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.)

Conclusion

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.

 

References:

  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. https://www.fda.gov/drugs/development-approval-process-drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products
  3. US FDA. Accelerated Approval. Current as of January 4, 2018. Accessed March 3, 2022. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval
  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. https://rarediseases.org/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/#:~:text=Approximately%207%2C000%20known%20rare%20diseases,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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PNAS Spearheads Effort to Streamline Authorship Transparency

Authorship is a hot topic in the scientific and medical publishing world. Who qualifies as an author? Who is the senior author? What are the responsibilities of the corresponding author? Opinions vary across disciplines and cultures. Whereas medical publications generally follow the recommendations of the International Committee of Medical Journal Editors (ICMJE; http://www.icmje.org/icmje-recommendations.pdf),1 academic publications may follow other guidance, or none at all. Is there a way to impose universal authorship criteria and quantify the work of authors so that their actual contributions can be tracked, giving them more than just their name on an article in the modern publish-or-perish environment?

A recent article by McNutt et al2 in Proceedings of the National Academy of Sciences of the United States of America (PNAS) seeks to create a framework for doing just that. As part of the global push toward greater transparency, with the goal of increasing integrity and trust in scientific publications, this article proposes that journals develop standardized authorship requirements and reporting, documented through ORCID identifiers (https://orcid.org) and the CRediT system (http://docs.casrai.org/CRediT).

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What the New ICMJE Requirement for Data Sharing Statements Really Means for Data Sharing

As of July 1, 2018, manuscripts submitted to International Committee of Medical Journal Editors (ICMJE)-member journals must be accompanied by a data sharing statement. What is the new requirement, how did it evolve, and what does it mean for data sharing?

In January 2016, the ICMJE proposed that authors of all clinical trial manuscripts published in member journals share de-identified individual-patient data (IPD) underlying their results within 6 months of publication.1 The proposal included data in tables, figures, appendices, and supplemental materials. The ICMJE invited comments on its proposal and a firestorm ensued. Although many individuals and groups applauded the ICMJE proposal, others raised legitimate concerns. Some were concerned about inappropriate analyses of data without statistical rigor, and authors were concerned about competition and losing control and/or credit for their work. Others voiced concerns about the practical aspects of how to share the huge amounts of data generated by some studies, particularly large, phase 3, randomized trials. Still others raised persistent concerns about patients’ right to privacy, particularly in the rare disease setting, where, despite de-identification efforts, patients still might be identifiable. Continue reading

The Target Product Profile—Your Blueprint for Drug Development

When utilized to its full potential, the Target Product Profile (TPP) is a dynamic, living document that ensures all stakeholders—clinical, regulatory, quality and manufacturing, commercial, market access, and medical affairs—are working from the same blueprint. Unfortunately, the TPP often has a bad rap within industry because many people think it is too rigid for today’s drug development environment. But often that reflects a failure to truly collaborate or a tendency to let the TPP get stale. To be effective, the TPP must be continually updated based on changes in the data and the competitive landscape. When companies take a balanced approach to developing the TPP and have a dynamic process that allows them to monitor and adapt it, as needed, they build agility into their drug development program that allows them to make critical go/no-go decisions or course corrections when necessary.

By using the TPP to ensure everyone is on the same page, drug developers can avoid costly delays when, for example, manufacturing isn’t ready to scale up to commercial production when the phase 3 data comes in ahead of schedule. Keeping a close eye on the evolving therapeutic landscape helps the development team anticipate what data will be needed to support labeling claims that may serve as a key differentiator from the competition and provide added value in the marketplace. So let’s look at how a dynamic TPP—one that is proactively updated—can help achieve the critical success factors introduced in the last installment. Continue reading

Co-pay card adjustment programs: How do they affect patients, payers, and pharma?

“Co-pay cards” (or “co-pay coupons”) are financial assistance programs from drug manufacturers (pharma) that drastically reduce the out-of-pocket (OOP) costs for someone who needs an expensive medication. These programs are controversial:

    • Pharma and patients believe that these programs allow sick people to afford the medications they need.
  • Healthcare payers (ie, insurance companies or their pharmacy benefit managers [PBMs]), however, regard such programs as schemes that circumvent their cost-management techniques (such as formulary tiers and patient cost-sharing). This is because with no financial impact from OOP costs, doctors and patients could decide to use more expensive drugs than the ones preferred by the insurance plans (eg, generic or well-established branded drugs).

Because of these opposing points of view, payers have tried (with limited success) to disallow co-pay cards if possible, and pharma is developing new ways to circumvent payer controls. This “cat-and-mouse” game has antagonized payer-pharma relationships as each are pursuing different goals: payers are trying to manage expensive medication use, whereas pharma is trying to maximize their sales and prescription volumes.
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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 www.clinicaltrials.gov 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