The Future of Pharmaceutical Regulation

The October 2008 issue of Nature Reviews--Drug Discovery contains a very informative perspective piece on how drug regulators negotiate uncertainty, risk, and benefit when making approval decisions ("Balancing early market access to new drugs with the need for benefit/risk data: a mounting dilemma"). I have long argued that novel biologics like gene transfer will require creative approaches from regulators, because on the one hand many types of adverse events might be latent and unpredictable, while on the other hand, many novel biologics will target highly morbid or lethal conditions like primary immunodeficiencies.

The authors (Hans-Georg Eichler et al) are all employees of drug regulatory agencies in Europe. Not surprisingly, then, the article is balanced and presents drug agencies as making appropriate trade-offs between patient access and public safety. The article studiously avoids any criticism of pharmaceutical companies. And it makes some questionable claims. For example, in several passages it suggests that drug regulation is increasingly "risk averse" (it seems to me the opposite, but who knows?). Another is that the article contains ample evidence that premature approval has had important costs in terms of health and economics. Nowhere does it provide clear evidence or anecdotes that delay of approval, or restrictive evidentiary standards have had important public health or economic impacts (it might, but if you are going to suggest that the balance is appropriately struck, one needs a clear picture of the benefit side of the equation).

The article contains a number of observations and policy approaches that cry out for careful ethical analysis. Here are two:

1- Drug regulatory agencies accept greater uncertainty about safety and efficacy when new drugs address serious, unmet health needs. Thus, new cancer drugs can be approved on a weaker evidentiary base than new acid reflux drugs (in several instances, new drugs were approved on the basis of uncontrolled, surrogate endpoints (e.g. gefitinib). Why should evidentiary standards be relaxed in this way? And to what degree? If the disease is serious enough and standard care non-existent, then what is the basis for any drug regulation?

2- The article states that "rare drug reactions will continue to be identified only after wider use in the market," and that more sophisticated approaches to drug safety will increasingly "blur the line between pre-marketing and post-marketing activities." How will this affect ethics review and oversight? How will privacy protections be maintained in this gulf-stream of flowing health data? How will trial registries absorb and respond to post-marketing studies?

This article contains multitudes– I highly recommend it to anyone interested, as I am, in the problem of uncertainty, risk, and drug regulation (photo credit: Alincolnt, schedule 5, 2006)