Day two of PFC’s FDA in the 21st Century conference begins with a morning plenary by the very fabulous Alta Charo, of the University of Wisconsin Law School, who is speaking on “Integrating Speed and Safety.”
Today Alta is presenting what she calls “more of an initial idea than an actual proposal,” and she notes that she’s very interested to hear responses to it, so comment away or contact her offline. She wants to integrate into the usual and longstanding “FDA speed versus safety” debate some concerns that should be of interest to industry. “In other words,” she said, “I’d like to be nice to the drug people.”
Alta begins with a brief history of the speed versus safety debate, which turns out to be quite cyclical. Before 1906, she asks us to recall, we had true snake oil: products with high toxicity and little or no efficacy. Often these products were nevertheless perceived as effective because they contained alcohol or other drugs, so made you feel better at least, but of course that’s part of what made these products so dangerous, especially for children.
And so with the Federal Food and Drugs Act of 1906, we get post-market remedies for misbranding, although they require proof of intent. And then in 1937 over 100 children die from elixir of sulfanilamide. And the following year we get the Food, Drug, and Cosmetic Act. But the FDCA targets only safety. (Although rightly Alta notes that it’s hard to see how regulators were truly only looking at safety and not also at some form of efficacy, since there is no such thing as safety in the abstract, only safety relative to purpose for which someone is taking the drug.)…Until 1962, when the thalidomide tragedy hits Europe, and the U.S. is spared its most serious effects precisely because the agency was slower than Europe in approving drugs. Building on what was seen as its strength, amendments to the Act passed that year additionally required drug sponsors to show efficacy. A slow, deliberative process that didn’t let drug out onto the market until they are fully vetted was seen as the gold standard of a food and drug agency.
…Until the backlash during the 1970s from cancer patients over access to Laetrile, followed by AIDS patient advocacy work by ACT-UP in the 1980s. This led to a paradigm shift in public opinion towards viewing a quality food and drug agency as one that would look to get drugs out more quickly. And this ethos fit well with the competitiveness of the 80’s and the fear that the U.S. was being outstripped by Europe. And so, during the 1980s and 1990s, the FDA responded to this paradigm shift in public opinion through a series of efforts to expand and speed access to drugs (e.g., the Orphan Drug Act, PDUFA).
…Until the 2000s, when new safety scandals emerge over drugs like Avandia, Vioxx, and Ketek. “Once again,” Alta notes, “fast is bad.” Until the 2010s, when speed once again is making a comeback. A notable example is von Eschenbach’s influential Wall Street Journal op-ed in which he argued that the FDA should make drug approval hinge on safety only, leaving determinations of efficacy for post-marking. On other words, Alta says, he wants us to move back to 1961. And so we get the Food and Drug Administration Safety and Innovation Act of 2012, with its invitation to sponsors to apply for a “breakthrough therapy” designation for any drug that treats a serious or life-threatening disease and for which the sponsor has preliminary evidence that it’s better than the status quo. (Alta notes, however, that it’s unclear what sponsors get here that’s really new or especially useful with this status.)
The history lesson complete, Alta makes the now-obvious point that the speed-versus-safety debate is a very old discussion. However, that discussion has been hampered, she says, by absolutist positions and by the fact that the FDA is not an agency that can change its culture every ten years, even if public opinion changes that quickly.
Alta wants to suggest a new approach, one captured in the image she shows the audience of children jumping on a backyard trampoline surrounded by a safety net. “You can jump higher on a trampoline,” Alta says, “if you have a net around you.”
Part of creating that net is ensuring better post-market surveillance. Pre-market trials have made faster in various ways, including through pharmacogenomics and the use of surrogate endpoints. But pre-market trials will never be good enough for safety or efficacy. They employ small sample sizes, homogeneous subjects who lack co-morbidities, they are short in duration, and so on. And so clinical trials are poor at identifying rare side effects and drug-drug interactions, and effectiveness in patients is not necessarily predicted by efficacy in trial subjects (the so-called efficacy-effectiveness gap).
We do, of course, have some post-market safety measures in place. But pre-approval safety meetings may be hurried, with little opportunity for the development of sensible post-market plans for surveillance and Phase IV trials. Phase IV trials themselves are not always completed. And the FDA lacks comprehensive data to determine whether risk evaluation and mitigation strategies (REMS) are effective in improving drug safety. All of this, moreover, is exacerbated by the inherent limits of the AERS and Sentinel systems; the fact that some agency divisions are looking only at risk only while others look to balance risks with benefits; the rapid diffusion by DTC advertisements of new drugs into a population before large-scale post-market exposure can be processed, to which Caronia threatens to add off-label promotion of secondary indications.
The different approach Alta has in mind takes its cue from Europe’s regulatory approach of granting drugs “conditional approval.” Under this regime, a drug is approved for one year based on preliminary data, but its renewal for a certain number of additional years is contingent on the sponsor gathering more data in the post-approval period. If the sponsor’s data contraindicates approval or if the sponsor fails to follow through with its commitment to collect data at all, then the drug approval automatically sunsets after the first year, without any need for a formal withdrawal decision by regulators based on complex risk-benefit criteria.
This approach, Alta says, would re-balance the emphasis from pre-approval to post-approval. It would seek to move drugs out of Phases II and III more quickly. It would increase the effective use of REMS and Phase IV trials for first-in-class drugs. And it would limit DTC advertisement and off-label prescribing in the early years following approval of such drugs.
The advantages of the model include: a focus on risk-benefit ratio in the context of real world use of a drug; a slower uptake of first-in-class drugs during its first years on the market when heretofore unknown risks begin to emerge, or when reduced effectiveness becomes clear; and forcing industry to provide high-quality, up-to-date data on their drugs as part of the reapproval process, thereby eliminating the logjam of FDA’s inability or unwillingness to withdraw drugs of questionable safety and/or efficacy from the market.
Alta acknowledged, of course, that the model also has drawbacks. For instance, early marketing could lead to the sale of unsafe drugs (although she notes that there is some early evidence out of Europe that conditional approval doesn’t undermine safety (see Boon, Moors, et al, 2010). Restrictions on off-label prescribing run counter to current medical practice and are, frankly, largely beyond the FDA’s authority (Alta notes that constraints on off-label prescribing might instead be achieved through tort law reforms). Restrictions on DTC advertising and soft forms of off-label promotion present similar First Amendment problems. And public and private insurers will have to recognize that conditionally approved drugs should be covered.
But Alta spent the remainder of her argument in chief, as it were, addressing a possible concern that industry may have about her proposed framework shift: namely, that any uncertainties added to a drug’s ROI in the post-approval period runs the risk of deterring investment in R&D. The current legislative model uses post-approval market advantage as the primary incentive for R&D, and pharma is highly dependent on that model, now to its detriment. So let’s shift to a new business model where incentives focus on the post-market period and come with more rapid diffusion of drugs. An analogy here is to the antibiotic resistance dilemma: We want to incentivize more development of antibiotics but, due to concerns about resistance, we don’t want them to be used; instead, we want to stockpile them for the day when strains are resistant to current antibiotics. This has posed a challenge for traditional incentives, which industry suggests we answer through, inter alia, giving tax credits for R&D, milestone awards for pay-for-performance options, guaranteed purchase, public-private collaborations (PPCs), and the Limited Population Antibacterial Drug (LPAD) mechanism. We should explore ways to use similar incentives in the drug space.
Alta concludes by asking some open questions about how realistic her proposal is. First, is it realistic to achieve her shift through legislative action? Her answer, to much audience laughter, is: “Not this year.” Second, even if we some day have a Congress willing to act, is it realistic to expect the public to tolerate push incentives to Big Pharma, such as pre-market payments before they produce drugs to help people? In the end, she says, it actually makes sense to do that, but she acknowledges that it will require a big sales job to convince the public. Is it possible to do this under current law, in the absence of offsetting industry incentives? We can already impose sunsets on breakthrough therapies or accelerated approval status. The rub, she says, is whether the agency has the will to enforce REMS and Phase IV studies.