The FDA is making moves to advance cancer research by finalizing three guidances aimed at encouraging trial designs that can deliver faster and better-quality results.

Last week, the agency published final versions of its draft guidances on using master protocols in oncology trials, enrolling older participants in earlier-phase cancer trials and on oncology trials that use multiple patient groups — known as expansion cohorts — to assess different aspects of a drug.

The final guidance on master protocol trials — which returning FDA Commissioner Robert Califf has encouraged as a way of getting answers from trials at a faster pace — was revised from the original draft to include information on selection of dose and preliminary safety assessments in studies of combined cancer therapies.

In general, the agency advises that sponsors establish the recommended phase 2 dose for the investigational drug prior to assessing it in a master protocol. However, the final guidance adds that individual studies under the master protocol may incorporate an initial phase to determine dose for special populations, such as pediatric groups, when there’s enough adult data to indicate the proper dose.

For basket trials, which study a drug or drug combo across multiple patient populations, the final guidance says that those evaluating a combination therapy may include initial components to select the dose and evaluate safety prior to assessing drug activity.

The agency says that master protocols can use statistical methods, including Bayesian methods, to make decisions about modifying sample size, dropping a trial arm and other strategies. The implementation of these methods should be described in the statistical analysis plan.

In addition, the agency said it made minor revisions to clarify informed consent requirements, specify the information that should be submitted for protocol expansion amendments, determine the frequency of safety updates and additional IRB meetings, and the role of the safety assessment committee. The draft guidance was issued in October 2018 (CenterWatch Weekly, Oct. 1, 2018).

The final expansion cohort guidance has been updated to explain that antitumor activity assessments can be done in nonrandomized groups using a Bayesian statistical approach; the draft guidance had only recommended using a traditional Simon two-stage design, in which participants are divided into two groups or “stages.”

The update is a direct result of industry feedback on the draft guidance released in August 2018 (CenterWatch Weekly, Aug. 13, 2018). The Biotechnology Innovation Organization (BIO), for example, suggested during the draft guidance comment period that other analytical approaches using a Bayesian framework are viable for expansion cohorts.

The final guidance also notes that smaller trials (no more than 90 patients in the dose-finding portion and no more than 200 patients across all dose-expansion cohorts) can use an internal safety assessment committee instead of an independent data monitoring committee as long as its members aren’t otherwise involved in the trial.

The guidance also includes minor revisions that clarify criteria for drug products suitable for trials with multiple expansion cohorts and the procedure for risk assessments when using an in vitro diagnostic to manage patients.

This pair of guidances are one way that the FDA is encouraging innovative trial operations and designs in oncology research, according to Sandy Smith, WCG’s vice president of clinical solutions and strategic partnerships. While innovative trials are complex and can be very hard to implement as they may be evaluating several disease states or study drugs at once, they will ultimately pay off in a big way in cancer research, she said.

“Opening up the lines of communication to say, ‘sponsor, come and talk to us when you’re doing this,’ and giving more guidance on protocol design, statistical approaches, all of that really underscores that yes, while they may be more complex, we’ll be able to reach more patients … and hopefully get to scientific discovery much more quickly, rather than having to do these routine protocol designs in a sequential fashion, which may take us decades,” Smith told CenterWatch Weekly.

Finally, the guidance on including older adults in oncology trials, which stresses the importance of including patients over age 75 to better understand a drug’s benefit-risk profile across an aging patient population, clarifies that the agency’s recommendations apply to both small and large studies. It also expands on recommendations for decentralization and recruitment efforts, provides advice on obtaining comorbidity information and clarifies how trials can group patients by age. The agency published the draft version in March 2020 (CenterWatch Weekly, March 6, 2020).

This guidance, Smith said, will help to address a concerning lack of patients over 75 in cancer trials, which can lead to them getting ineffective or even harmful therapies. A number of nuances contribute to their current lack of enrollment in cancer trials, she said. For example, they often have comorbidities, may have potential metabolic differences and might be on other medications that cause interactions with the trial drug. But it’s critical that they be included in cancer trials at a greater scale.

“We have an aging population. The last thing we want to do is exclude them just because of their age,” Smith said. “Healthy aging exists and people should be offered the same opportunities. If we actually include them in the trials, we’ll have our eyes wider open to be able to assess that impact and determine whether the results from these trials can adequately be generalized to this patient population.”

With the guidances, the agency said it is aiming to achieve recent goals set by the Biden administration to cut the cancer mortality rate by at least half over the next 25 years, improve the lives of cancer patients and their families and “end cancer as we know it today.”

“The FDA is recommending important principles that involve addressing inequities, targeting the right treatments to the right patients, speeding progress against the most deadly and rare cancers, and learning from the experience of all patients,” Richard Pazdur, director for the FDA’s Oncology Center for Excellence, said upon the guidances’ release.

Read the master protocol guidance here: https://bit.ly/34ayqva.

Read the expansion cohort guidance here: https://bit.ly/3tnP4QD.

Read the inclusion of older adults guidance here: https://bit.ly/3MifwU9.