Master protocol: umbrella-trial-based platform trial versus basket-trial-based platform trial

Biotech company Aerami Therapeutics announced that they are going to design a platform trial to test their pulmonary hypertension drug simultaneously in multiple indications (in this case, multiple WHO groups of pulmonary hypertension).

uniPHied: A Novel Platform Study Design for a Phase 2 Clinical Trial to Assess the Safety and Efficacy of AER-901 in Pulmonary Hypertension Associated With Interstitial Lung Disease and Pulmonary Arterial Hypertension

They stated the following "Phase 2 studies in pulmonary hypertension have been confined to one etiology, with large participant numbers relative to rare disease demographics. This platform study design allows for assessment of AER-901 across multiple forms of pulmonary hypertension within one efficient trial. The uniPHied study aims to assess AER-901 in pulmonary hypertension associated with interstitial lung disease (PH-ILD) and pulmonary arterial hypertension (PAH), with the option to expand to other forms of pulmonary hypertension via a protocol amendment".

Pulmonary Hypertension (PH) comes in multiple forms (phenotypes or genotypes). According to the WHO Pulmonary Hypertension classification, there are five different groups (see the table below). Each WHO PH class is considered a separate indication. Drug development programs in PH will include clinical trials for each WHO PH class. 

It is natural to think of a master protocol that can combine the clinical trials in different WHO PH classes into a single clinical trial (a platform trial). 

However, there are two issues in the uniPHied study design. 

This is not a typical platform trial design. the platform trial is usually based on an umbrella trial where multiple drugs are evaluated for the same indication. The platform trial has not been used for basket trials where the same drug is evaluated for multiple indications (here in multiple WHO PH classes). Here are the definitions for master protocol, umbrella trial, platform trial, and basket trial. 

FDA's guidance for industry "Master Protocols for Drug and Biological Product Development"

Master protocol: a protocol designed with multiple substudies, which may have different 22 objectives and involve coordinated efforts to evaluate one or more medical products in 23 one or more diseases or conditions within the overall study structure.   

Substudy: the information and design features (e.g., objectives, design, methodology, 26 statistical considerations) related to evaluation of a single medical product in a single 27 disease, condition, or disease subtype in the master protocol.  

     

The control group can not be shared across different sub-studies in different WHO PH classes. 

The uniPHied study is a basket-trial-based platform trial. Each indication (each WHO PH classes) needs to have its own control group. The data from control groups in different WHO PH classes can not be combined or pooled.

The platform trial in the FDA's guidance refers to the umbrella-trial-based platform trial. FDA guidance discussed the shared control group extensively. The control group in the umbrella-trial-based platform trial needs to be separated into a concurrent control and a nonconcurrent control. For a specific drug in the platform trial, FDA recommended the following: 

The control group used for the primary comparison of any given drug in a master protocol should generally include only concurrently randomized subjects (i.e., a concurrent control) and should not include nonconcurrently randomized subjects. 

Forward: When Worlds Collide: The Theory of Real-World Evidence Meets Reality

 A good article from The FDA Law Blog:

              When Worlds Collide: The Theory of Real-World Evidence Meets Reality

eIND: exploratory IND versus emergency IND

eIND may be referred to as either exploratory Investigational New Drug (IND) or emergency Investigational New Drug (IND). An "Exploratory IND" and an "Emergency IND" are both regulatory mechanisms used in the United States by the Food and Drug Administration (FDA) to allow for the use of investigational drugs in certain circumstances. It's important to note that the exploratory IND and emergency IND represent distinct concepts.

Exploratory IND (eIND):

exploratory IND may be called 'Phase 0' clinical trial. Exploratory IND was described in FDA Guidance for Industry, Investigators, and Reviewers "Exploratory IND Studies". The guidance defined the exploratory IND as the following:

Purpose: Used for early-stage clinical trials to explore the preliminary pharmacokinetics and the pharmacodynamics features, not the safety and efficacy of a new drug or treatment. The dose is sub-therapeutic level or micro-dose.

Timing: Typically used in the early stages of drug development, before a drug has been extensively studied in humans and before the phase 1 study

Process: Requires submission of an IND application to the FDA, detailing the proposed clinical trial protocol, preclinical data, and any available safety information. However, less pre-clinical data or animal data is required for the eIND study than for the typical phase 1 study.

Review: The FDA reviews the eIND application and provides feedback before the trial can proceed.

Requirements: Investigators must adhere strictly to the protocol outlined in the IND application, and any deviations must be reported to the FDA.

Emergency IND (eIND):

Emergency Use Investigational New Drug (IND) applications are part of expanded access program (also referred to as compassionate use). expanded access program was described in 21 CRF Part 312 "Subpart I—Expanded Access to Investigational Drugs for Treatment Use". FDA has a designated page to describe the "Expanded Access" process. 

emergency INDs may also be called single-patient INDs, Individual Patient Expanded Access, or Single Patient Expanded Access. They are initiated in urgent scenarios where immediate access to an unapproved drug is necessary, and the clinical circumstances do not permit the time required for a standard IND submission. emergency INDs are primarily utilized in cases of life-threatening conditions where no established treatment options are available.

21 CRF Part 312.310 described the process for expanded access for individual patients, including for emergency use. 

Purpose: Used in emergency situations where there is no alternative treatment available, and the patient's condition is serious or life-threatening.

Timing: Typically used when there is an urgent need to provide access to an investigational drug outside of a clinical trial setting.

Conditions: Reserved for cases where standard treatments have failed, are unavailable, or are not suitable for the patient.

Review: The FDA still needs to review the emergency IND application, but needs to provide feedback / approval in a very short period (hours/days).