The Food and Drug Administration’s (FDA) attempts at expediting and streamlining the approval of advanced new medicines is surely appreciated by those in the public that understand the importance of access to such therapies to address serious disease. And in fact, such a trend is the result of pressures that built up and led to legislation starting in the 1980s. Over the years, several different programs, methods and tools have been employed by FDA to accelerate the approval process. However, according to some recent research generated out of Harvard, the agency may be relying on less-robust evidence to speed up such decisions. There are more drugs on the market, available for those that could potentially benefit (assuming payer coverage), but are they as safe and effective if they are approved in a faster amount of time with potentially less evidence?
Harvard Group Thought Provoking Stance
A lot of smart people go into Harvard and the group that operates within the Harvard Medical School Program on Regulation, Therapeutics and Law is no exception. This team embarked on a study to better understand the wave of FDA approved drugs and determine if there were any risks involved with expedited candidates. Their research was published in the journal of the American Medical Association (JAMA).
General Trend toward Accelerated Approval
The potentially life and death situation with patients represents, first and foremost, the drive for expedited approval. But in the quest to make approvals faster, is the agency making questionable compromises with supporting evidence?
Legislative push has helped toward accelerated approval starting in the 1980s with Congress passage of the Orphan Drug Act, which focused on incentives for drug companies to develop therapies for rare diseases. Based on that milestone, the FDA required smaller trials and became established more malleable evidence standards in addition to offering companies extended periods of time without genetic competition.
Additionally, during the 1980s, HIV/AIDS activists took on the bottlenecks in approvals for HIV/AIDS drugs and helped to drive a more dynamic and rapid approval culture within the agency. By 1992, Congress passed the Prescription Drug User Fee Act, which allowed the FDA to collect fees from drug makers. Those fees were $29 million in 1993 and by 2018 equaled $908 million. The study found that industry fees represented 80% of the capital requirements for FDA employee salaries for drug reviews.
The Harvard team tapped into and probed the following sources for this study:
· FDA regulations (1962-2018)
· FDA databases of approved drugs (1984-2018)
· Generic drugs (1970-2018)
· Biologics (1984-2018)
· Vaccines (1998-2018)
· Priority Review and its predecessors (1984-2018)
· Accelerated Approval (1992-2018)
· Breakthrough Therapy category (2012-2018)
· Expanded Access (2010-2017)
· Risk Evaluation and Mitigation Strategies (2008-2018)
· User fees to FDA by industry (1993-2018)
The Harvard team reviewed a few data points including average new drug approvals which has increased to 41 in the 2010s. The FDA has organized itself to approve new drugs faster as by 2018 the median time for a new drug approval was 10.1 months which compares to 2.8 years for the time period of 1986 to 1992.
New biologic product approvals increased from a 2.5 median (1990-1999) to 5 (2000-2013) to 12 (2014-2018). Generic drug approvals greatly increased from 136 in 1970 to 588 from 2013-2018. As mentioned previously, user fees represent now about 80% of the salaries of review personnel responsible for the approval of new drugs.
Of note, the Orphan Drug Act, which was designed for specific rare-disease scenarios has been employed as a strategy for broader approval movement—such approved drugs increased from 18% in 1984-1995 (55 out of 304 total) to 41% in 2008-2018 (154 ou5 or 380 total). Not surprisingly, the Accelerated Approval, Fast Track and Priority Review tools FDA employs for accelerating drug approval processes have become quite standard—81% (48 out of 59 total approvals in 2018) benefited from at least one expedited program.
Pivotal trials have represented a key milestone for approval and the proportion of new drug approvals supported by at least two pivotal trials decreased from 80.6% in 1995-1997 to 52.8% in 2015-2017 based on 124 and 106 approvals, respectively while the median number of patients studied were comparable (774 vs 816). Overall, FDA drug review times declined by more than 3 years in 1983 to less than 1 year in 2017—however, overall time from the authorization of clinical testing has remained about 8 years.
The Harvard study team also offered accompanying editorial, calling for need of reform at the FDA. The growing emphasis on speed of approval, based on less evidence, underscores the point of the study and the findings—that priorities at FDA have evolved in a certain direction that may be diverting from its true mission.
Lead study author Jonathan Darrow, an attorney with Harvard Medical School’s Program on Regulation, Therapeutics and Law suggested that the study reveals “a gradual erosion of the evidence that’s required for FDA approval.” And consequently, declared that patients and physicians “should not expect that new drugs will be dramatically better than older ones.” Nearly half of the new medicinal products recently approved are based on merely one pivotal clinical trial rather than the previous norm of two such pivotal studies. Moreover, the increasing use of surrogate measures could be of concern, according to the academics.
Who is the real client? That is a fundamental question the Harvard researchers raise with the rapid growth of fees the approvals generate. Are the incentives now for the FDA to approve faster not due to patient need but industry?
Dr. Joshua Sharfstein, former FDA Principal Deputy Commissioner now on the faculty of Johns Hopkins, was quoted saying that although the FDA has accomplished the goal of a more dynamic culture of approval, he notes that it could be the case that more changes may be required to ensure medicines are appropriate for patients—not to mention a focus on the economics as many new therapies carry exorbitant price tags—out of reach for most Americans. Sharfstein believes that the FDA needs to do better and can.
The FDA is a well-intentioned group—most representing dedicated public servants that traditionally have been, in some cases, grossly underfunded and understaffed. Based on our knowledge, they have rarely possessed enough resource to carry out robust inspections at the level, pace and consistency truly required—and the matter gets more challenging with international inspections.
They have evolved to be more flexible with approvals because the political process drove them that way starting in the 1980s as new technological breakthrough in life sciences mandated such flexibility. As massive amounts of capital have circulated into life sciences, arguably the most important sector in the world if we consider that our health and special interests organize and mobilize to ensure conditions are at least somewhat more amenable toward a dynamic and flexible drug market.
By the 1980s, many patient-interest groups, from AIDs to various disease-based groups, sought more flexibility so loved ones could get access to more experimental medicines. Hence, the trend since the 1980s has been to make it easier to approve more drugs—that has been the message from Congress which in theory passes laws based on the people’s vote and interest.
Of course, special interests drive a lot of the narrative in today’s world and some groups and voices are louder than others—and those interests with greater organization, financial wherewithal and talent can influence the unfolding dynamics more than others, all things being equal.
It is probably true that most, if not all, federal agencies need at least some form of transformation as they could all be run better, more efficiently and effectively; the FDA is no exception. But on the other hand, we do have a special empathy for them—they regulated $2.6 trillion of the U.S. economy and, considering the magnitude of their responsibility and the brand that they must not only represent but constantly reinforce—the gold standard for drug regulators—they, in some way, must be always just hanging on.
In all reality, the Harvard study exposes a deeper and growing chasm of political, social, and economic interests in American society. The FDA is but one example of the upcoming battlegrounds.
· Jonathan J. Darrow, SJD, JD, MBA
· Jerry Avorn, MD
· Aaron S. Kesselheim, MD, JD, MPH