British Medical Journal
28 March 2015(vol 350, issue 8001)
http://www.bmj.com/content/350/8001

Feature
Commentary: Will 20th century patient safeguards be reversed in the 21st century?
BMJ 2015; 350 doi: http://dx.doi.org/10.1136/bmj.h1500 (Published 25 March 2015) Cite this as: BMJ 2015;350:h1500
Gregg Gonsalves, lecturer in law, Yale University, New Haven, CT, USA,
Diana Zuckerman, president, National Center for Health Research, Washington, DC, USA

Most physicians and patients assume that medications are proved safe and effective. This hasn’t always been the case. The US Food and Drug Administration was born out of a series of 20th century tragedies: contamination of vaccines at the turn of that century; dangerous substances found in commonly sold medicines in the 1900s; deaths of over 100 children and adults in 1937 from a sulfa drug dissolved in diethylene glycol (antifreeze); extensive birth defects caused by thalidomide in the early 1960s; and infertility and deaths caused by the Dalkon Shield intrauterine device in the 1970s.1 Those tragedies all inspired laws that strengthened the criteria used to allow medical products on the market.

Subsequently, the first effective challenge to the FDA’s growing authority came from an unlikely source: people with HIV/AIDS. In the 1980s, as people with AIDS faced certain death, they criticized the FDA’s drug approval process as too slow and unresponsive to their needs. AIDS activists pressed for expedited drug approval and making experimental therapies widely available, demonstrating at FDA headquarters, and speaking out to FDA officials, the media, and Congress. They were remarkably successful, helping shape FDA reforms, including pathways for accelerated drug approval and expanded access programs for experimental medicines.

AIDS activists quickly learnt, however, that speedier approval and wider access had risks as well as benefits. They had assumed that any drug would be better than nothing, and that new drugs would be better than old ones, so they were greatly disappointed when the first generation of antiretroviral agents were less effective than expected. In fact, research did not confirm long term clinical benefit of these medicines; conflicting trial results and inconclusive studies piled up in the early 1990s. The activists realised that access alone does not necessarily provide answers, which now were in short supply.2 Much of this debate, however, became moot after a new generation of AIDS drugs, protease inhibitors, were used in combination with the older medicines. These new combinations had transformative clinical benefits, with dramatic reductions in AIDS related morbidity and mortality, raising patients from their deathbeds in what was called the Lazarus effect.3

The arrival of the AIDS epidemic in the US coincided with conservative presidential leadership and a growing conservatism among Congressional Republicans. Together, they sought to limit the size of the federal government and the scope of its powers. Although they had far different politics, AIDS activists had helped grease the wheels for a deregulatory agenda at the FDA. Starting in the early 1990s, a series of initiatives supported by conservative think tanks and drug industry lobbyists sought to further weaken the FDA’s authority and mandate, often invoking the legacy of AIDS activists and the rights of patients. AIDS activists balked at the appropriation of their work for these purposes, and in another unexpected turn of events, now defended the agency. But this time their protests went unheeded.4

In the 1990s, Congress began to gradually erode the standards used for drug approval and the safeguards for patients: reducing the number of studies required to get new drugs on the market from at least two to one and reducing restrictions on the advertising and promotion of medical products. With AIDS, the FDA had shown it could expedite drug approval and access to experimental agents without new legislation, and many questioned the need for these new legislative initiatives.5

Despite numerous changes in White House and Congressional leadership, the 21st century has seen a steady escalation of legislation chipping away at the FDA. In response to legislative and political pressure, the FDA has offered numerous concessions to industry and its lobbyists. It now offers four pathways to speed the approval process for many drugs and biologics6 as well as an easier approval pathway for drugs for orphan diseases (those affecting fewer than 200,000 patients in the US).7 Though all drugs are supposed to meet “appropriate standards” for safety and effectiveness, the standards for most drugs approved through expedited pathways are clearly lower, with smaller and shorter term studies than are otherwise required. For example, in 2008, an average of about 100 patients were tested with new drugs that were approved through expedited pathways, compared with almost 600 for standard approvals.8 As a result, patients relied on drugs for which safety and effectiveness were not always confirmed when they were first on the market. Instead of requiring clear proof of safety or effectiveness before approval, most evidence is not required until afterwards. Sadly, “required” postmarketing studies are often delayed for years,9 and when problems are discovered, corrective action doesn’t happen swiftly. It takes on average 11 years after approval for the FDA to institute new black box warnings, rescind approval, or require new risk information or contraindications be made public.8

Medical devices are subject to even weaker approval criteria, with only 1% of devices reviewed through a process that requires clinical trials.10 Most of the thousands of medical devices not subject to clinical trials every year do not even get “approved” by the FDA, but are rather “cleared” for market—90% of them within 90 days.11 Nevertheless, the FDA has responded to political pressure by proposing a new expedited pathway for devices.12, 13

Now, Congress is proposing new legislation to further speed the drug approval process while further weakening the standards for safety and efficacy. It’s a trade-off with potentially deadly consequences. The 21st Century Cures draft legislation released by Republicans on the House health committee in January 2015 is sweeping and would jettison the phase III testing requirements for new drugs and largely dismantle the key components of the drug approval process in place since the thalidomide tragedy.14 Unsurprisingly, its proponents say the reforms are needed to meet patients’ needs. But patients need knowledge—answers about the drugs they put in their bodies—not just access.

If passed, this bill and other 2015 legislative proposals will radically alter the nature of drug, device, and biologics approval in the US, roll back patient safeguards, and leave an FDA that looks more like the one that existed in the mid-20th century, not one worthy of the 21st.

References at http://www.bmj.com/content/350/bmj.h1500