Tag Archives: Surrogate Endpoints

Neurology Takes a Page Out of the Oncology Playbook of FDA Accelerated Approvals

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The field of neurology is experiencing a significant upswing in innovative therapeutic development, propelled by advances in genetics, neuroimaging techniques, and biomarker research. However, neurological diseases are inherently difficult to treat, and there remains an urgent need to rapidly translate these advances into more effective treatments. It is timely then, that several recent drug approvals in neurology have benefited from FDA’s Accelerated Approval pathway— designed to expedite access to promising drugs to treat serious, life-threatening conditions with a high unmet medical need—a regulatory path most often traveled by oncology drugs.

Four recent accelerated approvals—2 for amyotrophic lateral sclerosis (ALS) and 2 for Alzheimer’s disease—appear to support a shifting regulatory approach to neurological drugs by the FDA, particularly in its willingness to deploy regulatory flexibility.

The ALS Treatment Landscape is Evolving Rapidly

On April 25, 2023, the FDA granted accelerated approval to Biogen’s Qalsody™ (tofersen), indicated to treat a rare, genetic form of ALS mediated by the superoxide dismutase 1 (SOD1) gene, referred to as SOD1-ALS. The approval was based on evidence that tofersen significantly reduced neurofilament light chain (NfL)—a marker of axonal degeneration that is elevated in the blood of many neurologic and neurodegenerative conditions—which correlated with a delay in disease progression and death. Although a failed clinical trial proved a barrier to full approval, the Peripheral and Central Nervous System Drugs Advisory Committee reviewed the data on March 22, 2023, and voted in favor of NfL’s utility as a surrogate endpoint supporting conditional approval. This marks the first instance of a blood biomarker being effectively used as a surrogate endpoint to secure accelerated approval for a neurology drug and underlines the potential benefits of incorporating NfL—and other blood biomarker measurements—into other neurology trial designs.

The FDA’s review of Amylyx’s Relyvrio™ (AMX0035)—a fixed-dose combination of sodium phenylbutyrate plus taurursodiol—was a closely watched regulatory event last year. Marginal efficacy in a phase 2 trial initially prompted the FDA to call for more data; however, they ultimately decided to review the application. Two advisory committee meetings were convened in 2022 and reached opposing outcomes. Panelists on the Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) voted in favor of approving Relyvrio™, just months after voting against the drug. The committee appeared to be swayed by additional analyses of survival benefit, a more acute focus on the unmet need, the FDAs own emphasis on exercising regulatory flexibility, and the sponsors statement that it would withdraw their drug if their phase 3 confirmatory trial fails. Subsequently, the FDA granted accelerated approval of Relyvrio™ for the treatment of ALS in September 2022.

A review in JAMA of oncologic drugs approved between 2000 and 2016 revealed that oncology drugs granted accelerated approval demonstrated a median overall survival (OS) benefit of 2.4 months1. Comparing this to Amylyx’s Relyvrio, which exhibited a 4.8-month median OS benefit, illustrates both a heightened standard of approval for neurologic drugs by the FDA and its advisory committees, and a gulf in the perception of meaningful clinical benefit in the fields of oncology and neurology. Patients and caregivers will argue that the benefit of adding a few months—and vital quality-of-life improvements—to the 3- to-5-year life expectancy of a patient suffering from ALS is just as clinically meaningful as in advanced cancers.

Alzheimer’s Accelerated Approvals Signal Renewed Scrutiny of Surrogate Endpoints

One key factor contributing to the success of accelerated approvals in oncology is the use of surrogate endpoints. These are indirect measures of clinical benefit that can be assessed more quickly than traditional endpoints, like overall survival, and are reasonably likely to predict clinical benefit.

The utility of amyloid-beta protein buildup in the brain (assessed by brain imaging) as a surrogate endpoint believed to be correlated with cognitive decline in Alzheimer’s disease was greenlighted with the approval of Biogen’s Aduhelm™ (adacanumab) in June 2021—the first accelerated approval of an Alzheimer’s drug.

The FDA’s recent willingness to apply regulatory flexibility when reviewing neurology applications, as in the case of Qalsody and Aduhelm—and subsequently approve these drugs under the Accelerated Approval pathway, has resulted in a shift in the regulatory strategy being employed by sponsors. The strategy to utilize the Accelerated Approval pathway in neurology drug development programs may, in part, be driven by (1) the evolution of imaging and biomarkers that can potentially be used as surrogate endpoints, and (2) the openness of FDA to accept those surrogate endpoints.

While the use of the expedited pathway and the decision to use amyloid-beta as a surrogate endpoint reasonably likely to predict clinical benefit was surprising in the case of adacanumab, it has changed the regulatory landscape in neurology by setting precedent. Eisai and Biogen subsequently capitalized on that precedent by picking up another accelerated approval for Leqembi™ (lecanemab) for Alzheimer’s disease, and on June 9th the PCNS voted unanimously for full approval of Leqembi, based on results of the confirmatory trial.

It appears that the regulatory environment surrounding the amyloid-beta class of treatments for Alzheimer’s disease—primed by Aduhelm and Leqembi—continues to bear more fruit. In Eli Lilly’s May 3 press release, we saw the most encouraging results yet for a drug that targets amyloid beta. In a phase 3 trial of more than 1,000 people with early signs of Alzheimer’s disease, donanemab treatment resulted in a slowing of cognitive decline by 35% compared to placebo. It also resulted in 40% less decline in the ability to perform activities of daily living.

Interestingly in that trial, biomarkers were used in a relatively dynamic manner. Firstly, patients were prescreened using a predictive biomarker—plasma p-tau-181—thought to select for patients with both amyloid and tau tangle pathology (the 2 prominent pathologies in Alzheimer’s disease). Subsequently, the data revealed that those who start the trial with fewer tau tangles benefitted the most from donanemab. Incidentally, donanemab slowed (but did not stop) tangle growth, underscoring the benefit of treating earlier in the course of disease.

Secondly, the amyloid beta surrogate biomarker was used to inform clinicians on when to complete patients’ course of treatment with donanemab—by reaching a threshold of amyloid plaque clearance—a strategy that has not been employed in other Alzheimer’s disease trials testing antibodies against amyloid beta.

The National Academies of Sciences, Engineering, and Medicine (NASEM) convened a workshop in January 2023 to examine the FDA’s use of the Accelerated Approval program. There was renewed criticism of the FDAs approval of Aduhelm and a call to increase the transparency around FDA decision-making and its stance on surrogate endpoints. According to Peter Stein, director of the FDA’s Office of New Drugs, “We don’t have a simple formula or algorithm for evaluation of a potential surrogate for accelerated approval.” He went on to emphasize the limitations of using a correlation between the surrogate and established clinical outcomes that demonstrate clinical benefit.

There is clearly a need for a set of transparent standards for the utility of surrogate endpoints, both in therapeutic areas where accelerated approvals have traditionally been applied (oncology and HIV/AIDS) and in neurology. FDA guidance on surrogate endpoints is being developed. Under the Food and Drug Omnibus Reform Act of 2022 (FDORA), the FDA must issue 4 guidance documents related to accelerated approvals within 18 months of FDORA being enacted in December 2022; 2 of which will address surrogate endpoints.

As a wave of innovation continues to crash on the shores of neurological research, the interplay between novel therapeutics, surrogate endpoints, and regulatory flexibility has brought about tremendous progress in the field of neurodegenerative diseases. The FDA’s updated guidance on surrogate endpoints is likely to further accelerate the development of novel treatments based on the best available science.

References

  1. Ladanie A, Schmitt AM, Speich B, et al. Clinical trial evidence supporting US Food and Drug Administration approval of novel cancer therapies between 2000 and 2016. JAMA Netw Open. 2020;3(11):e2024406. doi: 10.1001/jamanetworkopen.2020.24406.

Muzamil Saleem, PhD
Associate Scientific Director, ProEd Regulatory
Muz is a trained neuroscientist with a diverse skillset, combining a 10-year neurology-focused research career, scientific consulting experience, and a 3-year tenure in healthcare equity research on Wall Street before joining ProEd Regulatory—all supported by a passion for written and visual scientific communication. Connect with Muz on LinkedIn.

Surrogate Endpoints for Accelerated Approval

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Surrogate endpoints have been used for accelerated approval (AA) since the early 1990s, playing a vital role in getting therapies for serious conditions to patients sooner. The AA pathway was first created in 1992 to accelerate the approval of drugs intended to treat “serious conditions that fill an unmet medical need.” In the intervening 30+ years, surrogate endpoints have played a major role in oncology and rare disease clinical trials, but their appropriate use is still being debated in the literature. Most often that debate centers around whether an endpoint is a true surrogate that predicts clinical benefit in the clinical context in which it is being used.

What is a “surrogate”endpoint? How is it different from “clinical outcome”endpoint?

A “surrogate” endpoint is a biomarker, lab measurement, radiographic image, physical sign, or other measure that is “reasonably likely to predict clinical benefit” whereas a “clinical outcome” endpoint is one that “directly measures clinical benefit.” Importantly, the FDA definition of clinical benefit is how a patient feels, functions, or survives.

To illustrate the difference between surrogate and clinical endpoints, below are some oncology-specific examples:

Surrogate Endpoints Clinical Outcome Endpoint
Progression-Free Survival (PFS) Overall Survival (OS)
Objective Response Rate (ORR)
Duration of Response (DoR)

The FDA publishes a Surrogate Endpoint Table updated every 6 months and listing surrogate endpoints that can support approval of a drug or a biological product under both accelerated and traditional approval pathways.1 The FDA encourages development of “novel” surrogate endpoints; a novel endpoint can become established as a surrogate based on persuasive evidence that it predicts clinical benefit in the context of a specific disease and patient population. The FDA determines the acceptability of a surrogate endpoint on a case-by-case basis, dependent on context and influenced by the disease, patient population, therapeutic mechanism of action, and currently available treatments (ie, unmet need for new treatments). If a surrogate endpoint was previously used to support AA, but subsequent confirmatory trials consistently fail to demonstrate the expected clinical benefit, that surrogate endpoint should no longer be accepted for that use.

When is it appropriate to use a surrogate endpoint?

The main purpose for using a surrogate endpoint is to shorten clinical development timelines or improve the feasibility of clinical studies in rare diseases where the number of patients is limited and large, controlled studies are challenging. In many cases, a surrogate endpoint can be reached much sooner and with fewer patients than a clinical outcome endpoint such as overall survival (OS), which is a direct measure of clinical benefit. Sponsors must think about this in the context of the specific disease and indication for which they are developing the drug.

For example, in cancer patients with a long life expectancy, a surrogate endpoint such as progression-free survival (PFS) can provide a much earlier readout than a clinical outcome endpoint such as overall survival (OS). If PFS has been shown to correlate with OS in that specific disease and indication, there is a good chance that the confirmatory trial would be able to show an OS benefit. However, in some cases this can be challenging.

In the context of rare genetic diseases, for example, the surrogate endpoint is often a biomarker that can be easily measured with precision and that is reasonably likely to predict how patients feel or function. Because clinical measures of how patients function over time can be difficult to assess with precision, they often require much larger studies to demonstrate a clinically meaningful effect. For example, in Duchenne muscular dystrophy, rather than measuring functional outcomes such as ability to walk, which can vary from one day to the next, researchers will often use a surrogate endpoint such as quantitative measurements of dystrophin protein expression.

In severe respiratory diseases, measures of lung function are often used as a surrogate to predict how well the patient can perform activities of daily living, which can often be difficult to measure with precision. These few examples illustrate how surrogate endpoints can be used to facilitate clinical research.

How much time is saved by using these endpoints?

The amount of time saved by using a surrogate endpoint is disease dependent. For example, use of PFS rather than OS in breast cancer can save almost a full year, whereas the use of response rate (RR) versus OS can save 19 months.2 It all depends on the natural history of the disease and the nature of the endpoint being studied. So, while the use of surrogate endpoints can save time on the front end, and while patients will benefit sooner, the tradeoff is that the sponsor must invest in the development of an additional post-approval confirmatory trial—and there is no guarantee that a direct clinical benefit will be confirmed. Thus, there is a chance that the patient might be taking a drug that turns out not to help them in the long run.

What are “validated” surrogate endpoints?

A “validated” surrogate endpoint meets a higher standard and can be used to support full approval. This requires that the endpoint be “supported by a clear mechanistic rationale and clinical data providing strong evidence that an effect on the surrogate endpoint predicts a specific clinical benefit.”3

Two examples include:

  • HbA1c predicting improvements in long-term complications of type 2 diabetes mellitus
  • Virologic suppression of HIV as a proxy for preventing progression to AIDS

More than 75% of approvals that used a surrogate endpoint came through the traditional pathway using a validated surrogate endpoint.3 The AA pathway does not require the use of validated surrogate endpoints.

Aaron Csicseri, PharmD, Aaron has 10+ years’ experience as a Senior Scientific Director, Medical Director, or Clinical Strategist within the medical communication field. He is responsible for overseeing and developing high-quality scientific and medical content that incorporates key communication objectives and accurate representation of data. Aaron is experienced in the development of strategic scientific communication platforms, strategic publication planning and implementation, medical expert outreach and engagement, guiding and executing medical education programs, and support for medical affairs. He received his PharmD from the University of Buffalo.

 

Sources:

  1. US FDA. Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure. Updated February 28, 2022. Accessed March 8, 2022. https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure
  2. Chen EY, Joshi SK, Tan A, Prasad V. Estimation of study time reduction using surrogate end points rather than overall survival in oncology clinical trials. JAMA Intern Med. 2019;179(5):642-647.
  3. US FDA. Surrogate Endpoint Resources for Drug and Biologic Development. Updated July 24, 2018. Accessed March 8, 2022. https://www.fda.gov/drugs/development-resources/surrogate-endpoint-resources-drug-and-biologic-development