Saturday, March 11, 2023

Critical Dates after NDA/BLA submission: Filing Date (Day 1), Day 14, Day 60, Day 74, and PDUFA date

After the NDA/BLA is submitted to FDA, the FDA review clock starts. There are several critical dates relevant to the applicant (the sponsor).

Filing date (Day 1): the date that the NDA/BLA application is received by FDA. Nowadays, the NDA/BLA submission will be in eCTD format and go through FDA's electronic submission gateway. FDA will receive the NDA/BLA submission on the same day (or the next day) as the sponsor submits. The review clock (or PDUFA time clock begins when the application is received by the FDA. 

Day 14: FDA acknowledges to the sponsor in writing (filing letter) that the application is received. Between Day 1 - Day 14, the FDA could request the sponsor to correct the conformance issues. For example, the data sets in the SAS transport file were created using incorrect procedures and could not be opened by the FDA. FDA would ask the sponsor to resubmit the data sets in the SAS transport file using the correct procedures. 

Filing Letter – a letter issued to notify the applicant that their submission has been filed and will be reviewed. Note: The filing letter also includes information stipulated by PDUFA and may contain any identified filing deficiencies.

According to OFFICE OF MANAGEMENT: Effect of Failure to Pay BsUFA Fees

If the applicant (including its affiliates) is not in arrears and has satisfied any fee requirements for the application, then the RPM /RBPM aligned with the review division sends an Acknowledgement Letter within 14 calendar days of receipt of submission to the applicant.

Day 60: The sponsor will be notified within 60 days of submitting the NDA/BLA whether the application has been accepted for filing (or conversely, if the FDA refuses to file the application due to lack of information or studies).

According to CDER 21st Century Review Process Desk Reference Guide, by Day 60, FDA needs to: 

  • Inform the applicant of a Priority Designation in Writing Communicate Filing Determination to Applicant (for BLAs and priority NDAs) 
  • Notify Applicant of a Refuse-to-File determination. Communicate an RTF action to the applicant by day 60 in the form of official correspondence. Refusal to file (RTF) is the Food and Drug Administration (FDA)’s formal decision to deny review of a New Drug Application (NDA), Biologics License Application (BLA), supplemental NDA (sNDA) and supplemental BLA (sBLA) due to application deficiencies. 
If the sponsor requested for priority review and did not receive a notification by Day 60, it is most likely that the priority review was not granted by the FDA. The standard review (10-months) will follow. 

Day-74 (Deficiencies Identified) Letter – a letter notifying the applicant of issues identified during the filing review phase that were not communicated in the filing letter. It is likely that the issues related to the statistical analyses will be included in the Day-74 letter. 


Day 74 Letter: FDA will follow existing procedures regarding identification and communication of filing review issues in the “Day 74 letter.” For applications subject to the Program, the timeline for this communication will be within 74 calendar days from the date of FDA receipt of the original submission. The planned review timeline included in the Day 74 letter for applications in the Program will include the planned date for the internal mid-cycle review meeting. The letter will also include preliminary plans on whether to hold an Advisory Committee (AC) meeting to discuss the application. If applicable, the Day 74 letter will serve as notification to the applicant that the review division intends to conduct an expedited review.

Review performance goals: For NME NDA and original BLA submissions that are filed by FDA under the Program, the PDUFA review clock will begin at the conclusion of the 60 calendar day filing review period that begins on the date of FDA receipt of the original submission. 

Day 74 Letter: If the application is accepted for filing (60 days after submission), then the sponsor will receive an FDA 74-day letter, which contains a planned NDA review timeline that varies based on several factors such as whether other similar drugs already exist or whether your drug treats an unmet medical need.

The FDA 74-Day letter also confirms your action date (PDUFA date), confirms standard versus priority review, and identifies any preliminary deficiencies in your application. Sponsors must act quickly to resolve the deficiencies noted in the FDA 74-day letter during the NDA review process.

According to CDER 21st Century Review Process Desk Reference Guide, by Day 74 (i.e., Day 60 + 14 Days), FDA needs to:

  •  Communicate Filing Review Issues
  •  Communicate “Program” Review Timeline to Applicant (if applicable)

According to MAPP: OFFICE OF NEW DRUGS  Review Designation Policy: Priority (P) and Standard (S), the sponsor will be informed of the priority review designation by Day 60. If the sponsor is not notified of the priority review designation by Day 60, it means that the request for priority review is not granted, and the standard review designation will be applicable. 

The division will inform the applicant in writing of a priority review designation by Day 60 of the review. The division will inform the applicant of a standard review designation in the filing communication by Day 74 of the review.

PDUFA date (FDA action date): 

Prescription Drug User Fee Act (PDUFA) dates refer to deadlines for the FDA to review new drugs. The PDUFA date is 10 months after the drug application has been accepted by the FDA or 6 months, if the drug is given a priority review designation.

By the PDUFA date, FDA needs to notify the sponsor if its NDA/BLA application is approved, tentative approved (pending the patent issues or exclusivity issues), or given a complete response letter (CRL). FDA issues a CRL when declining the NDA/BLA. The CRL will include the reasons why the FDA can not approve the NDA/BLA in its current format. 

Notice that the PDUFA date (6 months for priority review and 10 months for standard review) may not be calculated from the filing date (day 1), but rather is calculated from Day 60 after the filing date - this essentially adds two months to the review timeline. Two months are necessary for FDA to conduct the initial review to decide if the application is reviewable. With these two months (60 days), the PDUFA date may actually be 8 months for some applications with priority review designation and 12 months for standard review after the sponsor submits the NDA/BLA. 

The initial scheduled PDUFA date will be extended if additional data or materials are submitted during the review period, which constitutes a major amendment to the NDA/BLA submission. 

This Youtube video explained very well about NDA and BLA Application Review Process as part of the REdI Annual Conference (2019)

I have collected some recent NDA/BLA (or supplemental NDA/BLA) submissions to see when FDA notification date is relevant to the submission date and how the PDUFA date is determined. 


Submission date/filing date

FDA notification date

PDUFA date

Actual Decision Date

Akebia NDA for Vadadustat for the Treatment of Anemia Due to Chronic Kidney Disease

March 30, 2021

June 1, 2021


By Day 60

March 29, 2022

Standard review – 10 months from Day 60

March 30, 2022


CRL was issued

Amarin sNDA for VASCEPA® for cardiovascular risk reduction

March 28, 2019

May 29, 2019


By day 60



September 28, 2019

Priority Review – 6 months from the filing date

December 13, 2019


3 months of delay due to conducting Adcomm

Amylyx NDA for AMX0035 for the Treatment of ALS

November 2, 2021

December 29, 2021


By Day 60

June 29, 2022


Priority review – 6 months from Day 60

September 29, 2022


3 months of delay due to conducting two rounds of Adcomm

Blueprint Medicines sNDA  for AYVAKIT® for the Treatment of Indolent Systemic Mastocytosis

November 22, 2022

January 23, 2023


By Day 60

May 22, 2023


Priority review – 6 months from the filing date


Acadia Pharmaceuticals NDA for Trofinetide for the Treatment of Rett Syndrome

July 18, 2022


September 12, 2022


Within Day 60

March 12, 2023


Priority review – 6 months from Day 60


Argenx BLA for efgartigimod for treatment of generalized Myasthenia Gravis

September 21, 2022

November 22, 2022


By Day 60


March 20, 2023


Priority review – 6 months from the filing date


Cidara Therapeutics NDA for Rezefungin for treatment of Candidemia and invasive candidiasis

July 27, 2022

September 20, 2022

Within Day 60

March 22, 2023


Priority review – 6 months from Day 60


Ionis with Biogen NDA for tofersen for ALS


July 26, 2022




Jan. 25, 2023

Priority review – 6 months from Day 60


Biomarin BLA Gene Therapy for Hemophilia A

September 29, 2022


October 12, 2022

March 31, 2023

6 months from resubmission date


Gamida cell BLA for Omidubicel for hematologic and solid cancer

June 2, 2022


August 1, 2022


By Day 60 

January 30, 2023

Priority review – 6 months from Day 60

PDUFA date is further extended by 3 months to May 1, 2023

Ascendis Pharma


August 31, 2022

October 31, 2022


By Day 60 

April 30, 2023

Priority review – 6 months from Day 60


Biomarin BLA Gene Therapy for Hemophilia A

December 23, 2019

February 20, 2020

By Day 60

August 21, 2020

Priority review - 6 months from Day 60

August 18, 2020


CRL was issued

Arcutis’ ZORYVE™ (Roflumilast) Cream 0.3% For the Treatment of Plaque Psoriasis

October 4, 2021

December 22, 2021

By Day 74

July 29, 2022

Standard review – almost 10 months from filing date

July 29, 2022



Apellis NDA for Pegcetacoplan for Geographic Atrophy

June 1, 2022

July 19, 2022


Within Day 60

November 26, 2022

Priority review – Less than 6 months from the filing date

February 17, 2023

Approved, Almost three months of delay due to a major amendment to the NDA (additional submission of long-term data)

TG Therapeutics BLA for Umbralisib for treatment of Lymphoma

June 17, 2020

August 13, 2020


With Day 60

February 15, 2021

Priority review – 6 months from Day 60

February 5, 2021

Approved, Then FDA withdrew the approval

Reata Pharmaceutics NDA for omaveloxolone for the Treatment of Friedreich’s Ataxia

March 31, 2022

May 26, 2022


Within Day 60



November 30, 2022

Priority review – 6 months from the filing date

February 28, 2023


5 months of delay due to a major amendment to include the OLE data

Prevention Bio BLA for Teplizumab for Type 1 Diabetes

November 2, 2020

January 4, 2021


By Day 60

July 2, 2021

Priority review – 6 months from Day 60

July 2, 2021

CRL was issued


Liquidia NDA LIQ861 for treatment of PAH

January 27, 2020

April 8, 2020


By Day 74


November 24, 2020

Standard review – 10 months from the filing date

November 25, 2020

CRL was issued

Horizon sBLA for KRYSTEXXA® for Uncontrolled Gout


January 10, 2022


March 7, 2022


Priority review -

July 7, 2022

Priority review – 6 months from the filing date

July 8, 2022



Friday, March 03, 2023

Risk of Stopping Trial Early for Treatment Benefit - Story of Veru's Sabizabulin for Treatment of Covid

Today, we learned that FDA declined to approve the emergency use authorization (EUA) for Veru's sabizabulin for the treatment of Covid. The decision is not surprising given that in Nov 9, 2022, the FDA advisory committee voted 8-5 against the sabizabulin treatment aimed at hospitalized patients with moderate to severe infection who are at high risk for acute respiratory distress syndrome.

However, this case is a perfect example demonstrating the risk of stopping a clinical trial early for treatment benefit (or for overwhelming efficacy). 

The pivotal study was an international, multicenter, randomized, double-blind, placebo-controlled, parallel group study of 60 days duration that evaluated the efficacy and safety of VERU-111 (sabizabulin) in hospitalized adult subjects with COVID-19 infection described as being at “high risk for ARDS”. Subjects were included if they met criteria for World Health Organization (WHO) ordinal scale category 5 (non-invasive ventilation or high-flow oxygen) or category 6 (mechanical ventilation); or category 4 (oxygen by mask or nasal prongs) with the following comorbidities: asthma, chronic lung disease, diabetes, hypertension, severe obesity (BMI ≥40), 65 years of age or older, primarily residing in a nursing home or long-term care facility, immunocompromised. The primary efficacy endpoint is all-cause mortality at Day 60. 

According to the study protocol, approximately, 300 subjects were planned to be randomized at a 2:1 ratio into two treatment arms (200 subjects in the VERU-111 treated group and 100 subjects in the Placebo treated group). The protocol also pre-specified a formal interim analysis conducted by an independent data monitoring committee:

An efficacy interim analysis of the primary endpoint, all-cause mortality at Day 60, will be conducted when approximately 67% of the subjects (~200 subjects) have completed day 60, died or withdrawn for other reasons. The interim and final analyses will follow an O'Brien-Fleming group sequential design, with a plan of stopping the trial at the interim analysis if the results are statistically significant in favor of VERU-111. The criterion for efficacy at the interim analysis will be a two-sided 0.0121 p-value (a one-sided p-value <=0.0061 in favor of VERU-111). If the criterion is not met, the trial will continue, and the final analysis will have a criterion for efficacy of a two-sided p-value <=0.0463 (one-sided 0.0232 in favor of VERU111).

The formal interim analysis was conducted after 204 patients were randomized into the study and followed up to 21 days (134 patients in Sabizabulin group and 70 patients in Placebo group). Sabizabulin treatment resulted in a 24.9 percentage point absolute reduction and a 55.2% relative reduction in deaths compared with placebo (odds ratio, 3.23; 95% CI confidence interval, 1.45 to 7.22; P=0.0042). The mortality rate was 20.2% (19 of 94) for sabizabulin versus 45.1% (23 of 51) for placebo.

Given that the p-value 0.0042 is less than the criterion for stopping the trial for efficacy (0.0121), the sponsor (Veru) stopped the study and declared the overwhelming efficacy in the hope of FDA's approval for emergency use authorization. 

The interim analysis results were then published in the top medical journal - New England Journal of Medicine "Oral Sabizabulin for High-Risk Hospitalized Adults with Covid-19: Interim Analysis".

The original sample size of 300 patients was already pretty small in trials for the treatment of COVID-19. The sample size was further decreased due to the early stop for 'overwhelming' efficacy. During the FDA's review, the small sample size was one of the big issues. FDA expressed their concern about the evidence for supporting the benefit outweighing the risk in their briefing document provided for the advisory committee:  

The FDA Review team acknowledges that Study 902 met its prespecified primary endpoint of all-cause mortality at Day 60. We also note that the VERU-111 program is quite small in size compared to other therapeutic programs for patients hospitalized with COVID-19. As detailed in the briefing document, our review has identified a number of uncertainties with the data, which we raise in the context of this small trial in critically ill patients. These include:
  • High placebo group mortality rate
  • Potential for unblinding events with enteral tube administration
  • Baseline imbalances in standard of care therapies
  • Differences in hospitalization duration prior to trial enrollment
  • Uncertain effects of goals of care decisions on all-cause mortality
  • Negative studies with other microtubule disruptors in COVID-19 
  • Uncertainty in identification of a clinically relevant patient population 

Based on our review, none of these uncertainties or imbalances alone invalidate the mortality benefit observed in Study 902, but all of these issues together in a small trial which is more vulnerable to imbalances raise questions about the results. We conducted sensitivity analyses to investigate the potential impact of the noted imbalances. However, these analyses cannot eliminate the concern that certain baseline imbalances across treatment groups may have impacted study outcomes, due to the small study size. In addition, these issues raise concern that, even when using an objective endpoint such as mortality, observed results can be subject to biases in a small trial of short duration in critically ill patients. We ask the AC panel to consider these uncertainties together and how they affect the interpretation of the mortality data. 

When considering whether to authorize the emergency use of a product under EUA, the Agency must determine, among other requirements (see section 2.1.3), whether “the known and potential benefits of the product when used to diagnose, prevent, or treat the identified serious or life-threatening disease or condition, outweigh the known and potential risks of the product”. Evaluation of the potential risks in the VERU-111 development program is limited by the atypically small safety database, comprising a total of 149 subjects who received VERU-111 for the proposed use in COVID-19. While the small safety database limits our ability to identify clinically significant safety signals, potential safety signals identified in our review are urinary tract infections (including serious infections), ......

There is no guarantee that Veru's EUA application would be approved had the study not been stopped early. But I think that the chance of EUA approval would be much higher if the study was allowed to be completed according to the protocol and 100 additional patients were randomized into the study. To decide whether a study should be stopped early for efficacy, the stopping criterion is not the only factor to consider. I wished that the sponsor had consulted with the regulatory authorities before the decision to stop the study early for efficacy. 

Tuesday, February 21, 2023

Analysis of Data from Open-Label Extension (OLE) Study

In the previous article, the open-label extension (OLE) study was discussed. The OLE study is usually designed as a separate study from the RCT (the parent study) with its own study protocol and a separate electronic data capture (EDC) system even though all participants in the OLE are rollovers from the parent study. 

When analyzing the data from the OLE study, the data from the parent study often needs to be considered or combined for the analysis. The data can be analyzed with three different baselines:

  • Baseline at the beginning of the OLE study - the data from the OLE study will be analyzed separately from the parent study
  • Baseline at the beginning of the parent study (at the randomization of the parent study (RCT)) – the data from the OLE study and the parent study are combined and delayed start analysis can be performed to look at the delayed effect or never catch up effect
  • Baseline at the first dose of the active drug – to look at the long-term trajectory of safety and efficacy variables for the experimental drug. For participants who were in the active arm of the parent study, the baseline would be at the randomization; for participants who were in the placebo arm of the parent study, the baseline would be at the beginning of the OLE study
If the efficacy outcome is a continuous variable, the delayed start analysis can be performed with the combined data from the parent and the OLE studies. See previous discussions: 

Here are some articles discussing the application of the delayed start analysis in this setting. One of the delayed start analysis approaches is to perform the non-inferiority test to see if the treatment difference observed at the end of the RCT is preserved at the end of the OLE. A non-inferiority margin is pre-defined, the Mixed Models for Repeated Measures (MMRM) method is used to analyze the combined data from the parent study (RCT) and the OLE study, and the results from MMRM analysis are compared to the non-inferiority margin.  

Two potential outcomes from the delayed start analyses are meaningful: 

Never catch up:
the placebo group (or delayed start group) will never catch up with the experimental treatment group after switching to the experimental treatment in the OLE study - suggesting the importance of the early treatment with the experimental drug and potential disease-modifying effect. For example, Chapman et al (2015) performed the delayed start analysis using the data from the double-blind trial and the subsequent open-label extension study. The results depicted below indicated the 'never catch up' scenario where the patients in the placebo group were never able to catch up with the AIPI (an enzyme augmentation treatment) group in terms of lung density change from baseline. 

Placebo group catch-up after treatment switching:

The placebo group (or delayed start group) catch up with the experimental treatment group after switching to the experimental treatment in the OLE study - emphasizing the treatment effects observed in the RCT. For example, Rosich et al (2022) performed the delayed start analysis using the data from a double-blind trial and its OLE study for the drug galcanezumab in patients with chronic migraine. After switching to galcanezumab doses at the start of OLE study (at month 3), the previous placebo group experienced a rapid mean reduction of 6.8 migraine headache days within the first month, catching up with the previous double-blind galcanezumab groups by month 4, and then maintaining that reduction over time.

If the efficacy outcome is overall survival (time to death), there is usually an insufficient number of death events from the randomized, controlled parent study for running the log-rank test or Cox regression. However, combining the data from the RCT and the OLE study, there may be enough death events for performing meaningful survival analyses. When performing the survival analysis using the data from the RCT and the OLE study, the start of the OLE study can be considered as treatment crossover or treatment switching - a situation often occurs in oncology clinical trials. Different approaches have been proposed to handle the treatment crossover or treatment switching due to the transition from the RCT to OLE study. These approaches were summarized in EMA's documet "Question and answer on adjustment for cross-over in estimating effects in oncology trials" and in a presentation by Norbert Hollaender (2014) "Methods to estimate survival time after treatment switching in oncology – overview and practical considerations".

Compared to the traditional intention-to-treat approach, it is better to perform the overall survival analyses using more sophisticated methods (such as the rank preserving structural failure time (RPSFT) method and The Inverse Probability of Censoring Weighting (IPCW) to adjust for treatment crossover or treatment switching due to the transition from the RCT to OLE study.  

Monday, February 20, 2023

Open-Label Extension (OLE) Study

I asked OpenGPT to write a blog article about the open-label extension study and got the following response. The contents from OpenGPT seem to be relevant, but not entirely correct. 

"An open-label extension (OLE) study is a type of clinical trial that allows patients who have completed an initial trial to continue receiving the treatment they received during the initial trial. This type of study is beneficial to both the patient and the researcher, as it allows the patient to continue to receive the therapy and the researcher to gain further insight into the effects of the therapy over a longer period of time. 

Open-label extension studies are often used when the initial trial was short-term and the therapy may have long-term effects. This type of study allows researchers to observe the effects of the therapy over a longer period of time and to determine whether the therapy is effective in the long-term. It also allows researchers to observe any possible side effects that may occur over a longer period of time. 

In an open-label extension study, the patient is aware that they are receiving the same therapy that they received during the initial trial. This means that the results of the study are not blinded, as the patient knows what they are receiving. As such, the results of the study may be subject to bias. To reduce the risk of bias, researchers may use a placebo or a control group in the study. 

In addition to the benefits mentioned above, open-label extension studies are also beneficial to patients as they can continue to receive the therapy they received during the initial trial. This is especially beneficial for patients who may not have access to the same therapy outside of the clinical trial. "

Open-label extension (OLE) study is an extension study of a randomized, controlled trial (where the word 'extension' comes from) and is an open-label study (where the word 'open-label' comes from) where all participants receive the experimental drug. OLE study may be sometimes called 'long-term extension study' and is a study following the traditional randomized controlled trial (RCT). All participants in the OLE study are rolled over from the leading RCT - the parent study. 

OLE study can play a useful role in drug development as the sponsors gather additional data on the long-term safety and/or efficacy of the experimental drug, while also giving the RCT participants free access to the drug in development that they are already familiar with after participating in a previous RCT.

In an article by Taylor and Weatherall (2006) "What Are Open-Label Extension Studies For?", the following three purposes were listed for OLE studies:

The first reason is simply to make the (now known to be) effective but as yet unlicensed drug available to participants who were randomized to placebo; this might have been a requirement of the ethics approval or a means of enhancing recruitment to the original RCT. This purpose does not require systematic data collection, and is not a sufficient reason for publishing the results of prolonged observation. 

A second reason is that further, more prolonged observation may disclose adverse effects that were not observed in the original parent RCT. The likelihood of observing such events is low, since the cohorts are almost always too small to reliably detect rare events. In the case of anti-tumor necrosis factor therapies, open-label extension studies failed to detect reactivation of tuberculosis, a problem that was only identified through post-marketing surveillance and national adverse event registries. Even in the case of the early studies of prednisolone in RA, failure to identify significant steroid-induced osteoporosis was more a function of inadequate technology (lack of bone densitometry) than lack of prolonged open-label extension. For example, the study of prednisolone remained randomized for 2 years2. The safety issues do not constitute a sufficient reason for conducting open-label extension studies. 

The third purpose may be to demonstrate continued efficacy of the drug over a longer period of time or to show that participants randomized to receive the active treatment during the open-label phase achieved outcomes similar to those of participants who received the drug from the beginning of the parent RCT.

An OLE study may be designed after a fixed-duration RCT trial where all participants who completed the fixed-duration of treatments in RCT will be eligible for enrolling in the OLE study. The participants in the active arm in the RCT will continue to receive the experimental drug in OLE and the participants in the placebo arm in the RCT will switch to receiving the experimental drug in OLE. This type of design may be called the 'delayed study design' since the participants in the placebo arm will eventually receive the experimental drug, just receive the experimental drug later than those participants in the active arm in the RCT. 

An OLE study may also be designed after an event-driven RCT where participants receive the study drug in various duration and participants will be rolled over to OLE when a non-fatal protocol-defined clinical event occurs or at the end of the study when the total number of events is reached. There will be four different groups of participants who are in the OLE study:

  • Participants in Active Drug group had a non-fatal clinical event during RCT and rolled over to OLE
  • Participants in Placebo group had a non-fatal clincial event during RCT and rolled over to OLE
  • Participants in Active Drug group did not have a clinical event and reached the end of the study in RCT and rolled over to OLE
  • Participants in Placebo group did not have a clinical event and reached the end of the study in RCT and rolled over to OLE

OLE studies have been commonly used in rare disease areas where there is an unmet medical need for the disease and in some cases, there are no alternative treatment options after the RCT participants are off the RCT. If I search using the terms "open-label extension" or "open label extension", there are more than 4000 OLE studies showing up. 

OLE studies may have different durations (usually greater than 1 year). The duration of an OLE study may depend on the success of the RCT (the parent study). If the RCT is a success, the OLE study will be continued for a longer period of time (perhaps until the drug approval and the commercial drug becoming available). If the RCT fails, the OLE study must be discontinued. 

The OLE study is against the concept of the clinical equipoise and statistical equipoise. Equipoise is defined as a state of genuine uncertainty on the relative value (risk-benefit) of two different treatment options being compared in a clinical trial and is the basis for designing randomized controlled trials. The OLE study following an RCT assumes there are benefits in the experimental drug. It is possible to receive criticism when an OLE study is designed while the risk-benefit profile of the experimental drug has not been sufficiently characterized to justify the extension. 

There may be a debate about the OLE study in terms of the utility of OLE study data and the ethics of enrolling participants in the OLE study. From the regulatory standpoint, given the lack of a control arm in the OLE study, the data from the OLE study may provide limited safety and efficacy support to demonstrate the substantial evidences of efficacy and safety. As such, conducting OLE studies is of unclear utility in terms of regulatory decision-making. There may be potential ethical concerns with continuing patients for a prolonged period on an experimental treatment for which there is minimal efficacy data. 

We do see that the OLE study data was used to support/strengthen the evidence of the effectiveness of experimental drugs in NDA/BLA submissions. For example, the data from an OLE study, along with the results from a phase 2 RCT, was included in the NDA submission by Amylyx for their drug (Phenylbutyrate–Taurursodiol) in the treatment of Amyotrophic Lateral Sclerosis (ALS). The survival data from both the RCT and the OLE study were analyzed to provide evidence of survival benefits. After two advisory committee meetings, FDA finally approved Amylyx's drug (Relvyrio) for the treatment of ALS based on the efficacy evidence from a small phase 2 RCT supported by the survival data from the combined RCT and OLE study.  

In summary, there are pros and cons to conducting the OLE study following an RCT. 


  • Ethical – allow the patients in the experimental drug group to continue the experimental drug or allow the placebo patients to have a chance to receive the experimental drug especially when there is no alternative treatment available
  • Collecting the long-term safety data
  • Collecting the long-term efficacy data such as the survival data
  • If designed appropriately, the data from an OLE study can be used to do “delayed start analysis” (i.e., never catch-up analysis)
  • May provide supporting evidence for regulatory decision making


  • Against the concept of clinical equipoise
  • For diseases that alternative treatments are readily available, there may be no strong ethical reason to provide the experimental study drug treatment through the OLE study
  • Limiting the patients to participate in other RCT trials in the same indication
  • Resource and cost for conducting OLE studies are not trivial 
  • Not considered an adequate and well-controlled (A&WC) study