After just presenting at a series of lectures for the drug safety (pharmacovigilance) side of the industry over the last few months, an alarming quasi-trend (anecdotally) seems to have arisen within the ranks of Drug Safety employees in various companies: Buying into the hype of small statistical sample sizes.

This seems to be due in large part to Wall Street’s (and Main Street’s) inability to properly appraise small sample size data of drug trials. Numerous are the cases of ineffective drugs showing a false signal of efficacy, eliciting the hype engine of Wall Street investors, driving share prices, revenue, and news cycles.

Almost equally represented, unsurprisingly, are the many cases of potentially promising drug candidates whose small clinical trial populations seem to be showing benefit on therapy relative to placebo, but the market reaction is resoundingly negative (or prosaic). This is an unfortunate side effect of media’s lack of data and evidence being able to roundly crush relatively solid science and sway market perceptions. Probably at the root of it: A fundamental lack of understanding of calculus, statistics, probability theory—both Classical and Bayesian—and basic biology. But don’t underestimate the ability of naïve sub-optimal decision-making being able to undermine an objectively successful drug treatment.  Here are a couple examples where data and behavior don’t seem to match in healthcare:

An effective, but underutilized treatment: Cardiac rehabilitation
For heart patients, cardiac rehabilitation is one of the most effective interventions in medicine. Cardiac rehabilitation is a particular set of exercises, typically three times a week, which includes 10-15 minutes of warm-up and stretching, 30-50 minutes of continuous aerobic activity, and 15-20 minutes of cool-down. Cleveland Clinic has done considerable research in this area, and Leslie Cho, MD, Director of Cleveland Clinic Women’s Cardiovascular Center stated that “If we had a medicine that could make this dramatic an impact, it would be the blockbuster drug of the century.”¹ Unfortunately, only 10 to 20 percent of patients who are candidates for cardiac rehabilitation participate.

A potentially over-optimistic approval: Muscular dystrophy
Or of Sarepta’s eteplirsen drug product for Duchenne muscular dystrophy, which was embroiled in controversy within FDA for its approval, for which many members internally sought to reject its approval initially.² Notably, Ellis Unger, MD, an internal expert at FDA, disagreed with the drug’s approval based on the available data.

What are some of the latest mis-readings of the tea leaves?
Among the latest in the non-evidence-based drug safety witchhunts: A ‘surge’ in Adverse Event (AE) reports for Regeneron’s Eylea drug product. And by ‘surge’ of course, the reports are referring to 71 potential cases out of 2.2 million vials sold—a 120% increase in units sold since 2014, when about 25 potential cases of AE were reported. This is less than 1 event per 10,000 patients receiving the drug, which is lower than the rate the company documented during the clinical trials. Score another one for good clinical trial data collection.
In Real World Evidence (RWE), continuous monitoring is a helpful practice, but reports of values of AEs that are no different from the clinical findings are not helpful for the media to glom onto, nor the public to crow about. They are in fact only counterproductive to good science and the provision of good healthcare therapies to the public.

Healthcare alarmism drives the public to seek either ‘no treatment,’ as in cases of anti-vaxxers and other treatment-resistant groups, or worse, ‘internet discussion group treatment,’ as in the case with Facebook groups and other social media hogwash, where anecdotes abound, good science need not apply, and the only threshold for good ‘evidence’ is someone’s individual post reporting how their life was transformed by following some sham ‘protocol’ for the last 3 months, where everyone else chimes in with emojis of high-fives. This is the fundamental basis for the psychology of incentivized behavior.

Drug safety signals in Europe: A public in crisis or nocebo effects?
At the moment in France, a similar behavioral trend is occurring. The thyroid drug replacement Levothyrox has recently been at the center of one of the most significant nocebo effect hype-cycles of recent history and perhaps, ever. At odds, the public full of speculation, suspicion, and a dearth of data. The other actor in this public health scenario is Merck. They changed the excipient in their Levothyrox drug product due to France’s National Agency for Medicines and Health Products Safety (ANSM) request for the change to increase shelf life and stability. Merck indeed conducted bioequivalence studies to demonstrate that the replacement drug therapy is no different from the prior version—bioequivalence results meet 95-105% pharmacokinetic specification over the shelf life of the drug.3 Nonetheless, the public has amassed more than 300,000 signatures—there are about 3 million patients on Levothyrox in France alone—of people who demand a return to the old formulation because they’re not feeling the same on the updated treatment.

Now, it was only about 6 years ago that I had helped identify drug safety signals within a generic version of Wellbutrin (budeprion), which, in certain doses, had a very strange signal of adverse events and lack of performance. Because of this, the FDA acted to have the manufacturer halt distribution and production of that particular drug in that dosage until specific cause for the difference in in vivo performance could be identified. The reason I mention this is crucially because an assumption of equivalence between generics and the branded version, or biosimilars and their progenitors, is specious at best.

In fact, the history of the thyroid replacement medication market even includes a couple-decades-old punctuation where Synthroid—another synthetic thyroid drug therapy, hence the portmanteau of ‘synth’(etic) (thy)’roid’—had problems with the stated levels of the active ingredient (thyroxine) from certain manufacturers. For the manufacturer Knoll in particular, there were 26 recalled lots in 1991, and others that followed. An FDA inspection in April 1991 of Knoll’s Synthroid manufacturing facility resulted in the firm being cited for two deviations from current Good Manufacturing Practices (cGMPs). Another manufacturing review upon return in December 1992 uncovered nine separate incidents of failure to follow cGMPs.

The Agency observed that “FDA also found that the firm had continued to manufacture and distribute low dosage Synthroid tablets during 1990, 1991 and 1992.” They further noted: “Although you claim that Synthroid has been carefully manufactured, the violations of cGMPs discussed above indicate that Knoll has not always manufactured Synthroid in accordance with current standards for pharmaceutical manufacturing.”—U.S. FDA Letter to Synthroid Manufacturer, Knoll Pharmaceuticals, April 26, 2001.

The variability in strengths in the case of Synthroid was too wide to be acceptable, especially in a drug therapy whose concentrations are measured in the tens or hundreds of micrograms per day of dose.

At the moment, it appears that all performance data suggest that Merck’s thyroid drug is indeed no different from its predecessor. If that’s the case, what’s different is the prevalence of social media and perception bias leading to heightened reports of drug effects where they in fact don’t exist. But in the world of social media anecdotes and free access to enormous datasets, the ability to misinterpret data by the unqualified is as unmitigated as ever before in the history of healthcare. Thankfully pharmacovigilance as a discipline endeavors to uncover the truth behind all drug safety signals, even false positives. 

For a list of references visit the online version of this story at ContractPharma.com.

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Ben Locwin

Ben Locwin, PhD, MBA, MS, MBB, is an international healthcare speaker, has been a long-time advocate for evidence-based medicine, and has advised and guided vaccine manufacturers, global immunization committees, and vaccine congresses on best scientific practice and principles for vaccine composition and schedules.