Real world data (RWD) and Real world evidence (RWE) in Drug Development

The 21st Century Cures Act (Cures Act), signed into law on December 13, 2016, is designed to accelerate medical product development and bring new innovations and advances faster and more efficiently to the patients who need them. Following the passing of the Cures Act, the Food and Drug Administration (FDA) has created a framework for evaluating the potential use of real-world evidence (RWE) to help support the approval of a new indication for a drug already approved or to help support or satisfy drug postapproval study requirements.

In December, 2018, FDA issued "Framework for FDA’s Real-World Evidence Program" and FDA's CDER and CBER divisions (now also including the oncology center of excellence) created the RWE program. A series of guidance documents were released. 

DEFINITION of RWD and RWE:

FDA GUIDANCE DOCUMENTS on RWD and RWE (as of November 2024):

Topic	Title	Category	Current Status
EHRs and claims data	Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products	Data considerations	Final, July 2024
Registry data	Real-World Data Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products	Data considerations	Final, December 2023
Data standards	Data Standards for Drug and Biological Product Submissions Containing Real-World Data	Data submission	Final, December 2023
Regulatory considerations	Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products	Applicability of regulations	Final , August  2023
Submitting RWE	Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drug and Biological Products	Procedural	Final, September 2022
Externally controlled trials	Considerations for Design and Conduct of Externally Controlled Trials for Drug and Biological Products	Design considerations	Draft, February 2023
Non-interventional studies	Considerations Regarding Non-Interventional Studies for Drug and Biological Products	Design considerations	Draft, March 2024
RCTs in clinical practice settings	Integrating Randomized Controlled Trials for Drug and Biological Products Into Routine Clinical Practice	Design considerations	Draft, September 2024

WEBINARS for RWD/RWE:

FDA officials have given various webinars to explain these RWD/RWE guidance documents and encourage the sponsors to apply the RWE to the drug approval process. A non-profit organization, the Reagan-Udall Foundation for the FDA, in collaboration with the Food and Drug Administration (FDA), hosted a series of free, public webinars to discuss FDA-issued guidance in the RWD/RWE. 

Title	Webinar Series	Date
Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products	https://reaganudall.org/news-and-events/events/public-webinar-series-fda-issued-guidance-real-world-evidence	November 4, 2021
Data Standards for Drug and Biological Product Submissions Containing Real-World Data	https://reaganudall.org/news-and-events/events/real-world-data-webinar-series-data-standards	December 3, 2021
Real-World Data Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products	https://reaganudall.org/news-and-events/events/real-world-data-webinar-series-registries	January 28, 2022
Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products	https://reaganudall.org/news-and-events/events/real-world-data-webinar-series-considerations-use-rwd-and-rwe	February 11, 2022
Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drug and Biological Products	No webinar was conducted
Considerations for Design and Conduct of Externally Controlled Trials for Drug and Biological Products	https://www.youtube.com/watch?v=5rfInDy7osw&t=1s	April 13, 2023
Considerations Regarding Non-Interventional Studies for Drug and Biological Products	https://reaganudall.org/news-and-events/events/real-world-evidence-webinar-series-considerations-regarding-non	May 30, 2024
Integrating Randomized Controlled Trials for Drug and Biological Products Into Routine Clinical Practice	https://reaganudall.org/news-and-events/events/real-world-evidence-webinar-series-integrating-randomized-controlled-trials https://youtu.be/VRaQyOvn3AM?si=YrM9pY6JhL3LBr_o	November 22, 2024

Duke Margolis Center for Health Policy, in collaboration with the FDA, also conducted a series of free, public webinars to discuss the application of RWD/RWE: 

Webinar Title/Link	Date
Optimizing the Use of Real-World Evidence in Regulatory Decision-Making for Drugs and Biological Products – Looking Forward	December 12, 2024
2024 State of Real-World Evidence Policy	July 25, 2024
The State of Real-World Evidence Policy 2023	September 28, 2023
Understanding the Use of Negative Controls to Assess the Validity of Non-Interventional Studies of Treatment Using Real-World Evidence	March 8, 2023
Workshop on Draft Guidance on Real-World Data: Electronic Health Records/Medical Claims Data and Data Standards	February 27, 2023
The State of Real-World Evidence Policy	May 12, 2022
An Introduction to Real-World Data & Real-World Evidence: A Virtual Training Series for the Patient Community	March 12, 2021

SUMMARY:

RWD / RWE play an increasingly vital role in drug development by complementing traditional clinical trial data. Derived from sources such as electronic health records, insurance claims, registries, and patient-reported outcomes, RWD provides insights into how drugs perform in diverse, routine care settings. RWE, generated by analyzing RWD, helps assess the safety, efficacy, and value of treatments in real-world populations, addressing gaps that controlled clinical trials may leave. These insights are particularly valuable in identifying long-term outcomes, supporting regulatory decisions, designing pragmatic trials and comparative effectiveness researches, and informing post-market safety surveillance. Regulatory agencies like the FDA and EMA are encouraging the integration of RWE to enhance decision-making, optimize study designs, and support label expansions or accelerated approvals.

Functional Unblinding in Double-blind, Randomized, Controlled Trials (RCTs)

Earlier this month, FDA advisory committee declined to endorse Lykos Therapeutics’ application to market its psychedelic drug MDNA, also known as ecstasy, as a treatment for post-traumatic stress disorder (PTSD). The panel voted 9-to-2 against the treatment when asked if data showed MDMA’s effectiveness, and 10-to-1 against when asked if the benefits of MDMA outweighed its risks. Both of Lykos Therapeutics’ pivotal studies (MAPP1 study and MAPP2 study) are positive. With relatively small sample sizes, both studies showed highly statistically significant results that MDNA-assisted therapy is highly efficacious in individuals with severe PTSD. The failure in earning the endorsement from FDA advisory committee was not due to the study results, but due to the concerns about the study design and the study conduct, specifically, potential abuse, functional unblinding, and expectation biases. Functional Unblinding was one of the sticky issues discussed during the advisory committee meeting. 

Functional unblinding refers to the situation in a clinical trial or research study where individuals involved (such as participants, investigators, or assessors) gain access to information that reveals the identity of the treatment or intervention being administered. Functional unblinding can happen inadvertently due to various reasons, such as unintended disclosure of treatment details (accidental unblinding), observation of side effects specific to a treatment, or recognition of differences between treatment groups. Clinical trial sponsors usually implement strict procedures to prevent accidental unblinding and manufacture the matched control treatments/using double-dummy technique to prevent recognition of differences between treatment groups. 

However, functional unblinding due to side effects (or treatment emergent adverse events (TEAEs)) may occur with any investigational drug. If the treatment group (or investigational drug) can cause significantly more side effects, study participants, investigators, or assessors can guestimate which treatment group the study participants are assigned to. For example, IGIV causes headache events; niacin causes red or flushed skin, sotatercept causes telangiectasia, bleeding events, and increased hemoglobin levels,... participants or investigators may be able to guesstimate if the participants are receiving the investigational drug based on these unique side effects (adverse events). 

Functional unblinding is an especially important issue in psychedelic drug (such as Lykos' therapeutics's MDNA) clinical trials. In FDA's guidance for industry (June 2023) "Psychedelic Drugs: Considerations for Clinical Investigations", 'functional unblinding' was discussed as the following. It raised the functional unblinding issue and provided some solutions for preventing/handling the functional unblinding: 

Functional unblinding is a critical concern in clinical trials where the investigational drugs have unique and distinctive side effects. Functional unblinding can introduce bias (consciously or unconsciously), affect participant behavior, influence how outcomes are measured and interpreted, and compromise the objectivity of the study's outcome.

If functional unblinding is suspected, it is difficult for sponsors to demonstrate that the functional unblinding does not occur. One approach to investigate/assess the functional unblinding is to employ questionnaires before the study unblinding to ask the participants and investigators which treatment group they think the participants are receiving. However, I see no or very few sponsors doing this. I described this in an earlier post "Assessing potential unblinding due to imbalance in side effects through exit questionnaires".

Expanded access, compassionate use, and eINDs

Traditionally, drug approvals relied on at least two adequate and well-controlled studies, each convincing on its own, to establish effectiveness. The adequate and well-controlled (A&WC) studies are referring to the randomized, controlled trials (RCTs). However, in some special situations (such as orphan drug development), one adequate and well-controlled study may be sufficient and the evidences from sources other than RCTs may be considered as substantial evidence of effectiveness. 

In FDAs guidance for industry (September, 2023) "Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence", the following seven types of evidences are mentioned as potential substantial evidence of effectiveness.

The one highlighted is 'evidence from expanded access use of an investigational drug'. FDA guidance explained this: 

FDA has a website "Expanded Access" to define the scope of expanded access and provide guidelines how expanded access application can be obtained. There are similar terminologies in 'expanded access', compassionate use', and emergency investigational new drugs (eINDs). These three terms are explained below: 

Expanded Access:

• Expanded access, also known as "expanded access programs" or "compassionate use programs," refers to a regulatory pathway that allows patients with serious or life-threatening conditions to gain access to investigational drugs outside of clinical trials when no other treatment options are available.
• These programs are typically initiated by pharmaceutical companies or drug sponsors and require approval from regulatory agencies such as the FDA in the United States.
• Expanded access may be granted on a single-patient basis or through larger-scale programs, depending on the circumstances and the availability of the investigational drug.
• The primary goal of expanded access is to provide access to promising therapies to patients who may benefit from them, while also collecting additional data on safety and effectiveness outside of the clinical trial setting.

Compassionate Use:

• Compassionate use is often used interchangeably with expanded access, but it specifically refers to the use of investigational drugs for individual patients facing serious or life-threatening conditions who are unable to participate in clinical trials.
• Compassionate use requests are typically made by healthcare providers on behalf of their patients and are evaluated on a case-by-case basis.
• The decision to grant compassionate use access is based on factors such as the patient's medical condition, the potential benefits and risks of the investigational drug, and the availability of alternative treatments.
• Compassionate use is guided by ethical principles of beneficence and nonmaleficence, with the aim of providing relief to suffering patients while minimizing harm.

eINDs (Emergency Investigational New Drug Applications):

• eINDs are a specific type of expanded access mechanism that allows for the emergency use of investigational drugs in situations where there is an urgent medical need and no approved treatment options are available.
• eINDs are typically requested in emergency or life-threatening situations where waiting for traditional regulatory approval processes would not be feasible.
• These applications are submitted to regulatory agencies like the FDA and are subject to expedited review and approval.
• eINDs are governed by strict regulations and guidelines to ensure patient safety and ethical use of investigational drugs in emergency situations.

In summary, while all three mechanisms—expanded access, compassionate use, and eINDs—serve to provide access to investigational drugs outside of clinical trials, they differ in their specific contexts, processes, and regulatory requirements. However, they share the common goal of addressing unmet medical needs and providing hope and relief to patients facing serious or life-threatening conditions.

In clinicaltrials.gov, expanded access is categorized into three types:

Individual Patients: Allows a single patient, with a serious disease or condition who cannot participate in a clinical trial, access to a drug or biological product that has not been approved by the FDA. This category also includes access in an emergency situation.

Intermediate-size Population: Allows more than one patient (but generally fewer patients than through a Treatment IND/Protocol) access to a drug or biological product that has not been approved by the FDA. This type of expanded access is used when multiple patients with the same disease or condition seek access to a specific drug or biological product that has not been approved by the FDA.

Treatment IND/Protocol: Allows a large, widespread population access to a drug or biological product that has not been approved by the FDA. This type of expanded access can only be provided if the product is already being developed for marketing for the same use as the expanded access use.

RCTs for Chinese Traditional Medicine and Botanical Drug Development

In the latest issue of JAMA (Journal of American Medical Association), Yang et al published a paper "Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction The CTS-AMI Randomized Clinical Trial". The CTS-AMI randomized clinical trial is one of the first times that a traditional Chinese medicine has been tested in a large-scale, Western-style clinical trial.

Historically, the efficacy and safety of Chinese Traditional Medicine are not based on randomized, controlled clinical trials and,  therefore, questioned by many. In the era of evidence-based medicine, researchers in China started to adopt and conduct the RCTs for Chinese Traditional Medicine. These RCTs were published primarily in journals in Chinese. It is rare for the CTS-AMI RCT study to be published in the prominent English journal, JAMA. 

In an article "Traditional Chinese Medicine Proves Effective in Modern Clinical Trial", Dr Matthew Saybolt, a cardiologist with the Hackensack Meridian Jersey Shore University Medical Center commented on the study 

"I am not aware of any other large, well-run trials like this studying traditional Chinese medicine. This is a rarely run type of study, and I congratulate the authors for their work and publication in such a prestigious medical journal. The study was well conducted with a large sample size that was well powered to measure the outcomes.

In this trial, there is clearly a benefit to patients treated with this Chinese medicine compound compared to placebo

A reduction in death, reinfarction or complications after a STEMI is a very exciting finding. We have for some time been trying to bend the curve and improve mortality and complications after STEMI. Any new therapy, if safe, that can accomplish this would be very appealing to patients and physicians alike."

Saybolt said he also observed some weaknesses in the way the study was conducted, one of which was that the participants were entirely Chinese citizens and predominantly male.

"Thus the findings may not be generalizable throughout the world or to women," he said. "Furthermore, the patients were less frequently—compared to the United States, for example—treated with traditional proven medicine after their myocardial infarctions. Therefore, the effect of the Chinese medicine may have been augmented by the lack of patient exposure to proven therapies.

"However, there was equivalent low utilization of these traditional medications in both groups," he continued. "Furthermore, the study drug Chinese medicine compound was composed of multiple plant and insect products. Thus, we do not know which component or combination of components were the active ingredients and what is the correct dose."

If Chinese Traditional Medicine Compound needs to be approved in the US or other countries, the RCTs need to be conducted in multi-national clinical trials with a broad patient population. Given that the Chinese traditional medicine Compound is extracted from herbals, the drug development program will need to follow regulatory guidance such as USFDA guidance for the industry "Botanical Drug Development". 

Recent years, psilocybin, the primary psychoactive substance in 'magic mushrooms' has been tested in clinical trials to study its effect on major depression disorder, PTSD,... the drug development process for psilocybin (if extracted from magic mushroom) will need to follow the FDA guidance ""Botanical Drug Development"" and "Psychedelic Drugs: Considerations for Clinical Investigations ".

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"
• 
  
• 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

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. 

Placebo effect and its impact on the overall treatment effect

RCTs (randomized, controlled clinical trials) are still the golden standard in clinical research. In RCTs, the most common control group is the Placebo. According to Wikipedia, a placebo is a sham substance or treatment which is designed to have no known therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. In order to maintain the blinding (masking), the placebo group may include additional excipients similar to the experimental drug so that the placebo group will have the same characteristics as the experimental drug in shape, size, color, texture, weight, taste, smell,......

Placebo is assumed to have no therapeutic effect or detrimental effect. However, the assumption may not be true especially when the composition of the placebo is in consideration. 

In previous article "Placebo Effect, Honest Placebo, Open-label Placebo", we discussed the placebo effect in diseases in the CNS and psychological area or in diseases with subjective symptom measures. In the post "Placebo effect and the choice of placebo", we discussed the composition of the placebo and some 'placebo' may actually have therapeutic effect. For example, in clinical trials to test the therapeutic effects of IGIV, the  low concentration of albumin may be selected as the placebo control - the low concentration of albumin may actually have the therapeutic effect. In both of these cases, the placebo effect or potential therapeutic effect from the 'placebo' can cause the unexpected higher response rate in Placebo arm, therefore decrease the difference between the experimental drug and the placebo groups, result in the failed trials. 

On the flip side, the placebo can have detrimental effect. There are quite some recent discussions about the placebo having the detrimental effect - consequently, the overall treatment effect observed in the clinical trials may not be due to the therapeutic effect of the experimental drug, but due to the detrimental effect of the placebo group. In other words, the overall treatment effect can be  overestimated due to the detrimental effect of the placebo.

Here are some articles discussing the potential detrimental effects of the placebo in clinical trials to study the effects of fish oil in the prevention of the cardiovascular events. The REDUCT-IT trial was published in NEJM and was the pivotal trial resulting in the FDA and EMA's approval. According to the study protocol, "the matching placebo capsule is filled with light liquid paraffin and contains 0 mg of AMR101 (icosapent ethyl [ethyl-EPA])." The detrimental effect of the placebo may come from the paraffin. 

• Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy
• Amarin stands behind Vascepa after new analysis raises questions about its efficacy
• New analysis of Amarin’s Vascepa resurrects big questions about effectiveness
• New Biomarker Data Add to Concerns Over REDUCE-IT Trial
• Mineral oil: safety and use as placebo in REDUCE-IT and other clinical studies

When we conduct the placebo-controlled clinical trials, the composition of the placebo needs to be carefully considered and the potential therapeutic effect from the placebo needs to be minimized.