Sponsors and regulators use surrogate endpoints to predict the long-term benefits of drug products that treat serious or life-threatening conditions for which clinical outcomes cannot be rapidly determined. For many conditions, particularly cancers, proving survival or decreased morbidity could require years, so sponsors can use surrogate endpoints to develop therapies that have a reasonable expectation of clinical benefit and deliver them to patients more quickly.

At the Drug Information Association (DIA) 2020 conference, Premier Consulting attended a session titled “Accelerated Approval and Emerging Surrogate Endpoints,” presented by representatives from the FDA, the EMA, Health Canada, and the Memorial Sloan Kettering Cancer Center. This blog post will explore questions about surrogate endpoints and accelerated pathways answered during the presentation.

How can products gain FDA accelerated approval using surrogate endpoints?

The FDA can grant accelerated approval for a product that treats a serious condition and fills an unmet medical need based the product’s effect on a surrogate or intermediate clinical endpoint. There are three types of surrogate endpoints, sorted based on their levels of clinical validation:

• Validated surrogate endpoints, which are used to support standard approvals
• Surrogate endpoints reasonably likely to predict clinical benefit, which are used to support accelerated approvals
• Candidate surrogate endpoints, which provide exploratory information and remain investigational

All drug products approved using surrogate endpoints must meet the same risk-benefit standards based on safety and efficacy as those developed using traditional clinical outcomes. However, those seeking accelerated approval must also provide meaningful benefit over existing treatments and use surrogate endpoints likely to predict clinical benefit. In 2019, the FDA granted accelerated approval to eight drug products developed using surrogate endpoints.

In addition, sponsors must conduct post-marketing studies to verify and describe a product’s long-term clinical benefit and ultimate outcome, and the FDA generally expects these studies to already be underway at the time of approval. If the sponsor does not conduct the studies, fails to adhere to any interim restrictions the FDA imposes, or is unable to successfully validate the clinical benefit of a drug, the FDA can withdraw its approval.

How are surrogate endpoints chosen?

The FDA has published, and continually maintains, a list of all surrogate endpoints used for past approvals to aid sponsors in choosing surrogate endpoints for their development programs. The list is separated into tables for adult and pediatric indications and details the disease, approval type, and drug mechanism of action associated with each endpoint, along with notes clarifying the FDA’s thinking on the use of some specific endpoints. While the tables are useful guides, it’s important to remember that even previously used surrogate endpoints should be discussed with the FDA to confirm their appropriateness for individual drugs and populations.

In cases where these already-established surrogates are not appropriate, or where none exist, sponsors can develop and propose novel surrogate endpoints for their programs. As medicine advances and patient access to therapies expands, surrogate endpoints for some conditions continue to evolve. Patients diagnosed with diseases with historically poor prognoses, such as multiple myeloma, are living longer as available therapies and the standard of care continue to improve, and previously acceptable endpoints are quickly becoming outdated. In such cases, the development of novel surrogate endpoints becomes a significant priority.

The FDA recommends a Type C meeting to discuss surrogate endpoints early in development to seek advice on the acceptability of novel surrogates and to discuss their proposed use in planned clinical trials.

How are regulators outside the US approaching the use of surrogate endpoints?

Regulatory bodies in Europe and Canada also have pathways for conditional approval based on surrogate endpoints, more or less equivalent to the US’s accelerated approvals, and these options are growing in popularity.

EMA: Conditional Marketing Authorizations

The European Medicines Agency’s (EMA’s) Conditional Marketing Authorization (CMA) program is designed for products for which less comprehensive clinical data are available but which target debilitating or life-threatening diseases. In order to qualify for accelerated patient access, a drug must have a favorable risk-benefit balance, address an unmet medical need, and represent an immediate benefit that outweighs the risks associated with early access, and the sponsor must expect to be able to provide more comprehensive data in the future. In 2019, the EMA conditionally approved seven products through its CMA program.

In order to gain eventual full approval after a CMA is granted, the product’s sponsor must typically conduct two efficacy and safety studies with different endpoints. It takes an average of four years to verify the clinical benefit of therapies issued CMAs.

Health Canada: Notices of Compliance with Conditions

Health Canada issues a Notice of Compliance with Conditions (NOC/c) for promising new drugs designed to address an unmet medical need in patients with serious, life-threatening, or severely debilitating conditions. The product must represent a substantially improved risk-benefit profile over current therapies and undergo a two-step authorization process. Health Canada first issues a Qualifying Notice listing the conditions that sponsors must meet for full approval, such as confirmatory trials, enhanced post-market surveillance, and transparency with patients and providers. Once the sponsor sends a Letter of Understanding agreeing to meet the conditions, Health Canada issues the NOC/c.

In 2019, Health Canada conditionally approved six products through the issuance of a NOC/c.

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Premier Consulting’s multidisciplinary team of experts can help you to select or develop appropriate surrogate endpoints for your program and identify whether your product may qualify for accelerated approval or other expedited development programs. Contact us to discover how we can partner with you to deliver therapies to patients as quickly and cost-effectively as possible.

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