The 21st Century Cures Act and a right-wing war on regulations are direct threats to FDA evidentiary requirements for drugs, biologics, and devices
By Tim Horn and Suraj Madoori
What could possibly be wrong with legislation beamishly called the 21st Century Cures Act? Signed by President Obama during his final days in office, the bill’s appeal and broad bipartisan support are understandable. It promises significant funding for the National Institutes of Health, genomics and cancer research, and opioid dependency prevention and treatment. However, it also contains some deeply troubling provisions in the name of developing and delivering novel therapies: it relaxes standards of evidence used by the U.S. Food and Drug Administration (FDA) to determine that drugs and devices are safe and effective for approval.
Much of the Cures Act language focusing on approval processes will be up to the FDA to translate into guidance and regulations. But while this legislation came into being under the evidence- and public-health-minded Obama administration, the still-unconfirmed FDA commissioner in the Trump administration—already committing itself to undo the “administrative state” across all branches of government—will be overseeing much of this work.
In a January 31 meeting with pharmaceutical executives, Trump said that regulations are impediments to drug development and fair pricing, adding “we’re going to be cutting regulations at a level that nobody’s ever seen before.” In March, Trump tapped Dr. Scott Gottlieb to serve as FDA commissioner. While arguably a more suitable pick than other rumored contenders, Gottlieb—a venture capitalist, senior fellow of the conservative American Enterprise Institute, and former FDA deputy commissioner under George W. Bush—is a longtime critic of the FDA’s current stringency and marketing requirements, arguing that they stifle competition, and has robust ties to the drug industry.
TAG is among several organizations concerned not only that the Cures Act will allow the new FDA commissioner to begin dismantling regulations widely considered critical to evidence-based medicine but that it is the first of several possible pieces of legislation aiming to curtail vital FDA stringency requirements that protect and advance public health both within and outside the United States. Key to advocacy resistance will be challenging the false narrative that the FDA’s drug and device approval processes are a primary obstacle keeping affordable treatments and cures out of the hands of the people who need them most.
The ultimate irony is that the FDA’s authority to ensure drug safety and efficacy was born of legislation seeking to rein in drug pricing. Beginning in 1959, Senator Estes Kefauver’s (D-TN) Antitrust and Monopoly Subcommittee held hearings on the pharmaceutical industry’s dubious marketing practices, including the aggressive promotion of drugs without safety warnings or proof of efficacy. In the wake of the 1962 thalidomide tragedy—thousands of infants worldwide were born with malformed limbs to women who were prescribed the drug as a mild tranquilizer during pregnancy, in the absence of any supporting safety and efficacy data—Congress ultimately (and unanimously) passed legislation strengthening the Federal Food, Drug, and Cosmetic Act, introduced earlier in the year by Kefauver and Rep. Oren Harris (D-AR).
Chopped from the Kefauver Harris Drug Amendments, due in part to pharmaceutical industry objections, was language supporting Kefauver’s broader desire to end drug monopolies and egregious pricing. He pushed for a compulsory licensing provision whereby exclusivity on new drugs proven to be clinically advantageous would be limited to three years (vs. 17 years under existing law), after which the manufacturer would be required to share its patents with competitors in exchange for royalty payments.
What ended up being signed into law by President John F. Kennedy in October 1962 was still profound: fundamental protections requiring manufacturers to provide supportive data from adequate and well-controlled studies as a condition of approval, along with FDA empowerment to ensure proper clinical trial conduct, drug production controls, and veracity in marketing. Not only does such rigorous premarket development provide a strong foundation of safety to protect healthcare consumers, it provides the efficacy outcomes required to make critical risk-benefit decisions in clinical practice.
Political criticism of the FDA begins with Kefauver Harris, which unquestionably added both cost and length to the drug development and approval processes. The extent to which this heightened stringency has prevented safe and effective treatments from reaching the market, particularly for rare and neglected diseases, continues to be hotly debated, along with claims that it drives up drug prices.
Claims of regulatory overreach and financial strangulation of biomedical ingenuity omit evidence showing that: 1) manufacturers probably spend far less on drug development and FDA-required trials than the numbers touted by industry supporters; 2) healthcare systems increasingly depend on rigorous data, made available as close to product launch as possible, to make cost-effectiveness determinations; 3) more, not less, oversight is required to minimize residual uncertainty following approval; and 4) the FDA has a great deal of flexibility to speed the availability of essential new medicines.
Critics have long argued that the FDA review and approval process can best be summed-up as a “gray zone”—too fast for some and too slow for others. But the FDA has both more than doubled the number of New Active Substances (NASs) approved annually since 2005 and reduced its review and approval time of New Drug Applications (NDAs) to a median of 10.1 months (compared with 20.8 months in 1993), effectively leading its European counterpart, the European Medicines Agency. Review times could potentially be reduced further with expansion of the FDA workforce—a feature of the Cures Act—but this runs counter to a Trump executive order instituting a federal hiring freeze.
A common thread in both the Cures Act and the mounting political rhetoric of FDA overreach is the potential for phase II studies, along with the use of “real-world” patient testimony and unvalidated surrogate markers, to be suitable stand-ins for phase III trial approval requirements. Though not yet peer reviewed, a January 2017 analysis by the FDA should temper these arguments. The analysis included 22 drugs, vaccines, and medical devices since 1999 that yielded promising phase II results that later were not confirmed in phase III trials. There were 14 cases of unconfirmed efficacy, one case of safety concerns documented in phase III but not phase II trials, and seven cases of important safety and efficacy concerns arising in phase III studies. The phase III failures occurred even when the phase II studies were relatively large and even when the product was already approved for another indication (6/22 drugs).
No less disingenuous are claims that the FDA is overly rigid in its approval processes. Due in large part to the influence of AIDS activism in the early 1990s, the FDA has demonstrated itself amenable to novel pathways allowing expedited access to unique new treatments without compromising the science required to confirm safety and efficacy. Many such processes also incentivize industry investments in research and development, particularly for rare and neglected diseases and diseases with limited treatment options.
In the early 1990s, the FDA formalized mechanisms for compassionate-use and parallel-track programs, providing patients with access to experimental drugs that have cleared phase II and are undergoing investigation in phase III trials. There is also the accelerated approval pathway, which permits lifesaving therapies to become commercially available based on validated surrogate marker data, intermediate clinical endpoints, and company commitments to provide gold-standard clinical trial results. A number of priority review designations are also possible—qualified infectious disease product (QIDP), fast track, and breakthrough therapy—and can reduce NDA review times to six months. Other incentives include additional years of marketing exclusivity awarded to drugs that receive QIDP or orphan drug designations.
With the Cures Act now codified into law, TAG and its advocacy partners will be keeping close tabs on draft guidance and other plans to operationalize one of the most significant legislative rollbacks of FDA authority. No less essential will be coalition efforts pressing for a Commissioner open to fresh regulatory thinking, while maintaining a course that unapologetically values evidence-based medicine over the profit-seeking interests of one of the wealthiest industries in the world.
FDA stringency is not just a function of regulations. Funding made available under the Prescription Drug User Fee Act (PDUFA) is a critical factor. The PDUFA allows the FDA to collect fees directly from manufacturers to expand and support the agency’s drug approval processes. Set to expire in September 2017, the law is now up for its sixth reauthorization, which would extend its fiscal security through 2022. PDUFA and the Generic Drug User Fee Amendment (GDUFA) currently supplement the FDA budget by $1 billion. Trump’s “skinny” budget sent to Congress in March proposes doubling this, though this is likely to be met with fierce resistance by the pharmaceutical industry and may result in costs being shifted to consumers in the form of higher launch prices for new drugs.
FDA reauthorization commitments include faster review times for drugs and biologics (e.g., 90% of approval applications to be reviewed in 10 months or less) and increased attention to surrogate-marker and real-world-evidence considerations. But it is worrying that the reauthorization process is occurring in the wake of the Cures Act and is being taken up by a Congress bent on scaling back regulations of all stripes. The potential for legislative add-ons designed to cripple the FDA or prevent the PDUFA reauthorization from passing, which would be all but fatal to the agency, is considerable.
The Cures Act may also be the catalyst needed by deregulation hawks to usher in additional problematic legislation. The Reciprocity to Ensure Streamlined Use of Lifesaving Treatment Act of 2015 (S. 2388), which may be revived under its lead cosponsor Senator Ted Cruz (R-TX), would limit the FDA to 30 days for review of requests from manufacturers of drugs or devices that have been approved by stringent regulatory agencies in other countries. Most concerning isn’t that it would most likely benefit only a small number of U.S. patients receiving treatment for rare diseases, according to a February 2017 British Medical Journal paper, but that the bill empowers Congress to override the agency if approval is denied. There is a sizeable chance that the possible benefits of this legislation will be offset by its possible harms.
There is also the Lowering Drug Costs Through Competition Act (H.R. 749), introduced by Kurt Schrader (D-OR) and Gus Bilirakis (R-FL). The bill aims to incentivize generics manufacturers to either shore up U.S. drug shortages or compete with other generics manufacturers engaged in monopolistic drug pricing. In addition to speeding FDA review, the bill would award manufacturers introducing needed generics with priority review vouchers (PRVs). PRVs are intended to motivate companies to invest in the research and development necessary to bring drugs for neglected tropical and rare pediatric diseases to market; vouchers can be applied to future drugs being developed by the manufacturer or sold to other manufacturers for millions of dollars.
Unfortunately, PRV program loopholes have already been exploited. Marathon Pharma’s Emflaza (for Duchenne muscular dystrophy), Novartis’s Coartem (for malaria), and Knight Therapeutics’s Impavido (for leishmaniasis) all received PRVs following U.S. approval, despite the fact that they were originally brought to market through other public or private ventures and are available generically in other countries for a fraction of the U.S. price. Before it expands the PRV program, Congress must fix loopholes to ensure that the United States is rewarding ingenuity, not opportunism.
The paradox of the Trump administration’s war on regulations, already catalyzed by the Cures Act, is that more targeted regulation is what’s needed to solve a range of treatment access issues, from developing and approving novel therapies for neglected or rare diseases to addressing egregious drug pricing. As president-elect, Trump emphatically stated that the pharmaceutical industry is “getting away with murder.” A war against regulations intended to hold manufacturers accountable, protect drug safety and the health of the American public, and advance evidence-based and cost-effective care is questionable at best—and dangerous at worst.