SPOTLIGHT with a liquid formulation of sulfanilamide that had been mixed with diethylene glycol ( a chemical normally used in antifreeze ) – that Congress passed the 1938 Federal Food , Drug , and Cosmetic Act . 3 The 1938 legislation , which requires that drugs be proven safe before they are widely used , has been modified several times but remains the basis for FDA regulation of these products .
Proving the safety and eventually the efficacy of drugs is no small task . The process of taking a drug from discovery through the clinical trials required for review can take up to a decade . Then , the FDA spends months or even years reviewing the data as it considers whether to approve a product . As this is happening , patients are waiting .
“ It ’ s a tough spot with serious diseases like cancer ,” explained S . Vincent Rajkumar , MD , Professor of Medicine and Consultant in the Division of Hematology at Mayo Clinic . “ We could have a very useful drug to treat cancer , but if we are required to conduct randomized controlled trials and to show improvement in survival , in some cases that could take 10 years or longer .”
So , over the past 40 years , the FDA has devised programs to expedite the process : orphan drug , priority review , and breakthrough therapy , as well as fast track designations and the accelerated approval pathway .
“ Each of these programs is designed to facilitate the development and approval of promising therapies to address unmet medical need in the treatment of serious or life-threatening conditions ,” FDA spokesperson Charles Kohler told ASH Clinical News . The agency defines “ filling an unmet need ” as “ providing a therapy where none exists or providing a therapy that may be potentially better than available therapy .”
The orphan drug program came first . Established by the Orphan Drug Act in 1983 , the program incentivizes pharmaceutical companies to take the financial risk of developing drugs to treat rare diseases – those affecting fewer than 200,000 people . 4 Developing these types of therapies has always been a challenge , one that wasn ’ t especially lucrative for companies given the small patient populations who would eventually be treated with an orphan drug . The act offered three main incentives : federal grants for orphan drug research , a 50 % tax credit to help cover the cost of clinical trials , and 7 years of marketing exclusivity for products approved as orphans . However , it does not necessarily speed up the approval or access to a drug .
Taking the idea a step further , the FDA enacted its expanded access program in 1987 . The program does not speed up the approval process itself but grants certain patients access to investigational drugs before they are approved , assuming the patient has no comparable alternatives and does not qualify for a clinical trial .
In 1988 , as the AIDS epidemic surged in the U . S ., the FDA launched its fast track program . 5 According to the FDA ’ s guidance , this program is reserved for drugs being developed to treat or prevent a condition with no current therapy or those that may show a major advantage over other available options , such as superior effectiveness , fewer serious side effects , or improved diagnosis of a serious condition . If a therapy receives a fast track designation , it means that the FDA will be available for additional support and feedback throughout the research and application process . It also provides an opportunity for rolling review , which means that a pharmaceutical company can submit individual sections of its application as they are completed . In theory , it could speed development by identifying and resolving issues quickly , although it does not explicitly expedite the review timeline .
Four years later , the agency added the accelerated approval pathway . This is the only pathway that allows drugs to be approved based on surrogate , rather than clinical , endpoints . 6 A surrogate endpoint can be a laboratory measurement , radiographic image , physical sign , or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit . “ For example , if a drug demonstrates a large improvement in a measure such as progression-free survival , it is likely that the drug would prolong overall survival eventually ,” explained Dr . Rajkumar .
But , he added , this does not guarantee clinical benefit . Once a drug receives accelerated approval , the pharmaceutical company that manufactures it is required to complete post-market confirmatory trials to demonstrate that clinical benefit . If the trial fails to do so , a drug can be removed from the market , which rarely happens , said Alison Bateman-House , PhD , MPH , Assistant Professor in the Department of Population Health at NYU Grossman School of Medicine .
The FDA also introduced the priority review program in 1992 , which sets a goal review time of 6 months – a process that typically takes about a year . 7 Again , this designation is intended for drugs that would provide significant improvements in safety and efficacy over existing options . The same year , Congress also passed the Prescription Drug User Fee Act ( PDUFA ), allowing the agency to collect fees from drug manufacturers at the time of application submission to help fund the review process . To collect the fees , the FDA is required to meet certain performance benchmarks with respect to response time during the review process .
Most recently , in 2012 , the FDA introduced the breakthrough therapy designation . If an investigational product is granted this designation , the developer receives the benefits of the fast track program , plus intensive guidance on an efficient drug development program such as the use of smaller trials with alternative designs . 8 Breakthrough therapy status is given based on early clinical data using established surrogate endpoints . According to the FDA , “ the primary intent of breakthrough therapy designation is to develop evidence needed to support approval as efficiently as possible .”
An investigational product can fall into more than one of these programs , but , according to Johnathan Darrow , SJD , MBA , Faculty Member of the Center for Bioethics and Assistant Professor of Medicine at Harvard Medical School , the breakthrough therapy designation is particularly appealing .
“ If you want to begin to condition the market to receive your drug , to value your drug highly , to prescribe your drug , having the word ‘ breakthrough ’ is a great thing ,” he explained . “ Your application
The FDA ’ s Expedited Pathways to Approval
Accelerated approval : Allows drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint
Breakthrough therapy : Expedites the development and review of drugs which may demonstrate substantial improvement over available therapy
Fast track : Facilitates the development and expedites the review of drugs to treat serious conditions and fill an unmet medical need
Priority review : Sets a goal to take action on an application within 6 months
also gets special FDA attention , but much of that attention was already available through the fast track program . So , one of the main benefits of the breakthrough therapy program that ’ s not available through the fast track program is the name .”
Drug Development Timelines
Whether these new regulatory programs actually quicken the pace of approval isn ’ t clear . To understand their impact on drug development , Dr . Darrow and colleagues reviewed data about the number of novel drug approvals – and the speed at which they get to market – from 1983 to 2018 . 9
The agency ’ s expedited-review programs are popular : 48 of the 59 new drugs approved in 2018 benefited from the accelerated approval , fast track , or priority review designations . Since 1986 , after the orphan-drug program was introduced , the time it takes for the FDA to review drug applications dropped from 2.8 years to 10.1 months for standard applications and 7.6 months for priority applications , suggesting that the newer drugs are being brought to market faster .
However , the total amount of time from when a company files an investigational new drug ( IND ) application – which shows that the risk-benefit ratio is likely to be reasonable enough , based on preclinical testing or experience with the drug in other clinical indications – that the drug should be tested in humans with a specific condition – to approval has remained steady , if not increased . From 1986 to 1996 , the average time from authorization of clinical testing to approval was 7.8 years ; between 1997 and 2007 , it dipped slightly to just 7.0 years , but jumped to 9.1 years between 2008 and 2017 .
While those overall average development times have stayed relatively long , drugs with breakthrough designations tend to be approved faster , in less than 5 years , the researchers noted .
Expedited or Shortsighted ?
A shorter review time means patients have access to new treatments faster , but a shorter review time also means that there are fewer data upon which to base approval . Several studies have looked at whether the trade-off is worth it . For example , despite faster approvals , a 2018 study found “ no evidence that these drugs provide improvements in safety or novelty [ and no ] statistically significant
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