Over the years, a number of different designations have been given to various categories of the drug approval process for potential major advances in patient care. Some recent designations have been “priority review,” “fast track,” and “accelerated approval.”^1-4 This has allowed drugs to be reviewed quicker than the standard drug review at the US Food and Drug Administration (FDA). Although this designation was helpful for both the pharmaceutical firms and the FDA, some people felt that it did not give enough priority to potential “game changing” drugs, especially for patients with serious or life-threatening medical conditions. The newest category to address this problem is the “breakthrough” designation.

The breakthrough designation is designed to expedite the development and drug approval process for drugs that are intended for the treatment of serious and life-threatening medical conditions. The designation will generally occur prior to submission of the drug’s new drug or biologics license application and most likely no later than the end of the phase 2 meetings.^1,3,5 To receive this designation, the drug must be used to treat a serious or life-threatening medical condition and have preliminary clinical evidence associated with surrogate endpoints that indicates the drug or combination of drugs may demonstrate substantial improvement over existing therapies.^1-5

By the end of August 2013, the FDA had received 82 requests for breakthrough designation: 25 have been reviewed and granted, 25 are still under review, and 32 have been denied.⁶ Examples of agents that have received the breakthrough designation are ivacaftor and ivacaftor with VX-809 from Vertex Pharmaceuticals for the treatment of cystic fibrosis; ibrutinib from Pharmacyclics for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, and Waldenström’s macroglobulinemia; palbociclib from Pfizer for the treatment of metastatic breast cancer; a combination of daclatasvir, asunaprevir, and BMS-791325 from Bristol-Myers Squibb for the treatment of chronic hepatitic C virus; asfotase alfa from Alexion Pharmaceuticals for the treatment of perinatal-, infantile-, and juvenile-onset hypophosphatasia; amifampridine phosphate from Catalyst Pharmaceutical Partners for the symptomatic treatment of patients with Lambert-Eaton myasthenic syndrome (LEMS); and serelaxin from Novartis for the treatment of acute heart failure.^6,7 Example of agents that have been denied the breakthrough designation are AP26113 from Ariad Pharmaceuticals for the treatment of lung cancer and nivolumab from Bristol-Myers Squibb for the treatment of various cancers.^8,9 However, most companies do not report this type of news, nor is it released by the FDA.²

It is unknown whether this process will really get the optimal drug therapy approved faster or whether it will get drugs approved based on surrogate markers that later end up being poor predictors of meaning patient outcomes. There are some concerns that the public’s health may be compromised by allowing these drugs to be approved through this type of process before important safety questions are answered.^10-13 Sidney Wolfe, cofounder and senior adviser to Public Citizen's Health Research Group, has stated “A discussion on this topic is reckless if it doesn't discuss the next stage after the drug reaches the market.”¹² Dr. Woodcock, the director of the FDA’s Center for Drug Evaluation and Research, has stated¹⁴:

Our decision-making on whether to approve a drug always involves an evaluation of many factors, such as the seriousness of the disease. However, ultimately any drug approved must show that its benefits outweigh its risks and regardless of which expedited development or review program or programs are used, FDA does not compromise its safety or efficacy standards in exchange for rapid approval. Like all drugs we approve, those approved after having been designated as breakthrough therapies will meet our usual rigorous standards for safety and effectiveness.

Some of the drugs (eg, vandetanib for the treatment of late-stage medullary thyroid cancer, fingolimod for the treatment of multiple sclerosis, and dabigatran for the prevention of stroke) were approved under the priority review process because of their potential beneficial effects in selected patient populations, but they also had limited safety data or safety concerns at the time of drug approval.^10,11 This does not mean that I believe these drugs or any other drug approved under the priority review process should not have been approved, but we need to be vigilante in making sure the risk versus benefit of these types of agents are continuously reviewed following their approval and marketing.

The key question for the health care industry is at what point in a drug’s development do we have enough information to decide the potential benefit versus risk ratio or will a Risk Evaluation and Mitigation Strategy (REMS) help minimize the safety risks associated with any drug and still provide patients with potentially useful medicinal agents. This type of accelerated drug approval process is going to impact how various formulary committees review these types of drugs, especially those that require full data sets and pharmacoeconomic analysis.

No drug has been approved that has received the breakthrough designation, but one may be approved in late 2013 or early 2014. It is going to take several years after the first drugs are approved, under this process, to see whether patient care has been helped or compromised, but there is at least hope for those patients affected by serious and life-threatening medical conditions. In the meantime, it is our responsibility to report all serious adverse events associated with the use of these new drugs to the FDA through the MedWatch (https://www.accessdata.fda.gov/scripts/medwatch/) program. This will enable the FDA’s ongoing surveillance program to determine whether new information regarding a drug’s safety justifies a reevaluation the drug’s approval status.