Fda Tortoise Hare Or Something Else

Thinking about Life Sciences: FDA: Tortoise, Hare or Something Else Pri...

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Thinking about Life Sciences http://blog.aesisgroup.com Tuesday, June 12, 2007 FDA: Tortoise, Hare or Something Else

Last year this column highlighted the debate around drug and device safety. At that time, I expected that the controversy would continue to grow. Indeed, the Avandia issue splashed across the headlines just this past month. One consequence was the congressional hearings last week lambasting the Food & Drug Administration (FDA) and its Commissioner Dr. Andrew von Eschenbach for what Rep. Henry Waxman (chairman of the Committee on Oversight and Government Reform) called “a major failure of our system.” It is human nature to blame individuals rather than the system. CNN reported Rep. Waxman’s exchange with the Commissioner as a “tongue-lashing.” However, when there are failures in succession such as we saw with Vioxx and now with Avandia, it may be evidence of what the statisticians call a systematic error. In seeking the source for such problems, the system itself deserves a closer look. The Avandia Controversy Avandia is a drug that controls blood-sugar levels in noninsulin dependent diabetic patients. For its manufacturer (GlaxoSmithKline) it is a blockbuster drug with sales exceeding $3 billion in 2006. The current debate was ignited by a May 21st New England Journal of Medicine article in which Dr. Steven Nissen of the Cleveland Clinic published a metaanalysis study reporting that Avandia (also known as rosiglitazone) increased heart attack risk by 43 percent. At the June 6th congressional hearing, Rep. Waxman stated that “The FDA never required the manufacturer to [conduct] a thorough post-market study of Avandia’s heart risks,” noting that the FDA requires such safety studies after they are approved. Safety: Takes a Back Seat As pointed out in previous postings, safety has always been a primary concern. Ironically, however, as modern medicine began to deliver an ever increasing supply of “medical miracles” during the last century, the increasing numbers of lives saved encouraged even bolder approaches to therapy. For example, radical surgery such as organ transplants were not only imagined but became routine. Ever more powerful drugs—even those such as many cancer chemotherapeutics that previously were weapons for chemical warfare—became standard pharmacopeia. Emboldened by these successes and to some extent encouraged by the system, the health care industry put safety second to bringing new therapies to market. However, my previous columns (in May 2006 and later in August 2006) pointed out how safety has become increasingly important for patients and society more generally. Some of the reasons for this apparent shift include: Greater efficacy of medicine. As treatments become more effective, the “blemishes” become more evident. In technical terms, the risk-benefit profile gets shifted towards a higher awareness of risk (e.g. safety). Baby boomer culture. This is a major population force as this group characteristically holds high expectations and little tolerance for failure. Chronic diseases. When people take drugs or use devices for extended periods of time, what might have been a mere side effect can metamorphose into a significant safety risk.

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Preventative medicine. Likewise in using drugs or devices for preventative purposes, safety becomes that much more important. It’s hard to justify a safety risk in the context of a condition with no symptoms. Quality-of-Life Treatments Drugs and devices that provide quality-of-life benefits rather than being explicitly life-saving are necessarily held to a much higher standard of safety. As the Avandia story reached the front pages, a number of related side stories also appeared. One recent report in the New York Times described the travails of University of North Carolina researcher Dr. John Buse. He testified at the Avandia hearing about being threatened by top GlaxoSmithKline officials and being called a “liar” and “scoundrel” after he had criticized the drug at a medical conference. Another New York Times report highlighted — citing the specific example of Dr. Rosemary Johann-Liang (a former deputy division director at FDA) — how “an increasing number of [the agency’s] drug-safety officers have been punished or ignored after uncovering dangers of popular medicines.” While society may be putting a premium on safety, this message has only incompletely reached government and industry. Those who are serious about safety apparently suffer more than just a lack of scientific glamour but also potentially risk their careers and reputation. Efficacy is King: What that implies Anyone from Wall Street to Main Street who follows drug stocks knows that FDA approval has the power to move billions of dollars. FDA approval is a huge event—not only for fledgling startups but also for the largest of pharmaceutical or device companies. Indeed, the ImClone case (e.g. Martha Stewart and Sam Waksal) brought the ordinarily secretive process of FDA approval out into public consciousness; as many know, both Stewart and Waksal went to jail for insider trading related transgressions. Drug approval is serious business. At present, the gold standard for drug approval is demonstrated efficacy — namely that the drug works. Safety is also a part of the process and ordinarily there are fairly extensive preclinical and animal studies designed to ferret out unsafe drugs. Most of these studies are fairly routine safety tests that simply set the backdrop to the “real” clinical trials that are of large enough size or are of clever enough design to optimize reaching the primary efficacy endpoint. “We have demonstrated the efficacy endpoint” is music to the ears of pharmaceutical executives because achieving that, more than anything else, is what it takes to gain FDA approval. After that, postmarketing safety studies take place, which, as in the case of Avandia, may or may not be to everyone’s satisfaction. We live in a world of limited resources. Given the high stakes involved (billions of dollars), this means that the best minds, the most money, and the most effort is expended in an all-out effort to achieve the efficacy endpoint. When efficacy is a priority other concerns , such as safety, are downgraded. By no means am I implying that anything necessarily fraudulent or criminal is going on. Rather, this is a natural consequence of system bias (one which some senior FDA officials have confirmed to me in private discussions). What is especially troubling (other than the intrinsic bias, of course) is when scientists and officials who do take up safety concerns suffer harsh critique. Ironically, they suffer double jeopardy because the business of safety studies is not known as a fast track to career success. The primacy of efficacy over safety: How did we get there? The primacy of efficacy over safety seems to be so deeply integral to the system that it might be helpful to realize that this has not always been the case. For much of its history, the FDA’s primary mandate was to protect the public’s safety. The original 1906 Food and Drugs Act, which created the FDA, prohibited the interstate transport of food and drugs that had been “adulterated,” formulated with additives “injurious to health,” or otherwise “misbranded.” The Chinese toothpaste problem, for example, would have been priority No. 1 for an FDA of 1906. In a decisive change for the agency, the 1962 Kefauver-Harris Amendment radically transformed FDA. This legislation mandated that all new drug applications had to demonstrate “substantial evidence” of the drug’s efficacy on top of the existing requirement for safety studies. Times were simpler back in 1962.

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Academic medicine was in its heyday and new, efficacious drugs seemed to drop from the heavens. The population was considerably younger as the baby boomers were mostly in their teens. Chronic diseases were much less common as many conditions such as cancer were effectively death sentences. “Living with Cancer” is largely a phrase of our present time. Of course, nobody at that time would have desired unsafe medicines. The thalidomide tragedy was, in fact, what sparked the 1962 legislation. However, 2007 is a very different time from 1962. Since then, it has since become enormously costly (both in terms of money and time) to generate the “substantial evidence” of drug efficacy. Drug development now takes much longer. And in shifting priority from safety to efficacy, the Kefauver-Harris amendment has had the unintended consequence of slowing down drug approvals in the present era. FDA: Tortoise or Hare? The New York Times article “Potentially Incompatible Goals at FDA” said that “Patients want immediate access to breakthrough medicines but also want to believe the drugs are safe … These goals can be incompatible.” While incompatibility shouldn’t necessarily be a foregone conclusion, the article does highlight an extraordinary tension that may radically reshape FDA over the coming years. Should the FDA be a tortoise and take more time in approving drugs or should it be a hare and allow drugs to hop quickly to market? Baby-boomers, who are used to getting what they want, desire both. The key to achieving both speed and safety will be to restore FDA’s primary emphasis on safety and allow the market (which is not just the commercial market but also the medical, academic, and scientific communities as well) to work out the efficacy of drugs. While some may call this heresy, in reality such a situation already exists in at least three forms. 1.

Regulatory approval in Europe by the European Medicines Agency (EMEA) is less dependent on demonstrating efficacy than FDA. The main concern is safety and that is one reason why Europeans receive breakthrough drugs and devices earlier than Americans.

2.

Off-label use in the United States has created a situation in which drugs and devices ostensibly deemed safe and approved for a single indication can, indeed, be used without approval for other uses.

3.

FDA monitors the vitamin and nutraceutical markets for safety only, and does not allow efficacy claims.

Interestingly, the off-label use loophole raises particular dangers because the safety and efficacy studies used in obtaining initial approval are generally pertinent only to very defined and limited indications. Indeed, as efficacy endpoints become even more of a challenge to achieve, limiting the scope of primary indications becomes increasingly necessary. Thus, safety information obtained as part of an application may not be relevant for unregulated off-label uses. It is also important to recognize another important trend, that of personalized medicine, that further complicates efficacy determinations. As personalized medicine becomes more prevalent, designing and implementing large double-blind, randomized clinical trials becomes increasingly difficult, as well as moot. And lastly, with the increasingly rapid pace of technology advancement, results from large and lengthy efficacy trial may be obsolete by the time their results are available. In short, the efficacy standard, while it has laudably served us well during simpler times, may very well be getting the way of bringing drugs safely and quickly to patients. Speeding Drugs and Devices (Safely) to Market In a CNBC special on June 4th, the question was asked “Should the FDA be speeding cancer drugs to market?” The President of FasterCures – an organization founded by Mike Milken and funded by the Gates Foundation and the Sumner Redstone Foundation – gave a rather unimaginative answer – “YES -if they work, NO – if they don’t!” In terms of bringing more drugs to market, we should realize that the true rate-limiting step is more likely to be the innovation gap highlighted in my previous Memorial Day column. While the protracted drug

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approval process is indeed a problem, there’s a plethora of innovative potential therapies being held up at earlier stages in the product development process. Indeed, the simplistic exhortation to place more drugs on fast-track status is less likely to be a construed as a desire for faster cures than a plea by proxy from drug companies for laxer regulation. The latter is certainly against the tide of public opinion in light of the recent controversies. FDA Reform: A Proposal The FDA doesn’t need to choose between being a tortoise or a hare. Rather, the agency should redefine itself outside of the terms that device companies want and end users think they need.. The proposal would be that FDA refocus its primary mission to ensure drug and device safety (both in development as well as formulation and manufacturing). To do so, FDA must make safety the primary endpoint for approval. Once safety is central to the approval process (and therefore receives billions in market capitalization) the best and the brightest will be set to this task which would also be more detailed and comprehensive in its scope, rather than the relatively routine tests currently conducted. Safety shouldn’t be just a matter of going through a check-list but should also inspire the same ingenuity has been applied to achieving efficacy endpoints. Efficacy would be determined in the market as it is in the European, off-label, and vitamin world. Some may argue that we need a strong, efficacy-driven FDA. But remember that in 1962, communication among and between clinicians, scientists, and the broader market was much less open and transparent than it is now in today’s Google and YouTube era. It is unlikely that blatantly ineffective treatments will gain significant traction in such a market especially because academic peer review and market-driven judgments can be more efficiently transmitted to all providers. Truth-in-advertising laws would need to be upheld (and indeed enforced aggressively) and just as with off-label use, manufacturers would be prohibited from making any specific efficacy claims. When it comes to accelerating new drugs to market and filling up the pipeline with new compounds, we should focus less on the last steps of the pipeline (speeding up FDA approval) and more on the beginning of the pipeline, which suffers now from an innovation gap. Bridging the innovation gap will require encouraging government and private institutions to further accelerate the transition of university-level science to the initial stages of clinical and commercial development. Obviously, all these ideas require much more space to develop so I’ll leave further details to later. For now, the take-home message is that while we need a strong FDA even more than ever, we need one that’s different from what it is today. Ogan Gurel, MD MPhil [email protected] http://blog.aesisgroup.com/ Drug safety clinical trials Avandia FDA reform health policy diabetes Aesis Research Group Ogan Gurel MD

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