Thank you for joining us for another episode of the Guidance Recap Podcast. The Guidance Recap Podcast provides highlights for FDA guidance documents straight from the authors. My name is Kylie Haskins, and I am the host for today’s podcast. In today’s episode, I am excited to be talking with Dr. Gregory Levin, the Associate Director for Statistical Science and Policy in CDER’s Office of Biostatistics. He will be sharing some thoughts with us on the newly published draft guidance titled, “Master Protocols for Drug and Biological Product Development.” Welcome, Dr. Levin. Thank you for speaking with us today.

For listeners less familiar with this topic, what is a master protocol and why are they useful in drug development?

A master protocol is a protocol for a clinical trial that is designed with multiple substudies, which may have different objectives and involve coordinated efforts to evaluate one or more investigational drugs in one or more diseases or disease subtypes within the overall trial structure. There are many different kinds of trials that can utilize a master protocol. These include umbrella trials, which evaluate multiple products concurrently for a single disease, platform trials, which evaluate multiple products for a single disease on an ongoing basis, with products entering or leaving the platform over time, and basket trials, which evaluate a product for multiple diseases or disease subtypes.

Master protocols can be useful because they can accelerate drug development by maximizing the amount of information obtained from the trial. They add efficiencies relative to conducting multiple stand-alone trials under separate protocols by leveraging shared protocol elements such as a shared control arm in an umbrella or platform trial and also by leveraging shared infrastructure and oversight such as with a common network of clinical sites and common steering and data monitoring committees.

Why is FDA issuing this guidance?

FDA believes that well-designed trials conducted under a master protocol can yield reliable data on drug safety and effectiveness while accelerating drug development in certain settings. Master protocols have played a critical role in drug development for COVID-19, and there has also been an uptick in their use in other settings. FDA is issuing this guidance to clarify expectations for the design, conduct, and analysis of these complex trials to help industry navigate potential challenges and to ensure such trials provide reliable data to inform regulatory decision-making. The guidance focuses primarily on randomized umbrella and platform trials that are intended to contribute to a demonstration of safety and substantial evidence of effectiveness of treatments. These are typically phase 3 trials.

Are there specific diseases or conditions where master protocols are particularly beneficial?

Well, master protocols may be beneficial in any therapeutic area, and this guidance is relevant for their use in general, but master protocols may be particularly useful in certain settings such as where subject recruitment is challenging. This is because comparing multiple drugs to a shared placebo arm can reduce the overall number of subjects required as well as the number of subjects that receive placebo relative to having multiple trials where each drug is compared to a placebo independently. So essentially, you're maximizing the use of your subject pool and providing more participants with the potential of receiving an active treatment rather than a placebo.

The caveat is that the master protocol also needs to be appropriate in the specific disease setting. For example, to conduct a phase 3 umbrella or platform trial, there needs to be several promising candidate drugs that are available and are ready to proceed into a phase 3 setting, for example, with sufficient prior early-phase tolerability and dose-finding data. In some settings, such as many rare diseases, there may not be multiple drugs ready for such a trial.

What are the complexities associated with master protocols?

The advantages of master protocols do come with some challenges and limitations. For example, master protocols can increase start-up time and require a high level of coordination due to involvement of multiple stakeholders. They also can lead to important design challenges such as in ensuring adequate blinding to treatment assignment. The guidance describes a variety of considerations and recommendations for sponsors to appropriately handle the different design complexities, and I may elaborate on a few of those throughout our discussion today.

Why is randomization important in trials conducted under a master protocol?

Randomization is a cornerstone of a well-conducted clinical trial. Randomization is critical for trials conducted under master protocols – just as it is critical for any trial – to remove systematic imbalances between treatment arms in both measured and unmeasured prognostic factors and to ensure reliable inference on drug safety and effectiveness. Therefore, FDA generally recommends that a phase 3 umbrella or platform trial includes randomization of subjects to receive one of the drugs being evaluated or an appropriate choice of control. The guidance also discusses some additional considerations related to randomization, such as the choice of randomization ratio, randomization schemes that facilitate partial blinding to treatment assignment, and how to handle in the analysis randomization ratios that change over time during the trial.

In addition to randomization, what other factors should drug developers consider when designing, conducting, and analyzing master protocols?

The guidance discusses many additional topics that are relevant to sponsors when designing, conducting, and analyzing master protocols, including considerations related to the control group, informed consent, blinding to treatment assignment, adaptive design, multiplicity, comparisons between drugs, and the evaluation of safety. As just a couple examples, I will highlight some important recommendations in the guidance related to the choice of control group and the approach for blinding to treatment assignment.

As with any trial, the choice of control group is a critical design element in a trial conducted under a master protocol, and the selected control should be appropriate for the specific clinical setting. That being said, there are unique considerations related to the composition of the control group for a given drug that arise in a platform trial.

A platform trial allows products to enter and exit in an ongoing manner, such that the control arm spanning the duration of the trial includes both subjects randomized to the control who were concurrently enrolled and could have been randomized to a given drug, as well as subjects nonconcurrently randomized to the control who could not have been randomized to the given drug. This creates the potential for the control group for a given drug to include subjects randomized concurrently or nonconcurrently to the control.

The general recommendation in the guidance is that the primary comparison for a drug should include only concurrently randomized subjects and should not include nonconcurrent control data. Use of a concurrent control maintains the integrity of randomized comparisons and avoid systematic differences between treatment arms and biases that could occur with the use of nonconcurrent control data due to temporal shifts in subject characteristics, trial conduct, or standard of care. That being said, the use of a nonconcurrent control data can bring efficiency gains and in rare cases may be scientifically justified, and the guidance talks through that in more detail.

Another example of an important design topic is the approach for blinding to treatment assignment. Blinding is a key design element in clinical trials, and a double-blind trial in which subjects, investigators, and sponsor staff are unaware of the treatment assignment is the optimal approach to avoid bias. However, blinding becomes complex in a platform trial with increasing numbers of drugs with different administration routes or dosing schedules. The guidance talks through the pros and cons and logistical considerations for different approaches to blinding. One option is use of a multiple-dummy design where subjects are completely blinded to their assigned treatment arm. Another option is to use a distinct, blinded control for each drug where subjects have knowledge of their assigned drug-specific substudy but are blinded to whether they are receiving the given drug or its matched control. This if often referred to as a partial blinding strategy. In general, some degree of blinding is important, but the most appropriate approach may depend on the setting.

For further details on these and other design considerations for master protocols, I would encourage listeners to read the guidance.

What are some considerations related to trial oversight, data sharing, and dissemination of information for a master protocol?

In general, the use of shared oversight committees, a central institutional review board, and a single independent external data monitoring committee to oversee accumulating safety and efficacy data can add efficiencies and also ensure standardized and effective oversight and monitoring. There also can be unique considerations related to ensuring trial integrity. For example, in an umbrella or platform trial, communication of results for one drug can inadvertently disseminate information about other drugs that are still under ongoing evaluation under the master protocol. The guidance discusses how this could occur in more detail and recommends that the data monitoring committee and study team carefully consider data access plans and how best to plan analyses and communicate results without jeopardizing trial integrity.

What are some of the important considerations in the guidance related to regulatory review of master protocols?

Good question. First, it’s important to acknowledge that regulatory considerations for a master protocol are more complex compared to a stand-alone trial given the involvement of additional stakeholders, the potential for frequent changes, and the quantity of documentation.

The guidance intends to help sponsors navigate these regulatory complexities by providing specific recommendations related to submission of documentation and communication plans in support of master protocols. For example, one important recommendation in the guidance is that each master protocol should be submitted to FDA as a new Investigational New Drug Application, or IND. The master protocol sponsor should also request a pre-IND meeting to discuss the protocol and submission details.

The guidance also provides considerations for a variety of other important regulatory topics such as cross-references between the master protocol IND and INDs for individual drugs and the submission of protocol amendments, which are common in platform trials as drugs are added to the platform.

How important is communication for master protocols, especially regarding safety?

Communication is crucial. A master protocol IND should have a robust communication plan to ensure timely and effective interactions between the many stakeholders involved. This plan should ensure quick communication of serious safety issues to clinical investigators and to FDA under IND safety reporting regulations, and the guidance provides more details related to such safety reporting.

For our final question, what are a couple of key items that you especially want listeners to remember?

I would like listeners to know that FDA issued this guidance to provide best practices and the Agency’s expectations for the use of master protocols to provide clarity for stakeholders and to help support the appropriate use of these innovative trial designs. Master protocols can be an important tool for efficient and effective drug development, but it’s important, just like in any trial, to ensure appropriate design, conduct, and analysis such that the trial provides reliable safety and effectiveness data and can inform regulatory decision-making. Hopefully, stakeholders find the guidance useful in that regard. And finally, I’ll just thank everyone for listening and for hopefully also reading the guidance.

Dr. Levin, thank you for taking the time to share your thoughts on the draft guidance on master protocols. We all have learned so much from your insights on this document. We would also like to thank the guidance working group for writing and publishing this draft guidance.

To the listeners, we hope you found this podcast useful. We encourage you to look at the snapshot and to read the guidance.