Author Archives: Angela Corona

EMDAC meeting for Intarcia’s Diabetes Drug-Device Combo ends in rejection, but is there a silver lining?  

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On Thursday, September 21, 2023, the FDA held a meeting of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) to discuss Intarcia’s new drug application (NDA) for ITCA-650, an implantable device intended to provide continuous dosing of a GLP-1 agonist (exenatide) to treat type 2 diabetes. In a highly unusual move, Intarcia opted to request a public FDA advisory committee meeting (AdCom) in lieu of a formal evidentiary hearing following 2 Complete Response Letters (CRLs) and several formal dispute resolution requests dating back to 2017. Given this history, the prospects of swaying the panel and the FDA in favor of approval was certainly a long shot. In the end, the panel voted 19-0 that the benefits of ITCA-650 did not outweigh the risks.

It appears Intarcia was motivated not only by the prospects of a positive vote but also by the chance to present their argument for approval in a public forum. In that respect, their strategy and perseverance may have paid off. The meeting highlighted a creative use of the FDA AdCom process to communicate directly with patients and the medical community. Let’s look at how Intarcia got there.  

The long path to a highly unusual EMDAC meeting: 2 CRLs, 3 rejected formal dispute resolution requests, and 1 citizen petition requesting a public AdCom

NDA #209053 for ITCA-650 (exenatide in DUROS device) was submitted on November 16, 2016. Exenatide is a GLP-1 receptor agonist, which is currently FDA-approved in formulations for subcutaneous injection twice daily or weekly. ITCA-650 is delivered by an osmotic mini-pump that is implanted under the skin and only needs to be refilled every 6 months.

The first CRL for ITCA-650 was issued by the FDA in September 2017, citing “clinical deficiencies, and device and product quality-related issues.” Shortly after the CRL, 2 ongoing trials for ITCA-650 were put on hold by the FDA due to serious safety issues, and the trials were later terminated by the company. Despite these setbacks, Intarcia resubmitted the NDA in September 2019, only to receive another CRL just 6 months later in March of 2020. 

Over the rest of 2020, Intarcia filed 3 formal dispute resolution requests (FDRRs). The first 2 FDRRs were promptly denied by the Office of New Drugs (OND), reiterating unresolved safety issues, including an imbalance in severe acute kidney injury (AKI) and deaths due to major adverse cardiovascular events (MACE), as well as issues with the implanted device appropriately regulating dose. The third and final FDRR was submitted in November of 2020—this time, Intarcia requested a public FDA AdCom. The third FDRR was also rejected.

On September 2, 2021— the FDA published a notice in the Federal Register of their intention to deny the NDA for ITCA-650, and offering the opportunity for Intarcia to request a hearing. The notice outlined the agency’s reasons for the 2 prior CRLs, the 3 FDRRs, and the unresolved safety and product issues that, in their view, had never been adequately addressed. The notice detailed the conditions under which a hearing would be entertained.

It is fair to say that at this point in the process, most companies would have resigned themselves to conducting additional clinical trials or discontinuing development of the drug. Intarcia, however, did not not give up. Perhaps anticipating that their pending request for a formal hearing would ultimately be denied, Intarcia opted to request a public FDA AdCom meeting in lieu of a closed-door, formal evidentiary hearing. This request was made on February 20, 2023, via a citizen petition submitted by Intarcia, arguing that they were entitled to a public AdCom under 21 CRF part 14.

On March 24, 2023, FDA Chief Scientist, Namandje Bumpus, issued a letter granting Intarcia’s request for a public AdCom. The EMDAC meeting would be conducted under “the typical process for convening an advisory committee under 21 CFR part 14.”

So, after nearly 6 years, Intarcia would get their public meeting, but only on CDER’s terms.

EMDAC discussion centers on safety concerns, benefit-risk

The discussion centered around serious safety concerns identified by the FDA reviewers, including a higher risk of AKI, an imbalance of deaths due to MACE, and uncertainties about the drug delivery device appropriately regulating dose.

The sponsor argued that the incidence of AKI was low overall and should be understood as a class effect of GLP-1 agonists. The approved injectable formulations of exenatide (eg, Byetta and Bydureon) include warnings that the drug should not be used in individuals who have kidney disease because of increased risk of kidney injury.

The FDA also noted that the risk of death associated with MACE was unfavorable with a hazard ratio of 1.12 (95% CI: 0.83, 1.51). This was especially concerning given that other GLP-1 agonists had shown favorable results in reducing the risk of adverse cardiovascular outcomes (Figure 1).

Figure 1: Screenshot from September 21, 2023 EMDAC meeting

Finally, the FDA presented data showing that there was large variability in the devices delivery of the drug that could potentially lead to large amounts of drug being suddenly released into the patient. They noted that the data provided by the applicant could not rule out the possibility that adverse events were associated with inconsistencies in drug delivery. Because of these concerns, the panelists sided with the FDA, recommending that an additional safety study would be needed prior to approval to determine if the increased incidence of AKI or MACE was being caused by the implanted delivery system.

A negative vote, but a silver lining?

While a 19-0 vote against approval was surely a disappointment for the sponsor, the meeting was not entirely negative. Several panelists highlighted the superior efficacy demonstrated by the drug in controlling HbA1C levels and helping patients lose weight. During the open public hearing segment of the meeting, patient and physician testimonials were passionate and overwhelmingly positive, highlighting the benefits of ITCA-650 in improving compliance and quality of life for patients. After implantation, ITCA-650 only needs to be refilled every 6 months, eliminating the need for multiple weekly or daily injections. Several panelists were moved by these testimonials and agreed that an implantable device for diabetes treatment has potential as an important innovation.

The panelists also provided feedback regarding the types of clinical data that would be necessary to demonstrate a positive benefit/risk. For example, panelists suggested that a clinical study comparing ITCA-650 to an active control arm (such as Byetta) could help elucidate if there is a “true” increased risk of AEs with the continuous delivery mechanism compared with injectable formulations. This advice could inform future clinical trials and increase the chances of success in eventually gaining approval for ITCA-650, or similar implantable drug-devices.

Notably, Intarcia’s clinical pipeline was acquired by i2o Therapeutics in August 2023. In addition to ITCA-650, i2o is continuing development of 5 additional pre-clinical stage drug candidates for type 2 diabetes, nonalcoholic steatohepatitis, and obesity—several of which are delivered via similar implantable osmotic mini-pump technology.

While it is unlikely that the FDA will approve ITCA-650 without substantial additional clinical data, Intarcia’s decision to persevere and demand a public meeting may have a faint silver lining.

Ultimately, there are potential benefits and advantages of enduring an uncomfortable AdCom that may extend beyond simply achieving a positive vote.

Angela W. Corona, PhD
Senior Scientific Director, Scientific Services
Angela is responsible for helping sponsors navigate complex regulatory communications, with a focus on 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. Connect with Angela on LinkedIn.

FDA Decision for Sarepta’s Gene Therapy for DMD Sets New Regulatory Precedent

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Historic Regulatory Decision for First FDA-Approved Gene Therapy for DMD

On June 22, 2023, in a-much anticipated decision, the United States Food and Drug Administration (FDA) granted accelerated approval for Elevidys (also known as SRP-9001), Sarepta’s one-time gene therapy for ambulatory children with Duchenne’s muscular dystrophy (DMD). However, the accelerated approval was limited to the subset of boys between 4 and 5 years of age who had the debilitating disease but were still able to walk. Sarepta had originally sought accelerated approval in ambulatory children aged 4 to 7 years of age, but the FDA pushed back, citing no evidence of benefit in the older patient subgroup (ages 6 to 7). Exploratory subgroup analyses are generally considered to be prone to statistical bias and/or misinterpretation; however, the FDA has used such analyses to limit indications to patients who are most likely to benefit (see our recent blog post to learn more).

While this approval is a symbol of hope for patients and families dealing with this devastating condition, the accelerated approval means that clinical benefit for SRP-9001 has not yet been established. As a condition of approval, Sarepta will be required to generate confirmatory data showing clinical benefit, including an improvement in motor function, compared with placebo. This confirmatory data will likely be forthcoming soon from the Phase 3 EMBARK trial. The FDA has promised to rapidly review these data as soon as they are available and, if necessary, adjust the indication further or recommend withdrawal of accelerated approval if clinical benefit is not confirmed.

Regardless of the ultimate outcome, this historic decision paves the way for future accelerated approvals of a rapidly growing class of gene therapies for rare diseases.

FDA sought expert advice on accelerated approval from their Cellular Tissue and Gene Therapies Advisory Committee (CTGTAC)

The FDA decision follows a May 12, 2023, meeting of the FDA’s CTGTAC where the topic of accelerated approval based on a surrogate biomarker, namely expression of micro-dystrophin (the transgene product of SRP-9001), was hotly debated. The FDA asked the committee to vote on whether the data generated from Part 2 of Study 102 were sufficient to support accelerated approval while “taking into account the existing uncertainties.”

The vote landed slightly in favor of accelerated approval, with 8 yes votes, 6 no votes, and no abstentions. However, the discussion revealed a dramatically split committee with considerable nuance associated with individual votes.

FDA commissioner, Robert Califf, has indicated that advisory committees should prioritize discussion and feedback over the strict, “thumbs-up, thumbs-down” results of the voting questions, which often receive the most media coverage. While the FDA usually makes decisions in line with the committee’s vote, it is not required to do so.

Notably, several panelists who voted “yes” revealed that they might have voted “no” on the basis of insufficient data to meet regulatory requirements but were swayed by the extremely high unmet need and the emotional testimonies of parents whose children appeared to have benefitted from SRP-9001 in videos shown during the open public hearing. Those statements, and the overwhelming unmet need likely factored heavily into the FDA’s ultimate decision to grant accelerated approval, despite major reservations on the part of FDA reviewers..

Surrogate endpoints and substantial evidence of efficacy called into question

In briefing documents released prior to the CTGTAC meeting, the FDA raised several concerns regarding Sarepta’s proposed surrogate endpoint, noting that expression of the micro-dystrophin transgene product (a purely synthetic protein not naturally expressed in skeletal muscle) does not necessarily translate into an improvement in muscle function. In other words, it is not known if expression of the transgene is “reasonably likely to result in clinical benefit” (an essential requirement for accelerated approval). This question likely cannot be answered without further placebo-controlled clinical study data. 

Importantly, the only randomized, double-blind, placebo-controlled clinical study (Part 1 of Study 102) failed to demonstrate a statistically significant treatment effect on muscle function versus placebo, as measured by the North Star Ambulatory Assessment (NSAA) Total Score. While an apparent effect could be discerned in the small subgroup of children aged 4 to 5 years, the study was not powered to detect a change in this group.

Slide 31 from the FDA’s CTGTAC meeting presentation (show below) illustrates these data. In the 4- to 5-year-old subgroup there was a 2.5 point difference in the change from baseline on the NSAA in patients treated with SRP-9001 versus placebo at Week 48 (P = .0172), indicating a possible clinical improvement. The 6- to 7-year-old subgroup treated with SRP-9001 had a decline in their NSAA score of -0.7 compared with placebo, indicating no apparent difference between the treatment groups. Sarepta’s scientists pointed out that an imbalance in the NSAA score at baseline may have affected the results in the 6- to 7-year-old subgroup, further confounding interpretation of the results.

Figure 1: Slide 31 from FDA presentation at the May 12th, 2023, CTGTAC meeting

The FDA concluded that

“the clinical studies conducted to date do not provide unambiguous evidence that SRP-9001 is likely beneficial for ambulatory patients with DMD. It is challenging to conclude with reasonable certainty from the data provided by the Applicant either that SRP-9001 is likely effective for younger patients, or that it is likely ineffective for older patients or those with somewhat poorer functional status. Additionally, FDA has safety concerns related to the possibility of administering an ineffective gene therapy.”

During the discussion, the CTGTAC panelists agreed that expression of the micro-dystrophin transgene speaks to the biological plausibility of SRP-9001; however, there was disagreement as to whether this expression could serve as a surrogate endpoint. Dr. Rajiv Ratan indicated, “I was not convinced, either by the nonclinical or the clinical data, that an effect on the primary functional endpoints really provided plausibility that expression of micro-dystrophin would predict clinical outcome,” and later voted “no.”

Dr. Caleb Alexander, a temporary panelist at the CTGTAC meeting and veteran of the Peripheral and Central Nervous System (PCNS) advisory committee, noted that nothing changes the fact that there was no significant effect on the primary endpoint, making it difficult to attribute any predictive power to expression of the transgene. He stated that

“…the threshold of substantial evidence has to be met whether or not a product is being approved under the standard pathway or accelerated pathways…the totality of evidence that we’ve reviewed today simply doesn’t rise to the threshold of substantial evidence that’s required for accelerated approval.”

It should be noted that the FDA has previously granted accelerated approval to 4 other therapies for DMD, three of which were developed by Sarepta – eteplirsen (Sarepta, exon 51 skipping), viltolarsen (NS pharma, exon 53), golodirsen (Sarepta, exon 53), and casimersen (Sarepta, exon 45).. These 4 therapies are all antisense oligonucleotides targeting specific mutational subtypes of DMD and use exon-skipping technology to remove a specific mutated region of the dystrophin protein to render it more functional. To date, however, none of those therapies have successfully confirmed clinical benefit, raising concerns about the feasibility of confirmatory trials in DMD.

The surrogate endpoint used in those prior approvals was expression of the “edited” dystrophin protein. The shortened versions of endogenous dystrophin produced by exon-skipping technology mimic the shortened forms of dystrophin protein found in patients who have Becker Muscular Dystrophy (a much milder form of DMD). In contrast, the expression of the SRP-9001 transgene lacks the type of empirical evidence that has been previously used to support a determination that a surrogate endpoint is reasonably likely to predict clinical benefit in DMD.

Difficulties in confirming clinical benefit following accelerated approval in DMD

Sarepta will be required to generate confirmatory data from the Phase 3 EMBARK trial to ensure that the expression of the micro-dystrophin transgene translates into significant improvement on clinical outcomes, including slowing of progression on the NSAA.

During the CTGTAC meeting, the committee emphasized the importance of the confirmatory trials to confirm clinical benefit, regardless of whether they voted yes or no, with Dr. Raymond Roos indicating that his yes vote “included the results of the [EMBARK] study that’s going to end in September 2023.”

The committee members who voted in favor of accelerated approval frequently cited the dire unmet need for treatments as their reason for voting “yes,” rather than the strength of the data package. With the added confidence that confirmatory results will be available soon, they argued that it is important not to delay treatment any longer. The dissenting committee members came to the opposite conclusion. They expressed concern that, given the uncertainty around the surrogate endpoint and the fact that a definitive answer would be available so soon, approval should only follow evidence of clinical benefit on muscle function.

Two additional considerations include the impact of accelerated approval on completing EMBARK while maintaining study integrity and what will happen if the confirmatory trial fails to generate conclusive data. Historically, withdrawal of accelerated approval after a confirmatory trial has failed has been a lengthy and complicated process resulting in potentially ineffective drugs remaining on the market for far longer than intended. We have previously written about the difficulties with confirmatory trials after accelerated approval on this blog.

Mitigating much of the concern around the confirmatory trial is the fact that the results are expected soon. The last patient, last clinical visit for EMBARK is expected to be completed by September 2023, which is very soon by accelerated approval standards. In addition, in September all patients who were on placebo are scheduled to switch over to SRP-9001. However, this does not mean that the accelerated approval will have no effect on completion of EMBARK. Patients currently in the placebo group of the EMBARK trial may demand to receive SRP-9001, rather than waiting an additional 3 to 4 months. If enough patients drop out of the study, it could reduce the ability to generate conclusive data.

In any case, the results of the confirmatory EMBARK study are highly anticipated and will determine the next steps for Elevidys. Positive results could lead to a potential conversion to full approval, along with a potential expansion of the label to include older children (6 to 7 years of age). Negative or inconclusive results, however, may result in the withdrawal of the accelerated approval.

New regulatory precedent may affect future approvals

There are currently more than 1,745 gene therapies in development, including several gene therapies for DMD (Pfizer’s gene therapy may be next in line). Indeed, gene therapy approvals seem to be gaining steam in the first half of 2023. The newest approval is Biomarin’s gene therapy for hemophilia A, Roctavian, which gained full FDA-approval on June 29. This new wave of gene therapies is promising but brings questions regarding multimillion-dollar price tags, safety of the gene delivery vectors, and longevity of transgene expression. Ultimately, many unknowns remain.

With so little precedence for gene therapy approvals, the accelerated approval of Elevidys is likely to have a major effect on future approvals for gene therapies in rare diseases. The approval establishes a regulatory precedent indicating that simply demonstrating that the transgene is expressed in the target tissue may be sufficient to use as a “reasonably likely surrogate endpoint” for accelerated approval. This indicates a willingness on the part of FDA leadership to expand the definition of what will be accepted as surrogate endpoints for gene therapies, especially when dealing with diseases of high unmet need.

Angela W. Corona, PhD
Senior Scientific Director, Scientific Services
Angela 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. Connect with Angela on LinkedIn.

Kathryn M. Madalena, PhD
Scientific Associate, Scientific Services
Kathryn provides scientific support for content development and FDA advisory committee meeting preparation across a broad range of therapeutic areas. A neuroscientist by training, with specializations in neuroendocrinology and neuroimmunology, she received her PhD in Neuroscience at The Ohio State University. Connect with Kathryn on LinkedIn.

Regulatory Policy Watch: The FDA Is Taking Accelerated Approval Pathway Reforms Into Their Own Hands

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On September 30, 2022, President Biden signed into law the reauthorization of the Prescription Drug User Fee Act (PDUFA VII), which will be in place for the next 5 years. Despite extensive bipartisan efforts to include reforms of the accelerated approval (AA) pathway as so-called “policy riders” in the bill, ultimately a “practically clean” version of the bill was signed.

While this news may have led to a sigh of relief for some sponsors, in the absence of formal measures to explicitly codify the FDA’s authority to tighten restrictions on AAs, it appears that the FDA has taken matters into its own hands.

FDA to ADC Therapeutics: “A randomized confirmatory phase 3 study must be well underway and ideally fully enrolled at the time of BLA filing.”

According to ADC Therapeutics, the FDA has “provided strong guidance that, for it to consider an accelerated approval path, a randomized confirmatory phase 3 study must be well underway and ideally fully enrolled at the time of any BLA filing.” As a result, ADC Therapeutics has taken a step back to reevaluate its experimental CD25-targeted antibody drug conjugate camidanlumab tesirine, which is being developed for patients with relapsed/refractory Hodgkin lymphoma. ADC had been planning to submit a BLA under the AA pathway based on a demonstrated ORR of 70.1% (95% CI, 60.9%-78.2%) in their phase 2, open-label, single-arm study in 117 heavily pretreated patients.

Because of the FDA’s guidance, ADC Therapeutics will no longer be submitting their BLA, and the future of the drug is uncertain. Enrollment for the planned confirmatory phase 3 trial for camidanlumab tesirine is estimated to take 2 years.

FDA regulatory policy shift for AA

A requirement for a fully enrolled confirmatory trial prior to granting AA represents a large shift in regulatory policy from the FDA.  

This move reflects the reforms advocated by the FDA’s Oncology Center of Excellence (OCE) to require confirmatory trials to be underway before an AA is granted. Such a requirement would likely lead to quicker confirmation of benefit and more timely withdrawal of an AA if clinical benefit is not confirmed. In support of this measure, studies have shown that among AAs that were withdrawn, the median time to withdrawal was 3.8 years if the confirmatory trial was ongoing at the time of AA, as compared with 7.3 years if such a trial had not been initiated.

Unfortunately, a requirement to have an ongoing, fully enrolled confirmatory trial at the time of filing for AA places a much greater burden on smaller drug development companies. Smaller companies in particular may depend on revenue from drugs marketed under the AA pathway to finance phase 3 confirmatory studies. Greater restrictions on the AA pathway may force smaller companies, such as ADC, to scrap certain drug development programs entirely.

The OCE has been vocal about improving the quality and efficiency of the AA pathway, and it does not appear to be waiting around for legislation to follow through on instituting more requirements for granting AAs and in rapidly withdrawing AA indications that fail to confirm benefit in subsequent phase 3 trials.

Angela W. Corona, PhD
Scientific Director, Scientific Services
Angela 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. Connect with Angela on LinkedIn.

 References

  1. Fashoyin-Aje LA, Mehta GU, Beaver JA, Pazdur R. The on- and off-ramps of oncology accelerated approval. N Engl J Med. 2022;387(16):1439-1442. https://www.nejm.org/doi/full/10.1056/NEJMp2208954.

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

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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

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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.

Pitfalls of Accelerated Approval: What Happens When Confirmatory Trials Fail?

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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 Please see Part 1 of this blog series for an introduction to the accelerated approval pathway and Part 2 for more information on how surrogate endpoints for accelerated approval are identified and validated.

Although AA can speed access to potentially lifesaving drugs years earlier than traditional approvals, the tradeoff for this quicker access is a period of uncertainty regarding the true efficacy and safety while confirmatory evidence is gathered. Confirmation of clinical benefit is often achieved but is not guaranteed.

In Part 3 of our blog series on AA, we will dive into a controversial aspect of the accelerated approval pathway: confirmatory studies.

What is a confirmatory study?

The FDA requires that drugs initially approved under AA are subject to postmarketing confirmatory trials that can directly confirm the clinical benefit predicted by the surrogate endpoint. Confirmatory studies are typically agreed on between the sponsor and FDA ahead of time and formally established as a postmarketing requirement (PMR) for continued approval.2 Usually PMRs for AA indications include large, phase 3 randomized studies with primary endpoints that assess direct clinical benefit. Overall survival, for example, is often used in oncology studies as a direct measure of clinical benefit.2

While straightforward in principle, designing confirmatory trials presents many practical challenges that can impede the completion of the trial and/or complicate the interpretation of the results. Most importantly, it is not always feasible to enroll patients in confirmatory trials once the drug is already on the market, particularly for very rare diseases. For this reason, sponsors may need to consider a randomized confirmatory trial in a clinical setting that differs from the approved indication, such as an earlier line of therapy or, for rare diseases, a less rigorous single-arm approach may be used. The nature of what evidence constitutes a confirmation of benefit remains a heavily debated topic that is outside of the scope of this article; however, some of these challenges were presented at a Friends of Cancer Research Annual Meeting in 2020.3

When a confirmatory study reaches its primary endpoints, this fulfills the PMR, and the clinical benefit is considered to be verified; at which point the AA is generally converted to a full approval. On the other hand, in cases where a confirmatory study fails to confirm clinical benefit, or an appropriate confirmatory study could not be conducted, the AA may be withdrawn by the FDA. The FDA is not required to withdraw the AA; however, there is no time limit for completion of confirmatory trails defined in legislation or regulatory guidance.

Conversion of AAs to full approvals: Is the glass half-full or half-empty?

Two separate studies found that approximately 50% of all AAs have successfully converted to full approval.

  • An investigation published in the British Medical Journal studied all 253 AAs granted by the FDA in the 28 years since the inception of the program in 1992, through 2020. Of these, 125 (49%) successfully confirmed clinical benefit, 44% had not yet completed confirmatory trials, and 6% had been withdrawn.4
  • In a study focusing only on oncology AAs, the record is slightly better. Out of 93 oncology indications granted AA between 1992 to 2017, 51 (55%) had fulfilled their PMR within a median of 3.4 years. Forty percent of oncology indications had not yet completed confirmatory trials, and 5% had been withdrawn from the market.5

From a “glass half-full” perspective, half of all drugs approved under the AA pathway are successful—delivering promising, life-saving drugs to patients years sooner than traditional approval pathways, with verification of clinical benefit confirmed in a timely manner. In this context, the 5-6% of AAs that were withdrawn demonstrate a commitment to removing AAs that fail to confirm benefit.

However, from the “glass half-empty” perspective, nearly half of AAs had not yet confirmed clinical benefit. In the case of more recent AAs, confirmatory trials may still be ongoing. However, a small number of AAs had not yet started a confirmatory trial or had  a failed confirmatory trial, yet they remained on the market. For critics, this is evidence that the FDA is allowing some AAs to “languish” in the pathway, without appropriate efforts to confirm clinical benefit. These critics believe that the number of AAs withdrawn should be much higher.

The most controversial situation with the AA pathway is the very small subset of AA drugs that have completed one or more confirmatory trials that failed to confirm clinical benefit, but the approval for that indication has not been withdrawn. These so-called “dangling approvals” often fall into a regulatory gray area, are a target of fierce criticism, and have been the subject of several FDA advisory committee meetings.

“Dangling” accelerated approvals: FDA advisory committee meetings

In April 2021, the FDA held a multi-day, multi-sponsor meeting of the Oncologic Drugs Advisory Committee (ODAC) to get expert advice on several immune-checkpoint inhibitors (“ICIs”) with dangling AAs. All the ICIs in question were PD-1/PD-L1 monoclonal antibodies. Each of these dangling AAs had failed to reach statistical significance on the endpoint of overall survival in one or more confirmatory trials. The FDA chose to use this meeting to publicly reevaluate these approvals. In the weeks leading up to the meeting, 4 of the indications were voluntarily withdrawn by the sponsors. Out of the 6 indications that were publicly reevaluated at the ODAC meeting, the panel voted against continued AA for 2 indications and voted in favor of maintaining AA for 4 indications. 

Importantly, in the cases where the AA indication was withdrawn, it wasn’t because of a lack of benefit, or even a failed confirmatory trial, but rather that the treatment landscape had evolved, so that other treatment options were available. In short, the urgent unmet need that had originally justified the AA in these cases, no longer existed.

FDA advisory committee meetings are often a clue as to how the FDA is thinking about regulatory policy and how they may make decisions in the future.

What does it mean when a confirmatory trial fails? The FDA weighs in…

When a confirmatory trial fails to meet its endpoints, these data cannot be used to confirm clinical benefit or fulfill the PMR. However, a failed trial is not necessarily evidence that the drug is ineffective. In a perspective article published in The New England Journal of Medicine shortly before the April 2021 ODAC meeting, Dr. Julia Beaver and Dr. Richard Pazdur, from the FDA’s Oncology Center of Excellence, wrote:

“The fact that a clinical trial did not meet its endpoints does not necessarily mean that the drug is ineffective. A failure to demonstrate efficacy might be attributable to the selection of the primary endpoint, the power calculation, hierarchical statistical testing procedures, biomarker selection, trial design, or an inability to select the patients most likely to have a response. If there are clear reasons why a trial may not have achieved its primary endpoint and an unmet medical need still exists, the FDA works with sponsors to identify subsequent clinical trials that could satisfy the accelerated approval requirement.”6 [emphasis added]

This perspective from the FDA provides an important clue into their thinking: unmet need is paramount. In many cases, drugs receive AA because there is an urgent unmet need. In these cases, the immediate removal of AA after a failed confirmatory trial could leave patients with severe or life-threatening diseases with no treatment options. So, while strict statistical requirements for fulfilling a PMR must be met, it is just as important for the FDA to weigh those criteria against the unmet medical need.

Conclusion

The AA pathway legislation allows for flexibility and discretion on the part of the FDA when enforcing PMRs for confirmatory studies. Proponents of AA, including the FDA itself, point out that this flexibility is necessary, given the complexity of these decisions and the need to balance benefit/risk with unmet need. Quoting the FDA, “the small percentage of drugs whose clinical benefit is ultimately not confirmed should be viewed not as a failure of accelerated approval but rather as an expected trade-off in expediting drug development that benefits patients with severe or life-threatening diseases.”6

However, critics believe there is too much flexibility in the pathway, resulting in arbitrary decisions that lack appropriate transparency, inappropriate use, and patients with serious diseases potentially being exposed to drugs that lack confirmed clinical benefit. Recently, these critics have called for reform of the AA pathway, and legislation is now being considered in Congress.

Coming next: Proposed reforms to the AA pathway

The AA pathway has far-reaching implications for patient access, coverage for new drugs under insurance plans and Medicare, and decisions made by sponsors in their clinical development strategy. In a future blog post, we will look in detail at proposed reforms that could impact the AA pathway and the surrounding regulatory landscape.  

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. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics
  2. For more information on the details of Postmarket Requirements (PMRs) for drugs approved under AA – an interested reader may wish to review the public PMR database maintained by the US Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm
  3. Friends of Cancer Research Working Group. Optimizing the use of accelerated approval. 2020. https://friendsofcancerresearch.org/wp-content/uploads/Optimizing_the_Use_of_Accelerated_Approval-2020.pdf
  4. Mahase E. FDA allows drugs without proven clinical benefit to languish for years on accelerated pathway. BMJ. 2021;374:n1898. https://www.bmj.com/content/374/bmj.n1898.full
  5. Beaver JA, Howie LJ, Pelosof L, et al. A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review. JAMA Oncol. 2018;4(6):849-856. doi:10.1001/jamaoncol.2017.5618. https://jamanetwork.com/journals/jamaoncology/article-abstract/2673837
  6. Beaver JA and Pazdur R. “Dangling” accelerated approvals in oncology. N Engl J Med. 2021;384:e68. https://www.nejm.org/doi/full/10.1056/NEJMp2104846