From  Steve Dubansky, MD, SVP, Medical Director, Palio

Below you’ll find a thought-provoking and informative editorial from the March 30 issue of the New England Journal of Medicine. The author is Professor of Medicine at Harvard Medical School and Chief of the Division of Pharmacoepidemiology and Pharmacoeconomics. He asks, but only begins to answer, the fundamental question above. Below are 2 quotes from the piece that should intrigue you enough to want to read on. At the editorial’s conclusion, you’ll find a hyperlink to a 1-minute-and-20-second excerpt from Dr. Avorn’s lecture on this topic at Harvard Business School.

“The evidence base available to clinicians to guide their therapeutic choices is still heavily shaped by industry-sponsored studies that often compare new products with placebo, measure their worth in terms of surrogate markers such as laboratory test results, or both.”

“They [package inserts] live on as tangled obfuscations filled with minimally usable data and liability-averting warnings.”

Perspective

Teaching Clinicians about Drugs — 50 Years Later, Whose Job Is It?

NEJM | March 30, 2011 | Topics: Drugs, Devices, and the FDA

Jerry Avorn, M.D.

This year marks the 50th anniversary of the Kefauver hearings, the pivotal 1961 Senate debate that transformed prescription drug approval and use. When Senator Estes Kefauver (D-TN) introduced legislation to regulate the drug industry, the Food and Drug Administration (FDA) still did not have legal authority to require pharmaceutical companies to demonstrate that their products actually worked. What physicians knew about prescription drugs was shaped predominantly by the claims their manufacturers made about them, and the evidence base underlying such claims was often rudimentary, or worse.

Closely related to the thinness of the science was the question of how information about a drug’s benefits and risks should be evaluated and communicated to physicians — and by whom. Then as now, pharmaceutical companies mounted aggressive promotional campaigns for their products. An unsigned 1961 Journal editorial titled “Ethical Drugs — Who Shall Educate the Physician?” noted with concern that “manufacturers spend about four times as much on the promotion of drugs as the total cost of running all the medical schools.” As a result, the editorial continued, “the majority of physicians get their first and often their only information about newly available drugs from these sources, which at best may be strongly prejudiced and at their worst are unreliable and misleading.”¹ No mechanism existed for robust, arm’s-length governmental determination of a drug’s efficacy and for the dissemination of such data — a solution that many clinicians did not favor in any case. As a result, practitioners were often left with little disinterested guidance about the usefulness or safety of new medications in comparison with their alternatives.

Among other things, the Kefauver legislation sought to have the federal government provide a more even-handed, public source of drug education for physicians: a leaflet that would accompany every prescription medication describing “all the information about the activity, uses, and untoward effects of the drug”; a compendium of such information for all products “in convenient and readable form” to be distributed widely; and an annual list of medications with high potential for serious side effects.

The American Medical Association (AMA), skeptical about any public-sector role in health care, argued that this was not a proper activity for government and that such communication should be the responsibility of the profession itself, along with industry. The AMA had been attempting to fill this function through its Council on Drugs, a group of researchers and clinicians that evaluated new medications and issued a “Seal of Acceptance” to those meeting its standards. Only drugs thus accepted could be advertised in the AMA’s journals.² However, NEJM‘s editorialist lamented in 1961 that the AMA had largely dismantled these programs, a decision that led to “encouraging the introduction of relatively inferior drugs . . . [and] the deterioration in the quality of advertising and promoting such drugs. These changes have done little to help but may have done much to confuse the physician in his efforts to practice good medicine.” The Journal noted that this failure undercut the AMA position that a governmental program was not needed.

The pharmaceutical industry and the AMA attacked Kefauver’s bill, and the idea that the government should play a central role in evaluating medications for efficacy and disseminating information about them seemed headed to legislative defeat. Then came the thalidomide disaster. That drug was being heavily promoted in Europe as a sedative and antinauseant, particularly for use during pregnancy, but a more cautious FDA approach had spared Americans the epidemic of fetal limb-reduction defects that plagued countries with more permissive drug regulatory systems. Empowered by this crisis, the Kefauver hearings resulted in a new law that gave the FDA the authority to require evidence of efficacy and safety before a drug could be marketed.³ The debates about disseminating drug information eventually led to the now-familiar “package inserts” that fit the law’s requirement for completeness, even if they have still not lived up to its larger goals of usability and readability.

Half a century later, the editorial’s question, “Who shall educate the physician?” is still hotly contested. Opposition to a role for government did not carry the day then but has dominated debate ever since; the letter of Kefauver’s legislation about drug information has been followed in one narrow sense, though its spirit has not fared as well. The evidence base available to clinicians to guide their therapeutic choices is still heavily shaped by industry-sponsored studies that often compare new products with placebo, measure their worth in terms of surrogate markers such as laboratory test results, or both.

The recent comparative effectiveness movement holds great promise for improving this evidence base, if it survives politically. Package inserts have been legally mandated, but until recently their content was determined primarily by the manufacturer, not the FDA. They live on as tangled obfuscations filled with minimally usable data and liability-averting warnings. Proposals for improving them are floated periodically, and 2007 legislation may give the agency more power to address this problem. But for the most part, the 1961 vision of an unbiased, user-friendly, practical summary of benefits and risks produced by the government for each prescription drug has not come to pass.

On the education front, recent reforms have only partially addressed concerns about the undue influence of drug companies on what physicians know (or think we know) about medications, mediated through aggressive promotion, less visible and more indirect public relations campaigns, and a manufacturer-dominated continuing medical education industry. The 1961 editorial’s reference to “ethical drugs” — an old term for prescription medications — seems oddly archaic in a time of scandals about deceptive marketing practices and heavily advertised, costly medications that turn out to have major unreported risks.

One positive response to the editorial’s question has been the outreach activities that have evolved to disseminate noncommercial drug information to clinicians. The Agency for Healthcare Research and Quality (AHRQ) has long tried to provide a public-sector source of evidence-based information on drugs and other interventions. It initially did its job so effectively that in the mid-1990s it was nearly defunded after pressure was exerted by advocates for treatments that were more lucrative than effective.⁴ A chastened AHRQ has remained engaged in this area but is reluctant to issue therapeutic guidelines that could again threaten its existence.

As the United States turns away from 1960s-era belief about government’s role in protecting the public health, and as concern grows about industry’s influence on federal policy positions, the answer to who shall educate the physician is increasingly unlikely to be “Uncle Sam.” Instead, an emerging answer may be public–nonprofit collaborations for which the government provides funding but profession-based nongovernmental entities with no ties to industry generate the scientific content. One illustration is the growth of support for “academic detailing” — educational outreach programs in which independent researchers and clinicians systematically review data for a given therapeutic area and develop noncommercial, evidence-based recommendations about treatment choices. Pharmacists, nurses, and physicians are then sent to visit practitioners in their offices to present these findings, drawing on the successful marketing strategies of industry but without its sales-oriented spin.⁵ Several states, insurers, and federal programs currently fund academic detailing programs based on content developed by nonprofit organizations free of industry ties. As concerns grow about the safety, complexity, and affordability of our expanding pharmacopoeia, demand for these programs increases.

Fifty years after the Journal grappled with these issues, they are even more relevant, and the need to provide reliable drug information to physicians is even more pressing. Enlightened by our tumultuous experience with medications and drug communications over the past half-century, we are still working on a sustainable answer to this question that lies at the heart of medical practice.

Source Information

From Harvard Medical School and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital — both in Boston.

References

1. Ethical drugs — who shall educate the physician? N Engl J Med 1961;265:910-912

2. Greene JA, Podolsky SH. Keeping modern in medicine: pharmaceutical promotion and physician education in postwar America. Bull Hist Med 2009;83:331-377

3. Carpenter D. Reputation and power: organizational image and pharmaceutical regulation at the FDA. Princeton, NJ: Princeton University Press, 2010.

4. Gray BH, Gusmano MK, Collins SR. AHCPR and the changing politics of health services research. Health Aff (Millwood)2003;W3-283-W3-307

5. Avorn J. Devising an antidote. In: Avorn J. Powerful medicines: the benefits, risks, and costs of prescription drugs. New York: Alfred A. Knopf, 2005:313-38.

http://www.youtube.com/watch?v=uONt4kumkIk

Palio is a full-spectrum global pharmaceutical and consumer advertising, marketing, and communications agency that excels in brand creation and specializes in brand strategy, product launches, global marketing, and digital and integrated media.

From Mark McCoy, Senior Vice President, Brand Planning Director, Palio

Published references and full prescribing information are the foundation upon which promotional claims for medical advertising are built. A medical writer can put his hand on his heart and state that his ad copy is “the truth well told” when that copy is backed up by a reference in a reputable medical journal. Drug marketers and advertising types can sleep well at night in the knowledge that, despite unflattering news stories about drug advertising, they can always pass the red-face test and defend their promotional claims as true facts backed up by data from peer-reviewed publications.

Or maybe not—

Scientific fraud finds its way into the world’s most trusted medical journals more often than one might think. A few notable examples are:

Science Magazine 2005: Hwang Wook-suk from Korea claimed that his lab cloned embryonic stem cells and tailored them to specific patients. This breakthrough would open the way to using embryonic stem cells to cure Alzheimer’s disease and autism.  Unfortunately it was later revealed that Dr. Hwang’s team fabricated their data and the paper was retracted in January 2006.

[In December 2005, Science posted an erratum regarding Table 2 in Hwang’s paper.  Why go to the trouble of correcting an error when all the data is made up in the first place?]

Anesthesia and Analgesia 2009: German anesthesiologist Joachim Boldt reported that HES (hydroxyethyl starch) was superior to albumin in patients undergoing CPB (cardiopulmonary bypass). Boldt stated that with HES, there was less inflammation, less endothelial damage and better coagulation than with albumin. Readers of the journal questioned that data because it seemed unbelievable. An investigation by German authorities found that the results were fabricated and that Dr. Boldt might not have even conducted the clinical trial at all.  Dr. Boldt has over 200 publications to his name. Was this latest paper a one-time failure of Boldt’s moral compass, or is he the most prolific writer of fiction since Sir Arthur Conan Doyle?

The Lancet 1998: Andrew Wakefield’s study linked the MMR (measles mumps and rubella) vaccine with the development of autism and inflammatory bowel disease. In 2004, 10 of the 13 authors of the Lancet paper signed a retraction that was published in BJM. The Lancet formally retracted the Wakefield study in early 2010.  Critics of the Wakefield paper have reported that the numbers reported in the published paper did not match the medical records of the patients involved.

NEJM 1985 and 1989: Dr. Roger Poisson, a Canadian surgeon was involved in 4 breast cancer studies published in the NEJM in 1985 and 1989. In 1990, a statistician for the National Surgical Adjuvant Breast and Bowel Project (NSABP) examined some of the data provided by Dr. Poisson and suspected that something fishy was going on.  It seemed that Dr. Poisson falsified his data and he accounted for almost 19% of the patients in 1 of the studies. He failed to report the correct dates for biopsies, surgeries and pathology reports and he enrolled patients that didn’t meet the inclusion/exclusion criteria for the studies.  His staff continued to create progress notes for a study patient after the patient had died. The trial results had to be reanalyzed after excluding Dr. Poisson’s data.

These examples of medical fraud are all from prestigious medical journals; the type that are seen as “leading the way” and driving professional practice. Marketers and advertising people have to assume that information printed in these journals is trustworthy until proven otherwise. However – don’t be too shocked the next time Dr. Alec Lentz proclaims that Devlin McGregor’s Provasic is a wonder drug with no side effects and later it comes to light that he tampered with the liver biopsy slides from the pathology lab.

Palio is a full-spectrum global pharmaceutical and consumer advertising, marketing, and communications agency that excels in brand creation and specializes in brand strategy, product launches, global marketing, and digital and integrated media.

From Mark McCoy, SVP, Brand Planning Director, Palio

Drug shortages are becoming much more common recently. Almost half of the drug shortages involve generic injectable drugs.

A recent NEJM article explains how shortages of generic injectable drugs come about in Economics 101 terms.

1.    The patent expires on an expensive injectable drug.

2.    Lots of companies introduce generic versions of the drug.

3.    The price of the injectable drug is driven down.

4.    Due to the low price, some generic makers exit the market.

5.    Remaining manufacturers maximize their efficiency and practice “just in time” inventory management.

6.    Any glitch in the system, such as a rejected batch, raw material shortage or drug recall can lead to shortages.

7.    The small number of manufacturers are not able to meet the demand for the drug.

In a free market, when the drug shortage occurs, the price of the drug that is in short supply will go up. Customers will have to pay more for a short while. Then other manufacturers will recognize the opportuntity and enter the market and meet the demand. In a short time, prices will begin to go down again due to increased competition. The invisible hand corrects the shortage and prices are normalized just as  Adam Smith predicted.

Sadly, the injectable drug market is not  a free market. Prices are not allowed to fluctuate with demand.  Medicaid sets prices at Maximum Allowable Cost (MAC) or Least Cost Alternative (LCA). Health care providers can’t pay more than the MAC or LCA price for a drug, because if they do pay more, providers know that they will lose money on that drug. The result is that prices do not go up. New manufacturers do not enter the market. Customer demand for the the drug that is in short supply is not met and the shortage persists.

A solution to the drug shortage is to have Medicaid do away with tying reimbursement to MAC and LCA prices and reimburse health care providers according to a drug’s market price. This change would put the invisble hand back into the game and drug shortages would be rapidly resolved.

Palio is a full-spectrum global pharmaceutical and consumer advertising, marketing, and communications agency that excels in brand creation and specializes in brand strategy, product launches, global marketing, and digital and integrated media.