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Continued from page 25 efficacy advantage when compared with non – breakthrough-designated drugs .” 10
Another study , published in JAMA Network Open , looked at trends in approvals since the introduction of fast track designation and identified changes in the evidence supporting these decisions . 11 Between 1995 and 1997 , 81 % of new drugs were approved based on at least two pivotal trials ; between 2015 and 2017 the proportion approved based on at least two trials was only 53 %. In addition , fewer of those trials used active comparators as opposed to a placebo or historical control arms .
However , using a smaller number of trials did not necessarily mean products were approved based on fewer data . The average number of patients the drugs were tested on remained the same . Trials also lasted longer : The proportion of drugs supported by a pivotal trial that lasted 6 or more months increased from 26 % in 1995 to 46 % in 2015 .
Over time , explained Dr . Nowakowski , scientists have begun collecting better and better preclinical data on which to base trials . “ The science that feeds the development of those drugs is much stronger than it was in the past ,” he said .
Dr . Darrow argued that the number of participants in these trials is less important than the extent of benefit the trials demonstrate . “ Patients ’ interests are not served by the amount of evidence available , but by the amount of benefit ,” he said , justifying the breakthrough therapy designation . “ You don ’ t need to give a thousand people a parachute to know it could save a life . One is sometimes enough .”
Still , there is some evidence that when cancer drugs are approved based on data outside of randomized controlled trials , they require more safety-related label modifications . 12 Of nearly 60 drugs approved between 2006 and 2016 , indications not supported by randomized clinical trials were more likely to require post-approval modifications for common adverse events ( odds ratio [ OR ] = 5.78 ) and major modifications in warnings and precautions ( OR = 4.61 ). “ Health care professionals should be vigilant for unrecognized adverse effects when prescribing drugs approved without a supporting randomized controlled trial ,” the authors concluded .
Having more participants in the trial makes it easier to show a miniscule improvement , but for rare diseases , it is difficult to find enough patients to create large control and experimental groups . To resolve that , Alan Mast , MD , PhD , Medical Director of Transfusion Medicine and Senior Investigator at Versiti Blood Center of Wisconsin and co-chair of the ASH Working Group on Innovations in Clinical Trials , noted that researchers have started using creative statistics to make sense of smaller numbers of patients . For example , “ researchers can have a common control group that can be used for multiple different studies .”
Mr . Kohler from the FDA stressed that “ none of the expedited programs change the evidence needed for FDA approval .”
For drugs approved through the accelerated approval pathway , though , experts suggest that the required post-market confirmatory trials are insufficient to verify a product ’ s clinical benefit . “ The compliance of sponsors to actually do those phase IV confirmatory trials in any sort of reasonable time is fairly low ,” said Dr . Bateman-House . Any time an adverse event occurs , even outside of these post-market trials , physicians are expected to report it through the FDA Adverse Event Reporting System , but she noted that underreporting is possible .
Recruiting patients for these trials also is a challenge , especially when the drug is already available , she added . In some post-marketing trials , there is a chance the patients will get a placebo or an older therapy ; if they refuse to participate , they may be able to guarantee they will get the newly approved drug .
Sometimes the trials are completed only overseas , meaning the participants are not reflective of the patients who would receive the drug in the U . S . or the control arms may not be typical for how patients are treated in the U . S ., Dr . Rajkumar noted .
Pressure to Approve
The speed with which drugs are approved also raises concerns about pressure from the political arena and patient-advocacy groups .
In 2016 , the FDA granted accelerated approval to eteplirsen , a muscular dystrophy drug , amid great controversy and with what was considered very limited evidence . The FDA had gone back and forth with the drug ’ s manufacturer , Sarepta , for months about a trial of 12 patients that suggested that the drug might increase levels of the dystrophin protein that patients lack and may have improved their performance on a 6-minute walking test . 13 Muscle biopsies revealed that the drug only increased dystrophin levels an average of 0.9 %. There was no placebo-controlled arm of the trial . In its decision , the FDA went against its own scientific advisors and its review panel that recommended against approval , which triggered a formal internal dispute process .
Muscular dystrophy patient advocacy groups were thrilled to have a new treatment available . 14 As Dr . Bateman-House put it , “ Patients may say , ‘ Let me make my choices , even if it ’ s a risky choice . What works for the mass population may not be what works for me . Let me just have it so I can take my chances .’”
When asked about allegations that political pressure played a role in these or other approvals , Mr . Kohler stated , “ The FDA is a science-based agency , and its decisions are made on the basis of science .”
Soon , however , the fact that the drug made it to market hardly mattered , as many insurance companies refused to cover the treatment , which cost $ 300,000 and which payers felt had too little evidence to support its efficacy . 15 Patients without the means to pay continued to be unable to access it , and some patients set up GoFundMe accounts to try to raise the money . “ This is a classic example of why it is so important that we have robust evidence , not only for patients ’ health , but also for their economic well-being ,” said Dr . Bateman- House .
SIDEBAR
Internal Pressures and “ The December Effect ”
Aside from review benchmarks associated with the accelerated-approval pathway , a recent analysis found that the FDA may be implementing its own internal deadlines to quickly approve drugs . Unfortunately , these pressures may be related to more safety events .
“ Absent explicit quotas , incentives , reporting , or fiscal year-end motives , drug approvals around the world surge in December , at month-ends , and before respective major national holidays ,” the researchers wrote . For example , looking at approvals between 1980 and 2016 , they found that approximately 15 % of all new drugs are approved in December , an increase of around 80 % relative to the average month .
The burst of activity has an unintended side effect : End-of-year approvals were eventually associated with more hospitalizations , life-threatening incidents , and deaths .
While they concluded that drugs approved at the end of the year should receive additional scrutiny , the authors noted that their analysis was based on absolute counts of drug approvals and adverse events . This means that they were unable to determine how many people used a drug or how many people benefited from having access to it .
Source : Cohen L , Gurun U , Li D . Internal deadlines , drug approvals , and safety problems . SSRN preprint . July 30 , 2019 . Accessed October 8 , 2020 from https :// ssrn . com / abstract = 3427338 .
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