The FDA’s attempt to minimise false conclusions about a drug’s effect in a clinical trial with multiple endpoints has reached its finish line. The agency released its final guidance on the problems posed by managing multiple comparisons during the analysis of several endpoints in a single study.

The FDA announced the initial draft guidance back in 2017, calling on the industry to provide comments on the challenges of data analysis and interpretation when more than one endpoint is included in the study. The aim of the guidance was to provide a perspective on the issue in more detail than the one stated by the International Council for Harmonisation (ICH ) guidance for the industry in the report, E9 Statistical Principles for Clinical Trials, which was released in September 1998.

While reiterating the common statistical knowledge and practices for different stakeholders in the clinical trial industry, the guidance did not break any new ground. Experts share their thoughts on the FDA’s guidance with Clinical Trials Arena and its impact on the future design and analysis of clinical trials.  

Clarity over endpoint terminology

The guidance made some of the terminology around different types of endpoints more explicit, says Dr Daniel Normolle, associate professor of biostatistics at the University of Pittsburgh School of Public Health. The final version includes clarified distinctions between secondary and exploratory endpoints, which was requested by Novartis and Boehringer Ingelheim.

Novo Nordisk requested to see a reference to ICH’s E9(R1) guidelines on estimands and its connection to primary and secondary endpoint families. Clinical Trials Arena has previously reported on the estimand framework and its benefits for dealing with missing data.

At the request of Merck , the appendix was expanded to include available statistical methods, which were originally incorporated into the body text of the draft guidance. According to the Regulations.gov submission portal, the FDA received a total of 20 comments and change proposals from the pharmaceutical industry on the draft guidance.

Overall, the guidance is informative and will be useful for the whole pharmaceutical industry, which ranges from multibillion-dollar global pharma companies to smaller-scale biotechs, points out Dr Chen Hu, associate professor of oncology at the Johns Hopkins University School of Medicine. “To have some common ground for people to start with is something that should be welcomed,” he adds.

Repetitive yet still beneficial

While the guidance provides clarity around endpoint terminology and types, it does not add much value when it comes to more complex clinical trials, Normolle says. “I found the FDA guidance to be somewhat disappointing. Frankly, it could have been written 20 years ago,” he notes.

Normolle explains that while this guidance is a useful document, it is limited to very low-dimensional problems. Indeed, the guidance provides scenarios where few endpoints are included in a clinical trial. However, clinical trial sponsors and researchers want to see a guidance that shows them how to deal with highly dimensional endpoints in more complex trial designs, Normolle says. “My takeaway from this was that you should talk to [the] FDA before you do anything significant. It is good advice, but why do you need that in a guidance?” he adds.

On the contrary, Hu says the FDA guidance cannot be very specific to overly complex scenarios. Instead of criticising what is missing in the guidance, it should be seen as the first version of a document that will keep evolving over time as this field matures. He adds that at some point, the FDA should renew this conversation with the industry and academia, especially statisticians.

In therapy areas such as oncology, there has been an increasing use of multiple endpoints, especially in large and randomised Phase III trials with multiple objectives and measured clinical benefits over the course of a disease, Hu says. He adds that this poses issues in properly categorising the totality of a treatment.

Even though the oncology field has been practicing a lot of what the guidance states, it still has value. Hu says that by repeating the same advice, it gives a good start to other people and encourages them to have a more focused discussion.

Last month, the FDA released a draft guidance on the inclusion of children in clinical trials. Experts told Clinical Trials Arena that while the draft is useful for certain stakeholders, most of the points made are already in practice.