FDA Working To Make Subgroups Stand Out

Data will be presented on dedicated website as part of a new action plan to enhance subgroup data collection in clinical trials.

FDA wants to highlight demographic subgroup information on newly-approved drugs outside labeling and review documents to improve the data’s accessibility and understandability for patients and providers.

Subgroup data also could receive a more detailed mention in product labeling as part of the agency’s Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, which was released Aug. 20.

The plan outlines 27 short, medium and long-term steps to improve the completeness and quality of subgroup data collection, identify barriers to subgroup enrollment in clinical trials, and make demographic subgroup data more transparent.

Making the data more easily available is part of the transparency portion of the plan. The agency said it will excerpt subgroup information from the pivotal trials or use hyperlinks to specific information in review documents for newly-approved products and post them on a special website.

Phase I and II trial data also could be included on the site.

Jonca Bull, director of the FDA Office of Minority Health, said in an Aug. 21 interview that the subgroup data will be part of meta-analyses that are done in the review, which could include early phase trials along with the pivotal studies, if appropriate.

“A lot of the data is going to be meta-analysis, pooled data from the integrated summary of effectiveness and the integrated summary of safety,” she said. “The data from the Phase Is and IIs are typically pulled into that analysis.”

The agency also plans to post demographic data from device pivotal studies and completed post-market and post-approval surveillance studies.

Both items could be completed within one to three years, according to the plan.

FDA admitted that subgroup data can be difficult to locate in review documents. They routinely number in the hundreds of pages and are usually posted several weeks (or many months) after the approval is announced.

Subgroup information also sometimes is included in documents prepared for product advisory committee meetings, but those are produced before the agency makes approval decisions.

Making the data available on a specific website illustrates the increasing importance subgroup analyses and personalized medicine play in drug development.

The agency said in an August 2013 report, which was mandated by the 2012 FDA Safety and Innovation Act along with the action plan, that more subgroup data was needed in clinical trials, but cautioned that simply requiring more diverse demographic subgroup data may not be the answer (Also see "FDA Acknowledges More Diverse Subgroup Data Needed In Trials" - Pink Sheet, 26 Aug, 2013.).

An Incentive For Industry

Not only would a dedicated website for subgroup data make the information more accessible, it also may put more pressure on sponsors to ensure the data is collected.

A number of stakeholders questioned whether industry will have an incentive to comply with the ideas and action items outlined in the plan during an Aug. 21 conference call.

Bull responded that FDA wants to hold sponsors accountable, but also must remain flexible.

“We have to ground how we view participation in trials from the standpoint of the disease indication, the disease states, what we know about who the population that will be most likely to use the product would be,” Bull said during the interview.

Some stakeholders argued during an April 1 public hearing on the issue, which helped inform the action plan, that the agency should consider withholding approval of applications that do not have the required subgroup data (Also see "FDA Carrots And Sticks Are Best Way To Get Subgroup Data, Advocates Say" - Pink Sheet, 7 Apr, 2014.).

More Subgroup Mentions In Labeling?

It also appears that the agency may eventually include more information about a product’s effects on specific subgroups in labeling, even if no differences were noticed.

Another action item in the plan, to be completed in up to three years, involves exploring potential methods to consistently communicate information about demographic analyses. “A standard set of concise statements could be developed for labeling,” FDA said.

Leading up to the April public hearing, agency officials were thinking about whether subgroup information, particularly if it is not relevant to efficacy or safety, should be included.

But the plan states that patients and providers “want information about the clinical trial population and the analysis of subgroups, e.g. if demographic analyses were performed, whether there were differences found among subgroups, and whether subgroup analyses were inconclusive due to limitations of sample size or missing data.”

The plan also says it will be “important to assess unintended consequences that could result” when subgroup data are inconclusive, such as driving a patient to stop taking a medication.

Bull said in the interview the idea remains under consideration.

Since product labels are already long and involved, FDA has been leery about adding potentially non-informing language (Also see "The Sound Of Silence: FDA Ponders How To Label When No Subgroup Difference Found" - Pink Sheet, 28 Mar, 2014.).

FDA To Mine Existing Data

In addition, FDA could mine existing clinical trial data for new subgroup information.

The plan indicates that when resources allow, the agency will create a program to conduct in-depth examinations of data among certain applications submitted in a selected disease area over a specified period.

Researchers would look for trends and assess the content and quality of subgroup analyses and determine whether they were adequate to find potential subgroup differences.

Potential diseases that could be researched are cardiovascular disease, HIV and hepatitis, Bull said.

Research projects also will address subgroup participation in clinical trials and other issues.

The Pharmaceutical Research and Manufacturers of America and National Minority Quality Forum in March announced a campaign called “I’m In,” which is intended to help improve minority inclusion in trials (Also see "PhRMA’s “I’m In” Campaign Looks To Connect Minorities To Studies" - Pink Sheet, 12 Mar, 2014.).

FDA also is pushing for broader patient inclusion in trials.

The action plan includes more reviewer training on the importance of demographic information inclusion, analysis and communication in clinical trials.

MedWatch forms will be updated to allow more standardized demographic data collection on adverse events. Guidance on the NDA Integrated Summary of Effectiveness section also will be revised “with particular attention to the importance of demographic and other subgroup analyses.”

In December 2013 the agency issued a Manual of Policies and Procedures (MaPP) document encouraging reviewers to prevent unnecessary patient exclusions in clinical trials (Also see "FDA’s Clinical Trial Inclusion Policy Sold As Mild And Gentle" - Pink Sheet, 31 Jan, 2014.).

Comments on the action plan may be submitted until about mid-October.