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.

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

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

Surrogate Endpoints for Accelerated Approval

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

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

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

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

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

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

When is it appropriate to use a surrogate endpoint?

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

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

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

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

How much time is saved by using these endpoints?

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

What are “validated” surrogate endpoints?

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

Two examples include:

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

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

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

 

Sources:

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

Introduction to the Accelerated Approval Pathway

The FDA has developed several mechanisms to speed drugs to market when a compelling medical need exists including Accelerated Approval (AA), Priority Review, Fast Track, and Breakthrough Therapy Designation. Accelerated Approval is an important regulatory pathway that provides patients with earlier access to treatments for serious medical conditions when there is an unmet medical need. This is the first post in a 3‑part series on the AA Pathway. Herein, I’ll focus on how this pathway is used to bring drugs to market and highlight some of the key issues surrounding it.

The AA Pathway was created in 1992 in response to the AIDS crisis and was codified in 2012 under the Food and Drug Administration Safety Innovations Act (FDASIA) in an effort to bring potentially life-saving drugs to market more quickly. The majority of drugs granted AA have been for AIDS, rare diseases, and cancer. Over the past 10 years, there has been a steady increase in the number of New Drug Applications (NDAs) seeking AA (Figure1,2); this increase has been driven largely by immune checkpoint inhibitors, which have transformed the treatment of many types of cancer.

Figure: Novel Drugs Approved Using the Accelerated Approval Pathway.

Data sources: Darrow JJ, et al. JAMA. 2020 (through 2017);1 FDA CDER reports 2017-20212

How does Accelerated Approval work?

Under normal or traditional FDA approval pathways, a drug must show evidence of clinical benefit based on endpoints that measure how a patient feels, functions, or survives. In contrast, AA allows FDA to grant a drug a “conditional” approval based on its effect on a surrogate or an intermediate clinical endpoint that is reasonably likely to predict clinical benefit.3 (We’ll share more on this in part 2 of this series.) In some cases, AA can shave years off the clinical development timeline. Under the same law, the FDA requires sponsors to conduct a confirmatory clinical trial in the postmarketing setting to confirm that the drug does provide meaningful clinical benefit, and FDA can withdraw approval if further trials fail to verify the predicted clinical benefit.

Pros of the Accelerated Approval Pathway

The majority of drugs granted AA are for rare diseases, where the unmet need is great (90% of rare diseases have no approved therapy),4 and for oncologic indications where the disease is often life-threatening. In the case of rare diseases where patients are few and far between, it can be extremely challenging to conduct controlled clinical trials of sufficient size to demonstrate clinical benefit using traditional endpoints. The use of surrogate endpoints under an AA may be the only feasible path to approval; however, it can often be difficult subsequently to confirm clinical benefit in the postmarketing setting. In the case of oncology drugs, clinicians want to have access to promising new therapies for patients who have limited time to wait for the latest, potentially life-saving innovation, so speed to market becomes paramount.

Cons of the Accelerated Approval Pathway

The nature of the AA Pathway allows drugs to be marketed for a given indication before clinical benefit has actually been demonstrated using validated clinical endpoints. Although a surrogate endpoint must be reasonably likely to predict clinical benefit, this anticipated benefit must be verified in a confirmatory trial.

FDA prefers that a well-designed confirmatory trial be planned or underway at the time of AA, but there is no action enforceable by the FDA to require completion of confirmatory trials. According to a recent investigation in the British Medical Journal, nearly half of the drugs granted AA have not confirmed clinical benefit,5 and only 16 AAs have been withdrawn. This calls into question whether some of the drugs approved through the AA pathway are actually providing the promised clinical benefit to patients. That being said, there are many situations, particularly in rare diseases, where it can be difficult to complete confirmatory trials.

Finally, even more problematic, is what to do when confirmatory trials fail. In some cases, FDA will convene an advisory committee meeting to discuss whether the unmet need still exists and whether additional ongoing trials may confirm clinical benefit. (We’ll share more on this in part 3 of this series.)

Conclusion

While confirmatory trials can be difficult to complete, the AA pathway has been used to approve an increasing number of novel drugs in the past 10 years and remains an important regulatory pathway that provides patients with earlier access to treatments for serious medical conditions. Stay tuned for our next installment, which will explore the use of surrogate endpoints in Accelerated Approvals.

Jackie Orabone, PhD, helps clients prepare for FDA Advisory Committee meetings by combining her scientific expertise and research knowledge in immunology with over 2 years of medical communications agency experience. Connect with Jackie on LinkedIn.

 

References:

  1. Darrow JJ, Avorn J, Kesselheim, AS. FDA approval and regulation of pharmaceuticals, 1983-2018. JAMA. 2020;323(2):164-176.
  2. US FDA. New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products. Current as of January 27, 2022. Accessed March 3, 2022. https://www.fda.gov/drugs/development-approval-process-drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products
  3. US FDA. Accelerated Approval. Current as of January 4, 2018. Accessed March 3, 2022. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval
  4. Huron J. New report finds medical treatments for rare diseases account for only 11% of US drug spending; nearly 80% of orphan products treat rare diseases exclusively. March 4, 2021; National Organization for Rare Disorders. Accessed March 3, 2022. https://rarediseases.org/new-report-finds-medical-treatments-for-rare-diseases-account-for-only-11-of-us-drug-spending-nearly-80-of-orphan-products-treat-rare-diseases-exclusively/#:~:text=Approximately%207%2C000%20known%20rare%20diseases,rare%20diseases%20have%20no%20treatment
  5. Mahase E. FDA allows drugs without proven clinical benefit to languish for years on accelerated pathway. BMJ. 2021;374:n1898.

Responding to FDA Information Requests: It Comes Down to Clarity of Messaging and Understanding the Therapeutic Landscape

No matter how well you have prepared your New Drug Application (NDA) or Biologic License Agreement (BLA) submission for the FDA, questions posed regarding the development of your product will arise. These are presented in the form of Information Requests (IRs) and Discipline Review Letters (DRLs). The FDA Guidance to Industry from the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER) outlines how the FDA uses these communications to obtain clarifying information to assist in reviewing submissions. Well-crafted responses to IRs and DRLs are critical in replying to regulators and keeping the review of your application on track.

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Do Decentralized Clinical Trials Hold the Keys to Future Patient Focused Drug Development?

There’s a lot of buzz around the concept of decentralized clinical trials, and rightly so, given the lessons learned from our experience with clinical trials during the COVID-19 pandemic.  Decentralized trials are executed through telemedicine and mobile or local healthcare providers.  They rely on technology (or medical devices) and information sharing to execute a study without the involvement of a large centralized clinic.  In a post-COVID world, drug development will likely employ more decentralized trials to reduce the time and cost of trial programs.

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Extending Asset Reach and Protecting Your IP Through the 505(b)(2) Pathway

Developing a novel pharmaceutical product from discovery to market launch can take up to 10 years and cost as much as $1 billion dollars1. The traditional 505(b)(1) approach to drug development involves a linear progression starting with nonclinical pharmacology, toxicology, and other PK studies, and typically culminates with large randomized phase 3 trials. This stepwise progression is time consuming and expensive, but essential to demonstrate the safety and efficacy of new molecules and gain FDA approval. Naturally, the cost associated with market entry discourages some smaller companies and restricts their focus to regulatory strategies with a lower financial barrier. The 505(b)(2) regulatory approval pathway presents a tangible opportunity for pharmaceutical companies to gain market entry and market share for a capital investment of $10-100 MM and 2-6 years of time. To put this into perspective, in 2019, approximately 65 505(b)(2) applications were filed in the United States compared with 48 505(b)(1) applications. In two parts, I will explore the utility of the 505(b)(2) pathway and offer insight into how both large and small pharma companies can capitalize on the innovative nature of this strategy.

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COVID-19 Vaccines: When Will the Pandemic End?

As Pfizer, Moderna, and other pharma companies prepare to seek emergency authorization for their SARS-CoV-2 vaccines, the FDA has laid out a roadmap designed to ensure appropriate scientific rigor and help engender public trust. That plan was the subject of a special meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) on October 22, 2020, where experts discussed 2 critical FDA guidance documents that provide a blueprint for development and approval of SARS-CoV-2 vaccines. That blueprint is at the center of a massive government effort to quickly and safely speed vaccines to the American public and bring the pandemic to an end.

Members of the VRBPAC, with expertise in infectious disease, epidemiology, and vaccine development, focused on issues around the FDA standards for safety and effectiveness that will support Emergency Use Authorization (EUA) of vaccine candidates. They discussed the need to continue the phase 3, randomized, placebo-controlled trials to completion after an EUA is granted. They considered how the vaccines will be rolled out to the American public, and they raised concerns about whether the public will embrace the vaccines and roll up their sleeves.

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PNAS Spearheads Effort to Streamline Authorship Transparency

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

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

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