Introduction to the Accelerated Approval Pathway

The FDA has developed several mechanisms to speed drugs to market when a compelling medical need exists including Accelerated Approval (AA), Priority Review, Fast Track, and Breakthrough Therapy Designation. Accelerated Approval is an important regulatory pathway that provides patients with earlier access to treatments for serious medical conditions when there is an unmet medical need. This is the first post in a 3‑part series on the AA Pathway. Herein, I’ll focus on how this pathway is used to bring drugs to market and highlight some of the key issues surrounding it.

The AA Pathway was created in 1992 in response to the AIDS crisis and was codified in 2012 under the Food and Drug Administration Safety Innovations Act (FDASIA) in an effort to bring potentially life-saving drugs to market more quickly. The majority of drugs granted AA have been for AIDS, rare diseases, and cancer. Over the past 10 years, there has been a steady increase in the number of New Drug Applications (NDAs) seeking AA (Figure1,2); this increase has been driven largely by immune checkpoint inhibitors, which have transformed the treatment of many types of cancer.

Figure: Novel Drugs Approved Using the Accelerated Approval Pathway.

Data sources: Darrow JJ, et al. JAMA. 2020 (through 2017);1 FDA CDER reports 2017-20212

How does Accelerated Approval work?

Under normal or traditional FDA approval pathways, a drug must show evidence of clinical benefit based on endpoints that measure how a patient feels, functions, or survives. In contrast, AA allows FDA to grant a drug a “conditional” approval based on its effect on a surrogate or an intermediate clinical endpoint that is reasonably likely to predict clinical benefit.3 (We’ll share more on this in part 2 of this series.) In some cases, AA can shave years off the clinical development timeline. Under the same law, the FDA requires sponsors to conduct a confirmatory clinical trial in the postmarketing setting to confirm that the drug does provide meaningful clinical benefit, and FDA can withdraw approval if further trials fail to verify the predicted clinical benefit.

Pros of the Accelerated Approval Pathway

The majority of drugs granted AA are for rare diseases, where the unmet need is great (90% of rare diseases have no approved therapy),4 and for oncologic indications where the disease is often life-threatening. In the case of rare diseases where patients are few and far between, it can be extremely challenging to conduct controlled clinical trials of sufficient size to demonstrate clinical benefit using traditional endpoints. The use of surrogate endpoints under an AA may be the only feasible path to approval; however, it can often be difficult subsequently to confirm clinical benefit in the postmarketing setting. In the case of oncology drugs, clinicians want to have access to promising new therapies for patients who have limited time to wait for the latest, potentially life-saving innovation, so speed to market becomes paramount.

Cons of the Accelerated Approval Pathway

The nature of the AA Pathway allows drugs to be marketed for a given indication before clinical benefit has actually been demonstrated using validated clinical endpoints. Although a surrogate endpoint must be reasonably likely to predict clinical benefit, this anticipated benefit must be verified in a confirmatory trial.

FDA prefers that a well-designed confirmatory trial be planned or underway at the time of AA, but there is no action enforceable by the FDA to require completion of confirmatory trials. According to a recent investigation in the British Medical Journal, nearly half of the drugs granted AA have not confirmed clinical benefit,5 and only 16 AAs have been withdrawn. This calls into question whether some of the drugs approved through the AA pathway are actually providing the promised clinical benefit to patients. That being said, there are many situations, particularly in rare diseases, where it can be difficult to complete confirmatory trials.

Finally, even more problematic, is what to do when confirmatory trials fail. In some cases, FDA will convene an advisory committee meeting to discuss whether the unmet need still exists and whether additional ongoing trials may confirm clinical benefit. (We’ll share more on this in part 3 of this series.)


While confirmatory trials can be difficult to complete, the AA pathway has been used to approve an increasing number of novel drugs in the past 10 years and remains an important regulatory pathway that provides patients with earlier access to treatments for serious medical conditions. Stay tuned for our next installment, which will explore the use of surrogate endpoints in Accelerated Approvals.

Jackie Orabone, PhD, helps clients prepare for FDA Advisory Committee meetings by combining her scientific expertise and research knowledge in immunology with over 2 years of medical communications agency experience. Connect with Jackie on LinkedIn.



  1. Darrow JJ, Avorn J, Kesselheim, AS. FDA approval and regulation of pharmaceuticals, 1983-2018. JAMA. 2020;323(2):164-176.
  2. US FDA. New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products. Current as of January 27, 2022. Accessed March 3, 2022.
  3. US FDA. Accelerated Approval. Current as of January 4, 2018. Accessed March 3, 2022.
  4. Huron J. New report finds medical treatments for rare diseases account for only 11% of US drug spending; nearly 80% of orphan products treat rare diseases exclusively. March 4, 2021; National Organization for Rare Disorders. Accessed March 3, 2022.,rare%20diseases%20have%20no%20treatment
  5. Mahase E. FDA allows drugs without proven clinical benefit to languish for years on accelerated pathway. BMJ. 2021;374:n1898.

Responding to FDA Information Requests: It Comes Down to Clarity of Messaging and Understanding the Therapeutic Landscape

No matter how well you have prepared your New Drug Application (NDA) or Biologic License Agreement (BLA) submission for the FDA, questions posed regarding the development of your product will arise. These are presented in the form of Information Requests (IRs) and Discipline Review Letters (DRLs). The FDA Guidance to Industry from the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER) outlines how the FDA uses these communications to obtain clarifying information to assist in reviewing submissions. Well-crafted responses to IRs and DRLs are critical in replying to regulators and keeping the review of your application on track.

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Do Decentralized Clinical Trials Hold the Keys to Future Patient Focused Drug Development?

There’s a lot of buzz around the concept of decentralized clinical trials, and rightly so, given the lessons learned from our experience with clinical trials during the COVID-19 pandemic.  Decentralized trials are executed through telemedicine and mobile or local healthcare providers.  They rely on technology (or medical devices) and information sharing to execute a study without the involvement of a large centralized clinic.  In a post-COVID world, drug development will likely employ more decentralized trials to reduce the time and cost of trial programs.

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Extending Asset Reach and Protecting Your IP Through the 505(b)(2) Pathway

Developing a novel pharmaceutical product from discovery to market launch can take up to 10 years and cost as much as $1 billion dollars1. The traditional 505(b)(1) approach to drug development involves a linear progression starting with nonclinical pharmacology, toxicology, and other PK studies, and typically culminates with large randomized phase 3 trials. This stepwise progression is time consuming and expensive, but essential to demonstrate the safety and efficacy of new molecules and gain FDA approval. Naturally, the cost associated with market entry discourages some smaller companies and restricts their focus to regulatory strategies with a lower financial barrier. The 505(b)(2) regulatory approval pathway presents a tangible opportunity for pharmaceutical companies to gain market entry and market share for a capital investment of $10-100 MM and 2-6 years of time. To put this into perspective, in 2019, approximately 65 505(b)(2) applications were filed in the United States compared with 48 505(b)(1) applications. In two parts, I will explore the utility of the 505(b)(2) pathway and offer insight into how both large and small pharma companies can capitalize on the innovative nature of this strategy.

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COVID-19 Vaccines: When Will the Pandemic End?

As Pfizer, Moderna, and other pharma companies prepare to seek emergency authorization for their SARS-CoV-2 vaccines, the FDA has laid out a roadmap designed to ensure appropriate scientific rigor and help engender public trust. That plan was the subject of a special meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) on October 22, 2020, where experts discussed 2 critical FDA guidance documents that provide a blueprint for development and approval of SARS-CoV-2 vaccines. That blueprint is at the center of a massive government effort to quickly and safely speed vaccines to the American public and bring the pandemic to an end.

Members of the VRBPAC, with expertise in infectious disease, epidemiology, and vaccine development, focused on issues around the FDA standards for safety and effectiveness that will support Emergency Use Authorization (EUA) of vaccine candidates. They discussed the need to continue the phase 3, randomized, placebo-controlled trials to completion after an EUA is granted. They considered how the vaccines will be rolled out to the American public, and they raised concerns about whether the public will embrace the vaccines and roll up their sleeves.

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Common Protocol Template—Streamlining Protocol Implementation

Study protocols are required for every clinical trial. Approximately 20,000 are submitted and posted to every year1—each one different. The format and core content can vary from sponsor to sponsor, costing the US Food and Drug Administration (FDA) time and resources to interpret, review, and ultimately, approve each uniquely complex protocol. This process, as it stands, slows down progress for new drug development. Clearly, there is a need to accelerate the pace at which protocols are approved so that new clinical studies can be initiated. In a world where technology continues to offer a platform for efficiency and accuracy, the development of the Common Protocol Template (CPT) is a welcome addition to the medical field. Common Protocol Templates can lead to faster review time, simplified trial startup, and prompt execution of clinical trials. Although the use of a CPT is not required for all new clinical trials, it is only a matter of time before its use becomes commonplace in drug development. Continue reading

Biosimilars—A New Frontier: Is the US Market Ready?


This post has been updated based on FDA approval of Celltrion’s Inflectra™, a biosimilar Remicade® (infliximab) for treating arthritis and other inflammatory diseases, on April 5, 2016. Inflextra is the second biosimilar approved by the FDA and the first to be granted multiple indications. This is an important milestone for biosimilars in the United States.

Since the first FDA approval of a biosimilar in March 2015, biosimilars have quickly become one of the hottest topics in the US pharmaceutical industry. Why is this such a big deal, and is the US market ready?

Biosimilars are alternatives to innovative biologic therapies (known as “originator” products) such as Humira® (adalimumab) and Enbrel® (etanercept) for treating rheumatoid arthritis (RA) and psoriasis, or Herceptin® (trastuzumab) and Avastin® (bevacizumab) for treating cancer.

Biosimilars promise to increase access to these life-changing biologic therapies by reducing costs, analogous to the cost savings of generic drugs over brand-named drugs. In fact, biosimilars could save American consumers about $250 billion over the next 10 years.1

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Making Sense of FDA’s Expedited Drug Approval Pathways and Designations – for the Non-Regulatory Professional

blog header linkedin - FDA Approval v6 blog sizeOne of the fundamental responsibilities of the US Food and Drug Administration (FDA) is to approve effective medicines for people who need them, while upholding high standards for safety. That mission also demands that the FDA work efficiently and not delay approval of life-saving medical advances. Today, the FDA is reviewing applications for approval of new medicines faster than ever, and that’s a welcome change from the status quo 25 years ago. In the era from 1962 (immediately following the thalidomide recall) to the early 1990s, FDA review times for a New Drug Application (NDA) or Biologic License Agreement (BLA) were often measured in years rather than months. In 1993, the standard review time (from NDA or BLA submission to decision) for a new molecular or biologic entity (parlance for a drug not previously approved for any other use) was about 28 months,1 and in some cases, approvals were delayed for many years.

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President Obama’s Cancer Moonshot 2020 Initiative: How Big Is the Challenge?

Apollo rocket blasting offWhen President Obama’s White House Task Force meets for the first time this week, it faces a lofty charge: “Let’s make America the country that cures cancer once and for all.” His proposed Cancer Moonshot 2020 initiative will provide much needed funding for research, will encourage collaboration between industry and academia, and will undoubtedly lead to important advances in our understanding of cancer and how to treat it.

Although this initiative is noble and well intentioned, calling for a “cure for cancer” oversimplifies the challenge and is based on an outdated understanding of the disease.

The public needs to understand that cancer is not one disease; it’s hundreds of different diseases, and it’s more complex than anyone imagined back in 1971 when President Nixon first declared war on cancer. Those involved in cancer research know that conquering cancer, in all its varied forms, is truly a global endeavor that will require a sustained commitment for decades to come. While a challenge to be the “country that cures cancer” stirs our patriotic spirit and conviction that American biomedical know-how can render cancer irrelevant in our lifetime, the reality is that meaningful progress will require international collaboration.

Are we, as a nation, prepared to take on that challenge and lead such a charge? The President has taken the first step, appointing Vice President Joe Biden to lead the White House Task Force. But now the difficult work begins. Can we balance competing priorities and sustain both our political will and financial commitment for the many years that such an effort will undoubtedly take? Continue reading

Can You Predict Whether You Will Face an FDA Advisory Committee?

blog header linkedin - Prediction Ad Com v5 resizeThe US Food and Drug Administration (FDA) review of drugs, although guided by broad standards, remains individualized. Each drug or drug class faces unique challenges during the FDA review phase – thus no two reviews are exactly the same. Each review division within the FDA has its own approach, and evaluations often differ among the centers. To help understand the review process, the team at ProEd Regulatory sought to learn from the past to inform our future. We reviewed applications submitted to the Center for Drug Evaluation and Research (CDER) data over the last 70 years to see what patterns might emerge. Although the largest proportion of products (drugs and biologics) fails between discovery and Phase 3, an evaluation of applications submitted to the FDA over the last 70 years shows that the vast majority of products that reach the submission stage are ultimately approved (Figure 1).1
predict_fig_1It wasn’t until the Kefauver-Harris Drug Amendments of 1962 that the FDA required sponsors to demonstrate both efficacy and safety of their drugs prior to market access. In the wake of this significant legislation’s impact on drug development, we still see a consistent flow of approved applications and a corresponding subset of new molecular entities (NMEs) (Figure 2).1

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