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 postapproval trials as a condition of approval. “In general, nothing prevents the FDA from requiring postapproval studies whenever it feels they are needed,” he said.

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“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.”

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“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.

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  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 Cancer Therapy Advisor