Delivering Promising New Medicines Without Sacrificing Safety and Efficacy

By Janet Woodcock, M.D., Director, Center for Drug Evaluation and Research and Peter Marks, M.D., Ph.D., Director, Center for Biologics Evaluation and Research

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The FDA walks a fine line. We must balance timely patient access to important new medicines with assuring they meet key standards. These standards exist to make sure that approved drugs have a high chance of helping those who use them. Medicines ultimately must lead to overall improvements in how patients feel, function or survive.

Janet Woodcock, M.D.

Not all diseases have the same impact. Getting a diagnosis of high blood pressure is not like learning that you have an incurable cancer. If your disease is serious and not well-controlled with available treatments, you may be extremely interested in how soon new medicines under development will be available. If your condition is also rare, you may be worried that no treatment will ever be found. If there are a lot of treatments available for your condition, you will want to pick the one best suited for you.

FDA is charged with regulating new medicines, including novel ones like cell and gene therapies, and we make decisions about whether these can be marketed. We apply the same statutory standards for safety and efficacy to all new medicines, but the overall benefit-risk evaluation, and the clinical trial programs, vary depending on the circumstances. For fatal diseases without available treatments, the risk of more significant side effects may be acceptable. For rare diseases, we can’t expect very large trials. For potentially fatal diseases with existing life-saving treatments, we expect new therapies to be as good or better than those already approved, or to decrease the significant side effects. For conditions like high cholesterol that have a lot of therapies available for their treatment, we expect new drugs to be very safe.

Over the past three decades, Congress has established five programs aimed at expediting patient access to important drugs that treat serious or life-threatening conditions. 1 These programs allow FDA to facilitate and expedite development of medicines that fill unmet medical needs, while maintaining FDA’s gold standard of safety and efficacy. Products may sometimes qualify for more than one of these programs.

Peter Marks, M.D., Ph.D.

Although all of these expedited programs are Congressionally mandated, and all preserve the bedrock standards of safety and efficacy, these programs have substantial differences which are commonly confused. Four of the FDA’s five expedited programs are called “designation programs, meaning that drugs approved under these programs belong to a special category. Three of these designation categories focus on the drug’s development prior to FDA receiving its application for approval. One designation (priority review) confers faster FDA review times. Our fifth expedited program (accelerated approval), which is an approval pathway rather than a designation program, enables initial approval based on ‘surrogate endpoints’ with a requirement for further study post-approval. Each is summarized below:

Three designation programs that assist drug development:

• Fast Track designation can be given if there is nonclinical or human data demonstrating the potential to address an unmet medical need. This generally means that the drug is intended to treat a serious disease and that laboratory, animal model, or human data show promise. A drug company must request the Fast Track designation.
• Breakthrough Therapy designation expedites the development of drugs for which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy. This is a higher bar than Fast Track designation, since there must be human data showing potential “substantial improvement.” A drug with Breakthrough Therapy designation is also eligible for the Fast Track process and Priority Review; however, if the drug does not demonstrate the same promise in the later clinical trials, the designation can be rescinded, and priority review will not be granted. A drug company must request a Breakthrough Therapy designation.
• Regenerative Medicine Advanced Therapy designation (RMAT) expedites the development of regenerative medicine therapy for serious conditions where preliminary clinical evidence indicates that the regenerative medicine therapy has the potential to address unmet medical needs for such condition. Such designation includes all the benefits of Fast Track and Breakthrough Therapy designation, including early interactions with agency. This designation is relatively new, having been created as part of the 21st Century Cures Act in 2016, but is already highly used.

One designation program relates to FDA review timelines:

• Priority Review designation means that FDA aims to take action on a marketing application within six months, compared to 10 months under standard review. A Priority Review designation directs attention and resources to evaluate drugs that would significantly improve the treatment, diagnosis, or prevention of such serious or life-threatening conditions. Priority review can also be designated for specific therapeutic areas (e.g. a qualified infectious disease product or label expansion for certain pediatric indications) or in response to a “priority review voucher,” for a drug developed for a rare tropical disease or a rare pediatric disease. Priority Review is only granted if the actual data submitted in the marketing application appear to show a significant improvement in safety or effectiveness for a serious condition, regardless of whether the drug originally had one of the designations above. Therefore, Priority Review designation is a higher bar than Fast Track or Breakthrough designation.

The final expedited program is Accelerated Approval:

• Accelerated Approval (AA) is the only expedited program that provides a different route to marketing approval. AA approvals meet FDA standards for safety and efficacy. AA allows for the approval of a drug that demonstrates an effect on a “surrogate endpoint” that is reasonably likely to predict clinical benefit. 2 A surrogate endpoint is a measurement like an x-ray or blood test that is likely to predict that the drug is working. This is in contrast to a “clinical endpoint” that measures how a person feels or functions or how long a person lives. AA is especially useful when the drug is meant to treat a disease whose disease course is long, and an extended period of time is needed to measure its effect. After a drug enters the market under AA, the drug maker is required to conduct studies to verify and describe the drug’s benefit. If such further studies fail to verify the predicted clinical benefit, FDA may withdraw approval, and has done so on prior occasions. Thus, the requirements for approval through this pathway have a key difference from traditional approvals: a post-market study to verify clinical benefit. Note that the purpose of such studies is to verify that the drug meets a clinical endpoint that shows improvement in how individuals feel, function or survive. A common misconception, for example among oncology drugs approved using surrogate survival endpoints (e.g., “progression free survival”), is that post-marketing trials must demonstrate an absolute improvement in “overall survival.” Such post-market trials are not always possible, however, and clinical benefit for such therapies can be verified based on other valid clinical endpoints.

Of note, we see frequently that the similar terms, “expedited,” “fast track,” and “accelerated,” are often confused by media sources and others, resulting in inaccuracies. For example, while it’s accurate to say that the FDA typically approves more than 50 percent of its novel drug (those never before marketed or approved in the U.S.) applications each year using at least one expedited program, it is inaccurate to say that FDA approves most novel drugs specifically using accelerated approval. Indeed, of the 367 novel drugs and biologics we approved from 2011 through 2018, we approved only 44, or 12 percent, under accelerated approval.

Over the years, the FDA has used these expedited drug development and review tools to help bring a wide range of new drugs to patients in need. For example, from 2011 through 2018, of the 367 novel drugs the FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) approved, 200, or 54 percent, used at least one expedited development tool.

Commentators have noted FDA’s increasing use of these programs over the last decade, often with a view that the increase is driven by a loosening of our approval standards. In reality, the FDA’s standards have not changed. Instead, the increased use of expedited approval pathways is directly related to the increasing numbers and scope of these programs provided by Congress, as well as the kinds of medicines that are being developed, and the types of diseases that are being studied. A few facts to illustrate the rapid evolution underway in drug discovery and development:

• Only 157 orphan drugs (those that treat rare diseases) were approved in the ten-year period, 1999 through 2008, whereas 436 have been approved in the 10-year period, 2009 through 2018. Orphan drugs are often candidates for expedited programs.
• The portfolio of cancer drugs, many for people lacking other options, has rapidly grown to currently comprise more than a third of novel drug approvals.
• In the last two years, FDA has approved the first four cell and gene therapy products, and now has more than 800 active investigational new drugs of this type under review — signaling the leading edge of a wave of these new therapies.

We would argue that this change in the mix of products and diseases has resulted in many more therapies being eligible for expedited programs than in the past.

It’s important to reiterate that all drugs approved under the Fast Track, Breakthrough Therapy, RMAT designation, and Priority Review expedited programs are held to the same approval standards as other FDA drug approvals. What changes is the time spent in various stages of development, the extra resources the FDA commits to assist with drug development (for Fast Track, Breakthrough and RMAT designations), and the shortened review time once a new drug application or biologics license application comes to the FDA for review (for Priority Review designation). Accelerated approvals also must meet the same statutory standard for approval but may use a surrogate endpoint reasonably likely to predict clinical benefit instead of a more time-consuming clinical benefit endpoint. However, in the end, the connection to clinical benefit needs to be made for the product to remain on the market.

Finally, the FDA actively engages patients in the new drug approval process. Patients share what is valuable to them, which helps us determine what endpoints are meaningful to patients. This patient-focused drug development has become an integral part of how drugs are evaluated at FDA. Over the past several years, we’ve engaged with many patients and caregivers to discuss their views on a wide range of diseases, including lung cancer and breast cancer.

We take our responsibility to execute flexibility and judgment in decision-making very seriously. Using expedited programs, including accelerated approval, helps us to do everything we can to bring important advances to those in medical need.

• 1 See Expedited Programs for Serious Conditions — Drugs and Biologics and FDA Guidance, Expedited Programs for Regenerative Medicine Therapies for Serious Conditions for detailed description.
• 2 FDA may also grant accelerated approval based on an effect on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit (i.e., an intermediate clinical endpoint). See guidance for industry Expedited Programs for Serious Conditions — Drugs and Biologics.