Primary C|are Corner with Geoffrey Modest MD: Postmarketing adverse effects of drugs

by Dr Geoffrey Modest

A recent article in JAMA, which made it into the popular press (see​ ), assessed post-market safety events of new drugs approved by the FDA between 2001 and 2010, finding a large number of serious adverse events after the drugs were approved and on the market (Downing NS. JAMA 2017; 317(18): 1854)


— all new drugs and biologics approved by the FDA between 2001 and the end of 2010 were assessed, excluding diagnostic agents, sunscreens, and drugs not intended for use in the United States, with follow-up through February 28, 2017. They did not include labeling changes and dosage form discontinuations.

— 222 novel therapeutics were approved, 183 pharmaceuticals and 39 biologics.

— 47 (21.2%) were for cancer treatment and hematology

— 37 (16.7%) for infectious diseases

— 26 (11.7%) for cardiovascular disease diabetes and hyperlipidemia

— 77 (34.7%) of these drugs received priority reviews and 28 (12.6%) received accelerated approval

— 62 (27.9%) were designated as orphan products

— median total FDA review time was 311 days, but was less than 200 days for 54 novel therapeutics, and greater than 400 days for 34.2%. 52 (23.6%) were within 60 days of their regulatory deadline approval dates.


— 123 new post-market safety events occurred, including 61 boxed warnings, during a median follow-up of 11.7 years, and affecting 71 of these new drugs (32% of all new meds).

— Three medications (valdecoxib, tegaserod, efalizumab) were withdrawn from the market

— median time from approval to first post-market safety event was 4.2 years

— post-market safety events were significantly more frequent among biologics vs meds, incidence rate ratio (IRR) 1.93 (1.06-3.52, 0.032), p=0.03.

— Within the therapeutics, those for psychiatric diseases had the highest IRR of 3.78 (1.77-8.06), p<0.001. Drugs for the treatment of cancer and hematologic disease had the fewest post-market safety events, with safety events at 10 years being reported in 60.0% for the psychiatric drugs and 21.4% for the cancer/hematologic ones

those medications receiving accelerated approval had IRR= 2.20 (1.15-4.21), p=0.02, as well as those approved within 60 days of their statutory decision deadline with IRR= 1.90 (1.19 -3.05), p=0.008

— no difference in post-market safety events among those drugs which were first-in-class versus the look-alikes


— as a baseline during this period, the FDA assessment of safety of novel therapeutics seems tilted toward approval: the majority of key (“pivotal”) trials, which served as the basis of FDA approval, enrolled fewer than 1000 patients and had follow-up of only six months or less; and approval seemed to happen more often just before the deadline for that decision

— one issue that is not commented on, at least that I have seen, is that several pivotal studies are terminated early, prior to their expected date, because of evident benefit. Sometimes this benefit is highly statistically significant, though the absolute benefit is not so great. And, by stopping the studies earlier than anticipated, there’s even less time for adverse events to manifest themselves.

— The above article highlights the problems with relying on postmarketing drug surveillance (which obviously needs to continue), finding that 32% of medications had postmarket safety events, and half of these were boxed warnings (ie, were considered severe). An even bigger issue is the poor compliance of drug companies and medical device companies to do and report postmarketing findings, despite these being specific FDA conditions for their approval. A blog on FDA-approved medical devices found that <20% of FDA-required post-marketing studies were actually done. A JAMA letter confirmed similar numbers for drugs (see Fain K. JAMA 2013; 310 (2): 202)

— BUT, the biggest concern now is that it seems that the FDA is poised for major changes which would lead to even more accelerated drug approval overall (the above study found that accelerated approval was itself associated with a higher incidence of postmarketing adverse events). Of the many many issues concerning the current Trump administration, I would like to highlight two:

— Trump  is fundamentally anti-scientific and anecdotal in his approach. This is concretely manifested by his ready denial of climate change and replacing 5-9 scientists on the EPA board with representatives of industry, since they “understand the restrictive nature of regulations”, and is planning a 40% reduction in funding for the scientific component of the EPA. He thereby shuts himself off from the potential to analyze policy from a scientific instead of a political or “gut” viewpoint. (see  for example).  In addition, his impetus to change the FDA, such that it leads to more rapid approval of medications, is grounded in an anecdotal example of a young girl with Pompe disease, a rare inherited disorder (which is even stranger since her father was in a position to found a company to develop enzyme replacement therapy). This rather extreme anecdote seems to him to justify really quick approval of drugs by the FDA, with less rigorous scientific evidence, and with the potential for real harm to lots of people.

— Trump just recently approved Scott Gottlieb as head of the FDA, with a commitment to get new drugs to the market sooner. Gottlieb is an advisor to several large pharmaceutical companies: “an unprecedented web of Big Pharma ties. He has spent most of his career dedicated to promoting the financial interests of the pharmaceutical industry”, per Dr. Michael Carome director of the Public Citizen’s Health Research Group ( ); the article also pointed out that “Gottlieb would be tasked by Trump with eliminating some of the regulatory burdens at the FDA”, getting new drugs to the market sooner.


So, I think that this postmarketing JAMA study and others suggest that the FDA may already be approving some drugs too quickly (and faster than their European counterpart), and this approval process is already slanted towards the drug companies (the studies are usually designed by the drug companies to get the outcomes they want through their own analyses of the results (see prior blogs, including a blog on empaglifozin and one on ezetimibe as cases in point ). And the current Trump administration changes are likely to make things a whole lot worse.  Even if there is a significant class action lawsuit and settlement against the drug company because of a severe adverse event found after FDA approval, even large settlement sums pale in comparison to the drug company profits from those drugs (at least in the cases I’ve seen).


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