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

Posted on October 2, 2023 by Angela Corona

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.

Communicating the Complexities of Subgroup Analyses at an AdCom

Posted on July 5, 2023 by Aaron Csicseri

Within clinical trials, exploratory or post-hoc subgroup analyses are widely recognized as only “hypothesis generating” due to their high potential for bias and/or misleading interpretation. This is the main reason why Sponsors cannot make efficacy claims or seek regulatory approval based on evidence of efficacy in a certain subgroup unless that benefit is consistent with the broader trial population and unless the trial is positive overall for the intention-to-treat (ITT) population. This begs the question, “Is it acceptable to use an exploratory subgroup analysis to restrict an indicated population when the data suggest less benefit in a particular subgroup?”

That is exactly what FDA asked the Oncologic Drugs Advisory Committee (ODAC) to consider in the case of the PROpel data, based on their conclusion that the combination of olaparib plus abiraterone has a favorable benefit/risk only in the subgroup of patients with advanced prostate cancer who test positive for a mutation in the BReast CAncer (BRCA) gene, which regulates homologous recombination repair of DNA. However, one might argue that the exploratory/post-hoc analysis on which FDA based their conclusion remains, by its very nature, fraught with potential for bias and/or misleading interpretation and is thus only hypothesis generating.

“Is it acceptable to use an exploratory subgroup analysis to restrict an indicated population when the data suggest less benefit in a particular subgroup?”

In the era of precision medicine, we expect that treatment choices are driven by biomarkers that can predict clinical benefit. In the case of poly ADP-ribose polymerase (PARP) inhibitors, like olaparib, BRCA mutations or deficiencies in homologous recombination repair (HRR) can predict clinical benefit. But there may be clinical situations where biomarker testing is limited or where patients without BRCA mutations might benefit from treatment with a PARP inhibitor. Indeed, the science suggests that patients with metastatic castration-resistant prostate cancer (mCRPC) may benefit from the combination of a PARP inhibitor with an antiandrogen, like abiraterone, regardless of BRCA mutation status, based on the synergistic activity of these 2 drug classes. In addition, the majority of patients with mCRPC (especially in disadvantaged communities) do not have definitive biomarker testing for BRCA mutations, usually due to cost and/or lack of available tumor tissue. That is the context for the PROpel study investigating the combination of the PARP inhibitor olaparib (Lynparza) plus abiraterone (Zytiga) as first-line treatment of mCRPC.

The PROpel trial was designed to assess the activity of this combination in the broad, unselected, ITT population, and data on BRCA mutation status by ctDNA and tissue tests were collected for the purpose of exploratory subgroup analysis. The trial met its primary endpoint in the ITT population, demonstrating a statistically significant 40% improvement in radiologic progression-free survival (rPFS). Therefore, AstraZeneca was seeking a broad indication that includes BRCA mutant, BRCA wild-type, and BRCA unknown patients. The Sponsor also presented evidence that patients without BRCA mutations or with unknown BRCA status benefited from the combination of olaparib plus abiraterone. However, on April 28, 2023, the ODAC voted 11 to 1 (with 1 abstention) to limit use of the combination to men whose tumors tested positive for a BRCA mutation, which represents only about 10% of patients with mCRPC. This was based on post-hoc subgroup analyses that created the perception of a less favorable benefit/risk in the BRCA wildtype or unknown patients.

On April 28, 2023, the ODAC voted 11 to 1 (with 1 abstention) to limit use of the combination to men whose tumors tested positive for a BRCA mutation

Dr. Chana Weinstock articulated the FDA’s position on this issue at the April 28 ODAC meeting. She said that the Agency discourages using subgroup analysis to try to argue for efficacy in a specific group, particularly in a failed trial (although PROpel was a positive study). However, she highlighted historical precedent for limiting indications based on post-hoc subgroup analysis suggesting that certain subgroups might have compromised safety or a potential overall survival detriment. Finally, she cited the FDA guidance that states that if a trial only shows benefit in a selected subgroup, the indication may be limited to a narrower population, especially if that same signal is observed in other comparable trials. (Figure 1)

Figure 1

Jorge Nieva, section head of solid tumors at the University of Southern California, objected to restricting the indication to only those patients with known BRCA mutations, saying “I worry that the approach used in this application can justify removing any subgroup from any application where that subgroup has an OS curve that crosses one. FDA seems to be looking at these OS curves in a vacuum and is ignoring the corroborating evidence that some non-BRCA patients could benefit significantly.”

“I worry that the approach used in this application can justify removing any subgroup from any application where that subgroup has an OS curve that crosses one.”

It is common for Sponsors to find themselves in this situation at ODAC where the data are somewhat ambiguous and the arguments/counter arguments are highly statistical in nature. This is especially true for subgroup analyses. The key communication goal when addressing an advisory committee is to make your position as easy to understand as possible by breaking down your argument into digestible bites. If your messages are too complex, statistical or philosophical, the committee may not fully appreciate your position. When this occurs at ODAC, the committee typically defers to the FDA’s position.

Aaron Csicseri, PharmD
Senior Scientific Director

Dr. Csicseri joined the ProEd team in November 2017 as a scientific director, responsible for scientific leadership, content development, strategic input, and effective moderation of team meetings. Aaron received his PharmD at the University of Buffalo, where he studied the clinical curriculum. He has 10+ years of experience as a medical director/clinical strategist in the accredited medical education field (CME), as well as in the non-accredited PromoEd sphere. Over the past 5 years, he has been guiding Sponsor teams in their preparations for FDA and EMA regulatory meetings in a wide variety of therapeutic areas. Aaron is based in Grand Island, NY, just outside of Buffalo, New York.

Connect with Aaron on LinkedIn.

Can You Predict Whether You Will Face an FDA Advisory Committee?

Posted on January 14, 2016 by ProEd Regulatory

The US Food and Drug Administration (FDA) review of drugs, although guided by broad standards, remains individualized. Each drug or drug class faces unique challenges during the FDA review phase – thus no two reviews are exactly the same. Each review division within the FDA has its own approach, and evaluations often differ among the centers. To help understand the review process, the team at ProEd Regulatory sought to learn from the past to inform our future. We reviewed applications submitted to the Center for Drug Evaluation and Research (CDER) data over the last 70 years to see what patterns might emerge. Although the largest proportion of products (drugs and biologics) fails between discovery and Phase 3, an evaluation of applications submitted to the FDA over the last 70 years shows that the vast majority of products that reach the submission stage are ultimately approved (Figure 1).¹
It wasn’t until the Kefauver-Harris Drug Amendments of 1962 that the FDA required sponsors to demonstrate both efficacy and safety of their drugs prior to market access. In the wake of this significant legislation’s impact on drug development, we still see a consistent flow of approved applications and a corresponding subset of new molecular entities (NMEs) (Figure 2).¹

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