Randomized withdrawal design in action - Accord trial in Alzheimer's agitation

The biotech company, Axsome Therapeutics, announced the positive results from one of their pivotal phase 3 studies (Accord study). 

Axsome's approved depression drug clears Alzheimer's agitation trial months after Lundbeck-Otsuka duo

The unique side of the Accord study is the use of a randomized withdrawal design. The study was registered on clinicaltrials.gov as "A Double-blind, Placebo-controlled, Randomized Withdrawal Trial to Assess the Efficacy and Safety of AXS-05 for the Treatment of Agitation in Subjects With Dementia of the Alzheimer's Type"

With the randomized withdrawal design, all participants were given the active drug (AXS-05) in a run-in phase in an open-label manner. Then, those patients who responded to treatment during the run-in phase were randomly assigned, in a double-blind manner, to either continue treatment with AXS-05 or switch to a placebo.

According to the sponsor, the basic idea behind this randomized withdrawal study design is to see whether those who initially experience a benefit stop doing so when moved to a placebo, indicating that the therapy itself is effective — as opposed to results being due to a placebo effect. The randomized-withdrawal design of this phase 3 trial simultaneously improved signal detection and mitigated placebo response. 

With the randomized withdrawal design, the sample size was reduced. Total 178 patients with Alzheimer's disease agitation were enrolled into the study run-in phase. 108 patients who achieved a sustained clinical response were then included in the randomized withdrawal period. 

"The ACCORD study was a double-blind, placebo-controlled, multi-center, randomized withdrawal, U.S. trial which treated 178 patients with Alzheimer’s disease agitation. Patients achieving a sustained clinical response after open-label treatment with AXS-05 were randomized (n=108) in a 1:1 ratio to continue treatment with AXS-05 or to discontinue AXS-05 and switch to placebo."

According to an article on evaluate.com:

"When Axsome decided to stop the Accord study of AXS-05 in Alzheimer’s disease agitation early, hopes for that trial took a nosedive. So it was clearly a pleasant surprise today when the company announced that the study had hit. Axsome’s stock opened up 33%, and some investors might be hoping for an earlier-than-expected filing, despite the fact that results from the pivotal Advance-2 study are not due until 2025. Accord had initially been intended as a second pivotal, alongside the previously completed Advance-1, but when the number of agitation events turned out lower than expected, management decided to switch focus to Advance-2. Despite this, Accord met its primary endpoint, time to relapse of agitation, and a key secondary, relapse prevention. One potential fly in the ointment could be Accord’s randomised withdrawal design; it comprised an open-label lead-in phase in which all 178 patients were given AXS-05, and those that had a sustained clinical response to the agent were randomised to either continue treatment or switch to placebo. AXS-05, a combination of dextromethorphan and bupropion, is approved in depression as Auvelity and moving into Alzheimer’s agitation would be an important expansion."

Given that Alzheimer's agitation is a common disease (70% of Alzheimer's disease patients may have agitation), more than one adequate and well-controlled study (or pivotal, confirmatory studies) are needed to demonstrate substantial evidence for effectiveness. Besides the Accord study (with randomized withdrawal design), two additional studies were conducted by the sponsor: ADVANCE-1 trial was a Phase 2/3 study with an active control arm. ADVANCE-2 trial is a phase 3 confirmatory study with the largest sample size (350 patients in a 1:1 randomization ratio). ADVANCE-1 study results had already been announced. ADVANCE-2 study has just started the enrollment. Both ADVANCE-1 and ADVANCE-2 studies were designed as traditional RCT design - randomized, double-blind, placebo-controlled, parallel groups. 

In a clinical program containing multiple pivotal clinical trials, it is appropriate to select different clinical trial designs. In Axsome's Alzheimer's agitation clinical program, a randomized withdrawal design was used in one of the three pivotal trials, and a traditional RCT design was used in the other two pivotal trials. If all these three trials are successful, the evidence for effectiveness will be more substantial and stronger than three studies with the same study design. 

Treatment Emergent AEs (TEAEs), On-Study AEs, On-Treatment AEs, Non-TEAEs

During the clinical trial, the adverse events (AEs) are collected from the signing of the informed consent to the last dose of the study drug plus some follow-time. For statistical analyses of adverse event data, the treatment-emergent AEs (TEAEs) are usually defined. AEs with an onset date at or after the first dose of the study drug will be defined as TEAEs. AEs with an onset date prior to the first dose of the study drug will then be defined as Non-TEAEs. 

For example, the TEAE can be defined as:

"TEAEs are defined as events that start within the day of the first dose of trial treatment until 28 days after the last dose of treatment" in an SAP for an EMD Serono study.

"Treatment-emergent AEs (TEAEs) are defined as AEs that are not present at baseline or represent an exacerbation of a preexisting condition during the treatment period. Therefore, referencing the protocol, TEAEs will be defined programmatically as any AE record with a start date/time on or after the first study treatment administration (greater than or equal to study day 1), inclusive to the end of the study (specifically the EOS visit or ET visit)." in an SAP for a Regeneron's study

The TEAEs can be further defined based on the comparison of the AE onset date with a cut-off date where the cut-off date may be the last dose date or 28 days after the last dose date. 

In FDA's clinical review document for AstraZeneca's asthma drug, the on-study AE and on-treatment AE were defined:

• On-study AE: events with onset between the first-day dosing and the scheduled follow-up visit. 
• On-treatment AE: events with onset between the first day of treatment and the scheduled end of treatment (EOT) or investigational product discontinuation (IPD) visit. 
• Post-treatment AE: events with onset after the on-treatment period defined above

 On-study AEs include all TEAEs - all AEs recorded on or after the first dose date. 

On-treatment AEs are a subset of all TEAEs or on-study AEs. The AEs with an onset date after the cut-off date will be excluded from on-treatment AEs. 

There are some clinical trials with on-treatment AEs defined as the same as traditional TEAEs (i.e., any AEs with an onset date on or after the first dose of the study drug regardless of the cut-off date).

In a recent workshop "Advancing Premarket Safety Analysis" organized by FDA and Duke Margolis Center for Health Policy, the on-study and on-treatment AEs were specifically discussed. Here are the presentation slides for this topic:

The concept of on-treatment AEs has already been implemented in some clinical trials. For example, in a GSK-sponsored trial "A Phase 3a, Repeat Dose, Open-label, Long-term Safety Study of Mepolizumab in Asthmatic Subjects", the primary outcome measure is "Number of Participants With Any On-treatment Adverse Event (AE) or On-treatment Serious AE (SAE)" where On-treatment AEs and on-treatment SAEs are the events occurring on/after the first dose of open-label mepolizumab date and before/on last dose+28 days.

In a BMS trial "A randomized, open-label, phase 3 study of  BMS-936558 vs. Everolimus in Subjects with advanced or metastatic clear-cell renal cell carcinoma who have received prior anti-angiogenic therapy", the on-treatment AEs were defined as the following with a cut-off date of 100 days of the last dose of study treatment.

"On-treatment AEs will be defined as AEs with an onset date-time on or after the DateTime of the first dose of study treatment (or with an onset date on or after the day of first dose of study treatment if time is not collected or is missing). For subjects who are off study treatment, AEs will be counted as on-treatment if event occurred within 100 days of the last dose of study treatment. No “subtracting rule” will be applied when an AE occurs both pre-treatment and post-treatment with the same preferred term and grade."

Defining on-treatment AEs will require specifying a cut-off date and the cut-off date may be different depending on the potential impact of the study drug after the drug discontinuation and the half-life of the investigational products. 

Defining on-treatment AEs may be necessary for studies with the treatment policy estimand where the efficacy data and AE/SAEs are continued to be collected after the study participants have discontinued the study treatment. 

Previous discussions: 

• Adverse events (AE),treatment-emergent adverse events (TEAE), and adverse drug reaction (ADR)
• Adverse Event Collection: When to Start and When to Stop?

Rolling Review, Real time oncology review (RTOR), and Split real time application review (STAR) Program

For New Drug Application (NDA) and Biological License Application (BLA), the usual process is to submit the entire package with different modules at the same time. The submission package will include the quality, CMC, non-clinical study reports, and clinical study reports,... However, there are processes by which the sponsor can submit the submission package piece by piece: rolling review, real-time oncology review, and split real-time application review (STAR) program.

Rolling Review

Rolling review was one of the benefits for drug products with Fast Track Designation. According to FDA's website "Fast Track" 

A drug that receives Fast Track designation is eligible for some or all of the following:

More frequent meetings with the  FDA to discuss the drug's development plan and ensure the collection of appropriate data needed to support drug approval

More frequent written communication from FDA about such things as the design of the proposed clinical trials and use of biomarkers

Eligibility for Accelerated Approval and Priority Review, if relevant criteria are met

Rolling Review, which means that a drug company can submit completed sections of its Biologic License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be reviewed. BLA or NDA review usually does not begin until the drug company has submitted the entire application to the FDA

Fast Track Designation was one of the expedited programs described in FDA's guidance "Expedited Programs for Serious Conditions – Drugs and Biologics". Other expedited programs are breakthrough therapy designation, accelerated approval, and priority review designation. In FDA's guidance, the Fast Track Designation contains the benefit of submission of portions of an application (Rolling Review): 

Here are rolling review examples: earlier this month, Iveric Bio Announces Submission of First Part of NDA for Rolling Review of Avacincaptad Pegol for the Treatment of Geographic Atrophy; in September, 2022, Vertex and CRISPR Therapeutics Announce Global exa-cel Regulatory Submissions for Sickle Cell Disease and Beta Thalassemia

Real-Time Oncology Review (RTOR) Program

For oncology products, FDA's The Oncology Center of Excellence has a program called "real-time oncology review (RTOR)". RTOR facilitates earlier submission of topline efficacy and safety results, prior to the submission of the complete application, to support an earlier start to the FDA’s evaluation of the application. FDA's website "Real-Time Oncology Review" described the details about RTOR program. 

Some companies have utilized this program in hope of expediting their submission/review process. 

In a press release "SpringWorks Therapeutics Announces Data from Phase 3 DeFi Trial Evaluating Nirogacestat in Adult Patients with Progressing Desmoid Tumors at the European Society for Medical Oncology (ESMO) Congress 2022", it stated that their Nirogacestat for R/R desmoid tumors will be filed through real-time oncology review (RTOR) program.

Nirogacestat has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma. The FDA also granted Fast Track and Breakthrough Therapy Designations for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. SpringWorks plans to submit a New Drug Application (NDA) to the FDA in the second half of 2022, which will be submitted for review under the FDA’s Real-Time Oncology Review (RTOR) program.

Amgen's Sotorasib was approved by FDA for the first and only targeted treatment for patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer. The Sotorasib's BLA submission was through RTOR:

"In the U.S., LUMAKRAS was reviewed by the FDA under its Real-Time Oncology Review (RTOR), a pilot program that aims to explore a more efficient review process that ensures safe and effective treatments are made available to patients as early as possible."

 An article in Life Science Leader magazine "FDA's RTOR Program: Draft Guidance & Insights" provides a good summary of the RTOR program.

Split Real-Time Application Review (STAR)

STAR program builds off the Oncology Center of Excellence’s Real-Time Oncology Review (RTOR) program, In the newly passed PDUFA VII for the years 2023 through 2027, a new program called Split real-time application review (STAR) was proposed. According to PDUFA reauthorization performance goal and procedures fiscal years 2023 through 2027, the STAR program was described as the following: 

D. SPLIT REAL TIME APPLICATION REVIEW (STAR) PILOT PROGRAM

FDA will establish a STAR pilot program, which has the goal of shortening the time from the date of complete submission to the action date, in order to allow earlier patient access to therapies that address an unmet medical need. The STAR pilot program will apply to efficacy supplements across all therapeutic areas and review disciplines that meet specific criteria. Accepted STAR applications will be submitted in a “split” fashion, specifically in two parts (with the components submitted approximately 2 months apart).

1. Scope: The STAR program will seek to expedite patient access to novel uses for existing therapies by supporting initiation of review earlier than would otherwise occur and therefore allowing earlier approval for qualified efficacy supplements. This program will apply across all therapeutic areas and review disciplines for applications that meet specific criteria. An application will be considered eligible for STAR if each of the following criteria are met: a. Clinical evidence from adequate and well-controlled investigation(s) indicates that the drug may demonstrate substantial improvement on a clinically relevant endpoint(s) over available therapies. Breakthrough Therapy Designation (BTD) or Regenerative Medicine Advanced Therapy Designation (RMAT) is not required, but above criteria must be met. b. The application is for a drug intended to treat a serious condition with an unmet medical need. c. No aspect of the submission is likely to require a longer review time (e.g., requirement for new REMS, etc.). d. There is no chemistry, manufacturing, or control information that would require a foreign manufacturing site inspection (i.e., domestic site inspections may be allowed if it does not affect the expedited timeframe).

FDA's website "Split Real-Time Application Review (STAR)" described how the STAR program should be operated.