The Food and Drug Administration (FDA) approval process for new drugs and biologics is a complex procedure aimed at ensuring that therapeutic agents are effective and relatively safe for their approved indications. A recent study examined the pivotal clinical trials that served as the basis of FDA approval and found a variation in the quality of the clinical trial evidence the FDA used to approve new drugs. Of the 448 pivotal trials that were identified, nearly 90% were randomized and almost 80% were double-blind. Slightly more than half of the trials (55.1%) used a placebo as the comparator treatment, 31.9% used an active drug as the comparator, and 12.9% used no comparator. The trials also varied with regard to endpoints, study duration, number of subjects enrolled, and number of subjects completing the trial.
We won’t go into detail about the study methodology and all of the results. You can read the full-text article, which was published in the Journal of the American Medical Association (JAMA), at the JAMA Network website. The findings support what we’ve been saying: Not all evidence is created equal. There is a hierarchy of evidence we need to recognize. The weakest form of evidence comes from single case reports. These are the observations and anecdotal reports of the outcomes seen in 1 or 2 patients. The strongest type of evidence comes from meta-analyses and randomized controlled trials that enrolled enough subjects so that the results have meaning.
Keep in mind that FDA regulations for approval address safety and efficacy but not cost, cost-effectiveness, or broader social issues. Sponsors must provide evidence showing that their products are as safe and as efficacious as the labels claim, but they are not required to show safety and efficacy relative to similar products. Thus, FDA-required studies generally do not produce comparative-effectiveness or cost-effectiveness data that may help clinicians choose among alternative products (e.g., different drug treatments), or alternative technologies (e.g., treatment with drugs versus surgical treatment). In addition, since October 1998 the FDA has offered a fast track drug development process for certain drugs being developed to treat life-threatening and other serious diseases if the drugs demonstrate the potential to address an unmet medical need for such a condition. The FDA works closely with pharmaceutical companies that receive fast track approval to expedite preclinical and clinical research and accelerate the drug-approval process.
The FDA also may grant orphan drug designation for a particular drug, biologic, or combination of agents to be administered by a certain route and in a specified dose range for the treatment of a certain disease or condition. This designation does not imply that the FDA has approved the drug or granted a license for marketing. To receive orphan drug designation, the drug must be intended for use for a disease that affects fewer than 200,000 persons in the United States. In addition, if the disease affects more than that number, but the sponsor cannot reasonably expect to recover the development costs associated with the FDA’s required before-market testing, the FDA may grant orphan drug designation.
The reality, as this study shows, is that some therapeutic agents are approved based on the results of only 1 clinical trial whereas others may have 2, 3, or more clinical trials that form the basis of their FDA approval. Consumers and clinicians need to be aware of this. Likewise, to ensure patient safety, we agree with the authors’ suggestion that regulatory agencies consider implementing a “life-cycle” approach. Such a process includes continuous monitoring of a drug’s risk and benefits after it comes to market and a communication plan to inform consumers and physicians about new information as it develops.