got
worse. With other profitable products
in their portfolios, these companies backed off on engineering and product
development for the beds. Very
recently we are starting to see a new generation of products coming out, but
for the period of roughly 1995 – 2010, we have been using not only the same
products, but some of the same filthy overused under-repaired individual
units that we did 20 years ago. When
the companies can no longer hear nor listen to the real clinicians – doctors,
nurses, therapists – then real product development languishes. You the prescriber and clinician have to
fight against the phony, the ersatz, the irrelevant, but likewise you have to
fight to preserve the products that matter, or we risk losing our medical
“civilization”. |
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After you have gone through the above checklist for a new
product, it is next time to add it all up and decide if the product is
fundamentally worthwhile or not. And
here to help you is Dr. Phelonius Cheatham, Professor of Snake Oil, from the
practice of Doctors Dewey, Cheatham, and Howe, in The matrix is a simple 2x2 cross between two generalized
parameters, Legitimacy versus Proof (each with a binary value). Is a product Legitimate? The answer is yes or no, some products are
bogus, and some are real. Even if you
do not know yet which way it goes, a product will be one or the other. Is there any Proof or confirmation of the
product? It is either yes or no, the
product either has some data, or it does not.
Every product, old or new, will fit in one of the four cells. Every product should get certain attention
and consideration from you which will vary depending on which cell a product
occupies. Products may migrate to
other cells as time, knowledge, and experience accumulate. The four states of the matrix are: (1)
a product may be worthless and pointless and have no data to support it; (2)
a product may be worthless and pointless but there will be some sort of data
purporting to confirm its virtues; (3) a product may be meritorious but
have little supporting evidence; (4) a product is meritorious and
there is legitimate confirmation of this. The matrix also has a sub-table of states that modify or augment
your basic analysis: (1) a product might be made or
marketed based on false pretenses and predicates, invalidating its use for
certain applications, even if it has merit for other uses; (2)
a bad product might be a consequence of bad design and engineering, even if
it is conceptually sound and nominally fulfills a real need; (3)
a product might get a false start or go in the wrong direction, but the
sponsor can correct early missteps and get it into a new cell on the
matrix; (4) a product introduced for one reason can prove to have other unforeseen
uses or horizons, expanding the original utility of the item. These concepts will all be explained in
further detail on slide 30. The image is of
John Greenleaf Whittier, 1807-1892, one of the Fireside Poets, and one of |
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Before looking more closely at the bogosity matrix, this and the
next slide mention a few random considerations, and re-emphasize some points
already made. Remember, we are now
discussing your evaluation of specific products. What is the conceptual
origin of product? Was the product demand
driven, designed or instigated by a clinician looking to solve a tangible
problem? Or, was it supply driven,
instigated by a technologist-engineer-inventor who had a clever idea that may
actually have little relevance to real clinical needs. There are of course many good, sometimes
great game-changing products made by the non-clinicians. This is not a pejorative statement against
non-clinical inventors. However, there
are products that clearly have the imprimatur of a non-clinician, backed by a
company looking to make a contrived need or market for a product that is
already overly invested. Regardless
how good and sincere the science and engineering are, if the product serves
no clinical purpose then it is bogus.
If your bogosity alarm says that there is no validity, do not be
beguiled by the fact that a product simply got manufactured. Does the
product fulfill real, perceived, or contrived needs? When a novel new product solves a real
problem, fulfills a real need, that is a boon to clinicians and their
patients. As “imitation is the
sincerest form of flattery”, the real measure of such success is the me-too
product. When a new product proves its
value, other manufacturers will try to get a piece of the market. The competition can spur technical
innovation and product improvement, and it can force lower prices and better
service. After a while though, the
value of competition declines as too many manufacturers offer too many
variations on the same concept, confusing prescribers. Sometimes the variations and marketing
claims on me-too products seem utterly frivolous and contrived, so beware
bogosity on new products, but also when new players try to stake a claim in
an already crowded market. However, if
the new player is offering worthy variations, the new product might supplant
your old choices, or give you an additional tool for specific situations. For example, there are many narcotic painkillers in the pharmacopoeia
that we prescribe every day. Do we
need codeine, morphine, hydrocodone, oxycodone, and hydromorphone, and then
all of the narcotic derivatives such as meperidine, pentazocine, fentanyl,
etc? Yes, we do. Given the wide range of pain and its
causes, the degrees of severity, comorbid pulmonary or neurological
disorders, psychological and dependency profiles, receptor chemistry
variations, and any number of factors, having a wide latitude for prescribing
helps us keep our many patients relatively comfortable. When a new concept comes along like
long-acting oral narcotics, it might at first seem like a minor variation,
but then after a few years of use we realize how nicely it has altered our
fundamental prescribing practices. In
reconstructive surgery, we are seeing a similar event with the regenerative
matrices (see slide 4). Some are
structurally weak but malleable and flowable to fit complex geometries, some
have an artificial epidermis that makes for excellent short term skin
substitution, some are structurally strong for use in high-load
musculoskeletal reconstruction, some are chemically cross-linked for long
term stability, and some are not to permit relatively rapid resorption. Each manufacturer touts its own virtues and
charms, but the reality is that these variations give the surgeon a range of
tools needed to solve a variety of different problems. However, we are starting to see too many
such products and companies (about a dozen in 2010), and soon enough the
market will thin or consolidate as over-supply breeds confusion and diluted
profits. The me-too mentality is also
seen in wound care products. Just as
for me-too pharmaceuticals, like cephalosporins, beta blockers, and ssri’s,
all kinds of wound care vendors want to sell a silver based product, an
alginate, a skin care cream, and so on.
While some variations of concept are worthwhile, there comes a point
at which a silver is just a silver, an alginate is just an alginate, a
topical steroid is just that, no more no less. The market for these products is huge enough
that every vendor can get a tasty and fulfilling piece of the pie, but things
do not work that way for more parochial products. Do not be beguiled by contrived claims of
greater efficacy, and always consider price, convenience, service, and
availability when specifying me-too variations. |
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. . . random considerations continued. Be aware of bogus
studies and marketing materials.
One of the problems with some products is that not only is the science
and clinical development inherently faulty or bogus, but the product is
touted with slick brochures with fancy color photos showing things that look
good to the naive observer, but which are erroneous, misleading, and
incorrect. Remember on slide 14 we
talked about wounds which would heal anyway, and the trap of thinking a
product is useful when all that was done was basic hygienic care to allow the
wound to heal at its natural rate? It
is common to see marketing materials that show: (1) healed wounds that would have healed
anyway, (2) wounds that healed because
of the initiation of basic hygienic care,
(3) wounds that healed slower than with natural or good care, and (4)
unhealed wounds that are claimed to be resolved. Sadly, some people know so little about wounds, including some
who develop, manufacture, and market wound care products, that these ironies
are common. Common, as will be
illustrated on slides below. The sad
thing is that a potentially good product with stupid lame bogus marketing
brochures risks being overlooked by knowledgeable practitioners. Sadder yet though, for medicine and our
patients, but a bright spot for bogus vendors, is that even many wound care
clinicians are sufficiently uneducated or gullible that such bogus claims can
be attractive and effective. You, as
the discriminating wound product evaluator and consumer, must not fall into
the traps these companies have laid before you. The unfortunate and embarrassing reality
for the Wound specialty as a whole is that many people simply do not know
that wounds heal naturally. There are
people and companies with no concept that wound healing is actually a normal
event. Nor do they know what proper
normal healing looks like day-by-day, nor how long the healthy normal process
takes. They simply do not know what
normal is, and they especially do not appreciate the crucial role of basic
care to allow a wound to heal at its natural rate (hygiene, debridement,
bioburden and edema control, compression, etc). Thus, when they see a wound heal, they
attribute it to their magic poo in a medicinal box with a fancy full-color
brochure – and they want you to believe the same . . . and too many do. The studies behind many on-the-market
products did have genuinely positive outcomes, but that was attributable to
standardizing the circumstances of the study so that patients were all
suddenly getting basic good care. In a
wound product study, when a patient goes from bad care to basic good care, then
any further success cannot be attributed to the test product. So, what should you, as the discriminating wound product
evaluator and consumer, look for as a sign of a proper wound care study? Studies are detailed things, but two major
items must be satisfied if the study is to be truly credible. (1)
Good wound studies must control the wound in advance of the test treatment. In bogus studies, many wounds will heal, and
the product will thus appear successful, because proper basic care is started
concurrent with the test agent (or not at all). Good studies will have a “run-in”
period. This is “phase 1” of all good
wound care, a period of about 4 weeks, getting basic hygiene and wound
control in place, taming the wild wound, and identifying those patients with
easy wounds that will heal promptly with nothing other than basic hygiene and
compression. This is no different than
proper everyday clinical wound care, where the first phase, averaging about 4
weeks, is spent controlling the bad wound before then choosing discretionary
options for stimulating or closing the wound.
(2) A good wound study should
have 3 arms, agent -vs- placebo -vs- standard. Granted, few studies do. The problem is that there is a well
documented placebo effect in wound care and wound studies, and many wound
product studies fail to standardize the conditions of the trial. When a study is designed that allows the
clinician-investigator to do his “normal thing” in one half of the study,
then his normal thing in the other half plus test agent, there will be no
standardization and no meaningful comparison.
The problem is that introducing the test agent will often radically
altered all of the other “normal things”, usually tightening up the details
of basic competent care. Good wound
studies, and especially those that are multi-center or multi-investigator,
should have 3 groups. One group, standard,
the study control, allows the clinicians and their clinics to follow their customary
protocols and practices and decision trees.
The second group, the placebo group, has a highly specified treatment
protocol, including (as best as possible) a blind substitute for the real
agent. The third group, the agent
group, has the same specified protocol plus the real test product (blinded as
best as possible). If you could take
many of the lesser or bogus products out there right now, and repeat their
“pivotal trials” with this framework in place, many of them would have to
abandon their claims. Many, it would
turn out, would have poor results in the standard group (poor compared to
accepted performance standards) and then appropriate but equal results in the
placebo and agent groups. Even for
good products, the placebo group should outperform the standard group, but
then the agent group should do even better.
The standard group would be less necessary in a well designed study
conducted by experienced successful clinicians and sponsored by experienced
reputable companies, but alas that is not the case for many new
products. As the discriminating wound
product evaluator and consumer, proper study design and analysis must be
scrutinized by you to see if there is real merit or just bogus nonsense
claims in the marketing materials shoved in your face. If the company reps or their higher-ups
cannot explain nor justify how they did a study – which is common – bogus. |
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Back to Dr. Cheatham’s Bogosity Matrix. On the attribute of legitimacy, all
products are either bogus or real. On
the attribute of proof, all products either have data or not. Any product, real or proposed, preliminary
or on the market, new or established, will fall into one of the four blocks
on the matrix. Then, there are four
ancillary analysis items that should help you think or rethink the position
of an item in the matrix, especially when first impressions might be in doubt,
or when prior art, knowledge, and truths conflict with proprietary claims. Serious products that need regulatory approval must show some
sort of evidence before authorization to market. This means that almost any regulated
product already on the market, bogus or real, must be in the “with-data” boxes. When a bogus product is on the market, it
means that its approval was based on bogus proof, meaning that the data is
pseudo. But, these are the data and
pseudo claims that will be hyped and sold to you. For most practitioners, trying to practice
honest medicine with verified and approved products, these are the bogus
products that you will generally encounter.
It is incumbent on YOU, for the sake of YOUR patients, to be cognizant
and wary of any claims and data until you can study, analyze, and verify
their legitimacy. There are bogus-no-data products, and they are generally of two
types. (1) They can be early products,
still conceptual, beta, or pre-market.
If you are involved in early product design, testing, or consulting,
you might run into these. (2) These
can be consumer products that require little or no regulatory approval or
oversight. You are likely to run into
these if you yourself, or else your patients and acquaintances use herbal,
folk, health-food and similar loosely regulated and tested remedies. Remember, many traditional materiae medica,
“health store” remedies, and a zillion over-the-counter non-prescription
remedies sold in pharmacies are legitimate, useful, and therapeutic. Being a more plebian remedy does not
invalidate it, even if formal evidence is scant, but these channels are more
permissive of illegitimate claims and patent medicine abuses. Sadly, the market for wound care products
includes many such bogus-no-data items that make wound healing claims (i.e.
proliferative, regenerative, and accelerative properties). Whether erroneous claims are made naively,
innocently, and in good faith based on subtly bogus study design and data –
or otherwise – it is up to YOU to be knowledgeable, discerning,
discriminating, and critical about all products you prescribe, so that the
“wool” is not pulled over your eyes. The next few slides will profile some real products to
illustrate the major domains on the Bogosity Matrix. These are all proprietary products, so
there are a few rules to remember.
First, I have no investment in any of them, nor any other relationship
nor conflict of interest. Second,
except for the badly engineered hernia product on slide 33, all products
mentioned are legitimate in one way or another, most meritorious. I have opted not to get mean and show the
dregs of incompetence among some of the truly bad products. The intent here is to show legitimate
products, but demonstrate how they must be critiqued and understood. Third, much more information about these
products can be accessed via the internet or from the company. |
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We will start these examples by looking at the domains on the
right side of the matrix, products whose legitimacy is real. The first product reviewed, Provant by
Regenesis, is in the category of legitimate
product with limited data. It uses
radiofrequency electromagnetic stimulation applied to the wound by
antenna. The company is in Is it worthwhile?
Yes. Does it have good
science? Yes. Does it have good pre-clinical data? Yes.
But does it have enough good clinical data to be persuasive to
everyone, or to clarify when it will work and when not? Not yet from my point of view. Granted, there are clinical papers, but
they are of limited experience, and from my point of view, not terribly
persuasive. But remember, less than
persuasive studies might reflect a lame product, but they might also reflect
just a lame study on a good product. (Parenthetically,
never forget that there are also way too many pseudo-persuasive studies on
lame products.) Remember too, as
discussed on slide 20, the “hearts-and-minds” liability that this product has
being a physics based device. I
believe in this product, but the reality of medical economy and manufacturing
is that if not enough people use it, the enterprise fails, and the product
never fully develops, then it goes away.
So, some products deserve good faith acceptance and usage for a period
of time, so the good items have a chance to become recognized and
self-sustaining. Recently, this
company switched from science-tech centric principals and management to
business centric upper management, and perhaps now the clinical development
and professional awareness that I believe this product needs will be
heightened. Consider the one special
value and virtue of this product: it
covers large areas, so it is very practical and cost effective for large
wounds In addition, there are no
toxicities, it is extremely simple to use, totally safe, hygienic, pragmatic,
useful for multiple wounds, no time or “dose” restrictions. As part of a strategy of sequential or
integrated therapies, this should have a prominent role in the early phases
of large wounds, when other modalities are limited by size, time, toxicity,
and expense. |
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The second example is also on the right side of the matrix, this
time a legitimate product with good
data. It is Fibrinet from Cascade
Medical. It uses autologous platelets,
prepared at bedside, and applied to wounds.
It has been on the scene for only about 2-3 years. At first glance this might appear like any
of the other half dozen or dozen autologous platelet products currently on
the market. All of these products were
developed to be hemostatics, to control bleeding, generally intended to be
used in the operating room. Most of
these products have also tried to extend their market into wound healing, the
idea being that since platelets release the growth factors and initiate the
events that lead to healing that they can be used as such. That concept might seem fair at first
perusal, but there are problems with it.
A dose of platelets might be made from 20 – 30cc of whole blood, the
dose prepared in the operating room, then squirted on the wound just prior to
closure. The fallacy is that during
the course of surgery, far more than 30cc of blood thrombose in the wound,
and platelets are being delivered, trapped, and discharged in high loads in
any acute wound. So, how is such a
product different than just normal bleeding and thrombosis due to the injury
or surgery? The hemostatic effects of
these products are useful and easy to measure and validate, but what about
wound healing effects? I have tried
these products – a sincere serious sustained effort during a one year period,
on many dozens of cases – to see if a wound healing effect could be
appreciated. It turns out that when
these products are applied to acute wounds, any nominal wound healing effect
washes out, gets buffered, is degraded, or is overwhelmed by other normal
events in the acute wound. There is no
appreciable difference in wound complication rates, nor have I seen any
published data or even company brochures that validate such claims. These autologous platelet products have
been engineered so that the platelets shoot all of their stuff at once, then
it is over. They do what they were
designed to do – stop bleeding.
Contrast this to the original platelet releasate product,
Procuren®. This too is made from an
autologous blood donation, but it is processed so that one donation yields
about 90 vials or doses of platelet material which can then be applied daily
to a wound. Procuren was specifically
engineered for wound healing therapy.
Likewise, purified PDGF (becaplermin, Regranex®) was also designed to
be used as a daily platelet substitute for wounds. At face value, Fibrinet, aka prfm or “platelet rich fibrin
matrix”, would appear to be similar to the other hemostatic platelet products
– draw the blood, spin it and process it right then and there, then apply it
to the wound. What makes it unique is
that the proprietary bedside processing “chemistry”, which includes precipitation
of autologous fibrin, traps the platelets and allows them to stay “alive” and
release their granules slowly, over a week or more. This slow sustained platelet release makes
it a weak hemostatic agent but a good wound healing agent, and that is what
it is intended for. The in vitro
science and data are very strong, and there is supportive clinical data. The slide shows two graphs of various
peptide growth factors found in platelet granules, specifically growth
factors relevant to wound healing, angiogenesis, and fibroplasia. They show sustained release for 7 days,
more than enough to have an effect on an acute trauma non-pathological wound,
and long enough to permit weekly or biweekly dosing for chronic and
pathological ulcers. The paper
referenced is “Autologous platelet-rich
fibrin matrix as a stimulator of healing of chronic lower extremity ulcers”. I have used this product too, and it does
have a demonstrable beneficial effect on certain wounds, “kick-starting”
impaired wounds that are not healing, or hastening closure of others that are
making inadequate progress. This
product thus fits in the category of stimulatory or accelerative wound
healing products. The fact that the product
is not yet widely marketed is due almost entirely to payment and reimbursement
issues dictated by third party payors who generally are as equally confused
about wound products as the government regulatory agencies. Remember, all good products have to start
somewhere, and they depend on pioneer users and adopters. Whether you choose to try a new product or
not should be predicated on whether it meets criteria of legitimacy. This product is conceptually legitimate,
and the available data, basic and clinical, is good, putting this product in
the most favorable quadrant of Dr. Cheatham’s Bogosity Matrix. If you are so inclined to test new products, to be the pioneer
who tries new things, you will discover soon enough that to do so responsibly
and to learn legitimate lessons means not getting overwhelmed or dividing
your attention between too many new things at once. Regardless how busy your practice is, you
still will have only so many patients, so many visits in a week. If you trial too many products at once,
each will have a diluted experience of just a few patients, and you will
never learn the nuances and sophistication that come from a robust
experience. So, from the clutter and
clatter of many new products, how do you decide which products are
meritorious and worthy of trial? Which
warrant your valuable time and attention to try to turn raw concept into
tangible therapy? The conceptually
legitimate product with good data, the right lower box of the bogosity
matrix, will always be a worthy prospect. |
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The next 4 slides illustrate the four ancillary analysis items below
the matrix. Here is an example of bad engineering (the product pictured
left).
It is also an example of a bogus
product with data. Remember, a
product without any data cannot make its way to market, so even bogus
products have some documentation. But
if it is a bogus product, then its data must be bogus. “Bogus data” does not imply illicit,
illegal, immoral, or deceptive. It
simply means that something about it is wrong, erroneous, incongruent with
proper methodology, misinterpreted, based on false pretenses and predicates,
or tainted by a bandwagon or emperor’s new clothes mentality of blind
enthusiasm when reason and ration should have prevailed. Brought to market by the nice folks at Davol-Bard
was the Kugel mesh, a hernia repair product whose introduction was trumpeted
with the regalia accorded to rock stars and messiahs. Nowadays the only fanfare for the product
is at the lowbrow websites of personal injury lawyers. (This is the one item here that is neither
made nor marketed for wounds, but it is a good example of bad engineering,
and since this subject is also an integral part of my own practice,
experience, and consulting expertise, it was an easy obvious pick.) This product was categorically brain dead from its
inception. It should never have made
it past any product review within the company. Its bogus engineering should have been axed
before it made its way off of the napkin it was first drawn on. Its very design and then its clinical
trials for abdominal wall reconstruction were done based on false intellectual
and clinical-scientific pretenses by investigators with no expertise in
musculoskeletal reconstruction. It
came to market at a time when the long term problems of alloplastic materials
for abdominal wall replacement were already quite evident. It was used mostly in patients where its
use simply was not required (in lieu of a proper musculofascial
reconstruction). Its approval was
based on short term followups that the company and FDA should have known were
too short for proper safety assessment.
Among the many problems with this device, here is the “are you smarter
than a fifth grader?” issue: it has a
stiff rigid rim of plastic, but it is being inserted in a flexor surface that
must bend. What happens when you bend
a paperclip too many times? It breaks. And then those pokey broken ends of that
rigid plastic thingamajiggy are going to poke and stab your chitlins inside
your poor sick tummy. (You can read
plenty more about this by searching on the relevant words.) Anybody with any basic knowledge of musculoskeletal
reconstruction and the use of alloplastic implants could have told you how
stupid this design was. What is
shocking is that this product was developed, manufactured, and marketed by an
extremely important reputable company that makes and sells many important
safe effective products, a company with rich engineering resources that
already makes other successful safe products for surgery and for various
abdominal and musculoskeletal applications.
Huh? What happened? In this era, circa 2000-2005, it seems that many manufacturers
had an idea about how to make hernia surgery better. Many went the way of developing biologics,
the regenerative cadaveric matrices that allow new tissue to grow (see slides
4, 20, 28). On the right of this slide
are some of the logos and names of companies and products in this biomatrix
category (even Bard has products in this category). Biomatrices are not perfect either, but
they are exceptionally safe, and they are highly effective when used properly
by someone who understands musculoskeletal reconstruction. Alloplastic meshes still have a useful but
narrow role, and we do need some basic cloths or meshes to support our
surgery. However, there is little
reason these days to continue developing complex or composite alloplastic
devices for abdominal wall reconstruction, yet several companies continue to
compete even against their own selves by developing new products along both
lines, alloplastic and biologic. Nonetheless,
several companies in this era came out with crazy complex alloplastic
abdominal wall substitutes. They
almost all suck. They almost all cause
needless severe complications and multiple redo operations as they are
inserted, removed, then replaced with something else. As wonderful and important as Davol and
Bard are (they are – no cynicism or sarcasm here), the Kugel mesh was an
example of a company straying into a field outside of its traditional or core
product lines and engineering expertise.
It represents the kind of groupthink me-too mayhem and “madness of
crowds” that makes you do things that on further reflection you know you
shouldn’t, a pied piper heralding the emperor’s new attire, lemmings on the
bandwagon that can make you abandon all sense and sweep you away on a ride to
hell. It is an example of the concept
“if you think you know the answer, you don’t understand the problem”, leading
to mistakes that should have been obvious. You, the discriminating medical product
evaluator and consumer have no control over how a company wastes its
resources on bogus products. However,
you can teach them a lesson and keep your patients safe by doing a thoughtful
assessment, not jumping on the lemming’s bandwagon, and not prescribing a bad
or useless product just because it has been hyped or just because “everyone
else” is using it. |
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This slide illustrates the next of the ancillary analysis items,
corrected missteps (with a bit of false pretenses and predicates). Apligraf®, made and managed by
Organogenesis, is a living cell therapy which has become extremely important
in chronic wound care and cure. In my
practice and clinic, it is one of the most important products that we use,
and we use it regularly. It is a wound
stimulatory therapy, exerting a “pharmacological” effect on the wound to
reverse chaotic dynamics and restore a proper wound healing trajectory to
wounds which have been refractory and non-healing. We think of it as a pharmaceutical packaged
in a living vehicle. The other
comparable living biologic on the market for wounds is Dermagraft® made by
Advanced Biohealing, Inc. It is also a
great product that we use. This slide
is an endorsement of the whole concept of living cell therapies for problem
wounds, and it is an endorsement for both products, neither one over the
other. I have used Apligraf as an
example because I am much more familiar with its story, and its story is
instructive. When this product was developed, it was marketed as
“skin-graft-in-a-box”. The product had
been developed by non-clinical biotech guys who get great credit for
developing the technologies and creating a distributable product. They figured out how to take a skin
specimen, extract pure fibroblasts and keratinocytes, re-engineer them into a
living skin equivalent, then deliver the cultured skin in a petri dish for
clinical application. They envisioned
that zip-top-cereal-box skin grafts would obviate the need for autogenous
skin grafts, thus emancipating every burn and trauma victim from the harsh
realities of skin restoration.
No. They might be forgiven
their point of view, because as biotech guys, they developed this in mice,
where immunogenic barriers to allotransplantation are not so strict. But people aren’t mice. Those were the false pretenses and predicates behind the early marketing of this
product, that because it worked in mice, they could now sell it as
do-it-yourself skin grafts. No. This concept runs headlong into the realities of allogeneic
cross-individual tissue transplantation, something that we collectively in
medicine had already been working on for over 200 years by the time this
product appeared in the late 1990’s.
Consider the “Transplantheon” illustrated. Alexis Carrel won a Nobel Prize in 1912 for
developing the technical arts of vascular surgery and organ
transplantation. Karl Landsteiner won
his Nobel Prize in 1930 for developing the knowledge and applications of the
ABO blood types, opening the door to safe effective blood transfusion. Peter Medawar got his Nobel in 1960 for
elucidating and applying the knowledge of leukocyte antigens (HLA), opening
the door to allogeneic tissue and organ transplantation. Joseph Murray won the Prize in 1990 for
being the first to actually transplant a whole major organ, the kidney. Thomas Starzl has not won a Nobel Prize,
but he has won many prestigious awards and is considered the Dean of modern
organ transplantation. And it all
began with Giuseppe Baronio, who in 1803 (yes, eighteen03) published the
first treatise on skin grafts. His work
was important enough to wound healing and reconstructive surgery that the
sheep he did his studies on are the logo of the Plastic Surgery Research
Council. The science and arts of skin
grafting and allogeneic transplantation are well developed, widely understood,
and proof-in-the-pudding successful.
With an historical and scientific pedigree that strong, it is rather
pretentious and presumptuous of any company to come along and say that they
have peel-and-press skin graft that can be “overnighted” by parcel post. But that is precisely the way that Apligraf
was introduced to us. Personally, I found the concept of handy-dandy grafts completely
erroneous and unbelievable. However,
being aware of its development and approval to market, I begrudgingly tried
it a few times, because when something is being that seriously hyped it
deserves some sort of personal trial and evaluation. The product quickly degenerated on the
wounds, and my first impression was “fly food”. It was certainly not a skin graft, but then
something else happened – problematic chronic and pathological wounds were
appearing healthier and starting to heal.
The grafts did not fuse to the host, but the living material applied
to the host had a beneficial pharmacological effect on the wound. The effects were conceptually and tangibly
comparable to the effects of therapeutic topical growth factors, which had
been introduced to the market and available practice in the few years before
Apligraf (as platelet releasates and recombinant PDGF). And then other doctors in our practice were
having similar experiences – bad wounds were healing better as Apligraf could
induce a wound module and ameliorate impaired wound dynamics. And then our nurses, doing the weekly
dressing changes, started reporting their own independent observations of the
same effects. And then other doctors
in other centers starting observing and discussing the same things. Apligraf is not a skin graft. It is a wound stimulatory wound healing
product, and it (along with Dermagraft) defined the concept of living cell
therapeutics for wound healing. As “skin-graft-in-a-box”, this was a bogus product. As a wound stimulatory therapy, it is an
item that we now find hard to live without in our wound care practices. How did it switch from lame to fame, from
bogus to by golly? Corrected missteps. Users questioned, observed, analyzed, and
the company listened. The company
listened (not just Organogenesis, but much of the credit also goes to
Novartis, the great pharmaceutical company that was managing and marketing
the product in its early years). Not
only did they listen, but they re-engineered their basic science, clinical
trials, and marketing and message to reflect the product’s corrected identity
as a wound healing biologic. Here is another example. Remember
Henry’s Carbolic Salve back on slide 16?
Killing germs with carbolic was never going to help Alphonso’s
acne. In fact, it risked making things
worse by creating a caustic dermatitis – or – making things better! Here is the interesting twist on this story. We use phenol for “skin peels”, a cosmetic
technique that induces a superficial chemical “burn” that leaves the skin
looking rejuvenated after it heals. As
a face peeler, phenol went out of favor in the 1980’s in favor of less toxic
chemicals, but the concept is a standard part of modern cosmetic medical
practices, including improvements for acne problems. Henry’s Carbolic Salve might very well have
actually done some legitimate good for Alphonso, but for reasons unrelated to
the germ concepts and marketing claims that its developers honestly believed
in. The pretenses and predicates were
wrong, but there might have been a genuine therapeutic benefit. A company that corrects its missteps or
false concepts can capitalize on that correction, for the benefit of its own
bottom line while delivering a useful product that benefits its
customers. These corrections all
depend on user-prescribers and a good company keeping an open honest mind to
realities and possibilities. For observant
physicians trying to use carbolic products in the early 20th
century, the utility of phenol for skin rejuvenation was recognized and
incorporated into practice, regardless of any germ claims or prior
conceptions. The lesson is that new products must be tried, analyzed, and
evaluated critically and objectively by YOU, the discriminating user of
medical products. They must be looked
at objectively, without bias, without preconception, and without paying too
much heed to the marketing claims of the manufacturer and distributor. Whether a product is purely bogus or of
stellar importance, it is up to you to discover and conclude so. Every inventor, manufacturer, and vendor
makes positive claims – (have you ever heard a company claim “our product
sucks, it’s dangerous and doesn’t do anything, but buy it anyway because our
investors need to recoup”) – so all such claims are meaningless until you
yourself are satisfied of their veracity.
A product that sounds good, or too good, might be bad. Or, as happened with Apligraf, a product
that first sounds bogus might just prove its worth once you figure out what
it is really good for. True bogus is
bogus, but perceived bogus might have its virtues waiting to be discovered,
and an intransigent company that will not listen to its users, customers, and
beneficiaries may lose good opportunities.
When a good company listens and reacts positively, the ultimate
results can be a benefit to all – company, investors, doctors, and their
patients. |
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This slide illustrates the next of the ancillary analysis items,
unforeseen horizons. There are
many bogus and so-what products that claim to do everything but actually do
nothing. There are also products that
make extravagant claims but turn out to have a legitimate but limited scope
of indications or uses. There are also
the many products where promises and performance are proper and aligned. Then there are the occasional products that
undersell themselves, like the one shown here, Integra artificial skin. In this case, the initial intent and first
impressions of the product were positive and as expected, but the original
principals had a rather narrow of view of its use – for burns only. However, it worked so well and was so
versatile that a much wider range of uses and applications was discovered by
surgeons, and indications exploded. It
is a regenerative matrix, an implant that allows for in situ “tissue
engineering” of embryonic new tissues, and it has found crucial roles in
critical wound closure, acute repair, essential coverage, chronic wound
closure, and functional reconstruction. Much more information on this product can be found at the arimedica.com website and
elsewhere. Illustrated are sample
cases. Left is a patient with streptococcal necrotizing fasciitis whose
life was saved and skin reconstructed with this product. Later reconstructive procedures for joint
mobilization and contracture release were never needed, because this material
creates an embryonic type of new dermis without scar. Top
left is a patient with staphylococcal necrotizing fasciitis whose many
wounds were closed, skin regenerated, and scars and contractures avoided by
using this product. Shown is the
dorsum of the hand and wrist where tendons were covered and closed without
using the flaps that conventional plastic surgery principles call for. Top
center is a hand with diabetic atherosclerosis and partial hand
necrosis. The open flexor tendon and
IP joint were closed and healed with no further risk to the patient or hand,
and without needing conventional flaps which were not possible in these
circumstances. Top right is a foot and ankle where pressure necrosis caused
large heel and achilles ulcers in an old woman with marginal independent
ambulatory ability. Simple closure of
tendon and bone with Integra averted amputation and prolonged care,
preserving her pre-morbid lifestyle, without flaps nor further jeopardy to
the patient. Center tier is a foot and ankle following atherosclerotic events
then operative revascularization. Open
bones, joints, tendons, and ligaments were closed with the Integra. Just as for the preceding heel and achilles
case, this elderly woman’s lifestyle and function were preserved without
amputation and without the risk of needing other donor sites. Bottom
tier is a chronic ankle ulcer in a patient with a lupus-like auto-immune
disorder, successfully closed with Integra when local flaps and other
autogenous reconstruction would have been at risk for necrosis, lysis,
dehiscence. After this product was introduced to market in 1996, for burn
closure, the wide ranging utility and value of this product was quickly
perceived by many surgeons who applied it to many situations never conceived
of by the original inventors and developers.
That is why the ultimate role of any product is determined by YOU, the
discriminating user, and not by the company, investors, marketers, or
regulators. Of course, all the good
insights and advice of users and customers mean nothing if the company does
not listen and respond, but for this product and company, the “partnership”
between company and surgeons was very healthy and productive. On slide 11, in discussing regulatory agencies (paragraph #3),
it was stated that “. . . good products [can] come to market with inane
restrictions on use . . .”, and this is a perfect example. For the physician experts and champions who
believed so strongly in this product, there was a sense that this was a
singularly important and revolutionary product that needed wide awareness and
acceptance. However, because the
company originally perceived this as a burn care product, it applied to the
FDA for a burn indication, and that is what was granted. Regardless how worthwhile it was for so
many other things, the company was muzzled from making any marketing claims or
talking directly to physicians about any indication other than burns. Communicating that message therefore
depended on physician-to-physician channels.
We would all agree that inter-professional communication and education
is the way that things should be. However,
getting that message out, which was considered so important by many of the
early users, was hampered by the company being silenced on all but burn
claims, and it took nearly ten years for these goofy and erroneous restrictions
to be amended. For those who have had
experience with this product, it is one of those few revolutionary products
that appears in the course of a career that fundamentally changes the way we
do things. It is hard to imagine
practicing modern reconstructive surgery without this product (and other
regenerative matrices). This means
that those who perceive the value of the product for their own patients and
practices also understand the need to promulgate the message, because if the
market for the product does not grow and mature, then the product risks dying
and disappearing. That is why YOU, as
the discriminating wound product user, must also be enthusiastic about worthy
new products, to help ensure that the full spectrum of uses and benefits is
realized, to help teach it to others, and thereby to help assure the
continuation of the product. It is the
free market at its genuine and meaningful best, and it does not depend on
“them” or “they” or “the company” or “the feds”, but on YOU. |
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This slide illustrates the last of the four ancillary analysis
items, false pretenses and predicates. The product
is Invanz, Merck’s proprietary name for its preparation of
ertapenem. Let us clarify up front
that this is an important antibiotic, and it is coming to market via one of
the oldest most venerable experienced pharmaceutical companies in the
world. Many of the successes in our
day-to-day care of sick people is thanks to this company and the products it
makes. Undoubtedly Invanz has helped
save the lives of many people with genuine infections and sepsis. It is a good product, indeed a very
credible and important product, when used for what antibiotics are needed for
– treating infections. However, it is
not a good product for treating stinky armpits, nor for smelly flatus, nor
for bad breath, dirty fingernails, nor belly button lint. It is not useful for wiping down your
kitchen counters, nor for cleaning your toilet bowl, nor brushing your teeth. Its property of killing or inhibiting germs
does not mean that it should be used for the quaint trifle of a pastime of
killing germs with your chemical shotguns for mere sport nor for germ bigotry
and germ fear-mongering. Yet much of
the market and profits from antibiotic use are for treating non-infections. Wounds are wounds and infections are
infections, and the two domains have a limited intersection. Yet when sophisticated problems like burns
or wounds are cared for by inexperienced physicians dealing with problems
outside their specialty, training, and education, then, the care always seems
to turn to germ killing. Why? It is erroneous and detrimental to patients
and the system for the many reasons discussed all along here. But it happens, and the companies who can
profit from it do. Are the companies
bad – is this a deliberate attempt to deceive doctors for corporate profit at
the expense of added morbidity to patients and our health care economy? Or is it that the companies are themselves
so naive about wounds that they make erroneous claims with bogus studies and
marketing materials but which at least are made in good faith? I don’t know. You will have to decide for yourself, case
by case. Here is one of those cases. Pictured is a burned foot.
There are exudates under the partial thickness blisters. The pattern of injury suggests a
neuropathic foot – perhaps a diabetic standing barefoot on a hot
sidewalk. Is this a trivial problem
that is likely to resolve itself with minimum care? No.
It is significant, and it warrants expert care. But any reputable burn or wound doctor will
have this trouble-free within days and healed within several weeks. Is it infected? Probably not. Not having the benefit of directly
examining the patient, one can only guess, but this is the appearance of any
such foot several days or a week after the injury if it has been neglected or
untreated. Erythema, mild edema, etc –
all typical of the primary injury.
What kind of care does it need?
Some cleanup (minor debridement), some good topical care and hygiene,
elevation and edema control, etc. Does
it need antibiotics at all? No, not
for the face value injury, not for what is shown in that picture. Topical antimicrobials – sure – but
systemic antibiotics – no. To the
extent that there is “pus” under the blisters, that goes away with simple
debridement and proper topical care.
Even if there is some infectious “cellulitis” component to this, does
it need intravenous antibiotics with one of the newest most expensive drugs there
is? The picture caption claims that
the patient had fever and lymphangiitis.
That claim would seem exaggerated given the picture shown – all the
more reason that if it was true, we should be shown the evidence so we can
understand the atypical advanced nature of the problem. Absent any meaningful, honest, forthright information
to let us judge for ourselves, these marketing materials remain
unprofessional, either deceptive or just dumb, and thus bogus. Proprietary marketing materials
notwithstanding, this wound needs the basics of care just described, along
with any prudent choice of safe,
inexpensive, easy-to-manage oral antibiotic to cover normal skin and foot
flora – e.g. tetracycline, sulfa, clindamycin, erythromycin, etc. If the patient is also vasculopathic with
arterial insufficiency, that is an added risk that could justify more
aggressive antibiotic therapy, such as cheap, effective, safe (when used
properly) vancomycin, and even then just for the few days needed to allow the
other components of care to correct the risks and acute conditions. I treat problems like this day in and day
out. So do my colleagues in my own
practice. So do my wound care brethren
in legitimate wound practices around the world. My patients get better. So do theirs, by doing the basics. I would never think that this requires a
hospital admission, nor would I ever contemplate giving intravenous
antibiotics for this situation, especially the newest most expensive drug. Note the other graphs in their materials. They show that compared to piperacillin-tazobactam,
there is no difference in therapy, but Invanz is implied to be cheaper and
easier to use. Part of this is
categorically true – that once-a-day intravenous administration is better
than four-times-a-day. Who can argue
with that? Of course, one also has to
know how much the drugs per se cost, per dose. While the cost of Invanz is not
reprehensibly high, there have been other antibiotics within the past decade
where the cost of the drug per dose way offset and overwhelmed the costs of
IV administration. But notice the two
bogosity trail markers here, the bold numbers and the graph axes. First, the big numbers – 75.0 versus 70.8,
green Invanz for go, red pip-tazo for stop.
The way the numbers are shown, they are meant to imply a difference. Think about it for a moment, and you
realize that there cannot be any statistical significance in those numbers –
and the fine print byline confirms “p = NS”.
From a technical statistical and regulatory point of view, that was
one of the purposes of this study, to show that Invanz was no worse than
pip-tazo, implying that if it is no worse than it is just as good, and thus
even better if it has some other virtue, such as less expense or less
frequent dosing. And that is the
honest message here – that there is no difference between the two drugs, but
Invanz need be given only once a day – and that is a genuine virtue and good
message. But the message that the
company really wants to convey to the consumer-prescriber, via these fancy
4-color marketing materials with pseudo-science and pseudo-doctor speak, is
really meant to sell you by a more visceral subliminal persuasion. You may not remember much from this
brochure, but odds are you will recall “Invanz, 75% is better than 70%”. Remember, the guys in their marketing
departments and ad agencies have four-year college degrees where they learned
to do just this kind of amoral stuff.
But even that is not the ultimate bogosity . . . The ultimate gut-wrencher for Dr. Cheatham are the axis labels
on the graph: “Clinical Success, %” –
versus – “”Follow-up assessment 10 days after the last dose of IV study
therapy or oral antibiotic”. First,
the graphics show IV therapy versus IV therapy, so where did “oral
antibiotic” come from? Did I miss
something, or did they, or are they trying to confuse me? More importantly – and this is what all
decent wound doctors know, and what companies and people who do these bogus
studies do not know – is that a 70 or 75% success rate treating this problem is
far too low, so low that it should be an utter embarrassment and cause for
close scrutiny of professional performance and quality control. A success rate of only 75% for this problem
is not standard of care and is not acceptable. Legitimate wound practice has certain
benchmarks of care and outcomes, and nobody in the legitimate practice of
wounds would accept such low numbers.
The problem with so many studies like this, is that they are done by
people who kill germs for a living, but who do not take care of wounds. They are done with protocols that define
the use of the study agent, but the patients rarely get any of the proper
wound care modalities that they need.
As a wound study, investigations like the one shown are almost invariably
designed improperly, designed to show what the company wants shown, and not
designed to show the legitimate wound care effects of the product. It would be as though a company is looking
at the effects of a broncho-dilator, and that everyone with a wheeze is
randomized to our drug versus their drug.
The cause of the wheeze is irrelevant – generic asthma, seasonal
allergies, the patient just had a myocardial infarction or his mitral valve
prosthesis just went kaflooey. No
matter, the patient gets the inhaler – just the inhaler – no steroids, no
diuretics, no antihypertensives, no inotropes, no angioplasty, no surgery, no
respiratory therapies – just the simple inhaler. And then, 1o days later you assess the
lousy outcomes and conclude that your drug led to a 35% success rate versus
the other drug which had just 30%, p = NS.
Welcome to the world of “wound studies” and the bogus ancillaries,
such as antibiotic studies to treat “skin problems”. The patient shown here had a wound, he got
treated for infection, and the overall outcomes are substandard because it is
all a classic “apples and oranges” confusion.
Is the company being deliberately deceptive or just dumb? You decide.
Either way, the patient(s) shown should have had far better than 75%
good outcomes if they were being treated properly for the correct diagnosis
by physicians who are experts or even just knowledgeable about the problem. Are these marketing claims made for the benefit of you and your
patient, or for the company to sell you something that was expensive to
develop and is expected to garner Billions of dollars in profit? Did the company know that this does not
require such expensive aggressive treatment, but they don’t care? Or did they really believe all of this,
because they are not experts on wounds, and they have wounds and infections
confused? Are they confused about the
two naively and stupidly, but nonetheless honestly, or have these companies
undertaken a vast social engineering project to deliberately confuse these
issues in the minds of inexpert physicians?
(It’s the Willie Sutton Rule - that’s where the money is.) I don’t know. You decide.
To reiterate – ertapenem is an important pharmaceutical. It earns its revenues for the company when
it is used for genuine infections. But
implying that the picture shown is an infection, and that it needs
antibiotics at all, and then to treat it with intravenous therapy, and then
to imply that the great outcomes were due to this, especially when there were
no wound controls and no third arm and no run-in period in the study – all of
this is ultra pure bogosity. The
saddest thing is that in the current meltdown of our medical education
system, young doctors and young minds are not getting their requisite
learning and mind-training from their schools, their professors, their
experienced attendings. They are
getting fud-based pseudo-information from marketing claims such as this from
companies who have boards of directors that demand billions in profits at the
expense of all else. Until Wounds
becomes a robust substantiated specialty with a normalized curriculum and
non-trivialized representation in universities, then bogus claims and
marketing materials, such as confusing normal wounds and injuries with
infection, and thereby using wrong therapeutics, will hold greater sway over
the (non)-intellectual development of young doctors and nurses. This case example is entirely based on
false pretenses and predicates. All of
the logic, all of the syllogisms, all of the conclusions of this study and
the marketing materials shoved in your face, all are based on the erroneous
predicate that this simple injury was an infection. Furthermore, it is all discolored and
fogged by the erroneous-at-best and immoral-unethical-at-worst pretense that any
skin or wound problem is an infection, and that uneducated physicians working
outside their specialty can be duped into spending money for one of the most
potent fud weapons that the for-profit fud mongers have – playing the
“infection card”. |
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On slide 30 I explained that most of the products shown here
were selected because they are not bad but must be critiqued, and you must
learn to see through the smoke and appreciate the wheat versus the
chaff. The four products shown on this
and the next slide are all of that sort.
These four products are all potentially meritorious in one way or
another, and they all deserve some nominal respect and a chance to get going
in the marketplace. The problems are
that, regardless whether the products work or not, either the development and
investigations behind the products or else the marketing materials are all
bogus – lame, ill-conceived, inexpert, poorly executed, illogical and
non-sequitur, predicated on false pretenses and lacking robust (or any)
knowledge of wounds, and dumbed down with advertising materials that
epitomize the “if you can’t dazzle them then baffle them” philosophy of
persuasive marketing. One would hope
that potentially good new products would have the benefit of honest expert
development, because everyone then benefits. The first product is upper
left on this slide – the armpit.
The product is for a honey based dressing. Remember what the first part of this talk
was about, a precis of medicinal history, in which we extolled the potential
value of the vulnerary remedies in the historical materiae medica. Any modern scientist or clinician looking
to develop a classical remedy for wounds could hardly do better than to focus
on honey. Honey has a long tasty
tradition of being good for wounds. It
should be noted though that when you read original sources about the virtues
of these remedies, that honey’s wound effects tend to be similar to the
balsamic resins (myrrh, benzoin, peruvian) – emollient, antiseptic, and
anti-inflammatory – all important properties to be sure, and in fact a rather
sweet and acceptable way to provide basic care for wounds. However, just like Paré and his use of rose
oil and turpentine, the effects are probably to restore the wound to an
environment that allows wound healing to progress at its own optimized rate,
not however to accelerate wound healing beyond its native kinetics – unlike
other vulneraries such as symphytum, achillea, prunella, and arnica in which
classic observations and use imply a genuine stimulatory effect. Either way, honey has an acknowledged place
on wounds, so we can readily conclude that what is shown here is a legitimate
potential product, but what has the company done to prove it or improve
it? Have they done right by the
industrious little bees who make it, enlightening us with a pathway to the
most effective use of this remedy for the sake of getting patients better
faster? Regardless whether the product
is good, great, or indifferent, the marketing materials are nothing but
patent medicine hype – trite, trivial, cliched, bogus. And that is too bad because potential real
therapies deserve a chance for genuinely good investigation and
development. Concerning the case
shown, the marketing brochure states “44-year-old
patient with hidradenitis suppurativa for 7 years; Wound excision and use of a variety of
dressing types were unsuccessful; The
wound healed in 5 months after application of OUR PRODUCT dressing”. The misleading problems here are
several. The wound excision was not
unsuccessful – it was completely successful in removing the primary disease,
and now she no longer has hidradenitis, just a residual wound without the
primary pathology. A transverse
axillary wound (after hidradenitis excision or for any other reason other
than radiation) is expected to heal rather quickly. If it does not, then there are just a few
reasons why – persistent primary pathology, versus some undiagnosed wound
pathology, versus biomechanical impairments of contraction due to scar and
motion, versus inept injurious care.
Absent any other history, no further inferences can be made. If we assume that any of these causes were
present, and then the patient switched over to good basic care using the
honey product, then we would expect to finally see a good outcome. If the excised wound was open and unhealed
for 7 years, then thick scar will impede contraction, and a 5 month interval
to closure is not surprising. If the
disease was present 7 years, but the excised wound is recent, then only 5
weeks should have been needed to get the wound closed with any reasonable
care. The point is that after so many
years of frustration, that whoever inherited this patient and took care of
her did a great job and the wound healed.
Kudos – whether by design or by the placebo effect (the placebo effect
in wound care happens when the patient or care provider, bored and disengaged
from the process, gets beguiled by an interesting new product enough to get
actively involved in the required daily care). Everyone in the wound business can
appreciate how nice this result is and understand that 5 months to a good
result is “within bounds”. The
question is, did bee goo save the day, or just the effects of non-specific
but competent care? While this is a
genuinely nice result, it probably just reflects basic competencies, and
nothing at all extraordinary about the dressing per se. If you are naive about wounds, if you do
not know what normal wound physiology is all about, then it is easy to imply,
via bogus marketing materials, that the wound would never have healed but for
the magic medicine. The disappointment
here is that the magic potion did not accelerate the wound such that it
closed in just 5 weeks – that would have been a genuinely notable result. Alternately, perhaps the wound would not
have closed in even another 5 years were it not for the honey – we can never
know. But the actual time frame
involved can be appreciated by an experienced wound observer to probably
represent the effects of competent basic care, not a pharmacological effect
of the honey. How could you ever know
the difference? By doing a randomized
controlled clinical trial – one that is done properly and done explicitly as
good wound RCT’s should be done – and there just aren’t very many of them. Will the honey product ever have a compelling
study behind it? Probably not. RCT’s are expensive. Making markets of new products is
difficult. Regulatory requirements can
overshadow all else, and when a safe natural remedy like honey can come to
market easily without too much scrutiny, no CEO is going to want to spend
millions that aren’t a regulatory requirement just to prove a point,
especially when the bogus marketing materials that they print will be
sufficiently persuasive to enough people to make their market. The other photos on this slide are case studies sponsored by the
manufacturer of another product, a “hydrolyzed collagen powder”. Collagen as a putative topical wound
healing agent has made its way into many products over many years. The romance of collagen is anchored in the
sciences of the 1950’s, and whether or not it is of any meaningful value as a
topical vulnerary is highly debatable.
Nonetheless, even today, companies keep trying to get a me-too piece
of the collagen pie, when their productive attention should be turned to
other chemicals of demonstrable significance (see slide 22). Two case studies are shown here. The right
column shows “a 71 year old
diabetic, hypertensive patient with a five month duration, non-healing post
surgical wound of the left foot”.
The photos show the wound over an interval of 35 days of treatment
with this collagen product. The wound
is not yet 100% healed, but the progress is excellent. The wound is clean, free of inflammation
and injury – obviously very well cared for by somebody with some knowledge
and competencies to do this. The center column is “a 75 year old obese patient with
peripheral vascular disease and chronic slow healing leg ulcers, partial
thickness wounds of bilateral lower legs”. The pictures cover an interval of 56 days with
all demonstrated wounds healed. Once
again, these same authors provided excellent care and got the wounds healed
in an admirably short time. Look
closely at the enlarged view (bottom). Do you see the imprint of the gauze
pads? This leg was being wrapped and
compressed and had all of the things that are crucially important to good
outcomes. These ancillary activities,
like compression and edema control, are the quintessentially crucial
activities that must be done if any wound is too heal quickly. These are the things that qualified wound
people do every day but which unqualified providers know nothing about, and
which are trivialized by reviewers at regulatory agencies and editorial
boards. So, are the good outcomes here
attributable to the good nurses who took care of these patients, or to the
magic collagen sprinkles? Herein is
the fundamental problem with “studies” like this: you just don’t know. These wounds had good care and they healed
properly. The time frame is “quick”,
but not extraordinarily so. The short
intervals could not have happened without excellent care, and many patients
with comparable wounds and care would have had similar good outcomes without
magic sprinkles. Yet our benchmarks
for good care would have allowed these patients twice as long to heal, so
perhaps the collagen powder did make a difference. The authors attribute the good results to
the powder without giving themselves enough credit, and that is a perfect
example of the placebo effect and “emperor’s new clothes syndrome” in this
business, getting so beguiled by what’s new that you lose sight of what
really matters. The problem is that
“studies” and case reports and marketing materials like this do nothing to
help discriminate good care from pharmacological effects. Without a properly done RCT, you cannot
answer this question. Furthermore, the
brochure states “the hydrolyzed collagen powder stimulated fibroblastic
activity within one week . . . “
Whether that is true or not is irrelevant, because it is just a trite
inference made without any histology or other micro-assay, stated improperly
without regard for the known biology of these systems. The patients got better quickly. Their nurses did a great job. Perhaps the collagen powder made a bit of a
difference. That is all you can say
without a formal investigation. Both of the products shown on this slide are nominally
legitimate, and both are potentially useful with theoretical positive
pharmacological effects on the wound.
Yet the documentary information that would make that case is non-existent,
and the marketing materials are naive and lame. The problems is that lame materials like
this can persuade those with little or no knowledge of the subject. If a potentially good therapy has only bogus
materials to support it, then what happens when illegitimate products shovel
the same nonsense in front of you?
Whether or not you prescribe something is your choice, but it is your
knowledge, good faith, and common sense that are the last line of defense
against bogosity and potential medical or economic harm to the patient. |
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This slide will focus on the bogosity in the brochures that are
waved in front of you in the competitive marketplace of the trade show
exhibition hall. Those brochures are
some of THEIR the companies main armaments to win your hearts and minds. These brochures are designed to be eye
candy, meant to tempt you even though the products they hawk may spoil your
dinner for good care, and your mom keeps telling you it’s no good for you. The bottom
panel shows some photomicrographs of a biologic, a regenerative matrix
made from human dermis. These products
are used in surgery for a variety of reconstructive purposes. Their value is affirmed, and many companies
offer competing products from human, bovine, ovine, porcine, and equine
sources. These products also have a
useful role in treating certain chronic wounds, so not surprisingly these
products are represented at the wound trade shows. The product is not bogus. It’s applications are not bogus. The bogosity here is in the sales brochure
– it is meant to dazzle you with pseudo science, little teases of technical
information that give an aura of legitimacy, but which are so scant on
meaningful information that knowledgeable observers will find nothing of
substance. I chose this example
because of the histological pictures.
Good histology should be one of the most valuable forms of information
to be shown for any wound product.
This is a good example of worthless histology. Being technical in nature, the mere fact
that a photomicrograph is included on the brochure gives a mien of authority
to the company-product-brochure. But,
this histology is badly presented, and in fact it may hide the real story
that discriminating users might want to know.
Left is a picture of bare
matrix sitting on top of muscle “explanted at day 1” (Masson’s
trichrome). There is no mention of how
the study was done, what kind of animal was used for the implants, where the
material was implanted, nor any explanation of what you are looking at. Do you know how to interpret this? The brochure gives absolutely NO other
information other than what is already given – trichrome, explanted at 1 day
– that’s it. There is a footnote
reference to a bibliographic entry that concludes with “unpublished
data”. Unpublished data is by
definition not a bibliographical entity at all, so a formal bibliographical
citation is nothing more than smoke and mirrors bafflement meant to give an
aura of legitimacy. Either way, if unpublished,
how do I find the article to find out what species was used or other details
of the study? Middle is a picture “explanted at day 7”. The general intent of the first picture was
to show that at day 1, there is no cellular ingrowth into the implant. At 7 days, the matrix is full of
cells. Or so they say. Can you really see what is going on in that
low power under-resolved 5cm picture?
Histology pictures can surely seem impressive, but you must not be
naive and be awed simply by the presence of the picture. You must be discriminating and analyze the
information on that picture. So, let
us “read between the lines”. There is
a general sense that cellular material has filled the matrix. For those of us who have spent years
studying these products and scrutinizing hundreds of histology specimens,
there is something not quite right here.
One week to filling of the matrix is wrong. Histogenesis will go faster in smaller
species, so if this was a mouse or a rat, that is partially understandable. But the arrows center-bottom are labeled as
neutrophils. (The arrow to the red
thing is labeled “blood vessel”, but how would I really know with such a
poorly resolved image?) The problem is
that neutrophils should not be there.
Period. But if they are there,
acute inflammation is one good reason why the matrix would have filled
quickly, just with the wrong stuff.
The regenerative matrices, used properly, suppress inflammation and
wound healing and trigger an embryonic type of histogenesis (tissue formation). Neutrophils have no business being there,
unless the implant was processed and handled improperly and got infected, or
unless the implant has triggered an immunogenic response. The poorly resolved view that they give us
suggests that there is no suppuration, so we can give them credit for a clean
product and clean surgery, no infection.
But the immune response question is key. Cross-species studies with these matrices
are prone to these events, and if the implant becomes inflamed, then it heals
with scar, and the whole premise behind regenerative matrices is invalidated
on these particular studies. The
manufacturers who make xenogeneic implants for human use understand this full
well, and they all claim their own proprietary process for removing collagen
epitopes or otherwise reducing immunogenicity. Since the product illustrated is from human
sources for human recipients, reducing immunogenicity need not be done, but
doing cross-species studies like this does little to inform anyone about the
virtues, uses, and pitfalls of the product.
But those histology pictures sure do look important, don’t they? Right
is a picture “explanted at week 8”. There
are no labels or other explanation. I
am guessing that the green band across the middle is meant to be the healed
or regenerated matrix. I am guessing
that the clear areas above are the panniculus adiposus under the skin. Nothing is labeled. That green band across the middle could
just as easily be the native endogenous muscular fascia that ordinarily
belongs there between muscle and adipose.
Notice how the green band seems quite thin compared to the matrix
thickness on the other images? Are
they deluding themselves – and you – by claiming that this is the regenerated
matrix? How is anyone going to know on
a tiny low power low-res image like this?
But it’s histology by gosh, it’s gotta count for something! The legitimacy of regenerative matrices is
not in dispute. This is a credible
product from a credible company. But
as soon as an ad agency is put in control of professional communications, all
you get is bogus brochures that have one and only one intent – to sell you
something. So, they can be completely
disrespectful of your knowledge, education, and intellect, yet still be
persuasive, and they can be equally persuasive for bad products as for good
products, and all the more so when the intent is to baffle you with stuff
that oftentimes neither the company people nor the ad people nor the target
audience has any real expertise with.
So, don’t be taken in by tricolor trichrome pictures. Analyze, learn, listen, question, be
skeptical until THEY can provide you with intelligent information, and never
let bogus brochures persuade you with pseudo-scientific drivel of no real
intelligence. The top panel shows
advertising materials for a prescription wound product. This topical ointment might be useful and
legitimate, maybe not, and it is certainly not harmful. The bogosity is in that even if it does do
something useful, that claim is never proven or supported, and the marketing
materials are a grotesquely bizarre mishmash of error, irrelevance, and
misdirection, a copywriting sleight of hand meant to imply magical effects
and results. The ointment contains
three chemicals derived ultimately from natural sources, and which have a
long safe track record in topical skin care products – benzoic acid,
salicylic acid, and oak bark extract.
Shown left is a venous
stasis ulcer of 7 years duration, healed in 90 days with the advertised
product. Is 90 days (13 weeks) to
closure a credible performance within or exceeding customary benchmarks of
good wound care? Yes, it certainly
is. Is it a magical performance? No.
Was the care accompanied by good hygiene, good compression and edema
control, periodic debridement and maintenance, et cetera? Not stated, but we all know that there is
no magic goo that works well without these other modalities in effect. Did the goo work, or just the good
care? Can’t say. The other picture right shows “deep second-degree burn”, healed in 12 days. Is 12 days to being healed something for
the caretakers to proud of? Yes, it
sure is. But did the magic goo help to
accelerate healing, or is it just that competent care in any form would have
allowed this to heal at its natural rate?
As a burn surgeon, I disagree that the injury shown was “deep second
degree”. It is a superficial partial
thickness injury that might well heal in 12 days with tip top care. Of course, many patients get care that is
not so good, and this patient could have done far worse. And even with good care, this could have
taken several weeks to closure, so the result is noteworthy, but the case is
not proven that the ointment had pharmacological accelerative effects on the
wound. There is more histrionics and melodrama in this advertising
brochure than there is substantive information that knowledgeable
practitioners and prescribers would want to know. The brochure presents several other cases
in which isolated wounds are shown with inaccurate diagnoses and no mention
of any of the other required ancillary care.
All had benchmark times to healing reflecting good general care, and
some of the times are good enough to wonder about possible pharmacological
effects. But the brochure has no
meaningful technical information.
There is no discussion of pharmacological properties or presumed
mechanisms of action. The brochure is
plastered with tables of bacterial susceptibilities, with the implication
that the product kills germs, ipso facto it heals wounds. The brochure flashes consumer marketing
graphics in your face claiming “stimulates re-epithelialization, debrides,
inhibits microbials, moisturizes, affects vasodilation”. No agent does all of those things. Even if the combination product did have all
of those effects, there should be some technical discussion to document or
explain these effects, and some tables or graphs of data or else
photomicrographs or something meaningful to confirm these effects. Of all the lousy brochures I have seen,
this one is uber-remarkable for the complete triumph of marketing over
science, data, and doctoring. And yet,
the product might actually be good.
Once again, we have here a product derived from natural sources that
has promise as a legitimate vulnerary.
Legitimate investigations should be done, laboratory and
clinical. But that will never
happen. Why? This is not a scientific pharma product coming
from an established company with proper resources, nor is it a novel
pharmaceutical coming out of a research lab in which clear cause-and-effect
on the wound has been demonstrated.
This is a compounding product.
Stock items, with putative wound care and-or wound healing properties,
were pulled from the shelf and mixed in a goo. The goal is to get this product to market
and make money. It is the type of
product more properly suitable for a health food store. The marketing materials are consumer
oriented and care little about the scientific basis for the product. The brochure was put together by the
marketeers, and there is marketing-speak all over this thing. The goal is to persuade and sell, not by
letting the product speak for itself, but baffling you with bravado and hype
because the science behind this product has no voice of its own. This is the patent medicine trade rearing
its ugly head, and shame on any doctor who falls for it. Except that this particular product has
some legitimate potential merit – it might actually be a good product – but
the company did not show you credible evidence, only the patent medicine
hype, the bogosity. Recall that I
opted not to get mean by showing the completely dishonest products but they
all have similar kinds of brochures – all hype but no legitimacy, all form
but no substance, all meant to persuade and sell at any cost regardless how
worthless the product is. There are
plenty of such products that make their way to market for shorter or longer
periods of time. The ultimate problem
is that if this kind of salesmanship can persuade you to prescribe this
stuff, then this kind of salesmanship can persuade you to prescribe
anything. If you are going to use this
or any other product with bogus brochures because you perceive the
possibility that the product itself might have some genuine usefulness, then
by all means do it – that is how progress is made. But do not use it blindly, stupefied into
obeisance by the pied piper of a company tooting a magic flute made of bogus
brochures. You must remain in charge
of the analysis and choices, and you should insist on better information. And if you do choose to try such products,
do it thoroughly, do it wisely, record legitimate information and results,
then good or bad share that information with your colleagues so that the
cream can rise to the top and the dregs can sink into oblivion. |
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Bogosity comes in many forms.
An item and everything about it may be worthless – a bogus product. Regardless of its intrinsic value, good or
bad, its proof may be faulty – bogus
data. Then regardless of its value
and the evidence behind it, it might by promoted by illegitimate claims or by
false pitches – bogus marketing. The final message in this section on the
Bogosity Matrix, with its case studies, is “do not get suckered in by bogus
pseudo-data”. Do not be hustled by
illogical and falsely substantiated claims, nor let your patients and their payors
be raped in the wallet with false expectations. Some products are just bad - period. You want to recognize and avoid them. Remember, if they are on the market, they
got there by pseudo-legitimate data, so you need to be alert to bamboozlement
and make your own discriminating analyses and judgments. However, on this slide, I also want to
emphasize the products that are potentially meritorious, but which have
problems with their proof and their marketing, so that even when you sense
some bogosity, you do not indiscriminately toss the whole product. Bogus products need to be discriminated
from bogus data and bogus marketing. Bogus data is that which
is based on false misleading pretenses, a lack of knowledge, and erroneous technical
concepts and investigative methods. Do
not be hoodwinked by it. In any in
vivo or clinical study of wound healing, especially the clinical studies,
always be alert to the placebo effect and the improved outcomes that result
just be doing an investigative study.
Very few wound products have done a three-arm study, as they properly
should. For any study, when all you
have to compare is a treatment group versus a non-specific control group,
then you cannot be certain that the good results are do to the test
agent. Good results might simply
reflect the effects of good general care and the “placebo effect” in wound
healing that results from good general care.
The corollary to this is that you must never confuse normal healing
and good care with a response to the test product. Remember, many physicians and nurses have
never witnessed proper wound care and normal healthy wound healing, and many
have never once in their entire careers prescribed proper care. On the contrary, many have prescribed
completely improper, erroneous, damaging, and destructive care that
perpetuates the wound and its problems.
So, when they get to witness normal natural wound healing at normal
natural rates because somebody prescribed or implemented some basic hygiene
to keep the wound healthy and allow it to run at its natural rate, they think
they have just witnessed a transcendent miracle. This evangelical approach to wound product
marketing is all too common. Unlike
overtly and knowingly bogus patent medicine claims, the claims from this kind
of experience can be in good faith, with the wound naives genuinely believing
they have witnessed the hand of an angel in the potion they have prescribed. An example worth mentioning is the famous “Steed study” (1: Steed DL and the Diabetic Ulcer Study
Group. Clinical evaluation of recombinant human platelet-derived growth
factor for the treatment of lower extremity diabetic ulcers. J Vasc Surg
1995;21:71-81. 2: Steed DL, Donohoe D, Webster MW, Lindsley L, and the Diabetic
Ulcer Study Group. Effect of Extensive Debridement and Treatment on the
Healing of Diabetic Foot Ulcers. J Am Coll Surg. 1996;183:61-64). This
was one of the pivotal studies that allowed Johnson & Johnson to bring
PDGF to market (Regranex®). It looked
at the use of this topical drug for diabetic foot ulcers. In analyzing the data, it was found that frequent
periodic wound debridement had a significant beneficial effect on healing
rates and outcomes. Regular periodic
debridement beat standard care. PDGF
beat standard care. Debridement plus
PDGF was even better. What does this
teach us? When Regranex® is used, the
wound surface must be prepared by curettage or other mechanical debridement
(this removes the inflammatory layer of the wound which has proteases which
would destroy the drug, and it also exposes the angiocyte and fibroblast
responder cells directly to the drug so that it is not wasted by buffering
from non-relevant cells or matrix). Good
wound studies should have three arms, a well defined “standard care “ group
versus a protocol placebo group versus a protocol drug group. It is easy to see how any poorly designed wound
study that has just “test” versus “control” groups could be a mistake. Imagine a control group (without the test
drug) that has just “basic care” with a generic dressing, never bothering to
do the curettage. If the investigators
only did curettage when the test agent is applied, and not otherwise, then the
effects of debridement versus test agent would be analytically inseparable. If the investigators were unaware of this
issue to begin with, they would falsely conclude that good results were due
to the test agent. The Steed study (an
early but good study in this young business of modern pharmacological wound
care) did not have three groups, but it did at least analyze the data that
way. In so doing, it uncovered not
just legitimate evidence for the positive effects of topical growth factors,
but it strongly illustrated the value of regular wound hygiene and
debridement. Regranex®-PDGF is an
important product, one of the few validated wound stimulatory therapies that
we have. However, assume for a moment
that it had no useful effect beyond good “placebo care”. It is easy to see how the effects of good
preparatory care could have been misconstrued as an effect of the test agent. You are probably saying though that “all good double blind
studies should be precisely detail-for-detail matched in technique, except
for placebo versus product X in the medicine bottle, and if that were true,
there would be no need for a third arm, and such analytical traps would be
preempted”. True, but in wound
studies, exact matching of groups is often impossible, and so too is blinding
the product or investigators – that is just the tangible reality of many
wound care items and modalities, and that is why a third arm is needed for
many clinical wound product studies.
Thus it is up to the investigators and their protocols to be as exact
and detailed as possible, to foresee all statistical pitfalls and design
around them, but alas, such is often not the case. It is also the duty of the FDA to be
discriminating about such details and catch the deficiencies, but when the
regulatory body has no expertise on the subject, they can be no better than
the imprecise investigator. The
reality is that there are many wound products on the market that have bad
studies behind them, purporting to show meaningful data when all they have is
garbage. Just because THEY said it,
doesn’t make it true. When bogosity
slips through the investigators, the regulatory agency, and the editorial
boards, the last line of defense against irrelevant and erroneous products is
YOU, the discriminating wound product user and prescriber. Finally, with regard to bogus data, remember that some
meritorious products may have little to go on in the early days of their
development. A product does not get to
market without evidence, sometimes robust and voluminous, sometimes rather
limited. However, it does not even get
to the point of being a potential product in front of the FDA without some
kind of preliminary evidence that curried the interest and efforts of inventors,
investigators, and investors. Keep an
open mind and use your knowledge and analytical skills to sort wheat from
chaff based on the available knowledge.
For a new or potential product, little data but with a rational and believable
concept, presented by moral and intellectually honest people is okay. Such concepts and potential products should
get your respect and some of your time to hear about them. Bogus marketing is of two
kinds, erroneous but excusable versus disingenuous. The trade card for Henry’s Carbolic Salve
was of the former. It attempted to
sell, but it did not attempt to deceive.
It made unsupported and overboard claims, and it embellished whatever
truth there was with unbridled zeal, but it was all done through the filter
of the pseudo-legitimate knowledge-of-the-day. The pitch was made in sincere good faith. It was honestly well intended. They hoped to make money selling you
something that seemed to have promise to do what they claimed. When the Pure food and Drug Act of 1906 was
established, the government basically said “prove it” – no unsubstantiated
claims – prove it. So products like
Henry’s could not survive, because they could not prove it – either there was
no proof, or else small potatoes companies could not muster the resources to
prove it. The same remains true
today. “Proof” in this business is a
complex and expensive affair of corporate, professional, and social
engineering. Without monetary
resources and a good pitchman to raise the initial capital, even the best
ideas sink into oblivion. Products
that do make it to market must be sold, to recoup investment and then make
profits. Good companies with good
concepts succeed by delivering good products, and everybody wins. However, if the product is marginal or
bogus, but everybody honestly buys into the bogus data, or is blind to the
faults in the proof, and if they genuinely believe in their “proof”, then
they will have an honest enthusiasm trying to sell what they believe is
good. The product may be bogus
nonetheless, but this kind of good faith use of erroneous or misunderstood
data should not engender any disrespect.
Try to communicate your thoughts and analysis to the company. Good companies listen (see Apligraf above,
slide 34), and eventually it might be re-engineered into something good, or
it might go away. In the end, it is
YOU, and only you, the discriminating prescriber of wound products who drives
the ultimate market for any product.
If a product is no good, honestly or dishonestly, just don’t prescribe
it. The dark side of bogus marketing is the disingenuous kind,
knowingly false and deliberately deceptive.
Under the regulatory laws of the past 100 years, a company cannot just
simply make outlandish claims and tell outright falsehoods. To deliberately and deceptively bring a bad
product to market and then strengthen that market by blatantly dishonest
miscommunication with professionals, prescribers, patients, the public, and
even the government regulators, that takes a deliberate and well-crafted
stratagem. And as we have seen
recently with a number of high profile criminal and civil liability actions
against several pharma companies and medical device manufacturers, some
companies or their top executives seem to have no morals or boundaries these
days. My earlier statement that
companies are not inherently evil remains true – they are big organizations
with many honest dedicated unimpeachably decent employees – but that does not
prevent a few immoral executives or boards from selling their souls on the
ride to the top. Sadly, we are hearing
more and more in recent years about illegality, deception, and moral betrayal
from these companies. How do they do
it? How do they get bogus data and
marketing claims past regulators? If
you exclude the cynical answer of “corruption in the highest places”, they do
it with statistics. Not real statistics. Bogus statistics. As in “there are three kinds of lies: lies, damned lies, and statistics”.
(This quote was mentioned by author
Mark Twain who attributed it to Prime Minister Benjamin Disraeli, although
the true origin is actually not certain.)
Data can be engineered – massaged, tweaked, edited, redacted, revised,
refined, reinterpreted. The data may
be numbers, spreadsheets, photographs, testimonials and endorsements – any
type of pseudo-technical information that can persuade someone else under the
mien of professional and scientific legitimacy. Wiley disingenuous folks bent on market
success and profitability can make data say anything they want it to,
anything they want you to hear. And if
the regulators aren’t sufficiently savvy – and for wounds they aren’t – then
they can persuade almost anybody about almost anything. “Our company is righteous. We don’t tell lies, neither little fibs nor
white lies, nor massive fraud and scam.
We tell neither the little lies nor the damned lies. No, we don’t ever lie, we don’t need to, we
have statistics, and we can make them say whatever we want.” If you haven’t read about the Pfizer criminal
settlement, you should – the details are dismaying but instructive about the
pitfalls in the modern “ethical pharmaceutical” industry, including the
“evidence based” tactics as well as the salesmanship tactics that created
such a big deceit. There are plenty of bogus products, for wounds and
otherwise. You need to discern the
bogus and say bye-bye. However, you do
not want to overlook the “gem in the rough” when a potentially good product
has only limited or bogus data. So
again, it is up to YOU to be knowledgeable, discriminating, and have an open
but wary mind. Of course, good
companies have their own responsibilities too. If they have a good product but bogus data,
they owe it to themselves and to all of the potential beneficiaries of their
good product to get better unbogus’ed data so that their claims have more
power. I am always looking for the
next great product, something that helps me get better results faster, and so
are you. However, there are only so
many hours in a day to study any of this, and there is a constant barrage of noise
in the wound and medical product marketplace.
Amidst the din of it all, amidst the clutter & noise of hundreds
of products, claims and pitches, the good companies with good products need
to give me something to go by to make me notice and persuade me to try them. But I also want to ignore the phonies and
the hucksters. How do I tell whom I
should give my time and consideration to?
Dr. Cheatham’s Bogosity Matrix.
Just remember, regardless what the company screams at you, regardless
what 4-color printed drivel they shove under your nose, a product is either
legitimate or not, and it either has good data or limited data. For each product or company, figure out
where the product sits in that 2x2 cross – legitimacy versus proof – and then
you can analyze the product based on the various issues discussed here. |
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Integrating New
Products and Technologies into Practice #9 General morals, principles, and preparation for
a new product. New products are good or bad, bogus or legitimate. Either way, they must prove
themselves. Ultimately, the validity
and utility of new products is established by the broad base of practitioners
who use and evaluate them as they try to make their sick patients get better. The ultimate place for each product, its
ultimate persistence or demise, is determined by the marketplace of professionals
who prescribe it, and not by the inventor, the company, nor the FDA. The companies will try and persuade you,
and regulators and payors will interfere with good practice, but ultimately
the real value of products is decided by you and us. For any subject or problem, if you are
satisfied with standards of care as they are and see no need for improvement,
then you do not need a new product.
But if you quest for better care, then new knowledge and good products
are the only agents of change. Good products
and also the good companies who make them are your allies in these endeavors. Illustrated is the
doctor, from “A Day with a Country Doctor”, Scribner’s Magazine v8, November
1890. There is an attitude with many
new things in medicine that the drug-device-technique-whatever is founded on
arcane specialized knowledge or else requires such extraordinary dexterity
that only the special few are smart enough or skilled enough to use the
gizmo, typically academic elitists in their venerable ivy halls and ivory
towers. The reality is that, except
for a few highly centralized services such as organ transplant programs, all
good care filters down to “the street”, where the country doctor in all of us
takes care of real people with real problems.
Most concepts and products in wound care are very accessible. All that is expected and required of the
practitioner is to be knowledgeable and discriminating, to remain in charge
of your own assessments and conclusions about whatever is new. |
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To reiterate, companies develop and bring new products to
market, but the real usage and truth of these products is discovered by the
users. As a matter of general
philosophy and a pep talk about you and your relationship to new products,
here are a few points. Do not be afraid of new products. If they have made it to market, they are mostly
safe if used properly, and they have some nominal validity. If they make sense to you, try them. Have
a plan for using and evaluating them.
Do not just dive in and prescribe indiscriminately. Work through in your mind your exact
technical use of the new product, what problems to anticipate, and how to set
up your staff and office logistics to use it.
Be responsible, scientific,
professional, learned, thoughtful, analytical. This is the only hedge against bogosity,
harm to your patients, and waste to “the system”. Learn
what you can from other users.
They will help you get going, and even when you are very familiar with
the product, others might show you new uses and pathways to better
results. Likewise, help the
novitiates, and share what you know with others. Work
with the company. While you must
remain in charge of your own assessments and conclusions, the company can be
your best source of meaningful new knowledge.
Even when a product is bad, information and resources from the company
can be the fastest way to come to a proper negative conclusion and abandon
it. When the product is good, the
company and its reps become your partners in delivering good care to patients
with real problems. If a new product has merit, then ideally you should be looking
for ways to get the maximum value and utility from it. This principle may lead you to novel
insights and uses, extended applications, and better or more efficient
results than what the original developers and manufacturers had
envisioned. Do not be afraid of
innovation. Do not shrink form the
role of innovator. In the |
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Integrating New
Products and Technologies into Practice #10 Integrating a new product into practice,
step-by-step & details. Practitioners have a moral and professional obligation to
evaluate new products. One must reject
those that do not work and adopt those which seem promising or are confirmed
to work. One must also decide which ones to trial yourself and which ones
to eye as others trial and confirm them.
For the adventurous and curious, be on the front lines of figuring out
how-to-make-it-work for novel products that tweak your interest. The philosophy behind all of this now leads into some pragmatic
suggestions and guidelines about hands-on work with new products. |
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Obviously, some product or concept has tweaked your
interest. So, here is a practical
guide to working with new products. 1 - Getting
Started The first thing
to do is get relevant information.
Reading the package insert is always a good start. The company website, company brochures, and
materials supplied by the reps always risk having some bias and bogosity, but
they will also have valuable information.
If you can access conference notes, journal papers, and other peer-to-peer
communications, do so. In our modern
era of information and internet technologies, getting information is easy. Also, speak directly to the reps, and if
they cannot answer your questions, they should be willing and able to get you
connected with company execs & scientists (if they cannot or will not,
that is a bogosity alarm). Obviously,
peer-to-peer discussions with other users is the best information, but only
after you have prepared yourself with the basics. Next, plan for
the technical medical use of the product.
Plan for the actual techniques of administration, the required
preparatory care, the required support materials and paraphernalia, the means
of delivery and the dosing, and the after care and follow-up frequency. Anticipate side effects, and how you will
handle them. For example, consider the
use of botulinum toxin for lupus angiopathy (slide 6). When I first heard about it, it made sense
and seemed like something worth doing, and it has certainly proven
itself. I did my first case within
weeks of first hearing it presented at a hand meeting. However, before doing it, I had to answer
these questions: how many units to use
on each hand; can two or four
extremities be done together; what are
the dose limitations; where precisely
will I inject; how much injectate or
drug at each injection point; what
pattern of injection to maximize therapeutic result without paralyzing the
muscles in the hand; what to do if
there is any palsy; how to make the
procedure comfortable in the face of dozens of individual needlesticks. This was all easy to figure out, but it is
best to do so in advance of the actual event. Next, plan for
the pragmatic and logistical use of the product. The product you want is not magically
teleported into your hands at the moment you need it. You need to plan its procurement. If it is a new-to-market product, count on
a bunch of payment-reimbursement bugs.
It may require extraordinary materials support, e.g. a refrigerator or
freezer, a centrifuge, a big roll-around cart, or lots of shelf space, If you practice elsewhere than your own
office, it may need to go through a product committee. Purchase orders, paperwork, and billing procedures
all need to be considered. These
issues are less relevant for smaller, safer, cheaper, more basic me-too
items, but they become all important for novel, risky, and big-ticket
items. Almost any reputable company
will do, or help you to do this grunt work (getting the product into your
hands and then onto the patient is the ultimate closure of “the deal” for
them, so they work hard at this; if
they do not help with these activities, bogosity alarm). Also, you must plan for charting and record
keeping issues, If you intend to review
your results or collate your experience, possibly even write a paper or
report at a meeting, then plan in advance for keeping the relevant data. Finally, your staff must be educated on all
aspects of this, since they will need to do most of the nuts-and-bolts work
that gets the gizmo in your hands and onto the patient. Educating home health agencies and other
allied providers may also be crucial. Plan how to
educate the patients. Anyone in
practice knows that patients and families have a variable capacity to
understand or interest in learning about their care. For simple safe products, not much
discussion may be needed. For many
patients, wound goo is wound goo, and the “red tube” versus the “blue tube”
is as sophisticated as it will get for them, so do not go overboard on new
product education where it is not relevant.
But when it comes to new products, a few important technical
challenges and morality issues must be addressed. If the treatment is complicated or requires
numerous visits or technical activities, especially those that require direct
patient participation, then more explanation is required. Even if the patients simply need to come to
clinic daily for some service, they need to buy into that before committing
to a course of care. None of this
benefits anyone if the patients drop out of the care before it is
completed. For willing and able and
committed patients, technical education may be required for the home based
activities they will do. When a
treatment is investigational, unusual, or risky, then some sort of disclosure
is needed. Institutional review boards
and ethics committees may be required for hospital based practices and
investigative protocols. For products
already approved for market, disclosure in a legal or moral sense may not be
mandatory, but if the product is new to you, then depending on the
circumstances, the patient, and your own disposition you must decide how much
to tell them, just as you do daily with well established products and
procedures. |
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So, you have started using a product, getting it on line and
ironing out basic usage. Maybe it is
working as expected, maybe not. After
your first few experiences with it, where do you go next with it? It all depends if it is working as expected
or not. 2 - Figuring
Out How to Make it Work When it works
as expected, then good. It is a good
product, honestly promoted, properly educated, with everybody doing their
part as required. Whether or not it is
a major product or a minor product, something to be used frequently or for
big problems versus not much is up to you, but now you know you have a useful
and predictable item for your toolbox.
If it doesn’t work as expected,
the problem might be with the product or it might be with you. Do not indiscriminately abandon it after
just one or two trials. The product
got to market based on some credible evidence. Many very important, in fact revolutionary
products are still not used by those who should be using it, even when mostly
everyone else is, and the excuses are often of the variety “it sucks, it doesn’t
work”. But when you listen to how they
describe their use of the product, they are doing everything improperly. Nothing can fix a bad attitude, and
ultimately some products really do suck, but if at first things seem wrong,
review everything about it. Reread and
re-listen how to use it. Rethink the
details about its application. Listen
and speak to others who are successful with it, and be ready and willing to
change how you use it to match those who get good results. Sometimes the buzz about new products is
just faddism and the madness of crowds (deliberate reference to Extraordinary Popular Delusions and the
Madness of Crowds, a treatise on popular folly by Charles Mackay, 1841,
something worth reading if you want to understand the perversions of group
psychology which lead to erroneous over-the-top enthusiasm for some new
products or concepts). Fortunately
most of the bad products will soon enough fall by the wayside, although
aggressive marketing to deliberately targeted naive consumers can and have
kept some bad products alive for decades.
So, if it is really bad, that will prove itself eventually, but just
because it didn’t work as expected the first few times, draw no immediate
conclusions, review the details, and try again to make it work. And
what if it doesn’t work as intended?
Good, it still works. Maybe it
works for the nominal indication, but it took real users like yourself to see
that the details of use need modification.
Maybe you or someone found a new use or indication that was not
originally intended. Many great
products have developed that way. If
it is working for you in ways different than promoted, you have some
obligation to pass this information along.
Discuss it with other users.
Present it at a local grand rounds.
Submit an abstract to a national meeting. Discuss it with the company reps who will
then get you in contact with influential people. Good ideas and results need to be
circulated, so do it. Assume now that you have started using a new product, it works
well, and you have rolled it into your regular practices. New products become the most fun when they
do more than expected, or you have some new insight or discovery that pushes
the frontiers of good results. If you have it figured out, and it exceeds expectations,
then take it to the next level. The
company and its reps are the first people to talk to. If some data collection or development
effort is needed, they can and usually will help. Presenting your work or findings is also
crucial, and this is done initially via presentations at meetings, and then,
if you have enough quality data, via journal articles. The same is true when you discover that the product works or not for its prime
use, but it is effective for another need or usage. Speaking to the company for some monetary
support to do your scientific investigation is usually easy to arrange. The companies are looking to expand their
markets and indications, and investigator initiated studies or pilot studies
are cheap in the big scope of things.
Remember, in spite of those stupid waivers that political
correctionists want you to sign, no medical product comes to market without
the company that makes it spending money on legitimate clinical testing, and
that means money paid to institutions and professionals. The companies and their products are not
evil. In spite of a few high profile
reports of scientific fraud in recent years, investigators and their host
institutions (and that means you) are likewise not evil. Yes some products and indications are lame
or bogus, so professional users have to make intelligent informed
choices. But every great product that
has made a significant difference, a significant advance, has started with
some dude in the trenches with some idea about some gizmo, and some company
fronted some cash to get the idea off the ground. That dude could be you. When you discover something good, make it
count. Finally, do not be afraid of going beyond label, nominal, or primary
usage. The difference between
regulatory controls on manufacturer’s claims and marketing versus the rights
and obligations of licensed professionals has been discussed. Your professional credentials and licensure
expect that you will be knowledgeable, thoughtful, wise, and analytical. Every time you apply any treatment, do any
procedure, use any medication or product, it was some other envelope-pusher
before you who did it first, and then everyone else established it as normal
practice. You too can be the innovator. |
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You have now established the new product in your practice. Perhaps you are doing novel things with it
and spreading the word. Though all of
this there will likely be some problems or perplexity. They might be unexpected complications or
caveats. They might be difficulties getting
product delivered to the patient, or getting authorization from payors who
have no knowledge of this new product.
What do you do? 3 - For
Problems or Perplexity With regard to unexpected medical issues, preemption and
prevention are best, by anticipating side effects and taking precautions. When expected or unexpected side effects
occur, manage them as required. This
is no different than for any other product of established usage. If you are the first to observe, treat and
report on a side effect, then you are the innovator. Sooner or later good new products become
established therapy, and the side effects and problems are well known. But in the early phases of using new
products, recognizing and treating the problems are part of the whole discovery. When problems are relatively serious, you
have to decide whether to discontinue use versus continuing and managing the
side effects. Nausea, hair loss, and
life-threatening neutropenia are expected side effects of cancer
chemotherapy. We accept them and
vigorously manage the life threatening risks of therapy, because ultimately
the cure is hoped to be better than the disease. Wounds do not have the same life-and-death
implications as cancer, so perhaps we are unwilling to use potentially lethal
wound therapies, but the balance of risk-versus-benefit governs all
therapeutic decisions. The more that a
good treatment makes a big difference, the more important it is to learn how
to manage side effects and see the treatment through to the end. Of course, odds are that others are starting to have the same
experiences and learn the same lessons that you are. So, read what you can about the issue and speak
to the company reps. For any reputable
company that I have ever worked with, if there is an unexpected issue of
clinical or scientific relevance, the reps will get you connected with
scientists and medical directors in the home office. They will have more information about the
subject, or else be willing (often enthusiastic) to hear about what you have
discovered. Of course, the adverse
event that you and your patient experienced may be new to everyone, and there
will be no answers nor knowledge other than what you can glean. So, do not be afraid to get blood tests,
biopsies, imaging, consultations, or whatever to try to elucidate answers and
solutions where none existed before. Critique and feedback to the company are crucial. The past decade has seen a few newsworthy
events of fraud and criminal activities by certain pharma and device
manufacturers, such as the brouhaha over cox-2 nsaid’s. Thus, while the companies are generally not
evil, the professionals need to be especially on their toes these days. When you communicate to a company that
there is a problem with a product, my experience is that they will take it
very seriously. If your adverse event
was a one-time idiosyncratic thing, then that is interesting, but just “so
what” in the larger picture. Odds are
though that other users will have similar adverse events, and if everyone
provides critique and feedback, then the significance builds, and the
companies themselves will incorporate relevant warnings and advice in their
communications. However, even the best
companies have an inherent conflict of interests, between sales versus the disclosure
of minutiae. So you, as the
professional, have other channels of unbiased and protected reporting. Presentations at meetings and in journals
is important when you notice peculiar problems and trends. Remember, complications are not necessarily
a proscription against use, just a warning that some other caveat needs
management. Learning how to
anticipate, avoid, and manage the complications is part of bringing any good
new product into wide use and acceptance.
That is what Withering did with digitalis. When a complication is particularly noteworthy or serious,
regulatory agencies should be informed.
There are plain and simply some bad or dangerous new products that
come to market that should never have, and if you recognize them, you should
do what you can to share your insights with those that can take corrective
action. However, the bad dangerous
scenario is very rare, since in principle the FDA regulatory process ensures
at least the safety of medical products (unless the company illegally scams
the process, which is the basis for recent penalties against certain
companies). What is more common is
that proven good products have some weird incidental adverse event, not likely
to recur for any single practitioner, and thus not big enough to become a
journal article, but nonetheless worth having on record for others who have
had a similar event and need to know if that drug or device might be the
cause. I have twice filed official
adverse reaction reports for serious events:
(1) a case of drug-induced lupus due to pregabalin, and (2) a
neuroleptic malignant reaction due to risperidone, triggered by hydrocodone. With all new products, you decide. Do you wait for others to test the waters
and figure it all out, and then you adopt it when it seems fairly
standard? Or, do you become the early
user because you understand the problem and the therapy and find it
intriguing or worthwhile? If you are
the early adopter, your professional credentials, morally and ethically, even
if not legally, obligate you to observe, collate, and report your own
experience, both good and bad. |
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This slide tells two short stories of
working with two companies and two products.
The simple message is that the best interests and good fortunes of the
patient, the product, the physician, and the company are all
intertwined. When you are working with
a credible product and a good company, you can expect good rapport and
liaison between physician and company to solve medical, technical, and
logistical problems that might arise. Both
of the products profiled here, Fibrinet® by Cascade Medical, and Apligraf® by
Organogenesis, have been discussed on prior slides (6 & 32). Fibrinet®: As a new product, we were excited about the
science and pre-clinical data behind Fibrinet® platelet-rich fibrin matrix. We wanted to begin using it as a stimulatory
wound healing agent for outpatient use.
However, although it is easy to use, it does require specific
equipment and procedures, and it could not be used until the equipment was
present, the staff had been trained, and payment and reimbursement issues had
been solved. The problem for many new
products is that if a third party payor does not recognize it, and thus it is
not reimbursed, then it is not affordable for the patient. The fact that many new medical products are
priced beyond the means of most users is a separate socio-economic issue that
you will have to ponder for yourself. The
conundrum is that payors often do not approve a product until it is “proven”
with a large clinical experience, yet that experience cannot be forthcoming
until the product is approved and thus available for large numbers of
patients. This particular platelet
product is priced competitively compared to other platelet products, and it
is a bargain compared to other wound stimulatory products that we use (1/3 – 1/2
the cost of clinically comparable biologics).
Nonetheless, as a new product, it is not “covered” by the payors, and
most patients could not afford it from their own pockets. A new company trying to promote a new
product should be willing and ready to offer product for free or at a steep
discount in order to get prescribers to experience it, and the
cost-to-the-company should be part of their capital investment and the “cost
of doing business”. However, companies
do not survive without revenue, and for small start-ups with just the one
product, gratis “freebies” can only go so far. So, the company and the prescriber have to
cooperatively understand each others situation and plan strategically, based
on the local payors, hospital or clinic procurement and reimbursement
practices, and other such factors that are categorically unrelated to the
core medical issues. Any company
serious about making a new product successful will work closely with their
“pioneer” prescribers. For Fibrinet®, there were two issues
that needed attention before using the product. The first was a technical issue. This is not a product where you just peel
the package and apply. Blood must be
drawn from the patient into the tubes and various paraphernalia of the
product. Then, the blood must be
processed by a two-step centrifugation.
Providing the special centrifuge and then training the nursing staff
were prerequisites to use. The company
did their homework in having an OEM centrifuge manufacturer make a machine to
their specifications, and the company was then able to supply us with the
machine at a partially subsidized cost.
The company staff flew to our facility for hands on training – very
thorough and well done.
User-prescribers should expect this kind of quality customer support
from any company serious about their product.
The second crucial issue was costs and reimbursements, always a thorny
issue for worthwhile but expensive new products. Working through the payment details
required close liaison between our clinic administrative staff and the
company, and that support came not just via the company reps, but directly
from company executives. Our ability
to use the product initially came from a batch of free product, and then
product at a discount. Concurrently
the company had ongoing activities to persuade payors to make the product
“formulary”, a persistent necessity for any company with a new product. Currently, our ability to prescribe the
product is still hampered by limited payor support in our particular
geographic market. However, our own
clinic staff also works this issue, case-by-case, by discussion with the
payors and appeals on individual cases.
The net result is that a product that we have seen compelling results
and have great faith in remains elusive for us. The “freebie” grace period is over, and we
use the product when we can arrange proper reimbursement, but we cannot use
it as much as we would like. The
battle goes on. Apligraf®: Our second short story is about Apligraf®,
another wound stimulatory agent, and one of our favorite products to use for
relevant indications. This product has
now been on the market for about 12 years, and its technical support,
procurement and reimbursement issues, formulary status for the payors, and
other such logistical issues were ironed out long ago. We still cannot use it every time we want,
because of payor-reimbursement issues, but the denials these days are
relatively few. This is a living cell
biologic, and it is manufactured with an extraordinary amount of safety
testing to make sure that the donor cells are free of any known
pathogen. The product is also proven
in clinical practice, with rare incidental and anecdotal problems related to
its presence on the recipient wound.
Recall that purified PDGF is a therapeutically comparable
product. Over the years, we have seen
several incidental contrary reactions to PDGF, where its use has resulted in
rapid intense inflammation and re-ulceration with enlargement of the
wound. We have observed this
exclusively in patients with connective tissue disorders, with or without
concurrent hypercoagulable states.
This might have been unexpected, but it is not all that surprising in
these patients who have bizarre immune and inflammatory profiles to begin
with. Many other patients with these
disorders have had PDGF with complete safety or effectiveness, so this
adverse event is very incidental and unpredictable, but we have learned to be
wary of using purified PDGF in our rheumatoid and lupus patients. For a number of years, we had not observed
a comparable event when using Apligraf®, so we therefore tended to use
Apligraf® preferentially for autoimmune wounds whenever we wanted to use a
biological stimulant, meaning we have had a large and safe experience with
Apligraf® in these patients. But then
it happened, just once, then not again for two years, and then we had two
such adverse events within a month of each other. The latter two cases are illustrated. Top is an 81 year old woman with a
chronic ankle ulcer following excision and radiation for melanoma. Left is the wound after
miscellaneous activities reduced the original large wound to a small area
over the tibialis tendon. Apligraf® to
stimulate the remaining area to close was a typical choice for us under these
circumstances, and considering the good uncomplicated improvements already
made, we expected the Apligraf® to carry this wound “across the finish
line”. As a radiation wound in a
patient with no other major diseases, immunopathic adversity would not have
been expected. At about three weeks
after placement, the wound became painful and inflamed, and there was
progressive ulceration. The middle
image shows the wound at 4 weeks at the peak of these events. Remaining material was removed and daily
topical care was restarted. Right
is the wound 4 weeks later, the wound back under control, but the damage
done. Subsequent wound histology
showed extraordinarily dense perivascular infiltrates with lymphocytes and
plasma cells. Whether they were
present before or induced by this turn of events (cause versus effect) cannot
be inferred, but this is the histological profile indicative of wound
immunopathy that we can equate with risk of this kind of reaction. The question was whether this represented a
non-specific immunogenic reaction related to standard wound immunopathy,
versus an HLA-type of donor-specific rejection (even though the graft does
not have leukocytes nor significant HLA antigens), versus some type of
induced acute inflammation or thrombosis.
Not having taken any biopsies at the peak of the event, this question
cannot be answered. Bottom is a 50 year old woman with a
chronic ulcer due to a primary hypercoagulable disorder with secondary venous
stasis. Her wounds healed with
anticoagulation and compression, but inconsistent follow-up and maintenance
care caused late recurrence. Shown right
is the leg after miscellaneous activities reduced the original large wound to
the area shown. The story is very
analogous to the first case, with no problems for two weeks after placement
of Apligraf®, and then sudden inflammation and thrombosis. Middle shows that the wound at
three weeks, infarcted. Right
is the wound 2 weeks later, cleaned up and under control after restarting
basic daily topical care, but the damage is done and the wound is bigger. The events were very suggestive of a
delayed immuno-sensitivity reaction.
The sensitivity may have been to HLA antigens or maybe to something else
in the graft. Absent biopsies and
histology from the time of the center images, the events cannot be inferred
with certainty, but the events fit with a delayed lymphoplasmacytic response. The indolent nominal uncomplicated progress
for two weeks fits. The time delay
until response of about 3 weeks fits.
The presumption is that once sensitized, then an acute neutrophilic
response was triggered which mediated the lysis and/or
thrombosis-infarction. In the top
case, the inflammatory-lytic appearance of the wound and peri-wound suggests
that acute inflammation predominated.
In the bottom case, the thrombo-infarctive appearance of the wound,
and the relative lack of peri-wound inflammation is consistent with her
confirmed history of a hypercoagulable disorder. The lymphoplasmacyte infiltrates seen later
in the top case, regardless whether cause or consequence, supports these
assumptions. Because these two events
occurred so close to each other, it was natural to wonder if the grafts were
from the same donor or from the same manufacturing lot, whether there was
something inherently antigenic about the donor(s), or some sort of production
quality control issue. The company
reps have always worked closely with us, and this time was no different. The information and case reports were
requested and submitted, and we were soon enough talking to the company’s
chief scientists. They were very
knowledgeable about relevant issues, and we had informative discussions. They did not eschew the possibilities
discussed here, but they were able to discuss the various reasons why at
least an HLA mediated reaction would have been unlikely. Production lots and donors were different,
and they had no other reports of problems.
Anecdotal cases are just that, incidental stories, and absent any
acute phase lab studies or specimens, nothing further could be learned from
these cases. However, the company did
offer any support needed for further investigations, including in-house study
of specimens, and the next rare time this happens, we will get relevant
specimens. The moral of both of these stories is
simply that reputable companies with good products, big and small, startup or
staid, stand behind their products and offer the kind of customer support and
service that you would want, through all phases of procurement, testing,
training, clinical use, and atypical situations. As the customer-prescriber who specifies
their products, you should expect no less.
Do not ever be timid about asking your reps to get you in touch with
company principals and scientists when there is a legitimate reason. Remember, the company’s motivations are
complex – their investors and employees want profits, but their founders and
scientists also want to save lives, cure the world, and see their widgets and
projects be successful. You want to
cure your patients, and to do so as efficiently and effectively as possible,
meaning having the most dependable tools, which come from the companies. The companies want you to prescribe their
products so that they can succeed, but never forget that you likewise want
the company to succeed so that their good product does not disappear. The better interests of the company, the
prescriber, the patient, and even the payor are intertwined, and what is good
for one is generally good for all. If
you find a new product that you believe in and it helps your patients, and
you would hate to see it fall off the market, then you have to help the
company make it successful before apathy or third-party-payor barriers sink the
product. What about bogus products? There are bogus products backed up by good
responsive companies, especially when the product is of the good faith honest-but-naive
variety of bogosity. Of course, if the
product is no good and you do not use it, then you will have no need to
interact with the company. However, be
wary not to be beguiled to use a bad product solely because the people and
practices behind the product are otherwise honorable. Bogus companies are to be avoided. You can recognize them by features such
as: their reps have marginal or no
meaningful knowledge, or they are disinterested or disengaged, or they fail
to make follow-up calls or leave samples, or they have no studies, literature,
white papers, technical briefs, nor anything else to show you; reps refuse to get you in touch with
company higher-ups; the reps have no
tools nor interest nor any personal effort or involvement to help with
third-party payor or hospital procurement issues; the company is non-responsive to requests
for more information; they eschew or
deny or have no follow-up on technical or clinical problems or adverse
events; marketing and promotional
materials are blatant bogosity; the
spokesmen and champions for the company (such as doctors on the lecture circuit)
have no credentials nor credibility, and are patently unknowledgeable about
wounds or the science behind the product. |
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In the never-ending business of staying current and finding the
best solutions for your patients, many acquaintances and associates will be
your network and support team.
Remember, no person can be aware of every new item to hit the shelves,
and even if you could, there is not enough time nor patients to fairly try
everything. You will try some things
and pass relevant information on to others.
Others will be doing the same thing and you will get valuable
information from them. Here are you comrades
and trusted sources: If you are a doctor, other doctors are doing what you are doing,
getting interested in a product, trying it, learning to use it, and passing
on that information. Doctors in your own
practice are a vital and a completely trusted source of information. The nurses in your practice have an intense
hands-on appreciation of what works or not, especially for items related to
basic daily care and patient support.
They will know better than anyone how patients themselves adapt to new
products. They are a key liaison
between you and the other doctors in your practice, reporting on the experiences
you all have with the different products you are all trying. Like any specialty, wound care is a brotherhood, and other
practitioners not in your own practice, around the country and around the
world, are also doing what you and your immediate colleagues are doing. You will hear from them at meetings and symposia,
via journal articles, and other standard means of inter-professional
communication. Dinner meetings are
especially valuable. They are
typically sponsored by a company with something to sell, so the cynics and political
correctionists all have some stupid opinion about that. But the doctors who are presenting are just
like you – they are doctors who care to get good results on behalf of their
patients, and in so doing, got interested in a particular product and learned
to make it work. Dinner meetings are
intimate, informal, and a good place for honest talk and the sharing of
experiences. Here is where you will
learn real details about a product, well in advance of journal articles, and
in greater depth than you can ever get from a podium speech at a
meeting. And always remember, YOU are
in charge of what you learn and take away from these experiences, not THEM. Wound journals and wound societies represent our specialty at
the organization level, and every specialty needs them. The specialty of wounds has developed some
very good high quality meetings and journals, and everyone with a sincere
interest in the subject will find them to be a crucial place for good
information about new knowledge, practices, policies, and products. There is an ever increasing number of wound
meetings, symposia, workshops. These
are somewhere between major society meetings and company-sponsored dinner
meetings in terms of intimacy and attendance.
The wound symposia I have attended in the past 15 years all seem to be
very high quality, in terms of content.
I think this is because this is a young specialty of interested,
enthusiastic like-minded people who want to crack this nut of making wounds
heal. Wound practice is a tough practice
to practice compared to many other specialties. It takes dedicated or whacky people willing
to do this stuff, and workshops and smaller symposia are where you will get
to meet many of them. The practice of chronic wounds is skills, resources, and time
and attention intense. Anyone who has
tried doing it as a matter of pure private practice has found it hard. The concept of dedicated wound clinics has
been amply validated over the past 15 years.
The hospitals and clinics which host these programs are a crucial
component of the whole process. The
administrators who manage these programs are essential, not just for general
operations, but for all provisioning, procurement, processing, purchase and
payment, and practice implementation of new products, devices, materials, and
supplies. The products you do use or will use are all made by
companies. They have executives and
scientists-engineers behind the scenes, and reps on the front line to liaison
with you and your practice. A good
product backed by a good company with good reps is every bit as vital and
valuable a part of your continuing education as the medical schools,
professional societies, and educational media. They help you hear about new products. They help you bring it on line, up-and-running
in real practice. They help you deal
with procurement and payor issues.
They get you connected to other professional users so that you can
hear presumably unbiased experience from colleagues. Granted, we have all experienced bad
products, bad companies, and bad reps.
Even when they are inherently good, competition between me-too
products can be tedious, boring, and embarrassing to deal with, such as being
harassed about just another cephalosporin or just another beta-blocker. Fortunately in wound practice, most of the
meaningful products are not direct competitors, and even nominal competitors
all have a relative place in the big picture and deserve your awareness and
understanding (remember the principles of tandem and sequential therapies). It has been my experience that when
potential problems or unanticipated issues arise, that the company scientists
and even executives take a very direct and cooperative interest in these
events. Remember, that even if you
take a cynical view of the execs and business people, that the
scientist-engineers are professionals like yourself with the same interest in
seeing products created and problems solved.
They are all an inseparable part of good wound practice. When a rep wants to demo a new product, make him prove himself,
the company, and the product. Is there
legitimacy to the concept. Who is the
company behind it? What is the basic
research to validate it? What is the
clinical research to prove it? Can
they answer your questions? . . . at all? . . . with meaningful answers? Can they fix procurement, payor, and
patient use issues for you. Is he a
portal or a barricade to company resources?
Remember, only you can make the ultimate decision about the value of a
product. Good products and reps make
it easy for you to decide, and so too do bad products and reps. But, for newbies, novel products, and early
phase development, it can be harder to decide good from bad, real from
bogus. So, make the reps prove
themselves. If they are weighed and
found wanting, feel free to banish them.
If they prove themselves, if they are legitimate, then make them part
of your professional family. |
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Summary New concepts, technologies, and
products are a fact of life in medicine.
Practitioners will always be obliged to evaluate new items, to be neither
intimidated nor beguiled by them, to
discriminate the good from the bad, the bogus from the real, then decide
which to reject, which to accept, and ultimately which to incorporate into regular practice. Slides 12 – 16 brought an historical
perspective to wound products and technologies. About 120 years ago, when the pictured
woodcut appeared in Scribner’s Magazine, (November, 1890) there were major
conceptual changes in medicine that introduced a century of amazing
progress. However, chinks have
appeared in that system, and while we are now on the verge of an era of great
progress in wounds, there are hangovers from this past century which can
affect that progress. Beginning about
120 years ago, the concept of pharmacological control of wounds evaporated,
while wounds became naively confused with infections. The patent medicine trade was quashed but
not buried, and it is rearing its ugly head again. During a time of profound stress on the
quality of medical education and medical practice, the confusion and
disingenuousness can be easily exploited by those with bogus products. Ultimately, the safety of the patients and
the validity of medicine itself rests with the professionals with degrees and
licenses. Part of professional
expectation and obligation is to make informed good choices about the old and
the new. To maintain
your intellectual independence, professional responsibilities, and moral
righteousness so that you decide what is meritorious rather than being sold
by somebody with something to sell, the following are important: Be learned about wounds. Understand the relative role and value of
each product. Keep an open eye to new
products. Listen to your colleagues. Keep an open mind to trying them. Recognize & reject the bogus. If it seems promising, work with it until
you can make it work. Work with the
company & reps. Share your
experiences. |
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End |
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Abstract (as submitted in advance of the meeting) INTEGRATING NEW PRODUCTS AND TECHNOLOGIES INTO PRACTICE Marc E. Gottlieb, MD, FACS meg99az@cox.net arimedica.com This is a simple conspectus of the
presentation that will be given. The
final presentation will be posted at the website arimedica.com. You can view the presentation and
annotations there. The main concepts presented are: 1
- Medical arts and sciences
evolve, and all practitioners will, in the course of their careers, be
expected to understand new advances in knowledge and the products that support
care of the patient. 2
- There has been an exponential
rise in new medical products and devices, attributable to: the general advance of medical knowledge,
advances in micro-level biological science, advances in materials and
electronic technologies, advances in computer and information technologies,
career track bioengineering and biotechnology, and changes in business
finance and investment. 3
- The deluge of new products is
muddled by a relaxation of standards and principles: formal medical education has been inept in
training new professionals to understand and critically evaluate new
technologies; business has become
business for its own sake (and the money), with disregard for science,
ethics, customers, patients, and prescribers;
regulatory oversight has become overly politicized, arbitrary,
bureaucratic, and inexpert. This has
led to the attrition of the principled "ethical drug industry" of
the 20th century, and the resurrection of the no-claim-is-too-stupid-nefarious-or-disingenuous-to-be-promulgated
"patent medicine era". 4
- While this sounds like an
overly cynical diatribe, it does reflect one facet of the current medical
landscape. Fortunately, the good side
prevails as well, giving us a dizzying array of new tools that can safely
treat and cure heretofore incurable problems. 5
- How does the practitioner
evaluate new products, decide which ones to trial, recognize the good and the
bad, then integrate the good therapies into daily practice? 6
- Practitioners must evaluate
new product claims based on: Does it
fulfill a need? Would it solve
problems in my patients, because current therapies are not good enough? Is there valid science behind it, does it
fit in with what is known and understood?
Has it been adequately tested for safety? . . . for efficacy? Who is the company, and who is behind the
product? . . . are they reputable or
credible? Have satisfactory clinical
or other real world trials and evaluations been made? Who represents the company, how well, and
can they answer your questions? Are
the marketing materials meaningful?
Who is their target market? Are
you dealing with real reps or with pitchmen?
Are they trying to dazzle you with legitimate brilliance, or are they
trying to muddle with manure? 7
- Among all the chaff of
endless new products are some nutritious grains that will fundamentally
change they way you and we all do things, so all practitioners are obliged to
keep an eye open for them. 8
- Depending on your knowledge
and interest in a particular subject, your experience and intimacy with that
subject in daily practice, and your temperament, you might be on the leading
edge of using a new product, or you might wait until others have established
the place for that product. 9
- Either way, the ultimate
utility and usage of new products is established by the broad base of
practitioners and prescribers working with their sick patients, and not by
the inventor, the company, the market, nor the FDA. 10
- All practitioners have a
moral and professional obligation to evaluate new products, decide which ones
to reject, which ones seem promising, which ones to trial, which ones to keep
an eye on as others trial them. One
must further be ready to reject those which do not work, adopt those which
are confirmed to work, and, for the adventurous and curious, be on the front
lines of figuring out how-to-make-it-work for novel products that tweak your
interest. 11
- These principles will be
illustrated through case examples of patients whose successful treatment was
significantly enhanced by the use of new products, and then by case examples
of novel therapies and companies that have come to market with good and bad
products. 12
- The talk will conclude with a
discussion of where to get information from, and how to stay abreast of
contemporary developments and new products. |
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INTEGRATING NEW
PRODUCTS AND
TECHNOLOGIES INTO PRACTICE Original presentation September, 2009, at the 4th Annual Wound Symposium of Baptist Health The presentation and related materials can be viewed and used
at: arimedica.com Content may be used for non-commercial educational purposes. Content may not be published or used for commercial purposes
without prior license or permission. Contact information is on the slide. Copyright © 2009, Marc E. Gottlieb, MD |
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