New data in the FDA deregulation debate



[This post originally appeared on on February 9, 2017.]

The Trump administration has pledged to “[cut] the red tape” at the FDA and “streamlin[e] the process” for drug approvals, and there’s a full lineup of agency critics auditioning to lead it–so we’re likely to hear many ideas to lower the bar for Americans to access new therapies.

But what would the clinical impact of these proposals be? For most of them, we have no idea how many patients would be helped–or harmed.

Now we have some data, at least for one of these proposals. My colleagues and I just published a peer-reviewed analysis of “reciprocal approval,” which would hasten Americans’ access to new drugs already available in other countries (free full text here). Our historical review shows that rubber-stamping drugs approved elsewhere would have mainly benefitted a small number of U.S. patients with rare diseases, while likely exposing the wider population to additional safety risks.

[Disclaimer: this post is solely authored by me, and reflects my views alone, not necessarily those of my co-authors in the published research.]

Advocates of FDA deregulation have made some cogent arguments in favor of reciprocal approval (e.g., here and here). Forcing the FDA to automatically green-light drugs approved in other countries could improve the agency’s efficiency and competitiveness, and there’s also an appealing logic to the argument that a drug that’s good enough for Europeans should be fine for Americans as well.

But the size of the potential clinical benefit has remained murky. Although Sen. Ted Cruz claims the reciprocal approval bill he co-sponsored would “unleash life-saving drugs and devices in the United States,”some industry-watchers have questioned how many medically important drugs would actually be affected (e.g., hereherehere and here). In addition, giving patients faster access to medicines could also lead to offsetting harms, if some drugs first available outside the U.S. and then reflexively approved here were later withdrawn due to safety concerns. (The legislation proposed by Sen. Cruz would give the FDA the option to deny reciprocal approval to drugs it deemed unsafe, but also grant Congress the right to overrule the agency’s decision.)

One way to tackle these questions is to retrospectively measure the effect if reciprocal approval had already been in place–which is what I did with my Pharmagellan colleague Matt LarochelleNick Downing of Brigham and Women’s Hospital and Joe Ross of Yale in our new paper, freely accessible at BMJ Open.

Joe, Nick and others previously found that from 2001 to 2010, about 40% of drugs approved by the FDA, the European Medicines Agency (EMA) and/or Health Canada were first approved outside the U.S. We focused on this subset of drugs, and asked what the clinical impact might have been on American patients if reciprocal approval had been in place during that period.

Before summarizing the results, let me highlight two limitations to our study (among several that we cited in the article). First, although we made some observations about increased exposure to safety risks, we focused our research on quantifying the potential positive clinical impact of reciprocal approval. And second, because our data set ended in 2010, we didn’t capture the effects of newer regulatory policies to accelerate approval of drugs for illnesses with high unmet needs. (More on both of these points shortly.)

With those qualifiers, our main finding was that reciprocal approval would have mainly benefitted patients with rare diseases. Among agents first approved outside the U.S. from 2001 to 2010, we only identified 10 drugs that were pharmacologically first-in-class and treated indications that lacked any other FDA-approved therapies. Of those, nine were for orphan indications, including five for metabolic enzyme deficiencies. Only a single one of these 10 drugs (Bridion (suggamadex), for neuromuscular blockade reversal) addressed a broad (non-orphan) patient population–so for the vast majority of Americans, reciprocal approval would have had minimal positive effect.

Importantly, this conclusion is not intended to minimize the fact that reciprocal approval could have benefitted patients with some rare diseases during the period we studied. But remember that our analysis set ended in 2010, and in the years since then, there’s been continued use and expansion of programs that accelerate rare drug R&D, including expedited review paths and orphan drug incentives. So our analysis may actually overestimate the potential positive effect of reciprocal approval in the future, even for patients with rare diseases.

With regard to safety–which, just to reiterate, was not our main focus–we identified some worrying cases in which reciprocal approval would have exposed American patients to additional harms. Of the pharmacologically novel drugs first available ex-U.S. during the period we analyzed, two were later withdrawn in Europe based on safety concerns (Pelzont (laropiprant/nicotinic acid) and Accomplia (rimonabant)). It would be wrong to make too much of these anecdotal cases, but given that these drugs address large patient populations, these examples highlight the need for a more rigorous analysis of the potential safety impact of reciprocal approval as the discussion advances.

Bottom line: based on historical approval patterns, our new data suggest the main clinical benefit of reciprocal approval would likely be felt by rare disease patients, and the potential safety issues for the broader population of American patients warrant closer examination. The debate over reciprocal approval (and FDA policy more generally) is far from over, but our paper adds a much-needed quantitative analysis to the ongoing conversation. Let’s hope that in the months to come, we can continue to use data to help us evaluate proposals to revamp the FDA’s regulatory approach.

In closing, and on a personal note, I want to highlight what a pleasure it was to work with Joe Ross and Nick Downing on this research effort. Industry folks like me rarely collaborate with academic investigators on peer-reviewed studies related to the pharma business–often due to a lack of existing relationships, mutual suspicion or both. But there’s both a need and an opportunity to bring a joint industry-academic perspective to pharma policy questions, and by combining our interests and expertise, I think we produced a more insightful and balanced analysis than any of us could have done alone. I hope others will follow our example.