Medical Device Blog – QA & Regulatory Updates from Emergo Group

Guidance published by the FDA in late 2011 intends to update regulatory requirements for medical device manufacturers responding to public and non-public requests for off-label information about their products.

Now that online forums, email, social networking sites and other more advanced communication methods have become more widely used, the FDA has revised its approach to off-label information requests to take into account these new electronic communication methods.

The guidance reiterates the agency’s longstanding policy that a manufacturer’s responding to unsolicited requests for off-label information in such a way that suggests an unapproved intended use for the device in question is prohibited.

Public requests for off-label information
The FDA distinguishes between public unsolicited requests for off-label information—those made in public forums and directed either to an individual firm or to a wider forum—and non-public requests, which are directed privately to individual firms using one-on-one communication methods.

The guidance includes electronic communications under the public request category; consumers more often conduct online research on medical products and technologies, and off-label use questions from consumers are often seen by other online consumers as well as firms. Concerned that manufacturers may respond to individual requests for off-label data via online, public methods—particularly if those responses include intended use information that does not square with FDA approval—the agency recommends responding privately to any public request for such information. In the event that a firm opts to respond publicly, however, the FDA guidance provides the following suggestions:

• A firm should only reply to online public unsolicited off-label information requests in terms of specific information regarding its own products—not competitors’ products
• A firm’s public  response to an information request should only consist of the firm’s contact details, not any off-label data
• Any representatives of manufacturers responding publicly to questions regarding off-label information should fully disclose their relationship to those manufacturers
• Public responses to such requests should not promote or market the device or manufacturer in question

Compliance issues
Medical device industry participants have until March to submit comments on the FDA guidance. Assuming the guidance is implemented, what will manufacturers need to do in order to comply? An analysis by MDDI suggests firms revise standard operating procedures and policies regarding electronic communications, as well as potentially rope in regulatory affairs departments for any online and social media campaigns that could result in unsolicited off-label information requests—and FDA scrutiny. 

New draft guidance from the US Food and Drug Administration recommends improvements to medical device manufacturers’ clinical study designs in order to better assess safety and effectiveness of their products according to gender.

The guidance aims to suggest methods to enroll more women in clinical studies in order to better represent demographic distributions of particular diseases; identify statistical analyses of study data that take into account gender differences; emphasize the need to consider gender differences during manufacturers’ study design phases; and spell out expectations of the Center for Devices and Radiological Health (CDRH) for reporting of sex- and gender-related information in study summaries and labeling for approved or cleared devices.

“Certain medical products elicit different responses in women compared to men,” the guidance states, citing ventricular assist devices and cardiac resynchronization therapy defibrillators as examples of devices with significant differences in effectiveness between male and female patients.

“Many clinical studies do not enroll proportions of women that reflect the underlying disease distribution in the affected population… This has contributed to a substantial lack of available data regarding the risks and benefits of medical device use in women.”

Historical barriers to enrollment of women in clinical studies, according to the FDA, include fears of fetal consequences, avoidance of female subjects by study sponsors, and study inclusion or exclusion criteria that inadvertently exclude women. To reduce these challenges, study sponsors and manufacturers should examine screening logs in order to track reasons for non-enrollment of women as subjects.

What to include in submission documents
The guidance recommends inclusion of information such as sex-specific prevalence of the disease in question, sex-specific diagnosis and treatment patterns, identification of proportions for women included in past clinical studies, and identification of any known clinically significant sex differences in outcomes regarding safety or effectiveness.

For new and ongoing studies, manufacturers and sponsors should include the afore-mentioned data as components of the risk analysis sections of their investigational plans. Firms should also summarize this information in their study protocols and training materials.

For completed studies, this data should be included as part of your marketing application under clinical investigation results. A draft PMA Summaries of Safety and Effectiveness or 510(k) Summary should also include this information.

Finally, for postmarket studies, this information should be included in interim reports as well as the results sections of final reports.

Other Recommendations
In addition, the FDA guidance recommends clinical study investigators take into account how the influence of subjects’ sex affects primary endpoints for safety and effectiveness. Analysis of subgroups and testing for interaction or heterogeneity may also be necessary, according to the agency.

Statistical analysis must also address sex-specific issues, recommends the FDA. Any clinically significant sex differences should be reported and discussed with FDA personnel to see whether further investigations are required based on those findings. Sex-specific information should also be reflected more thoroughly in study summaries and labeling, according to the guidance.

US consumer advocacy group Consumers Union is arguing that Congress strengthen the Food and Drug Administration’s ability to regulate medical devices in order to improve quality, safety and effectiveness.

The group has sent a letter to Congress contending that despite industry lobbying efforts casting medical device regulations as barriers to innovation, devices remain less regulated than pharmaceutical products in the US.

The Consumers Union letter also takes issue with the FDA’s practice of clearing most devices through the 510(k) process without requiring clinical trials, as well as the agency’s reliance on Substantial Equivalence as a key consideration during device reviews.

Recommendations for pre-market approval improvements the group’s letter imparts to Congress include:

• Replace “reasonable assurance” safety requirements for devices with “substantial  evidence” requirements currently in place for drugs
• Require all implantable and life-sustaining devices to go through premarket approval rather than 510(k) clearance
• Remove all recalled devices from list of predicates to prevent other devices from being cleared based on those recalled devices
• Require all devices cleared using a recalled device as their predicate to undergo safety reviews

Consumers Union also argues for improvements to the FDA’s post-market surveillance practices for devices:

• Implement a nationwide unique identifier system for devices for better communicating to patients and providers when device problems arise
• Providing the FDA with adequate resources to fully implement and enforce existing patient protection initiatives such s MedWatch, MAUDE and Sentinel
• Empowering the FDA to require longer-term post-market studies, and to require manufacturers to fully meet their post-market surveillance obligations
• Keeping current conflict of interest rules for federal advisory committees in place

These recommendations are not new, according to Consumers Union: along with other consumer advocacy organizations, the group argued for adoption of these steps five years ago.

Given the substantial resources and legislative connections industry lobbyists have at their disposal, however, Consumers Union will likely have to make the same argument in another five years.

US medical device industry lobbying efforts against current regulatory practices appear to be working. A bill introduced in the US Senate would require the US Food and Drug Administration to expedite medical device review times and subject the agency’s Center for Devices and Radiological Health’s (CDRH) regulatory processes to third-party review to assess their impact on innovation.

The Medical Device Regulatory Improvement Act would amend the Federal Food, Drug and Cosmetic Act in several ways:

1. Changes to the FDA’s premarket approval process would require reviewers to consider alternative methods of evaluating safety and effectiveness of devices in order to reduce approval time frames and costs, and to consider whether pre-clinical rather than clinical data can be used to determine approval of some devices.
2. New substantial equivalence determination rules would require the CDRH to focus only on whether a device submitted for clearance has the same intended use as its predicate device and is “as safe and effective as a legally marketed device,” and would forbid reviewers from requesting or accepting data irrelevant to the substantial equivalence determination process. In addition, reviewers should examine device labeling for assessing intended use, and “shall not evaluate issues that do not present a major impact on the intended use as set forth in the labeling.” The bill also would require reviewers to consider alternatives to substantial equivalence evaluations to reduce time and cost of the process.
3. The bill would also require a management and innovation review at the CDRH 60 days following its implementation. Carried out by a third-party entity, the review would examine all management and regulatory practices at the CDRH to ensure that the unit operates with a clear understanding of how its determinations impact innovation. One year following appointment of the third-party entity to the CDRH review, the entity would submit a report of its findings to Congress.
4. To address conflicts of interest, the bill would subject all advisory committees providing input to the FDA to provisions of the Ethics in Government Act of 1978 covering federal and special government employees.

Congressional interest in the US medical device regulatory process has increased steadily over the past several months. If it becomes law, this bill would stand as a substantial victory for industry advocates arguing that the FDA’s review process has hurt medical device manufacturers.