FDA Sets High Bar for Real-World Evidence in Rare Diseases

Real-world data (RWD) can be used to create historical control groups for clinical trials in rare diseases where a randomized controlled trial (RCT) is not feasible. But what happens when the US Food and Drug Administration (FDA) doesn’t accept it?

Since passage of the 21st Century Cures Act in 2016, FDA has promoted the use of real-world evidence (RWE) to increase the efficiency of clinical research. However, according to
FDA’s 2018 RWE framework, the use of RWE is primarily restricted to evaluating safety
(eg, monitoring postmarketing safety). It can only be used in limited circumstances to inform decisions about effectiveness.

When it comes to regulatory decisions about product effectiveness, FDA’s framework suggests that RWE can be used to support changes to labeling about product effectiveness, including adding or modifying an indication, such as a change in dose, dose regimen, or route of administration, adding a new population, or adding comparative effectiveness data.

So, where does that leave sponsors who want to compare the results of a single-arm clinical trial to a real-world historical control arm to demonstrate the effectiveness of a new product? Unfortunately, the FDA has set a very high bar.

Regulatory “Fitness” in Rare Disease Clinical Trials

At a joint FDA-National Institutes of Health workshop in May 2022, titled “Regulatory Fitness in Rare Disease Clinical Trials,” Katie Donohue, Director of the Division of Rare Diseases and Medical Genetics in the Center for Drug Evaluation & Research, said that the challenges facing sponsors attempting a single-arm approach to develop a first therapy for a rare disease are so daunting that development programs only “work when you are very lucky.” In particular, she pointed out that single-arm studies are vulnerable to changes in rare disease natural history.

Changes in natural history, response assessment, and standard-of-care therapy can have a dramatic effect on time-to-event endpoints such as overall survival (OS). So, for a single-arm trial, FDA recommends concrete, confirmed endpoints “like an x-ray or blood test.”

These comments highlight the strong preference FDA has for RCTs, in general, and even for rare diseases, where it is often extremely challenging to conduct an RCT with sufficient statistical power to demonstrate effectiveness.

FDA Has Set the Bar Very High

FDA’s draft guidance, titled Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products, acknowledges the potential utility of using RWD in interventional studies, including “to serve as a comparator arm in an external control trial.” However, the guidance focuses heavily on the use of RWD/RWE in non-interventional studies, such as observational cohort studies and case control studies that evaluate the safety and effectiveness of a product in routine medical practice and are not governed by a research protocol.

Although FDA is not opposed to the idea to using RWD to construct historical control groups also referred to as an external control arm – it is highly critical of that approach as the basis for regulatory approval of a novel drug.

Recently, Y-mAbs Therapeutics found this out the hard way. In collaboration with Memorial Sloan Kettering Cancer Center (MSKCC), Y-mAbs has developed a targeted radiolabeled antibody called 131I-omburtamab for the treatment of neuroblastoma that has metastasized to the central nervous system (CNS). This ultrarare pediatric indication affects only about 20 patients per year in the United States, and there are no approved therapies.

With traditional treatment approaches – surgery, radiotherapy (RT), and chemotherapy – most patients only survive a few months after diagnosis of CNS metastases. For about one third of patients who survive long enough to receive 2 or 3 treatment modalities, median survival is about 15 months. So, the clinical team at MSKCC, led by Dr. Nai-Kong Cheung and Dr. Kim Kramer, developed 131I-omburtamab, an anti-B7-H3 antibody, which they inject directly into the cerebrospinal fluid via an Ommaya catheter, as an adjunct to standard therapy. The goal is to eradicate residual tumor cells and increase the chance of achieving a cure.

The team at MSKCC has been studying the safety and effectiveness of 131I-omburtamab in this poor-prognosis patient population since 2004. In that timeframe, they have treated more than 100 children with CNS neuroblastoma, of whom about 40% have survived more than 8 years. Their treatment protocol demonstrated a median OS of 51 months, a milestone that clinical experts consider quite extraordinary.

Fast Forward to 2015

In 2015, Thomas Gad, whose daughter was successfully treated at MSKCC for CNS neuroblastoma, founded Y-mAbs Therapeutics to further develop 131I-omburtamab and get it approved in the US, so other children could have access to this potentially lifesaving drug.

To demonstrate the effectiveness of 131I-omburtamab, the company conducted its own single-arm multicenter trial in 50 patients, principally to confirm the results from the single-institution MSKCC trial and demonstrate objective responses to the drug. Given the rarity of this indication, an RCT was not feasible.

Y-mAbs then set out to obtain patient-level data from children with CNS neuroblastoma treated outside MSKCC and construct an external control arm for comparison with the MSKCC trial population. They succeeded in identifying only one suitable database, a neuroblastoma registry in Germany, and they were able to extract patient-level data from 120 patients who had a first recurrence of neuroblastoma in the brain. In collaboration with the FDA, Y-mAbs designed the comparative analysis using a propensity score model.

After carefully balancing the intensity of standard treatment with surgery, RT, and chemotherapy (modality group 2), the Y-mAbs biometrics team identified a cohort of 34 patients from the external control arm that they could compare to 89 patients in the MSKCC study. A comprehensive propensity score model that controlled for potential confounding factors demonstrated a 42% improvement in OS (hazard ratio = 0.58) compared with the external control arm. Sensitivity analyses showed a consistent treatment effect (hazard ratios ranged from 0.42 to 0.66) in favor of 131I-omburtamab.

Y-mAbs also went one step further, restricting the analysis to only patients in first recurrence, adjusting the index dates to control for immortal time bias, and removing patients from the external control arm treated prior to 1997. That analysis, which represents the best possible match between the populations, showed a 52% improvement in OS (Figure 1).

Figure 1.   Overall survival in patients in modality group 2 treated at first recurrence comparing index dates A vs D and excluding NB90 from external control arm

These data, along with supportive data from the multicenter trial, were the basis for the Y-mabs Biologics License Agreement filed in March 2022. However, after careful review of the data, FDA’s Oncology Division concluded that the external control arm is “not fit for purpose.” FDA argued that limitations of the data and multiple sources of potential bias resulted in a large degree of uncertainty regarding whether the observed OS difference was due to 131I‑omburtamab or differences between the populations, or a combination of these factors. FDA also had doubts about the objective response data.

FDA Oncologic Drugs Advisory Committee (ODAC) Meeting

At the ODAC meeting on October 28, 2022, the FDA presented its case that the 2 populations were not comparable, primarily because of differences in treatment intensity and era of therapy. They pointed out that none of the patients in the external control arm received craniospinal irradiation, a form of RT perceived to be more effective than the standard focal or whole-brain RT given to the German patients. However, there are no published studies to show that it is more effective in neuroblastoma. The FDA also presented evidence that clinical outcomes for CNS neuroblastoma have improved over time. Consequently, FDA restricted its analysis to only those patients in the external control arm who were treated from 2004 to 2015, the time period corresponding to the MSKCC study.

After adjusting for all these potential confounders, including immortal time bias, the FDA analysis showed a hazard ratio of 1.0, suggesting no OS benefit.

Ultimately, the committee voted unanimously that the Applicant had not provided sufficient evidence to conclude that 131I-omburtamab improves OS in the proposed indication. The committee wanted to see more data. Unfortunately, that may not be feasible.

This case sends a strong message regarding the rigor of data that FDA expects when establishing effectiveness based on a time-to-event endpoint in a single-arm trial with comparison to an external control arm, even in a rare disease where it exercises regulatory flexibility. The consequence of this ODAC decision means that sponsors will face a high bar when attempting to demonstrate that an external control arm is “fit for purpose.”

Jeff Riegel, PhD
SVP, Scientific Communications, ProEd Regulatory
Jeff combines his scientific expertise in molecular biology and immunology with more than 25 years of global healthcare agency experience guiding medical and regulatory communication strategies for biopharma companies. Jeff helps clients prepare for FDA Advisory Committee meetings and other health authority interactions. Connect with Jeff on LinkedIn.

The Alzheimer’s Conundrum

The United States is facing an avalanche of Alzheimer’s disease (AD). An estimated 12.7 million Americans over the age of 65 are projected to suffer from AD dementia by 2050,1 and yet, despite more than 30 years of intensive research, we have yet to develop a drug that provides a clinically meaningful slowing in cognitive decline. There are only 6 AD drugs currently approved in the US. Five of these are symptomatic treatments, such acetylcholinesterase drugs for mild AD and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, which is used as an add-on or second-line therapy in more severe cases. Aduhelm, a beta-amyloid monoclonal antibody (mAb) therapy, represented the sixth US Food and Drug Administration (FDA) approval in AD and is the first to target the underlying pathology of the disease. However, the beta-amyloid mAbs have failed to live up to the promise of delivering a curative, disease-modifying drug (DMD). We examine directions in research and development that contribute a set of diverse pathological targets—illuminating Alzheimer’s disease as a conundrum that will likely be solved with a multifactorial treatment approach.

The Alzheimer’s Conundrum

So, why have effective AD therapeutics been so elusive? A key factor is the cavernous deficiency in our pathologic understanding of AD. In the amyloid hypothesis, plaques composed of toxic beta-amyloid and phosphorylated tau protein are hypothesized to cause neurodegeneration leading to cognitive decline. This hypothesis has dominated the last 20 years of AD research and carries with it a storm of controversy, to the extent that two camps have formed (those who support the amyloid hypothesis, and those who don’t). At issue is the failure of a long line of drugs targeting beta-amyloid in clinical trials dating back to 2003. Interviews with multiple scientists suggest that any research that fell outside of the amyloid field was suppressed,2 likely slowing progress in the field. In addition, the dire unmet need for AD therapeutics has put a strain on translational research, such that biotech companies have scrambled to move drugs into clinical trials, perhaps before the science was fully baked.

The pathology of AD, best represented as a continuum (Figure 1),1 presents another challenge. Researchers and clinicians believe that therapeutic intervention stands the best chance of success in patients with mild cognitive impairment, but without a reliable biomarker, it can be challenging to identify an appropriate patient population for clinical studies.

Figure 1. Alzheimer’s disease continuum.

The pathological changes in the brain that cause the first noticeable symptoms of AD—related to memory, language, and cognition—are thought to start 2 decades or more prior.3-10 During this asymptomatic phase there may be measurable changes in a biomarker that could indicate future progression to clinical AD. Hence, there is a crucial need for a biomarker sensitive enough to detect AD in early stages. To date, the best available biomarker of AD is the assessment of abnormal beta-amyloid deposits in the brain by positron emission tomography (PET) imaging.

The Lumipulse® beta-amyloid test (Fujirebio Diagnostics) was FDA approved earlier this year and could potentially substitute for the use of PET scans to detect amyloid pathology; however, the test requires collection of cerebrospinal fluid (CSF), which is an unpleasant procedure. The search for a minimally invasive, blood-based biomarker has been at the center of a fervent research effort over the past decade.11 The PrecivityAD® is a blood test developed by C2N Diagnostics that has been shown to be 81% accurate in predicting the level of beta-amyloid in the brain; however, it is not yet FDA approved.

The First Drug to Address the Underlying Biology of Alzheimer’s Disease

The accelerated approval of aducanumab (Aduhelm™), an antibody that binds to and clears beta-amyloid plaques in the brain, in 2020 was a landmark in the treatment of AD, signaling the first new drug in 18 years. Aduhelm was studied in two large, randomized, controlled trials in patients with mild cognitive impairment and evidence of amyloid pathology by PET imaging. However, both trials were prematurely stopped for futility. The first trial (EMERGE) ultimately met its primary endpoint—patients on high-dose aducanumab showed a significant slowing of cognitive decline from baseline. The second trial (ENGAGE) did not meet its primary endpoint; however, patients from this trial who received sufficient exposure to high-dose aducanumab showed efficacy results supporting the findings of EMERGE. Both trials also showed a statistically significant, dose-dependent decrease in beta-amyloid and phosphorylated tau protein by PET imaging, which was the basis for accelerated approval.

Controversy ensued when an independent panel of scientific and clinical experts was assembled at an FDA Advisory Committee meeting to deliberate over the approval of Aduhelm. The committee advised unanimously against the approval of aducanumab. Despite convincing evidence that Aduhelm effectively removes beta-amyloid plaques from the brain, experts argued that the two large phase 3 clinical trials— one positive and one negative—did not conclusively demonstrate a slowing in cognitive decline.

The approval of Aduhelm has not quelled any of the controversy surrounding the amyloid hypothesis. There remains a significant unmet need for disease-modifying AD therapeutics that result in a slowing—or indeed a reversal—of cognitive decline. The following post in this Alzheimer’s series will explore the next wave of AD drug development. We will place our focus beyond aberrant amyloid and tau protein pathology, and examine a multifactorial set of disease mechanisms, including inflammatory cascades, gut-brain signaling, and axonal transport.

Muzamil Saleem, PhD
Associate Scientific Director, ProEd Regulatory
Muz is a trained neuroscientist with a diverse skillset, combining a ten-year neurology-focused research career, scientific consulting experience and a three-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.

References

  1. 2022 Alzheimer’s disease facts and figures. Alzheimers Dement. 2022;18(4):700-789.
  2. Begley S. The maddening saga of how an Alzheimer’s ‘cabal’ thwarted progress toward a cure for decades. STAT. 2019.
  3. Quiroz YT, Zetterberg H, Reiman EM, et al. Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional and longitudinal cohort study. Lancet Neurol. 2020;19(6):513-521.
  4. Barthelemy NR, Li Y, Joseph-Mathurin N, et al. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat Med. 2020;26(3):398-407.
  5. Villemagne VL, Burnham S, Bourgeat P, et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013;12(4):357-367.
  6. Reiman EM, Quiroz YT, Fleisher AS, et al. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol. 2012;11(12):1048-1056.
  7. Jack CR, Jr., Lowe VJ, Weigand SD, et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer’s disease: implications for sequence of pathological events in Alzheimer’s disease. Brain. 2009;132(Pt 5):1355-1365.
  8. Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9):795-804.
  9. Gordon BA, Blazey TM, Su Y, et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 2018;17(3):241-250.
  10. Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011;70(11):960-969.
  11. Shi L, Baird AL, Westwood S, et al. A Decade of Blood Biomarkers for Alzheimer’s Disease Research: An Evolving Field, Improving Study Designs, and the Challenge of Replication. J Alzheimers Dis. 2018;62(3):1181-1198.

The Saga of PI3K Inhibitors: Part 2 – The shifting role of overall survival

In Part 1 of our blog series on the saga of PI3K inhibitors, we reviewed the FDA’s recent Oncologic Drugs Advisory Committee (ODAC) meeting on April 21, 2022, to discuss the agency’s concerns about PI3K inhibitors (PI3Kis). The panel voted resoundingly (16 yes votes; 1 abstention) that future approvals of PI3Kis should be supported by randomized data that would allow an assessment of overall survival (OS)—an action that makes accelerated approvals less likely and more difficult to obtain in slow-growing cancers with a long median survival.

At the heart of the FDA’s concerns with the PI3Ki class is an apparent excess of deaths in clinical trials of PI3Kis, indicating a potential detriment to long-term survival in patients who were treated with PI3Kis. However, assessing OS in patients with indolent blood cancers, who have very long lifespans, can be exceedingly difficult—and the results are not always interpretable.

In this second installment of this blog series, we will focus on the OS data for PI3Kis presented by the FDA, the complexities of evaluating OS in blood cancers with long lifespans, and the broader regulatory implications of an increased focus on OS as a safety endpoint in patients with indolent diseases.

Regulatory pressure to withdraw PI3Kis continues…

The Class 1 phosphatidylinositol-3-kinases (PI3Ks) are master regulators of cell proliferation, growth, survival, motility, and immune cell function that are highly dysregulated in blood cancers. Four PI3Kis (idelalisib, duvelisib, copanlisib, and umbralisib) have been approved by the FDA for B-cell malignancies such as chronic lymphocytic leukemia (CLL), and indolent non-Hodgkin’s lymphomas (iNHL), including marginal zone lymphoma (MZL) or follicular lymphoma (FL). Please see Part 1 for additional background on PI3Kis.

As of writing this post, all accelerated approvals for PI3Kis in iNHL have been withdrawn, mostly due to a failure to complete a confirmatory trial. These withdrawals also likely reflect the ODAC decision in favor of a requirement for randomized data to support future approvals for PI3Kis (rather than single-arm trial data, which are often used to support accelerated approvals in oncology).

Currently, there are 2 PI3Kis (idelalisib and duvelisib) with full approval in later-line treatment of CLL that remain on the market.

Since the April ODAC, however, the FDA has increased pressure on sponsors to withdraw even fully approved indications for PI3Kis on the basis of a potential detriment to overall survival. The most recent development came on June 30 with a warning issued by the FDA that Secura Bio’s PI3Ki, duvelisib, may increase the risk of death when used as a third-line treatment for patients with CLL. Duvelisib received full approval for CLL in 2018 on the basis of the phase 3 DUO trial. The FDA warning stated that the agency plans to hold a future public meeting to discuss the updated overall survival data of duvelisib, and whether duvelisib should continue to stay on the market – hinting that another potential ODAC meeting may be on the horizon.

Since the April ODAC, however, the FDA has increased pressure on sponsors to withdraw even fully approved indications for PI3Kis on the basis of a potential detriment to overall survival.

“The ultimate safety endpoint”: Do PI3Kis lead to a detriment in OS?

The FDA views OS as “the ultimate safety endpoint” because it encompasses deaths directly caused by adverse events related to the drug, and deaths that might be related to long-term side effects of the drug, which can be difficult to identify. Importantly, the FDA specifies that OS “does not require [the] same statistical considerations when used as a primary safety endpoint.” The FDA’s viewpoint is straightforward: The ultimate goal with any drug therapy should be to prolong life without inflicting long-term harm. From this viewpoint, OS has a dual purpose of providing information about the effectiveness of a drug, while also informing safety.

The FDA presented data at the April ODAC showing that in six phase 3 randomized trials for the approved PI3Kis, most had OS hazard ratios (HR) >1 (Figure 1) . An HR >1, based on Kaplan-Meier estimates, suggests that more patients died on the experimental arm (in this case the PI3Ki) than on the comparator arm. In 3 trials with idelalisib (the first approved PI3Ki drug), there was a much higher risk of death in the idelalisib arm, with a nearly 5× greater risk of dying in the 313-0124 trial in iNHL, and a more than 3× greater risk of dying in the 312-0123 trial in CLL.

The FDA views OS as “the ultimate safety endpoint” because it encompasses deaths directly caused by adverse events related to the drug, and deaths that might be related to long-term side effects of the drug, which can be difficult to identify.1

The OS results in trials with other PI3Kis across various patient populations and treatment regimens (DUO, CHRONOS-3, and UNITY CLL) did not show a survival imbalance as extreme as that observed in the idelalisib trials. Although most of these trials exhibited OS HRs >1, the 95% confidence interval was very wide and included 1. The CHRONOS-3 trial of copanlisib in iNHL was an exception, with an HR of 0.87 (95% CI: 0.57, 1.35) (Figure 1).

Figure 1: Summary of overall survival data and toxicity risk in FDA-approved PI3Kis. Slide 45 of the FDA presentation at the April 21 ODAC meeting.   

The FDA interprets these data to indicate an overall pattern of potential detriment to survival in patients treated with PI3Ki as a class, possibly linked to an increased risk of infection or immune-mediated adverse events, or unidentified long-term effects of PI3Kis that may negatively impact the efficacy of subsequent therapies.3

Imbalances in OS are not unheard of in blood cancer clinical trials…

The FDA repeatedly describes a pattern of detriment in survival with PI3Kis as “unprecedented” in oncology, but are unfavorable imbalances in OS in blood cancer trials really unprecedented? A quick review of the literature disproves this notion.

The Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib was approved for previously untreated CLL in January 2019 on the basis of the iLLUMINATE trial. At the final analysis from iLLUMINATE, there was an OS HR of 1.08 in favor of the comparator arm. Similarly, venetoclax, a B-cell lymphoma 2-targeted inhibitor (BCL2i), was approved for first-line CLL treatment in May 2019 on the basis of the CLL14 trial with an initial OS HR of 1.24 at the time of approval, although with 4 years of follow-up the OS HR improved to 0.85, albeit with results that were still not significant. Importantly, both ibrutinib and venetoclax are approved in multiple indications and are considered successful and paradigm-shifting drugs, despite never having shown a significant improvement in OS in blood cancers (nor have they definitively ruled out potential detriment).

These examples cast doubt on a narrative that PI3Kis are somehow uniquely detrimental to survival in indolent blood cancers. Rather, the problem with evaluating OS in blood cancer trials may be a reflection of the disease itself, rather than any particular class of drugs.

These examples cast doubt on a narrative that PI3Kis are somehow uniquely detrimental to survival in indolent blood cancers. Rather, the problem with evaluating OS in blood cancer trials may be a reflection of the disease itself, rather than any particular class of drugs.

The complexities of evaluating OS in blood cancers with long lifespans

There are several considerations that make OS data difficult to interpret in blood cancers with very long life expectancies. Most importantly, because there are few deaths, it is not feasible to appropriately power these trials to assess OS with statistical confidence. As a result, OS analyses tend to have wide confidence intervals that are highly unstable over time. For these reasons, OS is not used as a primary endpoint in indolent blood cancers. Instead, studies are typically powered for the primary endpoint of progression free-survival (PFS), which provides more clearly interpretable results. OS is often included as a secondary or exploratory endpoint, but is not usually considered conclusive.  

The interpretation of OS is further challenged by trial design realities in indolent diseases; for example, patients may go on to receive several different lines of therapy before their death and trials often include a crossover arm (wherein patients on the control arm may choose to receive the experimental treatment after disease progression). Consequently, analyses of OS may be confounded and rendered uninterpretable. Finally, identifying the cause of death is fraught with difficulty when a large number of deaths may occur years after patients have discontinued study drug.

It is also worth mentioning that COVID-19 deaths present a unique challenge to interpreting OS in indolent blood cancers (and, to some extent, all clinical trials affected by the pandemic) not only because of the timing of COVID-19 infection waves and deaths, but also because of shifts in standard of care that can no longer be controlled for by randomization. Given these circumstances, it is possible, or even likely, that a pattern of OS detriment seen with the newer PI3Kis in recent clinical trials is a chance finding, rather than a real reflection of risk.

How should sponsors use OS to support benefit-risk assessments?

If it is not possible to adequately power a trial for OS or to interpret the results, how exactly should an “assessment” of OS be performed to support benefit-risk evaluation of PI3Kis? When asked this question directly by a panelist, the FDA fell back on its stance that the burden is on sponsors to prove that PI3Kis are not producing a detriment to survival – a difficult situation for drug developers. However, the FDA provided few clues as to what it is looking for (see slide 75 of the FDA presentation).  

Sponsors developing new PI3Kis should be prepared to incorporate detailed analyses of the causes of death on each arm into study protocols, with the goal of providing assurance that the experimental arm is not causing excess deaths related to immune-mediated toxicity or an increased risk of infection due to PI3K inhibition. This type of analysis would require a much more in-depth investigation than is typically done, given the problems discussed above with tracking deaths that occur long after a patient has left the study. Sponsors should also attempt to design future studies so that the OS data are better able to withstand an increased level of scrutiny. For example, trial designs that include an option to cross over to the experimental arm after progression may not be advisable.

Ultimately, even following the FDA’s suggested changes to clinical trial design, there is no guarantee that OS can be evaluated with sufficient statistical clarity to definitively show that PI3Kis are not causing a detriment to survival.

What do the experts think?

Notably, not all physicians agreed with the FDA’s conclusion of a pattern of detriment to OS with PI3Kis. In a public docket comment in response to the April ODAC meeting, Jennifer Brown, MD, PhD, “urge[d] caution in the interpretation of trials in different clinical settings,” “as well as the interpretation of long term follow-up data which may be confounded by subsequent therapy choice and crossover study design.” Dr. Brown went on to note that PI3Kis have provided “transformative and life-saving” benefits, and “in patients who are heavily pretreated, as is the case with all the existing approvals and the drugs in development, the toxicity is readily managed.”  

In the context of excellent benefits in progression-free survival with PI3Kis and high unmet need for alternative therapies in heavily pre-treated patients, many physicians still view the benefit-risk profile for PI3Kis as favorable. On July 1, the CLL Society sent a letter to the FDA that received signatures of support from 40 of the top CLL/SLL physicians in the country, which urged the FDA to maintain approved PI3Kis as an option for patients with CLL:

“Going forward and looking more widely at the CLL therapeutic landscape, safety must never be compromised. But drug innovation should continue to be encouraged. We believe the FDA can leverage the power of electronic medical records and real-world data to further assess the safety of PI3K inhibitors. Delays associated with the wait for overall survival data have already started to dampen research efforts in CLL and have slowed patient access to potentially life-saving therapies. CLL is a chronic cancer, and patients are often exposed to multiple therapies over the span of their disease. Survival data will come too slowly for many patients and will never be ‘statistically pure.’ CLL Society and many others have pushed for crossover in clinical trials to ensure equipoise, which while further confounding the survival data, saves lives. In the opinion of CLL Society, clinical trial design focused on overall survival endpoints will ultimately delay or deny the best possible care to patients with CLL.”

Coming Next: Part 3 – How should dose optimization be conducted in drug classes with known immune-mediated toxicity risks?

The FDA has raised concerns that for the approved PI3Kis, dose modifications or treatment interruptions due to AEs are too common in clinical trials, indicating that the dose may be too high. The dosing regimen for all approved PI3Ki was selected based on standard, phase 1, single-arm dose escalation studies in small cohorts of patients. However, in the FDA’s view, this standard approach may lead sponsors to default to selecting the maximum tolerated dose, rather than the optimal (likely lower) dose that might achieve similar efficacy with less toxicity.

InIn Part 3 of this series, ProEd will review the panel discussion of how best to optimize drug dosing for PI3Kis, the broader FDA regulatory initiatives (ie, “Project Optimus”) surrounding dose optimization, and how these considerations may impact clinical trial design and dose-finding studies for targeted oncology drugs that modulate the immune system.

Angela W. Corona, PhD
Scientific Director, ProEd RegulatoryAngela is a Scientific Director for ProEd Regulatory. She is responsible for helping sponsors navigate complex regulatory communications such as FDA advisory committee meetings. She develops clinical and regulatory strategy along with high-quality scientific and medical content across a wide range of therapeutic and drug development areas. Angela received her PhD in Neuroscience from The Ohio State University and completed her postdoctoral training at Case Western Reserve University in Cleveland, Ohio.

References

  1. Pazdur R. The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint. Lancet. 2022 April 14 [Online ahead of print]. https://doi.org/10.1016/S1470-2045(22)00200-5
  2. FDA Presentation, Introductory Comments; Presented by Nicole Gormley. Oncologic Drugs Advisory Committee Meeting. Phosphatidylinositol 3-Kinase (PI3K) Inhibitors in Hematologic Malignancies. April 21, 2022. https://www.fda.gov/media/157837/download
  3. FDA Briefing Document. Oncologic Drugs Advisory Committee Meeting. Phosphatidylinositol 3-Kinase (PI3K) Inhibitors in Hematologic Malignancies. April 21, 2022. https://www.fda.gov/media/157762/download
  4. Moreno C, et al. First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase 3 iLLUMINATE trial. Haematologica. 2022 Jan 13 [Online ahead of print]. https://doi.org/10.3324/haematol.2021.279012.
  5. Fischer K, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. https://pubmed.ncbi.nlm.nih.gov/31166681/
  6. Al-Sawaf O, et al. Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: extended off-treatment follow-up from the randomized CLL14 study. J Clin Oncol. 2021;39(26):4049-4060. https://pubmed.ncbi.nlm.nih.gov/34709929/

The Saga of PI3K Inhibitors: Part 1 — The ODAC Decision

The FDA’s Oncology Division has recently taken a hard stance on PI3K inhibitors, a novel class of drugs that inhibit various isoforms of phosphatidylinositol 3-kinase (PI3K) and are approved for treating blood cancers. Recent actions by the FDA, including withdrawing some approved indications, indicate that they will likely be seeking a higher bar for new approvals of PI3K inhibitors for certain blood cancers. So, why is this promising class of drugs suddenly in the hot seat? At the heart of the issue is an excess of deaths in clinical trials of PI3K inhibitors and the FDA’s concern about their safety profile.

On April 21 of this year, the FDA convened a public Oncologic Drugs Advisory Committee (ODAC) meeting to discuss the agency’s concerns about PI3K inhibitors. The panel voted resoundingly (16 yes votes; 1 abstention) that future approvals of PI3K inhibitors should be supported by randomized data, which would allow for an assessment of overall survival (OS)—an action that makes accelerated approvals less likely and more difficult to obtain in cancers with a long life expectancy.

The panel voted resoundingly (16 yes votes; 1 abstention) that future approvals of PI3K inhibitors should be supported by randomized data, which would allow for an assessment of overall survival (OS)—an action that makes accelerated approvals less likely and more difficult to obtain in cancers with a long life expectancy.

We’ll take you inside this evolving saga. This first installment describes the drug class and what happened at a recent ODAC meeting, with top-line takeaways for drug developers in this field. Subsequent installments will analyze the implications of the panel discussion and the broader regulatory implications of that ODAC meeting and the FDA’s recent actions.

“Not a Typical ODAC Meeting”

The FDA used the April 21 ODAC meeting to zero-in on safety concerns with the class as a whole and to reevaluate the appropriate regulatory approach for future approvals. Nicole Gormley, MD, Director the Division of Hematologic Malignancies, opened up the FDA presentation by first explaining that “this committee meeting is not a typical ODAC where we would discuss the risk-benefit profile of a specific product. But instead, we will discuss the class of PI3K inhibitors as a whole, the unique toxicities that they present, and the best development approach for future drugs in this class.”

This is actually quite unusual—typically, FDA does not ask ODAC panels to provide forward-looking advice for hypothetical future new drug approvals.

Some panelists questioned if it was appropriate to make determinations for an entire drug class on the basis of collective data rather than the individual merits of each drug. Indeed, the one panel member who abstained from voting, Anthony Sung, MD, from Duke, cited this fact as the reason for his abstaining, “I still feel uncomfortable labelling an entire class and requiring that future drugs in that class be supported by randomized data. If the phase 1 data [are] not concerning, then I don’t know if randomized studies should be needed in that case.” While Dr. Gormley assured the panel that flexibility would be applied in specific cases, saying “nobody has a ‘crystal ball’,” the nature of the ODAC and recent agency actions suggests that the FDA plans to apply this advice broadly.

I still feel uncomfortable labelling an entire class and requiring that future drugs in that class be supported by randomized data.

Approved PI3K Inhibitors: Promising efficacy, paired with lingering safety concerns

The Class 1 PI3Ks are master regulators of cell proliferation, growth, survival, motility, and immune cell function. They have long been recognized as one of the most frequently aberrantly activated pathways in cancer, making this a “holy grail” drug target. Certain PI3K isoforms are implicated more strongly in different cancers. PI3Kδ and γ, for example, are preferentially expressed in B lymphocytes and are often constitutively activated in B-cell malignancies.1 Consequently small-molecule PI3K inhibitors with varying levels of selectivity for several PI3K isoforms have been developed, mainly for B-cell malignancies like chronic lymphocytic leukemia (CLL), and indolent non-Hodgkin’s lymphomas (iNHL), including marginal zone lymphoma (MZL) or follicular lymphoma (FL).

Table 1 summarizes the FDA-approved PI3K inhibitors that were the subject of the April 21 ODAC, and the history of FDA approvals for each. As of writing this article, most accelerated approval indications in Table 1, and several new marketing applications for PI3K inhibitors in blood cancer, have been withdrawn (including applications for accelerated approval in MZL/FL for MEI Pharma’s zandelisib (ME-401) and Incyte’s parsaclisib, and most recently, TG Therapeutics’ umbralisib).

Drug Name, (Company) PI3Ki Isoform Selectivity Indication(s) Monotherapy/ Combination Approval History
idelalisib/Zydelig
(Gilead)
PI3Kδ inhibitor R/R CLL Combination with rituximab 2014, Regular approval
FL/SLL after ≥2 prior systemic therapies Monotherapy 2014, Accelerated approval
2022, Voluntary withdrawal
copanlisib/Aliqopa
(Bayer)
Pan-PI3K inhibitor FL after ≥2 prior systemic therapies Monotherapy 2017, Accelerated approval
Relapsed iNHL Combination with rituximab 2022, Voluntary withdrawal of marketing application
duvelisib/Copiktra
(Secura Bio)
Dual PI3Kγ/δ inhibitor CLL/SLL after ≥2 prior systemic therapies Monotherapy 2018, Regular approval
FL after ≥2 prior systemic therapies Monotherapy 2018, Accelerated approval
2021, Voluntary withdrawal
alpelisib/Piqray*
(Novartis)
PI3Kα inhibitor Advanced breast cancer (PIK3CA-mutated, HR+, HER2–) Combination with fulvestrant 2019, Regular approval
umbralisib/Ukoniq
(TG Therapeutics)
PI3Kδ inhibitor (also inhibits CK1ε) CLL/SLL, treatment-naive or relapsed Combination with ublituximab 2022, Voluntary withdrawal of marketing application
R/R MZL/FL Monotherapy 2021, Accelerated approval
2022, Voluntary withdrawal

Table 1: Summary of FDA-approved PI3K inhibitors and current status of approvals and new marketing applications for additional indications.

CLL=chronic lymphocytic leukemia; FL=follicular lymphoma; HER2, human epidermal growth factor receptor-2–negative; HR+, hormone receptor-positive; iNHL=indolent non-Hodgkin’s lymphoma; MZL=marginal zone lymphoma; PI3K=phosphatidylinositol 3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; R/R= relapsed/refractory; SLL, small lymphocytic leukemia. *Because of the FDA’s focus on PI3K inhibitors in blood cancer, the PI3Kα inhibitor, alpelisib, approved for advanced breast cancer in 2019, was not included in recent ODAC discussions and is not discussed in this post.

These approvals validated the promising clinical activity of PI3K inhibitors in blood cancers based on improvements in progression-free survival (PFS) and overall response rates (ORR); nevertheless, the class has been associated with safety issues. Because PI3K regulates the immune response, inhibition of this pathway leads to immune-related adverse events such as transaminitis, pneumonitis, diarrhea/colitis, and rash that are sometimes severe.2 These agents are also associated with an increased risk of infection. This means that adverse events and infectious complications need to be carefully managed by the treating physician.2

The core of FDA’s concern was a pattern suggesting a potential detriment in overall survival (OS) in patients treated with PI3K inhibitors. The FDA presented data at the ODAC showing that in 6, randomized, phase 3 trials for the approved PI3K inhibitors, most demonstrated an OS hazard ratio (HR) >1. A HR >1 means that there were more patients who died on the experimental PI3K inhibitor arm than on the comparator arm. The FDA hypothesized that this pattern could be caused by an increased risk of infection or immune-mediated adverse events or by unidentified long-term effects of PI3K inhibitors, which may negatively affect the efficacy of subsequent therapies.4

The core of FDA’s concern was a pattern suggesting a potential detriment in overall survival (OS) in patients treated with PI3K inhibitors.

Not all PI3K inhibitors have identical safety profiles. To minimize risks, drug companies have developed next-generation PI3K inhibitors, such as umbralisib and duvelisib, with greater selectivity for specific PI3K isoforms. These developments have led to hope in the scientific community that next-generation PI3K inhibitors are “finally coming of age.”5 However, infections and immune-mediated adverse events are still important recognized risks related to the class.

Topline Takeaway: Randomized trial data with an evaluation of OS to support new approvals of PI3K inhibitors

The primary outcome of the April 21 ODAC was the panel’s unanimous vote that randomized trials should be necessary to support future approvals of PI3K inhibitors. Sponsors should anticipate that the ODAC vote will likely translate into regulatory policy. While this does not necessarily affect the regulatory threshold for full approvals (where randomized data has always been required), this decision would make accelerated approvals based on single-arm trials less likely for PI3K inhibitors. Sponsors seeking new approvals for PI3K inhibitors should plan to base their New Drug Applications on randomized clinical trial data and should design clinical trials to include an evaluation of OS. Sponsors should be aware, however, that FDA appears to be looking for an OS hazard ratio of <1.

Sponsors seeking new approvals for PI3K inhibitors should plan to base their New Drug Applications on randomized clinical trial data and should design clinical trials to include an evaluation of OS. Sponsors should be aware, however, that FDA appears to be looking for an OS hazard ratio of <1.

Coming Next: Part 2 — How Should Overall Survival Data Be Evaluated in Blood Cancers?

The rationale for requiring randomized trials specifically for PI3Kis was to allow for an assessment of OS as a safety endpoint. However, assessing OS in patients with indolent blood cancers, who have very long lifespans, can be exceedingly difficult—and the results are not always interpretable. Many panelists questioned the feasibility of assessing OS and how this information should be used in regulatory decision making moving forward.

In Part 2 of this series, ProEd will review in detail the OS data for PI3K inhibitors presented at the April 21 ODAC and the broader regulatory implications of an increased focus on OS as a safety endpoint in patients with indolent blood cancers.

Angela W. Corona, PhD
Scientific Director, ProEd Regulatory

Angela is a Scientific Director for ProEd Regulatory. She is responsible for helping sponsors navigate complex regulatory communications such as FDA advisory committee meetings. She develops clinical and regulatory strategy along with high-quality scientific and medical content across a wide range of therapeutic and drug development areas. Angela received her PhD in Neuroscience from The Ohio State University and completed her postdoctoral training at Case Western Reserve University in Cleveland, Ohio.

 

References

  1. Phillips TJ, Michot JM, Ribrag V. Can next-generation PI3K inhibitors unlock the full potential of the class in patients with B-cell lymphoma? Clin Lymphoma Myeloma Leuk. 2021;21(1):8-20.e3.
  2. Hanlon A, Brander DM. Managing toxicities of phosphatidylinositol-3-kinase (PI3K) inhibitors. Hematology Am Soc Hematol Educ Program. 2020;2020(1):346-356. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727518/
  3. FDA Presentation, Introductory Comments; Presented by Nicole Gormley. Oncologic Drugs Advisory Committee Meeting. Phosphatidylinositol 3-Kinase (PI3K) Inhibitors in Hematologic Malignancies. April 21, 2022. https://www.fda.gov/media/157837/download
  4. FDA Briefing Document. Oncologic Drugs Advisory Committee Meeting. Phosphatidylinositol 3-Kinase (PI3K) Inhibitors in Hematologic Malignancies. April 21, 2022. https://www.fda.gov/media/157762/download
  5. Vanhaesebroeck B, Perry MWD, Brown JR, André F, Okkenhaug K. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov. 2021;20(10):741-769.

Regulatory Policy Watch: Proposed Reforms to the Accelerated Approval Pathway

By Jackie Orabone, PhD and Angela Corona, PhD

The accelerated approval (AA) pathway was introduced in 1992 (in response to the AIDS epidemic) to shorten the FDA approval process for drugs to treat serious or life-threatening diseases or rare diseases where there is a high unmet medical need. AA allows for drugs to be approved on the basis of surrogate endpoints that are “reasonably likely to predict clinical benefit.”1 Part 1 of this blog series provided an introduction to the accelerated approval pathway, and Part 2 explained how surrogate endpoints for accelerated approval are identified and validated. In Part 3 of this series, we explored what happens when confirmatory trials are not completed or fail to confirm clinical benefit.

Here in Part 4 of this series, we will review recently proposed reforms to the AA pathway. Each proposed reform has slightly different provisions, but all strive to modify and update policies and procedures, better define surrogate endpoints, and implement mechanisms to ensure that confirmatory trials are completed in a timely manner.

Why are calls for reform of the AA increasing?

Most criticism of the AA pathway stems from the perception that there are insufficient guardrails, a lack of transparency in decision making, and/or a lack of sufficient incentives for sponsors to complete confirmatory trials once a drug has been granted AA. For example, there is currently no defined requirement for FDA or sponsors to withdraw an AA indication when confirmatory trials fail to confirm clinical benefit, nor is there a defined time limit for AAs. In addition, there are no strict rules defining surrogate endpoints. Therefore, calls for reform of the AA pathway have grown louder, and investigations and legislation that seek to amend the current AA process are now making their way through Congress.

US Department of Health and Human Services (HHS) Review

In August of 2021, the US HHS Office of the Inspector General announced its intent to conduct a Review of the FDA’s AA Pathway.2 This was spurred by the controversial approval of Aduhelm (aducanumab) based on an unvalidated surrogate endpoint despite the FDA advisory committee’s nearly unanimous vote against approval. HHS will review how the FDA makes decisions about when AA is appropriate. In particular, they will scrutinize how regulators apply AA in cases where a surrogate endpoint is not accepted by the scientific community to be “reasonably likely to predict clinical benefit”—as is often the case in neurology indications. Completion of the report is expected in 2023; however, legislators are not waiting for the results of this report to propose reforms.

Accelerated Approval Integrity Act of 2022 (HR 6963)

The Accelerated Approval Integrity Act of 2022,3 proposed on March 7, 2022, takes aim at a highly criticized issue with the AA pathway—the fact that there is no mechanism in place to ensure that confirmatory trials are completed in a timely manner.4 The bill proposes several reforms to the AA pathway intended to expedite the completion of confirmatory trials, and importantly, the speedy withdrawal of AAs that fail to demonstrate clinical benefit. Key proposed revisions are listed below:4

  • Codifying requirements for manufacturers to conduct post-approval studies. Provisions include
    1. Allowing the FDA to require that studies be underway at the time of AA,
    2. Requiring an agreement on how the studies will be conducted before FDA can grant AA, and
    3. Requiring more frequent updates on the status of post-approval studies.
  • Outlining expedited procedures for the FDA to withdraw approval, which would include due notice and an opportunity for a written appeal to FDA, which may result in the FDA consulting an advisory committee more frequently on these topics.
  • Requiring that AA status be reflected in the product label.
  • Proposing, most controversially, a 5-year deadline for completing confirmatory trials, and automatic expiration dates for AA status 1 year after post-approval studies are scheduled to be complete. Automatic expiration of AA would eliminate any flexibility on the part of FDA to consider the unmet medical need when making decisions about withdrawal of AA, which has advocates of AA and the medical community concerned.
  • Including, importantly, provisions to make certain actions by the sponsor, such as failure to submit reports, prohibited and subject to penalties and fines.

Accelerating Access for Patients Act of 2022 (HR 6996)

The Accelerating Access for Patients Act of 20225 is the competing bill to the AA Integrity Act. It is similar in that it requires the FDA to establish requirements for confirmatory studies following AA and expedited procedures to withdraw AA if post-marketing requirements are not met or confirmatory studies are not conducted with due diligence. A key difference, however, is that this bill does not include a provision for automatic expiration of AA status or penalties for sponsors (a measure that is perceived to be more favorable to industry).6 In addition, 2 provisions seek to “modernize” the definition of surrogate endpoints and the design of confirmatory clinical trials:5

  • The bill clarifies the type of evidence that can be used to justify a surrogate endpoint and appears to be directed towards identifying surrogate endpoints suitable for supporting AA in neurodegenerative and rare diseases, where AA has previously been controversial.
  • The bill requires that the FDA issue guidance on the “use of novel clinical trial designs that may be used to conduct appropriate post-approval studies,” which may allude to the potential use of real-world evidence in confirmatory trials.

The Promising Pathway Act (S 1644)

Some legislators have opted to propose an entirely new regulatory framework for AA, rather than incrementally reforming the existing pathway.7 The Promising Pathway Act,8 reintroduced to the Senate in May 2021, would allow for time-limited, “provisional” approvals on the basis of substantial evidence of safety, along with relevant early evidence of efficacy—such as data that could be provided by a phase 1/2 study. Under the act, a provisional approval would be limited to a 2-year period and would include strict requirements for patients receiving provisionally approved drugs to join a patient registry. The act relies heavily on real-world evidence (RWE), which would be collected from patient registry data and submitted in regular reports to the agency. Importantly, the act would require the FDA to accept real-world data and surrogate endpoints as evidence to demonstrate efficacy and convert a provisional approval to a full approval.

Needless to say, regulators have raised some concerns regarding this proposal. The reliance on RWE has been identified as particularly problematic, given that studies have cast doubt on the feasibility of replicating high-quality clinical trial data using RWE.10 It’s unclear if the required patient registries under the act would be sufficient to make rigorous RWE studies feasible. However, this proposal has received vocal support from patient advocacy groups, especially in the ALS community,9 where surrogate endpoints have not been identified and few to no treatment options are available.

Accelerated approval reforms tacked onto “must pass” FDA user fee (PDUFA) renewal legislation

We now know that some of these proposed reforms are likely to become law, albeit in slightly watered-down form, as part of the PDUFA reauthorization bill. In draft legislation released on May 4, 2022, provisions were included to speed the withdrawal process for AAs and strengthen requirements for speedy confirmatory trials. Other provisions grant FDA the authority to require that confirmatory studies be underway at the time of AA and that product labels note AA status along with details on the surrogate endpoint used and any uncertainties about anticipated clinical benefit. Missing from the legislation was the controversial 5-year deadline for confirmatory trials proposed in HR 6963.

With bipartisan support, the PDUFA reauthorization bill is expected to pass and be ready for President Biden’s signature before August. Sponsors should prepare for increased scrutiny and tightened regulations around accelerated approvals.

Jackie Orabone, PhD
Scientific Director, Scientific Services

Jackie combines her scientific expertise in immunology and research knowledge with more than 2 years of medical communications agency experience to help clients define their strategy and develop their core content in preparation for FDA Advisory Committee meetings and other scientific communications. She has experience in a variety of therapeutic areas such as oncology, dermatology, and HIV, and in products such as vaccines and targeted biologics. Jackie earned her PhD in Pathology from Case Western Reserve University, Cleveland, Ohio, where she went on to complete a post-doctoral fellowship in genomics and bioinformatic techniques. Connect with Jackie on LinkedIn.

 

Angela W. Corona, PhD
Scientific Director, ProEd Regulatory

Angela is a Scientific Director for ProEd Regulatory. She is responsible for helping sponsors navigate complex regulatory communications, such as FDA advisory committee meetings. She develops clinical and regulatory strategy along with high-quality scientific and medical content across a wide range of therapeutic and drug development areas. Angela received her PhD in Neuroscience from The Ohio State University and completed her postdoctoral training at Case Western Reserve University.

 

References:

  1. US Food and Drug Administration. Expedited programs for serious conditions – drugs and biologics. May 2014. Updated June 25, 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics
  2. US Department of Health and Human Services, Office of Inspector General. Review of the FDA’s Accelerated Approval Pathway. August 2021. https://oig.hhs.gov/reports-and-publications/workplan/summary/wp-summary-0000608.asp
  3. Congress.gov. H.R.6963 – 117th Congress (2021-2022): Accelerated Approval Integrity Act of 2022. March 7, 2022. https://www.congress.gov/bill/117th-congress/house-bill/6963
  4. House Committee on Energy & Commerce. Pallone Introduces Bill to Improve FDA’s Accelerated Approval Program [press release]. March 7, 2022. https://energycommerce.house.gov/newsroom/press-releases/pallone-introduces-bill-to-improve-fda-s-accelerated-approval-program
  5. Congress.gov. H.R.6996 – 117th Congress (2021-2022): Accelerating Access for Patients Act of 2022. March 8, 2022. https://www.congress.gov/bill/117th-congress/house-bill/6996/text#:~:text=Introduced%20in%20House%20(03%2F08%2F2022)&text=To%20amend%20the%20Federal%20Food,condition%2C%20and%20for%20other%20purposes
  6. Cafero B and Reuter T. Competing bills propose amendments to FDA’s accelerated approval program. Health Industry Washington Watch. March 18, 2022. https://www.healthindustrywashingtonwatch.com/2022/03/articles/legislative-developments/competing-bills-propose-amendments-to-fdas-accelerated-approval-program/
  7. Pitts PJ. Creating a promising pathway for faster access to new drugs — and a Califf confirmation. STAT. February 14, 2022. https://www.statnews.com/2022/02/14/creating-promising-pathway-to-new-drugs-califf-confirmation/
  8. Congress.gov. S.1644 – 117th Congress (2021-2022): Promising Pathway Act. May 13, 2021. https://www.congress.gov/bill/117th-congress/senate-bill/1644.
  9. I Am ALS. Senator Mike Braun reintroduces Promising Pathway Act (PPA) & The Accelerated Drug Approval for Prescription Therapies (ADAPT) Act. May 14, 2021. https://iamals.org/updates/senator-mike-braun-reintroduces-promising-pathway-act-ppa-the-accelerated-drug-approval-for-prescription-therapies-adapt-act/
  10. Wallach JD, Zhang AD, Skydel JJ, et al. Feasibility of using real-world data to emulate postapproval confirmatory clinical trials of therapeutic agents granted US Food and Drug Administration accelerated approval. JAMA Netw Open. 2021;4(11):e2133667. doi: 10.1001/jamanetworkopen.2021.33667.

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.

Continue reading

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.

Continue reading

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.

Continue reading

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.

Continue reading