US new drug applications
In the United States a sponsor seeks approval to market a product as a new prescription drug through a new drug application to the FDA. The application carries the results of development in sections on quality, nonclinical studies and clinical studies, which the agency's reviewers read by their area of expertise. The FDA takes about a year to decide on an application, expedited pathways bring some drugs to review or approval sooner, and the FDA's review times can be set against those of other agencies.
The application
A new drug application is the means by which a sponsor seeks approval from the FDA to market a product as a new prescription drug in the United States. It includes and summarises all the results, from chemistry, manufacturing and controls (CMC), nonclinical studies and clinical studies through phase 3. The quality, safety and efficacy information is documented in the CMC, the nonclinical and the clinical sections of the application, respectively.
The FDA assigns each application submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act a new drug application classification code, and reassesses the code at approval. The codes run from Type 1 to Type 10. Not every 505(b)(1) application is a new molecular entity, which is Type 1; a new indication or claim for the same application, for example, is Type 6. The codes help the FDA coordinate an effective review process in its Center for Drug Evaluation and Research (CDER) and promote consistency across review divisions.
The review
As of 2011, the FDA took about a year to review the application and decide whether the product could be marketed. During that time it may ask the sponsor questions and request additional analyses of the data, and in some cases these requests may stop the review clock until the sponsor responds appropriately.
FDA reviewers are assigned to the components of the application in their own areas of expertise, and they use those documents to write their own reports supporting their recommendations to approve or deny the application. All functional-area members of the review team, however, are likely to read and refer to the summary and overview documents to gain an overall understanding of the product. In addition to its own review, the FDA may convene a panel of experts, an advisory committee, which reviews the documents the sponsor submitted and gives an opinion on whether the FDA should approve the drug.
As of 2015, CDER typically approved more than 100 new medications every year. In 2014, as many as 41 of the newly approved agents were novel molecular entities or new therapeutic biologics, considerably more than in previous years. Many of these new drugs were expected to make a significant contribution to the management of serious or life-threatening diseases. Also in 2014, an exceptionally large number of drugs for rare diseases, 17, were approved, which is of particular merit because diseases occurring in small populations often have no drugs, or no sufficiently effective ones, to treat them.
Expedited pathways
Early and regular communication between drug developers and health authorities allows the authorities to apply tailor-made review and approval procedures, which aim to make important new medications available quickly. In the United States these include Fast Track, Breakthrough Therapy, Priority Review and Accelerated Approval. Fast Track and Breakthrough Therapy designations are intended for drugs to treat serious conditions with unmet medical needs, while Priority Review is granted for drugs expected to provide a significant advance in medical care. For such medications, CDER shortens the review period from 10 months to 6 months.
Accelerated Approval allows early approval of drugs to treat serious or life-threatening illnesses for which less effective treatments are available. Such approval is based on a surrogate endpoint, such as a laboratory value or a biological marker, or on an intermediate clinical endpoint thought reasonably likely to predict clinical benefit. After approval, additional clinical studies are usually required to confirm the predicted benefit.
Review times against other agencies
The Prescription Drug User Fee Act came into force in 1992 to allow the FDA to charge fees for reviewing drug applications. The revenue from the fees is dedicated to providing sufficient resources for the review processes. At each five-year renewal of the act, stakeholders voice their opinions on whether they are getting value for their fees. A recurrent criticism of the FDA has been that its review cycles take too long, so review times were one of the focuses of the renewal of the act due in 2012.
A comparison of review times for novel therapeutics, reported in 2012, found those of the FDA significantly shorter than those of the EMA and Health Canada: 303 days for the first review at the FDA, against over 350 days at each of the other two. Its authors point out that these findings would seem to contradict the criticism that the FDA's review cycles take too long.
One writer sets out caveats to the comparison:
- The FDA was more likely than the EMA to require more than one review cycle, but even when this was taken into account, its overall review times were still shorter.
- Some applications for novel therapeutics in the European Union follow a mutual recognition procedure rather than the centralised one, and these may well be the smaller applications that are faster to review.
- The analysis includes only successful applications, because information about unapproved ones is not publicly available.
- The analysis covers only novel therapeutics, while manufacturers of generics have complained of a backlog in the review of their applications.
Short review times are desirable: pharmaceutical companies enjoy longer market exclusivity, and patients can benefit earlier from new treatments. They should not, however, be attained at the expense of thoroughness, particularly on safety, because the primary remit of regulatory agencies is to protect patients. The quality of a review from a safety perspective is harder to assess. The same writer suggests that one way to assess it would be to look at label changes and drug withdrawals, though the writer knew of no attempt at such an evaluation as of 2012. The same writer holds that the EMA does not come out of the comparison that badly, even taking review time only as a limited measure of efficiency: the pan-European EMA is by necessity organised in a more complex way than the more homogeneous FDA, so a somewhat longer review time could be expected, though there is still room for improvement.