An ongoing push to speed new medicines to patients has led to the growth of new Food and Drug Administration programs with relaxed evidence standards for approving drugs, according to an analysis from researchers at Harvard Medical School and Brigham and Women’s Hospital.
The findings, released Tuesday, mean patients and their doctors may not fully understand the risks and benefits of taking the latest medicines, especially when the majority of newly approved drugs offer “extremely modest benefits” over existing therapies, corresponding author Jonathan J. Darrow said in an interview.
“There’s nothing inherently wrong with faster approval of drugs. It has to do with the approval of the drugs on the basis of less evidence—or really less certainty,” said Darrow, who’s part of Harvard’s Program on Regulation, Therapeutics, and Law. “We’re talking about an erosion in the amount or quality of the evidence.”
Joshua M. Sharfstein, a former second-in-command at the FDA, said in a separate commentary that the findings highlight the need to modify a drug approval process that’s evolved into “a thicket of special programs, flexible review criteria, and generous incentives.”
FDA spokesman Nathan Arnold said the agency is concerned, based on a “preliminary analysis” of the study, that it doesn’t “adequately consider the marked changes in the types of drugs that the FDA now reviews.” The agency is conducting a more detailed analysis of the study’s recommendations, he said.
Richard Pazdur, director of the FDA’s Oncology Center of Excellence, rejects the notion that the agency has sped approval times by lowering standards. There’s a much better understanding of how well the therapeutic agents in the drugs work compared to 20 years ago, he said during a Friends of Cancer Research briefing in December. Response rates to new drugs have gone from 5%-6% to 60%.
“Our standards haven’t changed. The drugs changed. The drugs are better drugs, and that’s the bottom line,” Pazdur said.
The study’s authors call on Congress and the research community to periodically reevaluate whether they’ve hit the right balance between speedy development of innovative medicines and requiring drug companies to produce rigorous evidence.
The analysis, which appears in the Jan. 14 issue of the Journal of the American Medical Association, examines how the FDA’s drug approval process has evolved over the last four decades. The 1983 Orphan Drug Act (Pub. L. 97-414) was the first legislation to allow for different standards for clinical trials when there are unmet medical needs for rare diseases.
Since then, Congress has authorized four other programs to expedite new therapies: fast-track designation, accelerated approval, priority review, and breakthrough therapy. Many of the programs grew out of a very different FDA, when the major complaint was that the agency took too long to review drugs and fell behind its international counterparts.
The study found that the accumulation of such special approval programs led to more drugs entering the market based on surrogate endpoints, such as tumor shrinkage, rather than more clearly beneficial clinical endpoints, such as increased survival rate.
The FDA is also approving more drugs based on one pivotal trial—a study used to support a marketing application—instead of two. More clinical trials haven’t been randomized, the amount of time the FDA spent reviewing a drug went from about three years in the 1980s to less than one year in 2018. Clinical trials under an expedited program are less likely to be randomized or double-blinded, the study found.
Jeff Allen, CEO of the nonprofit Friends of Cancer Research, said the breakthrough therapy designation has shown to reduce drug development times by 40% while improving response rates, reducing death rates, and lowering adverse events. Those results equate “to a remarkable success for people with previously untreatable diseases.”
The Friends organization successfully advocated for the breakthrough approval process, which became law in 2012 to speed the development and review of new drugs for serious or life-threatening conditions.
“I commend the authors on their thorough analysis,” Allen said on Tuesday. “Perhaps one consideration to add to their findings is the scientific progress that has occurred over this same period. At least in oncology, the drugs being developed in the 80s and 90s were very different than those of today.”
This progress is likely “the key factor in modifications to development and led to opportunities to apply different regulatory tools,” he added.
Designated as ‘Special’
The proportion of drugs approved with at least one special review program has increased substantially to more than 80% in 2018, compared with 48% from 1986 to 1996.
“Maybe I should put special in quotation marks because they are actually now the rule rather than the exception,” Darrow said. The programs have formalized flexibilities and exceptions to the FDA requirements for demonstrating the drug is safe and effective, he said.
But the FDA is working within the framework Congress gave it, Sharfstein said in his commentary calling for changes to the FDA. Sharfstein is vice dean of public health practice and community engagement at the Johns Hopkins Bloomberg School of Public Health.
“The thicket of incentive programs was largely created by Congress, so legislation will be necessary for some of the important steps forward,” he said.
Sharfstein, who was the FDA’s principal deputy commissioner during the first two years of the Obama administration, said he didn’t work specifically on modernizing the drug approval process. But he set up FDA Track, a performance management system, to help the agency better understand its data.
“This is the kind of system that could be used to assess how these incentive programs are working, and what could be done to make them more efficient and effective,” he said.