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By Carol Rados
The rapid development of better drugs to treat life-threatening illnesses is in everyone's interest. To address this important health care issue, the Food and Drug Administration has developed three distinct approaches that are intended to make important treatments available more rapidly to those who desperately need them: "fast track" designation of drugs, "accelerated approval," and "priority review."
These three approaches expedite the development and review of innovative agents for the most serious or life-threatening conditions, but represent very different kinds of effort. Because they all imply speed--and in order to avoid confusion--it is important that people understand the specific meaning of each and the distinction among them.
Fast track designation was part of the FDA Modernization Act (FDAMA) of 1997, important legislation that made significant changes in the regulation of food, medical products, and cosmetics. This approach is a process designed to facilitate the development and expedite the review of drugs that treat a broad range of serious diseases and fill an unmet medical need. Filling an unmet need means providing therapy where none exists or demonstrating superiority of a drug to existing therapies.
"Determining whether a disease is serious," says Patty Delaney, a public health specialist in the FDA's Office of Special Health Issues, "generally is based on whether the drug will have an impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one." AIDS, Alzheimer's disease, heart failure, and cancer are examples of the more obvious serious diseases. Epilepsy, depression, and diabetes, however, are also considered serious.
Any drug being developed to treat or prevent a disease that has no current therapy is directed at an unmet need. If there are existing therapies, a fast track drug must show some advantage over them, such as:
Drug manufacturers may request fast track designation at any time during the drug development process. The FDA will review the request and make a decision within 60 days, based on whether the drug fills an unmet medical need in a serious disease. Once a drug receives fast track designation, early and frequent communication between the agency and the drug company is encouraged throughout the entire drug development and review processes. The frequency of communication ensures that questions and issues are addressed quickly.
"With the fast track designation, FDA agrees to meet frequently with sponsors throughout the drug development process to agree on study designs and appropriate outcome measures," says Robert Temple, M.D., director of the FDA's Office of Medical Policy. "This allows companies to plan and carry out the most rapid possible responsible development," he says, "and it is perhaps the most important, yet under-appreciated, aspect of fast track."
In addition to the opportunity for frequent communications with the FDA, a drug that receives fast track designation is eligible for two other important programs:
When a new drug is being studied, it can take many years and very large studies to learn whether patients experience such clinical benefits as having fewer strokes or living longer. In some cases, however, there is an effect on a measurement like blood pressure or cholesterol that can serve as a surrogate for a showing of the hoped-for clinical benefit. The accelerated approval process was developed to make new drug products available for life-threatening diseases without adequate treatment before those clinical benefits were shown, but on the basis of a well-thought-out surrogate endpoint.
Temple says that some surrogate endpoints, such as lowered blood pressure, are so well-established that drugs for high blood pressure are granted regular--not accelerated--approval. Accelerated approval is for less well-established surrogates--those that are reasonably likely to predict clinical benefit based on epidemiologic data, results with other drugs that affect the same endpoint, or understanding of disease mechanisms.
For example, instead of having to wait to learn whether a drug actually can extend cancer patients' lives, the FDA might approve a drug based on evidence that the drug shrinks tumors at a reasonable rate, because that would be considered reasonably likely to predict a real clinical benefit--longer life. The use of such a surrogate endpoint can considerably shorten the time required to receive FDA approval.
Velcade (bortezomib), an injection to treat multiple myeloma, the second most prevalent blood cancer in the United States, was approved in less than four months under the FDA's accelerated approval program in May 2003. The results of two studies showed partial or, in some cases, complete disappearance of tumors. The main study involved 202 people whose cancer had progressed even though they had received at least two previous types of chemotherapy. Velcade, which is marketed by Millennium Pharmaceuticals Inc., of Cambridge, Mass., is indicated only after two previous treatments have failed, since other treatments exist for earlier stages of multiple myeloma.
Most important, the drug showed a significant effect on people with multiple myeloma who have not responded to other treatments, which means it is likely to result in significant clinical benefit.
The agency bases its decision on whether to accept a proposed surrogate endpoint, such as tumor shrinkage, on its scientific support as a predictor of clinical benefit. The studies that demonstrate the effect of the drug on the surrogate endpoint must be adequate and well-controlled, the only basis, by law, for finding that a drug is effective. All treatments approved under the accelerated approval process must undergo further studies for clarifying a drug's clinical benefits. Therefore, the drug company would still need to conduct studies to confirm that tumor shrinkage, for example, actually does predict that patients will live longer or show improvement in their symptoms.
If these follow-up studies show that the drug actually provides a clinical benefit, then the FDA would grant traditional approval of the drug. If not, the agency has regulatory procedures in place that could lead to removal of the drug from the market.
Prior to approval, each drug marketed in the United States must undergo a detailed FDA review process. The FDA has been classifying the likely benefit of a drug since the 1970s, initially in three categories: (A) a major advance over available treatments, (B) a modest advance, or (C) no real advance. More recently, the classification has been in two categories: a real advance (priority or P), or about the same effectiveness as available therapies (standard or S). The kinds of advances a priority drug might represent include:
In 1992, under the Prescription Drug User Fee Act (PDUFA), a law that requires fees be paid by drug manufacturers when they submit an application to market a drug, the FDA agreed to specific goals for completing its review and taking action on drugs. These goals were different for priority and standard drugs.
For standard drugs, which offer at most only minor improvement over existing approved therapies, review and action were to be completed in 12 months. The 2002 amendments to PDUFA changed that goal to 10 months.
Priority drugs, or those that offered a significant improvement over marketed treatments or provided a treatment where no adequate therapy existed, were given a six-month review and action goal.
Priority review status can apply both to drugs that are used to treat serious diseases and to drugs for less serious illnesses. Most drugs that are eligible for fast track designation are likely to be considered appropriate to receive a priority review. Designation of a drug as priority does not alter the scientific or medical standard for approval, or the quality of evidence needed. Priority review also does not affect the length of the clinical trial period.
Since 1996, 68 drugs for cancer therapies have received priority review and approval. In some cases, reviews and actions have been considerably faster than six months. The agency reviewed Gleevec (imatinib mesylate), a treatment for chronic myeloid leukemia, a rare, life-threatening form of cancer, in less than three months. The approval of Gleevec, manufactured by Novartis Pharmaceuticals Corp. of East Hanover, N.J., was based on evidence that the drug could substantially reduce the level of cancerous cells in the bone marrow and blood.
Shortened review times also have brought promising treatments to patients with AIDS more quickly, such as Kaletra (lopinavir/ritonavir), manufactured by Abbott Laboratories of Abbott Park, Ill., which was reviewed and approved in three and one-half months. Pegasys (peginterferon alpha-2A), a combination product for the treatment of hepatitis C, manufactured by Hoffman-LaRoche of Nutley, N.J., was approved for marketing in four months.
"Fast track, accelerated approval, and priority review have evolved over time," says Delaney. "The FDA has been vigilant in assuring that reducing the time necessary for drug development, associated with these approaches, has not compromised the safety and effectiveness of drugs for patients with serious diseases."
Since 1990, the average or median time for approving a priority drug--one that offers a significant improvement over a marketed drug or provides a treatment where none exists--decreased from about 25 months to six months. The average or median time for approving a standard drug--which offers at most only minor improvement over existing approved therapies--was cut in half, from 26 months to 13 months.
Office of Special Health Issues
(301) 827-4460