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The Food and Drug Administration (FDA) is an agency of the United States Department of Health and Human Services. Among its many responsibilities is the regulation of $275 billion worth of domestic pharmaceutical sales each year and the protection of consumers from unsafe or ineffective drugs manufactured by over 20 thousand human drug and biologic firms, worldwide.
The FDA’s origins can be traced back to 1848 when the U.S. Patent Office was authorized to carry out chemical analyses of agricultural products. Its modern regulatory functions began with the passage of the 1906 Pure Food and Drugs Act, a law that prohibited interstate commerce in adulterated and misbranded food and drugs. Over the following decades, the governing statues under which the FDA functions continued to be revised and updated.
FDA Granted Federal Authority for Drug Approval
The 1938 Food, Drug and Cosmetic Act replaced the outmoded 1906 law and significantly increased federal authority over the pharmaceutical industry, mandating a pre-market review of the safety of all new drugs. In 1951, the Durham-Humphrey Amendment defined the kinds of drugs that cannot be safely used without medical supervision and restricted their sale to prescription by a licensed practitioner. The 1962 Kefauver-Harris Drug Amendments required drug manufacturers to prove to the FDA, not only their products’ safety, but also their effectiveness before they could be marketed, and that effectiveness had to be proved by “substantial evidence,” defined as including “adequate and well-controlled clinical studies.” With that mandate, the introduction of new drugs to the marketplace was now heavily dependent upon the FDA’s ability to process, review, and approve any new applications.
While these and other reforms were enacted with the intent of protecting the American public from unsafe or ineffective pharmaceuticals, they had the ancillary effect of increasing the time required to bring a drug to market. Often, it can take 10 or more years to move a drug from conception, through investigation and testing, and finally to the medical community and consumers. With the passage of the Kefauver-Harris Amendments, a typical drug was taking an average of 30 months after its application to receive FDA approval. By the late 1980s, AIDS activists were demanding that the agency speed up access to life-saving drugs to combat what, at the time, looked like an inexorable epidemic. Pharmaceutical companies were also lobbying for more speed, threatening to move research, development and clinical studies abroad where it was easier to initiate patient trials and get a drug through the approval process.
FDA Reduces Drug Approval Time
In 1992, in response to increasing pressure, Congress passed the Prescription Drug User Fee Act (PDUFA). Under the act, the FDA agreed to specific goals for improving the drug review time and created a two-tiered system – StandardReviewandPriority Review.Standard Review is applied to a drug that offers at most, only minor improvement over existing marketed therapies and its review would now take no longer than 12 months. A Priority Review designation is given to drugs that offer major advances in treatment, or provide a treatment where no other adequate therapy exists. These drugs could earn six-month reviews. In exchange for speed, the act required the pharmaceutical industry to pay new user fees to underwrite the FDA’s need for augmented resources, including an increase in the number of reviewers examining new drug applications.
With industry dollars rolling in, the FDA began to approve drugs much more quickly. In 1993, the median time for a Priority Review was 16.3 months. A Standard Review, by contrast, took20.8 months. By 1995, Priority Reviews took 7.9 months while Standard Reviews took 16.2 months. By 1997, user fees were adding $87.5 million to the FDA’s annual budget. In 2009, the agency’s budget request was just under $2.4 billion, with $628 million of that total coming from pharmaceutical company user fees.
Fast-Track Program Created
In 1997, the Food and Drug Administration Modernization Act directed the FDA to create a mechanism whereby important new drugs could get to patients even more quickly. Drugs could be designated as “Fast Track” if they met two criteria: first, the drug must show promise in treating a serious life-threatening condition (such as AIDS, Alzheimer’s, heart failure, cancer, epilepsy, depression and diabetes), meaning that it 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; and second, the drug must have the potential to address an unmet medical need, meaning that no other drug or remedy either exists or works as well. If there are existing therapies, a fast track drug must show some advantage over available treatment, such as superior effectiveness or avoiding serious side effects that occur with an already-available medication.
A drug that receives Fast Track designation is eligible for some or all of the following:
- More frequent meetings with FDA to discuss the drug’s development plan and ensure collection of appropriate data needed to support drug approval.
- More frequent written correspondence from FDA about such things as the design of the proposed clinical trials.
- Eligibility for Accelerated Approval – i.e., approval on an effect on a surrogate, or substitute endpoint, reasonably likely to predict clinical benefit. For instance, a drug that promises to extend the survival of cancer patients can be approved even if it has only been shown to shrink tumors in a clinical trial. Shrinking tumors is a surrogate endpoint because it is a meaningful outcome in and of itself, and an indirect measurement of the drug’s effectiveness. Final approval of a drug based on such endpoints is given on the condition that post marketing clinical trials verify the originally claimed benefit. If a confirmatory trial proves otherwise, the FDA can remove the drug from the market. The Accelerated Approval process was codified in the 1992 PDUFA.
- Rolling Review, which means that a drug company can submit completed sections of its New Drug Application (NDA) for review, rather than waiting until every section of the application is finished.
- Dispute resolution if the drug company is not satisfied with an FDA decision not to grant Fast Track status.
In addition, most drugs that are eligible for Fast Track designation are likely to be considered appropriate to receive a Priority Review. Fast Track designation must be requested by the drug company. The FDA reviews the request and will generally make a decision within 60 days based on whether the drug fills an unmet medical need treating a serious disease. The request can be initiated at any time during the drug development process, but typically, the Fast Track designation will occur during Phase 2 or 3 of the drug’s clinical trials.
Ever-Increasing Drug Approval Rates
By 2008, manufacturers had requested Fast Track designation for 569 drugs and 195 biological products since the Fast Track program was set into law. The FDA granted the designation to 74.5 percent of those drug requests and 63.6 percent of the biologics requests. Of the products with Fast Track designation, the FDA eventually approved 10.6 percent of the drugs and licensed 17.7 of the biologics. The FDA receives approximately 100-130 applications a year, and has stated that “close to 80 percent of all filed applications will eventually be approved.”
Because the compressed timeline of a Fast Track application narrows the already thin margin for error of a standard NDA, criticisms of the FDA’s approval procedures began to be levied by those who contended that the sped-up process allowed drugs to enter the marketplace prematurely. Numbers from the early years of the new system seemed to lend credence to the claim. From 1993 to 1996, 1.6 percent of new drugs approved by the FDA were taken off the market because of safety problems. Of the drugs approved between 1997 and 2000, 5.3 percent were later withdrawn.
Nonetheless, proponents of the FDA’s Fast Track, and other expedited procedures, maintain that the changes in the approval process help patients with debilitating diseases get new treatments and critical medications quickly – treatments that were previously denied them because of bureaucratic regulations.
Critics point to the very public recalls of drugs like Vioxx, a painkiller taken by millions of Americans that caused heart attacks and strokes, Rezulin, a diabetes drug that caused 58 deaths due to liver problems, and Avastin, a breast cancer drug that proved ineffective, among others, as evidence that the FDA now moves too swiftly, often under pressure by the pharmaceutical companies, to expedite approvals. Frequently, these drugs are cash cows for the companies that manufacture them, and they fight to keep them on the shelves, even as post-marketing evidence shows them to be dangerous or unproductive. Merck & Co. sold $2.5 billion of Vioxx worldwide in 2003, yet before it was recalled, an FDA senior reviewer estimated that up to 139,000 people taking the drug had suffered a heart attack or stroke, and 40 percent of them died, because of the agency’s haste to get Vioxx approved.