Non-binding Guidance: Expedited Review Programs for Drugs and Biologics

September 5, 2019
13:10 minutes

The fifth installment of Ropes & Gray’s podcast series, Non-binding Guidance, is the first part of a two-episode discussion of FDA expedited review programs. In this episode, Ropes & Gray lawyer Greg Levine interviews his partner Kellie Combs, who provides an overview of the four expedited review programs for drugs and biologics: the Fast Track, Breakthrough Therapy, Priority Review, and Accelerated Approval programs. These programs, which are broadly intended to address unmet needs in the treatment of serious or life-threatening conditions for which existing therapies are insufficient, are associated with significant benefits for manufacturers, such as earlier and more frequent FDA interactions, streamlined clinical development requirements, and a shorter FDA review clock—all of which may accelerate time to market and improve the bottom line. In this episode, Kellie discusses the eligibility criteria and benefits associated with each program, and describes timing and other practical issues for product manufacturers to consider. Tune in to this discussion to learn more about the expedited review programs and how to secure the benefits.

Next week, we’ll release the second episode of this two-part series, which will focus on the Breakthrough Devices Program. Please stay tuned.


Greg Levine: Hi. I'm Greg Levine, a partner in the life sciences regulatory and compliance practice group at Ropes & Gray, based in our Washington, D.C. office. Welcome to Non-binding Guidance, a podcast series from Ropes & Gray focused on current trends in FDA regulatory law, as well as other important developments affecting the life sciences industry. I'm here today with my partner Kellie Combs. Today's podcast will discuss FDA's expedited review programs for drugs and biologics. In addition to providing an overview of the programs, we'll talk about eligibility criteria, benefits, when to apply, and some of the practical considerations associated with these programs. Kellie, can you first tell us what expedited programs are available for drugs and biologics?

Kellie Combs: Sure. Thanks, Greg. There are four types of expedited programs: Fast Track, Breakthrough Therapy, Accelerated Approval, and Priority Review. In general, these programs are all intended to expedite the development and review of drugs and biologics so that therapies can get into the hands of patients quickly and efficiently. Now a drug or biologic may qualify for more than one program, but there are some important differences between the programs, which we'll talk about in more detail today. In particular, there are different eligibility criteria, features and benefits, and timing considerations associated with each.

Greg Levine: Thanks, Kellie. Are there any common concepts among the programs that we should understand?

Kellie Combs: Absolutely. All four expedited review programs are intended to expedite the development and review of new drugs and biologics that (1) address an unmet medical need, (2) treat a serious or life-threatening condition, and (3) are for diseases or conditions that are not otherwise addressed by available therapies. Now for a drug to address an unmet medical need, it means that it must address an immediate need for a defined population or a longer-term need for society—just as one example here, a treatment of a serious condition for which there is no other alternative. In determining what a serious or life-threatening disease or condition is, FDA considers factors like survival—the likelihood a disease, if left untreated, will progress from a less severe condition to a more serious one. For example, if a product improves the diagnosis or directly affects a serious symptom or manifestation of the disease. And finally, to determine whether a condition is not otherwise addressed by available therapies, FDA considers whether there's another therapy that's approved or licensed in the U.S. for the same medication and is also relevant to the current U.S. standard of care. Now interestingly here, FDA will also consider whether there might be unapproved therapies that can be used for off-label uses and that are supported by compelling evidence. And to determine the standard of care, FDA will consider recommendations of authoritative scientific bodies as well as other experts. FDA makes these sorts of assessments at the time of the relevant regulatory decision, so very early on in the process for the breakthrough and fast track designations, and then during the time of NDA or BLA review for accelerated approval.

Greg Levine: You mention that there are four of these programs. What are the features and benefits of each one?

Kellie Combs: So the Fast Track program, which is available for drugs that are intended to treat a serious condition where non-clinical or clinical data demonstrate the potential of the drug to address an unmet medical need or for drugs that have been designated as qualified infectious disease products, or QIDPs, fast track designation means that you can get more frequent meetings with FDA, particularly early in the development process. And then you can also get rolling review, which means that rather than submitting all the various components of an NDA or BLA at the same time, you can submit certain components first and other components as that information rolls in.

For breakthrough therapy, drugs can be eligible for this designation if they're intended to treat a serious condition where preliminary clinical evidence indicates that the drug can demonstrate substantial improvement on a clinically significant endpoint as compared to available therapies. A key distinction here from the Fast Track designation that I just mentioned, is that preliminary clinical evidence is actually required to get the breakthrough therapy designation. Substantial improvement here can be demonstrated in a variety of ways, such as by showing a greater treatment response to a new drug than to an available therapy, or showing that the drug will treat the cause of the disease rather than the symptoms. And a clinically significant endpoint is one that would measure an effect on irreversible morbidity or mortality, or on symptoms that represent serious consequences of the disease. Now, in terms of the benefits for breakthrough therapy, it has all the same features as fast track designation, so those frequent meetings early in the process, as well as rolling review, plus early and intensive guidance from FDA and a cross-disciplinary team of FDA senior reviewers to help advise a sponsor throughout the drug development process.

With respect to accelerated approval, drugs and biologics are eligible for this program if they're intended to treat a serious condition that provides “a meaningful advantage” over other therapies and demonstrates an effect on a surrogate endpoint or on an intermediate clinical endpoint. Typically, here we're talking about drugs that are used to treat diseases where the course of progression is long and it would take a long time to measure the intended clinical benefit in an ordinary clinical study. A surrogate endpoint here could be a lab measurement, such as prolonged suppression of viral load in HIV, or a physical sign, or a size of a tumor in cancer, and so on. An intermediate clinical endpoint is an endpoint measured earlier than an effect on irreversible mortality or morbidity. Accelerated approval is ultimately based on the surrogate or intermediate clinical endpoint that's reasonably likely to predict the clinical benefit of the product, but in and of itself is not sufficient to predict a clinical benefit. And as a result, FDA requires that after a product is approved through the accelerated approval process, the sponsor has to conduct confirmatory studies that ultimately show that clinical benefit over a longer period of time. There's more flexibility under accelerated approval for FDA to withdraw an approval, so it's thought almost as like a conditional approval. For example, FDA can withdraw approval if there's other evidence to demonstrate that the product is not safe or effective, or that the confirmatory studies do not pan out as expected.

Finally, with respect to Priority Review, this program is available for certain drugs that treat a serious condition and that would provide a significant improvement in safety or effectiveness over available therapies. Priority review ultimately gets you a shorter review clock at FDA. So typically, we're thinking of a 10-12 month FDA review period, but if you have that priority review designation, the target review period is about six months. There are three types of priority review vouchers, including tropical disease vouchers, rare pediatric disease vouchers and MCM vouchers, or medical counter measure vouchers. These vouchers are available for tropical diseases, which can be designated by FDA. The rare pediatric disease voucher is for new drugs to treat diseases that affect fewer than 200,000 children or adolescents. And the MCM vouchers (the material threat to medical countermeasures), are available for new drugs intended to diagnose, prevent, or treat diseases or conditions associated with chemical, biological, and nuclear threats and emerging infectious disease, or those that are intended to mitigate, prevent, or treat harm from condition that may result in adverse health consequences or death and may be caused by administering a drug of a biological product.

All three types of these vouchers are awarded at the time of product approval and they're transferable. And that's really important because the voucher can be used by the sponsor itself in connection with its next drug application, but it can also be sold and transferred to another manufacturer. Just to get a sense of how valuable these vouchers can be, pediatric review vouchers have sold for up to $350 million.

Greg Levine: Clearly, there are a lot of benefits associated with these pathways. When is it that a sponsor should request designation under these programs from the Agency?

Kellie Combs: Well, in general, Greg, we would certainly recommend that sponsors communicate with FDA as early as possible in the development process about their various designation requests. For fast track designation, though, a sponsor should request a designation along with their IND application, or at a pre-BLA or pre-NDA meeting. Similarly, for breakthrough therapy designation, a sponsor can submit the designation request with the IND or no later than the end of Phase II meeting. If a sponsor is seeking accelerated approval, it should initiate discussions with FDA really as soon as possible to reach agreement on the use of a planned endpoint and the design of the confirmatory study. As previously discussed, priority review vouchers are awarded at the time of approval and sponsors should include request for these vouchers in their NDA or BLA submission. As a practical matter, FDA encourages sponsors to submit these requests as soon as possible.

Greg Levine: Are there any recent developments or trends we should be aware of involving these expedited programs?

Kellie Combs: Absolutely. So these expedited review programs are becoming increasingly popular at FDA. In 2018, 73 percent of novel drug approvals were in at least one expedited review category, and this is up from previous years. On average, these programs have generally been shown to decrease clinical development times, with the biggest difference seen in breakthrough designation. In 2017, there was an article published in The Journal of the American Medical Association that looked at expedited programs and clinical development times for novel therapies for a time period spanning from 2012-2016. And the authors found that clinical development time was generally 7.1 years if a product was in one expedited program, compared to eight years for drugs that weren't in any of the expedited programs. For breakthrough designation, there's a really significant advantage. For those drugs, the authors found the development time was only 4.8 years and that's compared to, again, the eight years for drugs that are not in those sorts of programs. For fast track, it's seven years. There wasn't a significant difference seen for accelerated approval or priority review pathways, but certainly in general, there is a significant timing benefit to these sorts of programs.

Greg Levine: Can you give us some examples of drugs that have recently been approved under these programs?

Kellie Combs: Sure. There are two that are really interesting that have been approved in the last year or so. The first is Epidiolex, which is manufactured by GW Pharmaceuticals. This product was approved last summer, in June of 2018, and it's a drug that contains the active ingredient plant-derived CBD, or cannabidiol. It's indicated for seizures associated with two rare and severe forms of epilepsy. GW had requested fast track designation for one of its indications, and as a result of that designation, they were able to get early and very frequent interactions with FDA. They submitted a pre-IND meeting request in 2014 – the IND was submitted shortly thereafter. And the NDA was submitted in October 2017 and was approved well before the PDUFA date.

The other product that comes to mind is Emgality, which is manufactured by Eli Lilly. That's indicated for cluster headaches, which is a rare and very serious headache condition. The product had originally been approved in September 2018 for migraines and was approved over the summer for cluster headaches based on a different set of clinical studies. This example, I think, is particularly interesting because it demonstrates that breakthrough therapy status can be used for a new indication of a drug that's already been approved and also that breakthrough therapy designation requires some pretty rigorous clinical evidence as opposed to fast track designation.

Greg Levine: Kellie, what are some practical considerations to keep in mind with these expedited review programs?

Kellie Combs: Certainly a lot of important considerations to keep in mind here. As I mentioned at the outset, a product may qualify for more than one expedited review program. In addition, a product could also be eligible for orphan designation, which is associated with other significant benefits, including seven years of market exclusivity. So it's important to think not just about the expedited review programs, but also what other incentives might be available. It's also important, as I've been mentioning, to communicate early and often with FDA, both to understand whether certain designations may be available and so you get frequent and intensive guidance from the FDA as you're designing your clinical development program. It's also important to pursue a rapid manufacturing development program and make sure you have the capacity to scale up manufacturing. So as I was saying a little bit ago, we have seen a pretty significant timing advantage with the products that are approved through the various expedited programs, so you need to build that into your assumptions when you're planning for scale up. You also need to anticipate FDA's need to inspect clinical studies and consider the implications for coverage and reimbursement.

Greg Levine: Thanks for tuning in to our podcast, Non-binding Guidance, which is brought to you by our attorneys in the life sciences regulatory and compliance practice at Ropes & Gray. For more information about our practice or other topics of interest to life sciences companies, please visit our FDA regulatory practice page at You can also subscribe to Non-binding Guidance and other RopesTalk podcasts in Ropes & Gray's podcast newsroom or on our website by searching for Ropes & Gray podcasts in Apple or Spotify. Thanks again for listening.

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