Taking The Mystery Out Of Expedited Approvals

By Emily Krulewitz

In order to incentivize the development of drugs to fill an unmet medical need for a serious condition, FDA has developed various programs to expedite drug development and review. These four programs are: fast track, breakthrough therapy, accelerated approval, and priority review. Over the years, we have learned that guiding clients through the process and choosing the right procedure can have great benefit. Understanding which track best suits each product really aids in creating an effective regulatory strategy and drug development process.

Before discussing the programs in detail, it is useful to review some definitions:

Serious condition:

  • Is a “disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible if it is persistent or recurrent.”
  • “all conditions meeting the definition of life-threatening….would also be serious conditions”

Available therapy:

  • “is approved or licensed in the United States for the same indication being considered for the new drug,” and
  • “is relevant to the current U.S. standard of care (SOC) for the indication”

Unmet medical need:

  • “is a condition whose treatment or diagnosis is not addressed adequately by available therapy.” Examples include:
    • Where there is no available therapy;
    • Where there is available therapy:
      • Drug has effect on a serious outcome that is not known to be influenced by available therapy,
      • Drug shows improved effect on a serious outcome,
      • Drug has effect on serious outcome in patients who are unable to tolerate or fail to respond to available therapy,
      • Drug can be used effectively with other agents that cannot be combined with other therapy,
      • Drug provides comparable efficacy to available therapy by avoiding serious side effects, and/or
      • Drug has comparable safety and efficacy to available therapy but has a documented benefit; and/or
    • Where the only available therapy was approved under accelerated approval and clinical benefit has not been verified post-approval.

There is often confusion regarding these four programs, as they have many similarities and overlapping benefits. All four programs are designed to address an unmet medical need for a serious condition.

We review the 2014 procedural guidance from FDA regarding these programs, with an emphasis on comparing and contrasting the four programs. The table below provides an overview of all four expedited programs.

 

Type of Data Required Data Should Demonstrate Benefits
Fast Track Designation Preliminary nonclinical, mechanistic, or clinical data Potential to address an unmet medical need for a serious condition
  • More frequent meetings with FDA
  • More frequent written communication from FDA
  • Rolling review
Breakthrough Therapy Designation Preliminary clinical data Substantial improvement on clinically significant endpoint(s) over available therapies
  • More frequent meetings with FDA
  • More frequent written communication from FDA
  • Rolling review
  • Intensive guidance on an efficient drug development program
  • Involvement of FDA senior managers to expedite development
Accelerated Approval Pathway Not specified; Sponsor should make justification of alternate endpoint based scientific support Generally provides a meaningful advantage over available therapies AND demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or a clinical endpoint that can be measured earlier than irreversible morbidity or mortality
  • Approval based on a surrogate or intermediate endpoint (often allows for shorter development time)Note: FDA requires clinical trials to be conducted post-approval to confirm clinical benefit
Priority Review Designation Data contained in the final NDA submission Significant improvement in safety or effectiveness of the treatment, prevention, or diagnosis of a serious condition
  • Review of application in 6 months

 

Fast track and breakthrough therapy are the most similar programs designed to expedite the development of drugs for serious conditions. The most significant difference in these two programs is related to the type of data needed to substantiate the request. Fast track can be granted based on preliminary data, such as activity in a nonclinical model or pharmacological data, or a mechanistic rationale. Breakthrough therapy must use preliminary clinical data, and therefore activity in a nonclinical model or a mechanistic rationale alone would not be sufficient.

Sponsors should also note the subtle differences in the designation criteria: drugs seeking fast track must only have the potential to address an unmet medical need, while drugs seeking breakthrough therapy must have preliminary data which demonstrate substantial improvement on clinically significant endpoints over available therapies. The benefits of fast track are more frequent meetings with FDA, more frequent written communication from the Agency, and rolling review. Rolling review refers to the ability of FDA to begin review of the NDA as sections are completed, rather than waiting for the entire NDA finalized to begin the review. Breakthrough therapy drugs have all the benefits of fast track drugs, but also are given intensive guidance on an efficient drug development program and have the involvement of FDA senior managers. In a sense, fast track can be thought of as a junior version of breakthrough therapy, and it is not uncommon for a drug with fast track to be granted breakthrough therapy during the drug development process.

Accelerated approval is perhaps the most “different” of the programs for drugs intended to treat a serious disease because it is an approval pathway rather than a designation. An approval pathway is a mechanism to market authorization whereas a designation is granted to a drug based on meeting certain criteria and which provides certain benefits, such as speeding the approval process for priority review designations or providing tax credits and exclusivity for orphan drug designations. Accelerated approval allows for the use of a surrogate endpoint that is reasonably likely to predict clinical benefit or an intermediate clinical endpoint that can be measured earlier than irreversible morbidity or mortality. Drugs using the accelerated approval pathway must also generally provide a meaningful advantage over available therapies. This pathway has been used extensively for drugs to treat cancer and HIV, as one can obtain a relatively good idea of how a treatment is working by measuring tumor size or viral load rather than waiting for long-term survival data. Accelerated approval does have one major caveat; the Sponsor is required to conduct additional clinical trials after the drug is approved to confirm the clinical benefit. Until the benefit has been confirmed in a post-market setting, the labeling has special language to indicate that the use of the drug has not yet been shown to have a clinical benefit. Additionally, if a drug fails to show a clinical benefit after approval, the drug can be removed from the market.

The final expedited program is priority review, which is a requested by the Sponsor with the initial NDA submission. While most NDAs have a 10 month goal date, priority review drugs have a 6 month goal date. In order to qualify for priority review, the Sponsor must show that if approved, the drug would provide a significant improvement in safety or effectiveness of the treatment, prevention, or diagnosis of a serious condition.

Drugs intended to treat an unmet medical need for a serious condition will often use more than one of these programs. A Sponsor wishing to use all four pathways could first seek fast track with nonclinical data, and could then seek breakthrough therapy using clinical data. The Sponsor could then discuss the possibility of using accelerated approval and obtain FDA agreement on endpoints before moving forward with clinical trials. Finally, the Sponsor could request priority review upon the submission of the original NDA.

Given the tremendous benefits of using these programs, it is not surprising that many Sponsors are taking advantage. According to FDA’s Novel New Drugs Summary, 46% of the novel new drugs approved in 2014 were designated as fast track, breakthrough therapy, or both. Drugs granted priority review made up 61% of the novel new drugs, while 20% were approved using accelerated approval. There are many caveats to these programs as well as additional ways to qualify for the benefits, and so Sponsors should review the guidance to see if one of these programs may be appropriate for their drug and to ensure all relevant criteria are met.

Emily Krulewitz is a Consultant at The Weinberg Group, the world’s leading food and drug consulting firm. If you have any questions or thoughts on this blog post or others, please reach out to us by email.