FDA Guidance Addresses Master Protocols for COVID-19 Drugs

FDA recently released guidance about evaluating COVID-19 drugs and biological products for the treatment or prevention of the coronavirus.

In section A, the agency stated that all sponsors developing COVID-19 treatments should consider several guiding principles when determining whether to conduct a master protocol or stand-alone trial.

The guidelines include the strengths and limitations for both of these trial options.

For example, although master protocols can boost drug development by maximizing the amount of information obtained, this type of trial has limitations, including complexity.

On the other hand, a stand-alone trial is easier to conduct, but with this type of trial, fewer questions can be addressed.

Therefore, FDA suggested a development program that includes both master protocols and stand-alone trials. For trials in the program, a sponsor should clearly identify objectives to allow for the selection of an appropriate trial design.

Additionally, sponsors should provide justification for the to-be-evaluated doses. The justification may require overall biological activity within a product.

Section B pushes master protocols to consider FDA’s trial design and conduct considerations.  

For example, a master protocol should include an appropriate randomized comparator arm and seek concurrence from FDA before implementing a drug change into the trial.  

And when a participant is not eligible to receive a particular drug for any reason, protocols should be designed to prevent participants from being randomized to drugs they are not eligible to receive.

But FDA stressed that master protocol sponsors should make every effort to incorporate blinding into their trials and should discuss endpoint selection with the agency due to the potential challenges in trial design, conduct, and analysis.

Additionally, sponsors should consider four main points when determining if selective safety data collection for a product is appropriate.

First, the type of master protocol and drugs expected to be evaluated may impact the approach to safety data collection.

“In a master protocol with a selective safety data collection, if collection of additional safety data is needed for a new drug in a subprotocol, the comparisons of that outcome could only utilize the subset of participants in the control group for whom the appropriate safety data were collected,” FDA explained.

Additionally, master protocol sponsors should provide justification to support a selective safety data approach. And master protocol sponsors must understand that selective safety data collection does not alter safety reporting requirements.

And finally, in trials with a selective approach to safety collection, sponsors should address the impact of such differences in their risk-based monitoring plans.

FDA highlighted that before involving any subjects in clinical investigation under a master protocol, the investigator must obtain the legally effective informed consent of the subject.

In section C, FDA noted some additional statistical considerations for master protocols.

For example, if sponsors are considering alternative drug approaches, they should seek concurrence from FDA.

And if the overall randomization ratio to an investigational drug and its comparator changes during the trial, comparisons between the investigational drug and comparator group should account for time periods of different randomization ratios.

Finally, in section D, FDA noted administrative and procedural recommendations.

Master protocols sponsors evaluating drugs to treat or prevent COVID-19 should consider the following:

• The master protocol IND should include only the master protocol and the master protocol should be conducted under the IND only
• An IND proposed for evaluation in the master protocol should be submitted as a protocol amendment to the master protocol IND
• A master protocol sponsor should ensure the dissemination of information and advice from FDA to the individual investigation drug sponsors
• The master protocol sponsor should establish a systematic approach that ensures the rapid communication of serious safety issues to clinical investigations and FDA under IND safety reporting regulations

The guidance will remain in effect for the duration of the COVID-19 pandemic, which was declared a public health emergency by HHS in January 2020.

“The FDA expects master protocols to continue to play an important role in addressing the public health needs created by the pandemic and in generating clinical evidence in general,” the agency said in a statement.