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 ".

Operationally seamless design versus inferentially seamless design

Biotech company, Aerovate Therapeutics presented a Phase 2b/Phase 3 study of their inhaled imatinib in the treatment of pulmonary arterial hypertension. The study is dubbed as IMPAHCT study and is posted on clinicaltrials.gov. The study used a so-called 'operationally seamless design' to combine the phase 2 and phase 3 studies. 

“This operationally seamless approach to the Phase 2b/Phase 3 clinical trial design for AV-101, with continued enrollment and collection of multiple endpoints, underscores Aerovate’s commitment to making new treatment options available to patients with PAH as soon as possible without compromising safety and scientific rigor,”

Traditional clinical development program includes phased clinical trials including at least one phase 2 dose-finding study and at least one phase 3 confirmatory or pivotal study. A 'seamless design' is intended to combine the studies in different phases in the hope of expediting the clinical development. When adaptive clinical trial design was initially introduced, the 'seamless phase 2/3 study

• Jeff Maca, et al, 2006 Adaptive Seamless Phase II/III Designs— Background, Operational Aspects, and Examples, Drug Information Journal
• Chen, YJ, et al, 2015, A Seamless Phase IIB/III Adaptive OutcomeTrial: Design Rationale and Implementation Challenges, Clin Trials
• Jenkins, M, et al, 2011, An adaptive seamless phase II/III design for oncology trials with subpopulation selection using correlated survival endpoints, Pharm stat.
  

In FDA's final guidance "Adaptive Designs for Clinical Trials of Drugs and Biologics", the terms 'seamless design' or 'adaptive seamless design' was no longer used, instead, they were described under the 'Adaptations to Treatment Arm Selection' section. The term 'seamless' occurred only once throughout the guidance in the following sentence: 

In general, seamless designs that incorporate both dose selection and confirmation of efficacy of a selected dose (based on data from the entire trial) can be considered if the principles outlined in section III (Principles for Adaptive Designs) are followed.

Operationally Seamless (or simply Seamless Design)

A "Seamless Design" combines two separate trials (individual Phase 2 and Phase 3 trials) into one trial. "Operationally seamless design" specifically refers to the strategic and efficient organization of various aspects of the clinical trial process to ensure smooth and effective operations. Clinical trials are complex endeavors involving multiple stages, from protocol development and participant recruitment to data collection, analysis, and reporting. Operationally seamless design in this context aims to optimize these processes for enhanced efficiency and effectiveness.

Key features of operationally seamless design in clinical trials may include:

Separate Statistical Analyses: Statistical analyses for Phase 2 and Phase 3 trials are separated, not combined. The data from the Phase 2 study will not be included in the statistical analysis of the Phase 3 data - therefore, the issues with multiplicity adjustment, handling of the immature data during the interim analysis, ... may be avoided. 

Integrated Workflows: Streamlining the various stages of the clinical trial, from patient recruitment to data collection and analysis, to minimize delays and improve overall trial efficiency.

Technology Integration: Leveraging technology solutions for data management, patient tracking, and communication to enhance the overall efficiency of the trial. This may involve using electronic data capture (EDC) systems, remote monitoring tools, and other technologies.

Collaboration and Communication: Fostering effective communication and collaboration among different stakeholders, including researchers, sponsors, regulatory bodies, and clinical sites, to ensure a cohesive and coordinated approach.

Patient-Centric Approaches: Implementing strategies that prioritize the experience of trial participants, making it easier for them to participate and comply with the trial requirements. This might involve the use of telemedicine, remote monitoring, or other patient-centric technologies.

Regulatory Compliance: Ensuring that the trial design and operations adhere to regulatory requirements, which helps in avoiding delays and ensuring the validity and reliability of the trial results.

Risk Management: Proactively identifying and managing potential risks throughout the trial to mitigate issues that could impact the overall progress and success of the study.

In summary, operationally seamless design in clinical trials is about creating a well-integrated and efficient process from the planning stages through to the conclusion of the trial. This approach aims to improve the quality of clinical trial data, reduce operational costs, and accelerate the development of new treatments.

The IMPAHCT study mentioned above is a operationally seamless design and the study design is described as the following: 

PART 1 (Phase 2b): Part 1, which is the Phase 2b portion of the trial, will assess the safety, tolerability, and efficacy of three twice-daily doses (10, 35, or 70 mg) of AV-101 against placebo and establish an optimal dose for Phase 3. The primary endpoint for this part is change in pulmonary vascular resistance (PVR) after 24 weeks compared to placebo. (note: it is said that approximately 200 patients (50 per arm) will be enrolled in this part of the study)

PART 2 (Intermediate, Phase 3): PART 2 begins immediately following enrollment of the last participant in the Phase 2b part of the trial and signifies the start of enrollment in the Phase 3 trial. Part two uses the same dosing as in the Phase 2b part of the trial with participants randomized across three AV-101 doses and placebo. Enrollment in part two will continue until the optimal AV-101 dose is selected based on results from the Phase 2b analysis.

PART 3 (Phase 3): This part of the trial will start once an optimal dose of AV-101 has been selected based on the Phase 2b results. All patients enrolling during this part of Phase 3 will be randomized to either the optimal dose of AV-101 or placebo. The primary endpoint for Phase 3 is change in six-minute walk distance (6MWD) at 24 weeks for the optimal dose of AV-101 compared to placebo.

In order to be operational seamless, the IMPAHCT employed a PART 2 (intermediate, Phase 3) portion of the study. During this stage, all patients for Phase 2b portion of the study have been enrolled, but are being followed up for reaching the endpoint (24 weeks) and for conducting the interim analyses. In PART 2 (intermediate, Phase 3) stage, patients are still randomized to one of three dose arms or placebo. The data collected from two active arms that are not selected for PART 3 will not be included in the final analyses and will be wasted. For example, if the 35 mg BID dose is selected as the optimal dose for PART 3, the final analyses will be comparing the 35 mg BID dose with the Placebo. The data from the 10 mg BID and 70 mg BID treatment arms will be wasted. Suppose it takes 28 weeks from the last patients randomized in Phase 2b to the sponsor establishing the optional dose for Phase 3, if additional 100 patients were enrolled into the PART 2 (Intermediate, Phase 3), 50 of these patients (not in the optimal dose or placebo) will be wasted. 

With the operationally seamless design, the efficiency is sacrificed for the speed.  

Inferentially Seamless Design (Adaptive Seamless Design)

An adaptive seamless design makes use of information (data) from patients enrolled before and after adaptation (pulls together data collected in both the Phase 2 and Phase 3 trials) in the final analysis. 

The primary purpose of using the adaptive seamless design is to combine both the dose selection and confirmation phases into one trial, so information from the learning stage (Phase 2) can be combined with the confirmatory analyses of Phase 3.

"Inferentially seamless design" refers to an approach that emphasizes the seamless integration of data and statistical methodologies to derive meaningful inferences and insights throughout the course of the trial. The goal is to enhance decision-making by continuously analyzing data, drawing inferences, and adapting the trial design based on emerging findings.

Adaptive seamless design is one of the adaptive designs. The typical setting for adaptive seamless design (inferentially seamless design) is to start the study with multiple active dose groups. At the interim analysis at the end of Phase 2 or close to the end of Phase 2, the data monitoring committee will review the unblinded data accumulated so far to select an optimal dose for Phase 3 portion of the study. The phase 2 data from the selected dose group and the placebo group will be included in the final analyses and contribute to the inferential analyses. The appropriate statistical methods need to be applied. For example, Grifols is conducting a phase 2/3 study with adaptive seamless design "Study of the Efficacy and Safety of Immune Globulin Intravenous (Human) Flebogamma® 5% DIF in Patients With Post-polio Syndrome (FORCE)" where a method proposed by Posch et al "Testing and estimation in flexible group sequential designs with adaptive treatment selection" was used to combine the data from phase 2 and phase 3.

The inferentially seamless design can be illustrated as the following (cited from the paper by Maca et al "Adaptive Seamless Phase II/III Designs— Background, Operational Aspects, and Examples"

Putting them side by side, here is the table to compare the operationally seamless design and the inferentially seamless design: 

Operationally Seamless Design	Inferentially Seamless Design
Integration of processes and systems for smooth operation.	Integration of data and insights for seamless decision-making.
Not an adaptive design - since the data from the phase 2 study is not included in the inferential analysis	One type of adaptive designs - Adaptations to Treatment Arm Selection
Emphasizes operational efficiency and workflow integration.	Focuses on integrating data and deriving meaningful insights.
Data collected from the phase 2 and phase 3 portions of the study is analyzed separately and separate clinical study reports may be written	Data collected from phase 2 the selected arms (the selected dose and the placebo arm) is combined into the phase 3 portion of the study and contributed to the final inferential analyses
Data collected from the phase 2 portion of the study is not included in the final inferential analyses
Overall sample size is larger since the data from Phase 2 and the data from the unselected arms in Phase 3 will not be used in the final inferential analyses.	Overall sample size is smaller since the data from some patients in the phase 2 portion of the study are used in the final inferential analyses
No pre-specified rules for dropping the inferior arms or selecting the optimal dose arm for confirmatory portion of the study	Pre-specified rules for dropping the inferior arms or selecting the optimal arm for the confirmatory portion of the study.
Dose selection is at the hand of the sponsor (the sponsor can unblind the phase 2 portion of the study data upon the completion)	Dose selection is implemented through the data monitoring committee (only they can review the unblinded data).
No need to deal with the multiplicity issue since the Phase 2 data is not used in the final analyses	Multiplicity issue needs to be considered and alpha needs to be adjusted since the portion of the phase 2 data will be included in the final analyses
Overrunning issues and handling of immature data (i.e. incomplete data at the time of data cut for interim analysis for patients who haven't reached the study endpoint) need to be considered

Additional reading: 

• the blog article by Esha Senchaudhuri (2014) "Operationally Seamless & Inferentially Seamless Adaptive Designs"
• Bhatt and Mehta (2016) Adaptive Designs for Clinical Trials
• Aerovate Therapeutics Announces Simultaneous Completion of Enrollment in Phase 2b Portion and Enrollment of First Patient into Phase 3 in the IMPAHCT Trial Evaluating AV-101 for the Treatment of Pulmonary Arterial Hypertension - the press release said IMPAHCT is "a seamless adaptive Phase 2b/Phase 3 design", but it is not. It is an operationally seamless design, not adaptive since the Phase 2b data will not be used for the final analysis. 

Walk Distance versus Timed Walk - endpoints for measuring patients' function in clinical trials

Drug development is now moved to the patient-focused era. Patient-focused drug development (PFDD) is a systematic approach to help ensure that patients’ experiences, perspectives, needs, and priorities are captured and meaningfully incorporated into drug development and evaluation. With PFDD, the endpoint or outcome measure needs to be meaningful, it should reflect or describe how the patient feels, functions, and survives.

Various tools can be used to measure functions. The most commonly used functional measure may be the measure of the walk distance or the walking speed.

Measuring the walk distance by fixing the time: six-minute walk test (6MWT) to measure the distance the patient can walk in six minutes (6MWD), two-minute walk test (2MWT) to measure the distance the patient can walk in two minutes (2MWD). 6MWD and 2MWD can provide a functional, therapeutic response and prognostic data that is valuable in the care of patients with respiratory, cardiac, and neurological diseases. It can also be used as the endpoint for clinical trials to evaluate the treatment differences.

There is also a 10-minute walk test to measure fatigability and walking economy, but it is not commonly used as primary efficacy endpoint in clinical trials. 

Measuring the time/speed by fixing the distance: The 10-meter Walk Test is a performance measure used to assess walking speed in meters per second over a short distance. It can be employed to determine functional mobility, gait, and vestibular function. Timed 25 Foot Walk (T25FW) is a quantitative mobility and leg function performance test based on a timed 25-walk. The time to complete 25-foot walk can be used to calculate the walk speed (ft/s). 

Examples/applications:

6MWT/6MWD

The 6MWT is a sub-maximal exercise test used to assess exercise capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. There is a specific guideline developed by ATS (American Thoracic Society): Guidelines for the Six-Minute Walk Test.

6MWT/6MWD was the primary efficacy outcome measure in pivotal studies in pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD).

Bridgebio had a pivotal study to assess the efficacy and safety of the acoramidis in treatment of
ATTRibute-CM (a heart disease) with two parts: 6MWD was the primary efficacy endpoint for part 1 of the study and

Part 1 of the study failed to demonstrate the treatment difference in 6MWD

Part 2 of the study successfully demonstrate the treatment difference in win ratio in clinical events (deaths and cardiovascular related hospitalization)

Alnylam's pivotal study (APOLLO-B study) demonstrated the statistical significant difference in primary efficacy endpoint of 6MWD at week 52. However, the magnitude of the treatment difference was merely 14.7 meters. The study results were published in New England Journal of Medicine and had a positive vote in favor of the approval by the Advisory Committee, however, FDA declined the approval. 

6MWT/6MWD may also be used in neurology diseases, for example: The 6-minute walk test and other endpoints in Duchenne Muscular Dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study

2MWT/2MWD:

Both 6MWT and 2MWT are clinical assessments to evaluate a patient's functional capacity and endurance, particularly in individuals with cardiopulmonary or musculoskeletal conditions. Compared to 6MWT/6MWD, 2MWT/2MWD was less commonly used in clinical trials. However, 2MWT is a shorter, more focused test designed to quickly assess walking capacity and is often used in situations where a shorter test is preferred. 2MWT can be conducted in a smaller space, making it more suitable for clinics or confined settings. 2MWT is particularly useful for assessing functional capacity in situations where time constraints or physical limitations may necessitate a shorter test, and offers a quicker assessment of walking capacity and can be used for patients who may have difficulty completing a longer test.

Two- and 6-minute walk tests assess walking capability equally in neuromuscular diseases

Grifols conducted a pivotal study to assess the efficacy of IGIV in the treatment of post-polio syndrome and used 2MWT as the primary efficacy endpoint. The study is still ongoing. 

MedDay Pharmaceuticals SA conducted a phase 3 study "MD1003-AMN MD1003 in Adrenomyeloneuropathy" with 2MWD as primary efficacy endpoint

Adamas Pharmaceuticals conducted a phase 3 study "Safety and Efficacy of ADS-5102 in Multiple Sclerosis Patients With Walking Impairment" where 2MWT used as the secondary endpoint (T25FW used as the primary endpoint)

The 10 Metre Walk Test

Instructions for conducting 10 Meter Walk Test or Core Measure 10 meter walk test

Sarepta Therapeutics recently released their confirmatory study results of gene therapy for the treatment of DMD (Duchenne Muscular Disease) and 10-meter walk test was one of the secondary efficacy endpoints. The 10-meter walk test results are shown here. The treatment differences are expressed in time (seconds). While all treatment differences are statistically significant, the clinical meaningfulness needs to be vetted by the experts and the regulators. 

Timed 25 Foot Walk (T25FW)

The T25FW is a quantitative mobility and leg function performance test based on a timed 25-walk. The patient is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the patient has reached the 25-foot mark. The task is immediately administered again by having the patient walk back the same distance. Patients may use assistive devices when doing this task.

The drug AMPYRA® (dalfampridine) was approved for improving walking in adult patients with multiple sclerosis (MS). The drug label stated that the T25FW was the primary efficacy endpoints:

The primary measure of efficacy in both trials was walking speed (in feet per second) as measured by the Timed 25-foot Walk (T25FW), using a responder analysis. A responder was defined as a patient who showed faster walking speed for at least three visits out of a possible four during the double-blind period than the maximum value achieved in the five non-double-blind no treatment visits (four before the double-blind period and one after). 

Acorda Therapeutics conducted phase 3 studies "Study of Fampridine-SR Tablets in Multiple Sclerosis Patients" and "Study of Oral Fampridine-SR in Multiple Sclerosis" where T25FW was used as the primary efficacy measure.

The paper by Cohen et al "A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment" stated the following:

Walking speed ft/s was used for T25FW since walking speed is more normally distributed as compared to walking time, and is therefore a preferred approach. A 20% change in T25FW is considered a meaningful change in patients with MS

FDA medical review document on ocrelizumab for treatment of RMS discussed the missing data imputation for T25FW. 

Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis

The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis

All four measures discussed above (6MWD, 2MWD, 10-meter walk test, T25FW) can be an acceptable endpoint for confirmatory trials. Which measure to use in a specific trial depends on the indication and the study population. The endpoint selection should be discussed with the review division of regulatory agencies such as FDA.