How the FDA tries to balance urgent needs against real risks when evaluating new drugs
Update (April 15, 2014): This story has been updated to reflect that there is now a new FDA office, the Office of Health and Constituent Affairs, whose job it is to serve as a liaison between the FDA and various outside stakeholders, including patient advocates and consumers. See Resources, below.
Original story (April 1, 2013):
The approval of new drugs in the United States is a complex process that seeks to balance the need to protect the health and safety of the population with the need to provide treatment as soon as possible for serious or life-threatening disorders.
Reasonable people may disagree about whether a drug approval process is too fast or too slow, and opinions often change with circumstances. A drug that has even the slightest chance of providing benefit for a disorder that shortens lives may be demanded by families, even if taking it entails considerable risk. On the other hand, when an approved drug is found to have serious side effects, the public often wants answers as to why the medication was moved through the regulatory process so quickly.
|Several mechanisms speed up the review process the FDA uses for new drugs, but only accelerated approval changes the criteria used to approve a new drug.|
The U.S. Food and Drug Administration (FDA), in recognition of the complexity of “too slow” versus “too fast” approval of new drugs, has put into place several measures that apply to serious or life-threatening diseases and allow the agency some flexibility in the review and approval process.
None of these measures changes the requirement that the developer of a new drug conduct adequate, well-controlled studies demonstrating safety and effectiveness in the targeted condition.
“Well-controlled” studies are those in which it is clear that what is being measured is the effect of the experimental treatment itself and not something else (such as a person’s eating habits or beliefs about the treatment).
However, there is no absolute FDA requirement that a specific number of phases of a clinical trial be conducted before a drug can be approved. If a phase 2 study is well-done and persuasive and can be interpreted as meeting safety and efficacy criteria, it can provide the basis for FDA approval. There is no absolute requirement for a phase 3 study.
Below is an explanation of some of the options open to the FDA when considering new drugs for life-threatening diseases.
When time is of the essence, the FDA has three special designations it can bestow on an experimental drug.
Fast track: To qualify for this designation, the drug developer must provide early evidence that the new drug may provide benefit over available therapies (if there are any). The evidence can come from animal or other laboratory studies or from human testing.
Breakthrough therapy: This designation is similar to fast track designation, with one important difference — the evidence for benefit over available therapies must come from humans, not from laboratory experiments.
When an investigational drug is given either fast track or breakthrough therapy designation, the following things happen:
An example of a drug that has received fast track designation is RG3039, an experimental drug for spinal muscular atrophy (SMA) developed by the biotechnology company Repligen, with support from MDA.
Priority review: This designation applies to a later stage of the drug approval process — after the drug’s developer has submitted a complete new drug application (NDA) to the agency but before that application has received a complete review.
To qualify for priority review designation, a new drug must appear to provide:
If the new drug is a biologic substance, such as a protein, it can qualify for priority review only if it is directed at a serious or life-threatening disorder.
If the new drug is a chemical not directly derived from a biologic substance, it can qualify for priority review if it’s aimed at any condition.
Accelerated approval: While the previous designations are aimed at making the FDA’s review of a new drug faster, the accelerated approval mechanism actually changes the basis on which a new drug can be approved.
|A company whose drug is designated a breakthrough therapy gets advice and meetings from the FDA early in the drug development process, involvement of senior FDA staff members and other experts, and the ability to submit parts of the new drug application as they become finalized.|
In general, approval of a company’s application to market a new drug requires studies that show an effect on an endpoint that clearly reflects clinical benefit, such as an improvement in function or survival.
Endpoints, also called outcome measures, are the measurements taken during a clinical trial. For example, if the goal of the treatment is weight loss, then change in weight would be a good endpoint for the trial. If the goal of the treatment is migraine headache prevention, a good endpoint would be the number of headaches in a given time period.
The accelerated approval mechanism, added to FDA regulations in 1992 for treatments for serious or life-threatening illnesses, allows regulators to use what is called a surrogate endpoint rather than a true endpoint as a measure of a drug’s effect in a trial. These substitute endpoints are particularly useful in conditions where a true endpoint, such as survival time or avoidance of disability, would require exceptionally long or exceptionally large clinical trials.
The FDA defines a surrogate endpoint as an outcome measure that is either known to predict a clinical benefit or is “reasonably likely to predict clinical benefit” but does not itself reflect a direct clinical benefit.
A mainstream example of a surrogate endpoint is blood cholesterol level, which is associated with clinical benefit but does not directly show clinical benefit in some cardiovascular conditions. Other surrogates include shrinkage of a tumor, which is reasonably likely to predict clinical benefit in some cancers but does not necessarily do so; and shortterm reduction of viral levels, which is reasonably likely to predict clinical benefit in HIV/AIDS but is not a clear indicator of long-term benefit.
In amyotrophic lateral sclerosis (ALS), a true endpoint would be survival time or duration of walking ability, which generally take years to assess. A possible surrogate endpoint, however, might be the estimated number of surviving motor neurons, measured by electrophysiological testing.
In Duchenne muscular dystrophy (DMD), a true endpoint might also be survival time or duration of walking ability, again requiring years of observation. But a widely accepted surrogate endpoint is the distance a child can walk in six minutes; and a proposed surrogate endpoint is the level of dystrophin protein in a muscle biopsy sample.
Accelerated approval always comes with a requirement that the company continue to study the drug post-approval to confirm its benefit.
Expanded access: Companies can submit an application to the FDA to make a drug available to people with a serious or life-threatening disorder before it is approved for that condition. Such an application has a reasonable chance of succeeding when there is no existing treatment for the condition and when there is some evidence that the new drug is effective.
For example, the drug 3,4-diaminopyridine is available under an expanded access program to people with Lambert-Eaton myasthenic syndrome (LEMS).
A major concern the FDA has about expanded access is that it will interfere with ongoing studies. Therefore, the agency is most likely to allow an expanded access program when there is some assurance that the program won’t do this.
Companies must continue to collect safety data from people who are receiving a drug under an expanded access program. They’re allowed to charge for the drug, but so far, most have opted not do so.
|Orphan drug designation provides financial incentives to companies for developing drugs for rare (“orphan”) diseases.|
Orphan drug designation: This mechanism is designed to encourage development of drugs for certain types of diseases. Unlike the mechanisms above, orphan drug designation doesn’t hasten the review process, change the criteria for approval, or allow early access to a drug.
It does, however, provide financial incentives for companies to develop drugs for rare (“orphan”) diseases, which the FDA defines as those affecting 200,000 or fewer people in the United States. Without these incentives, a company may estimate that the cost of developing a drug for a rare disorder will not provide an adequate return for its investment.
In January 2013, the Dutch biopharmaceutical company Prosensa announced it had received orphan drug designation in the U.S. for its experimental DMD drugs PRO045, PRO052 and PRO055.
The experimental SMA drug ISIS-SMNRx, in development by Isis Pharmaceuticals and Biogen Idec, has both orphan drug designation and fast track designation.
In general, MDA would like to see a drug development process that is as fast as possible but slow enough to allow reasonable assurance of safety and efficacy.
In her January 2012 Quest article Why Does It Take So Long To Go from Mouse to Man? MDA Vice President of Research Jane Larkindale said, “MDA’s goal is to accelerate the process as much as possible in order to get drugs to people quickly — but only in such a way that those drugs are both safe and effective … The process is slower than we would like. But it is essential in order to get a safe and effective drug into clinical trials — and ultimately into the hands of the people who need it.”
For more information, see: