The FDA Approval Process Needs Refinement, Not a Total Overhaul

A group of studies, editorials, and exposés have been published this week that criticize the US Food and Drug Administration’s (FDA’s) role as gatekeeper for new therapies. And, while some of the coverage could seem too critical, the approval processes and mechanisms that speed drugs to market appear to need tweaking, rather than a complete overhaul.

Take, for instance, the overall development time for a drug, which is defined as the date of an Investigational New Drug (IND) application to approval of a New Drug Application (NDA) or a Biologics License Application (BLA). This pace has remained relatively stagnant at 8 years, despite the introduction of many new policies and expedited programs during the period of 1983 to 2012, according to a new paper published in JAMA.1

What has changed dramatically, however, are review times by the agency: they went from more than 3 years in 1983 to less than 1 year in 2017 and by 2018, median review time was just 10.1 months for standard drug applications and 7.6 months for priority applications.

Out of 59 new drugs developed in 2018, 48 of them, or 81%, benefited from an expedited pathway (Accelerated Approval, Fast-Track, or Priority Review). New biologic approvals, specifically, shot up from a median of 2.5 drugs in 1990 to 1999, to a median of 12 therapies from 2014 to 2018. More than half (58%) of the 59 new drugs in 2018 had an Orphan designation, 41% of them used the Fast-Track pathway, and 24% harnessed the Breakthrough Therapy designation to get approval.

Not only has the agency seen shortened FDA review times but it is requiring less evidence of clinical benefit for approval to occur, the authors of the JAMA article asserted. The proportion of approvals based on single-arm, nonrandomized trials increased from 4% in 1995 to 1997, to 17% during the period of 2015 to 2017. Over the same time, the proportion of new drugs that were supported by at least 2 pivotal trials dropped from 80.6% to 52.8%.

“By the 2015-2018 period the FDA approved 90% of 172 drugs (both priority and standard) after just 1 review cycle, compared with 77% of 137 drugs from 2011 to 2014,” the authors observed. It also appears that simply applying for a NDA or BLA means a manufacturer will have a good chance of having an investigational drug approved; since 1988, the agency has approved approximately 80% of NDAs/BLAs.

Meanwhile, approvals that rely on surrogate end points are increasing. Surrogate measures of benefit were used in 44.3% of new drug approvals from 2005 to 2012, whereas this percentage rose to 59.3% for drugs approved from 2015 to 2017. Of most concern, wrote the study authors, was that the use of surrogate measures that were “not yet designated as well established” but that were still used for justification of approval under the Accelerated pathway, rose from 9% during 1993 to 2001 to 13% in 2011 to 2018.

The fact that overall development times have remain unchanged, but drugs are getting through the regulatory agency more quickly, could reflect the type of drugs being pursued, the authors reasoned, which include more drugs for rare diseases and cancer. Therapies for these conditions generally have smaller patient populations and are in areas of unmet need and it may take longer for drug sponsors to prove a meaningful clinical benefit (or any benefit).

So if the total time from when sponsors get the “ok” for clinical testing to approval has stayed flat at about 8 years, but FDA review time has dropped, what is taking longer in the scheme of a drug’s development and why haven’t overall clinical development times actually gotten shorter? “It’s a good question, but we don’t discuss that in the paper, and I don’t know the answer,” article coauthor Jonathan J. Darrow, SJD, JD, MBA, of the Program On Regulation, Therapeutics, And Law (PORTAL) within the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, wrote to Cancer Therapy Advisor in an email. “Phase 1, 2, and 3 are often overlapping (eg, multiple indications), so [they] do not necessarily progress as neatly as the schematics often portray.”

While drugs granted Accelerated Approval will be “subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit,”2 according to 21 CFR. 314.510, Darrow noted that for all other drugs, the FDA can (and frequently does) require post-approval trials as a condition of approval. “In general, nothing prevents the FDA from requiring post-approval studies whenever it feels they are needed,” he said.

“The bigger problem is not the failure to require postapproval trials for all expedited drugs, but (1) the failure to complete them, (2) the failure to timely complete them, and (3) the failure to confirm clinical benefit (as required by law), such as when the FDA accepts trials based on surrogate end points as the confirmatory trials,” Darrow said. “A related issue is that fewer people will pay attention to new evidence about a drug approved 5 or 10 years ago, and by that time, thousands of patients may have been exposed to the drug so the clinical impact of delayed evidence may be both too late for some, and too slowly disseminated into clinical practice for others.”

“And an even bigger problem occurs when insurers, physicians, and/or patients focus on the fact of FDA approval or the existence of inadequate evidence rather than focusing on what the evidence shows,” Darrow continued. “Often, there is enough evidence at the time of approval to tell that a new drug offers, at most, modest benefits over existing treatments, but what is uncertain is whether the benefit is small, very small, or very, very small (safety issues aside). In those cases, physicians and patients don’t need to wait for confirmatory trials to know that the drug probably isn’t a very valuable addition to the therapeutic arsenal.”

Darrow also said that if a confirmatory study is delayed by, say, 13.5 years (the average length of the exclusivity period, as mentioned in the paper), “and a postapproval study happens to find lower efficacy, or greater safety problems than was initially believed, guess what? The exclusivity period is just about over by then. At that point, patients (and in some cases, taxpayers, insurers, or employers) have already spent a lot of money on the drug, and the disappointing confirmatory trials may serve to push the market to the next, new expensive drug that, in turn, is supported by limited evidence. And that cycle can potentially continue, indefinitely.”

As a result, the researchers concluded, while the efforts to expedite drugs may have made some medications more accessible than would have been possible through standard approval pathways, the use of these hurried pathways also introduced more uncertainty about drug benefit — and may have also introduced the potential for more harm. “Congress, the research community, or both should periodically reevaluate the balance between these consequences,” the authors wrote. “The test of whether the drug approval framework is successful ultimately turns on the extent to which those drugs contribute to or detract from patient well-being, including the effects of high drug costs.”

And, the author of an accompanying editorial, Joshua Sharfstein, MD, vice dean for public health practice and community engagement at the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, argued that so far, these expedited pathways have not revealed many game-changing drugs — or at least, any drugs that have improved survival times in a substantial way. “I think the solution is to evolve the incentives and special programs for approvals, rather than end them,” Dr Sharfstein wrote in an email to Cancer Therapy Advisor.

He wrote in the editorial that this reform should be driven by changes to the system, including promoting better competition for non-Orphan indications of an Orphan drug, updating the requirements for the receipt of Fast-Track and Breakthrough designations, ensuring better oversight of postmarketing requirements, and a retooling of the special marketing promotions that have historically allowed for a drug to stave off biosimilar competitors.3 Perhaps most controversial of his suggestions included a recommendation that Congress use patent and pricing incentives to “accelerate the generation of definite evidence under accelerated approval.” In other words, market exclusivity would only be awarded if the sponsors complete studies that deal with clinically meaningful end points (as opposed to merely showing surrogate results).

But when it comes to whether FDA will ever begin to consider cost when evaluating a drug, Darrow pointed out it is not currently part of the statutory mandate, and is unlikely to be added. “Purchasing decisions are made by physicians, patients, and insurers, among others … a huge problem and another story, because the person who chooses the drug doesn’t pay, and the person who pays doesn’t choose. It is a truly dysfunctional market.”

Disclosure: Dr Sharfstein reported serving as Principal Deputy Commissioner of the US Food and Drug Administration from March 2009 to January 2011 and receiving funding from Arnold Ventures for work related to drug pricing.


  1. Darrow JJ, Avorn J, Kesselheim AS. FDA approval and regulation of pharmaceuticals, 1983-2018. JAMA. 2020;323(2):164-176.
  2. US Food and Drug Administration. Federal Register. Code of Federal Regulations Title 21, 21CFR314.510. Revised April 1, 2019. Page updated September 19, 2019.
  3. Sharfstein JM. Reform at the FDA—in need of reform. JAMA. 2020;323(2):123-124.

This article originally appeared on MPR