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: 

• Demonstrating the disease-modifying effect through delayed start study design or delayed start analyses
• Randomized withdrawal design and delayed start design in rare disease clinical trials
• Randomized Start Design (RSD)

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.  

• Lynch et al (2022) Efficacy of Omaveloxolone in Friedreich’s Ataxia: Delayed-Start Analysis of the MOXIe Extension
• Liu-Seifert et al (2014) A Novel Approach to Delayed-Start Analyses for Demonstrating Disease-Modifying Effects in Alzheimer’s Disease
• Liu-Seifert (2015) Delayed-start analysis: Mild Alzheimer’s disease patients in solanezumab trials, 3.5 years 
• Vershuur (2019) Randomized Delayed-Start Trial of Levodopa in Parkinson's Disease - the protocol/SAP
• Cohen et al (2019) An open-label extension study todemonstrate long-term safety and efficacyof ABP 501 in patients with rheumatoidarthritis

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.  

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 clinicaltrials.gov 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. 

• Ethics of continuing to provide a drug on an open-label extension study for an "unapproved indication"
• An Open-label Extension Study to Evaluate the Safety and Efficacy of Subcutaneous Injections of Pegvaliase (> 40 mg/day Dose) in Adults with Phenylketonuria  
• Micetich (1996) The ethical problems of the open label extension study
• Taylor et al (2014) Ethics of continuing to provide a drug on an open-label extension study for an "unapproved indication"
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• Consent to open label extension studies: some ethical issue
• Post-Trial Access to Treatment Corporate best practices

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.  

• Amylyx Pharmaceuticals Submits New Drug Application (NDA) for AMX0035 for the Treatment of ALS
• Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis
• Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis

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

Pros: 

• 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

Cons: 

• 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