Worldwide Medical Device Regulatory Updates

As medical device quality assurance and regulatory affairs professionals, it can be challenging to stay on top of changes happening in our industry. Few people have the time to read lengthy articles these days and although many online newsletters exist, they are often packed with PR releases, ads or unrelated information. That\'s why we started this blog for QA/RA professionals in the medical device and IVD industry. The idea is to give you short updates on quality and regulatory topics that may be of interest to you. No fluff, just straight to the point. We hope you\'ll enjoy the content.

GAO: FDA Medical Device Review Timeframes Increasing

A new report from the US Government Accountability Office (GAO) provides yet more data showing that total average review times for FDA 510(k) medical device applications has increased despite the regulator’s meeting other 510(k)-related performance goals.

Specifically, the average total time from 510(k) application submission to final decision increased from 100 days in 2005 to 161 days in 2010—an increase of 61%. However, the report also points out that the FDA has reviewed more than 90% of 510(k) submissions within 90 days each year since 2005; the agency was also able to review 98% of all 510(k) submissions within 150 days. It is important to note that FDA “review times” exclude the time it takes for manufacturers to respond to FDA requests for additional information on their submissions, whereas the total time periods evaluated by the GAO do include time required to respond to additional requests for information from the agency.

Furthermore, the GAO found inconsistencies when it came to FDA reviews of pre-market approval (PMA) applications. For “original” or standard PMAs, the FDA met its performance goals for four out of seven years that those performance goals were in place, but for “expedited” PMAs—available for devices deemed to treat or diagnose life-threatening diseases and meet unmet medical needs—the FDA met its performance goals for only two of the seven years of record.

GAO investigators interviewed industry and consumer advocacy groups as part of its study. Based on these interviews, the report identifies four most common complaints regarding dealing with the FDA for medical device clearances and approvals:

Inadequate communication between FDA reviewers and stakeholders
Lack of predictability and consistency in reviews
Increasing time to final decisions
Insufficient assurance from the FDA regarding devices’ safety and effectiveness

The GAO study clearly breaks no ground in terms of FDA medical device review times—other studies have also come to similar conclusions. What these findings perhaps most importantly demonstrate, however, is the need for manufacturers to make every effort to ensure they do not have to deal with additional requests for information from the regulator.

Markets: USATags: 510(k), 510-k, 510k, FDA, GAO, Government Accountability Office, medical device, PMA, premarket approval

Author: Stewart EisenhartDate: April 2, 2012

New FDA Guidance Emphasizes Gender Differences in Clinical Studies

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.

Markets: USATags: 501(k), 510k, clinical study, FDA, PMA, postmarket surveillance, premarket approval

Author: Stewart EisenhartDate: December 19, 2011

FDA Guidance on HUD Designations Out for Comment

The US Food and Drug Administration has opened a 90-day comment period for draft guidance on Humanitarian Use Device (HUD) designations.

The HUD designation program, run by the Office of Orphan Products Development (OOPD), enables qualifying medical devices to be considered for marketing approval via a Humanitarian Device Exemption (HDE) application. HDE applications are similar to premarket approval applications, but do not require manufacturers to demonstrate reasonable assurances of effectiveness.

The draft guidance covers the following HUD-related issues:

Demonstrating that the device seeking HUD designation targets diseases affecting less than 4,000 people annually in the US
Variations of that demonstration depending on whether the device is designed for therapeutic or diagnostic use
How device properties affect that demonstration
Definition of a plausible patient population for the disease in question

Interested parties have 90 days to submit comments on the FDA’s proposals.

Markets: USATags: FDA, HDE, HUD, Humanitarian Device Exemption, Humanitarian Use Device, PMA, premarket approval

Author: Stewart EisenhartDate: December 14, 2011

FDA Panel Sets Meeting Date to Discuss CES Reclassification

The Neurological Devices Panel of the US Food and Drug Administration’s Medical Devices Advisory Committee will hold a public meeting on February 10, 2012 to consider requiring premarket approvals for cranial electrotherapy stimulators (CES).

Although currently classified as Class III devices, CES products are allowed to go through the 510(k) premarket notification process in order to be sold in the US market. The agency first proposed the more stringent premarket approval pathway for CES devices in August 2011. Prior to the meeting, the FDA will make available reclassification petitions that have been filed in response to its proposed rule, as well as other pertinent background material.

The meeting will examine existing data supporting CES safety and effectiveness, as well as whether that data is robust enough to support classification of these devices under Class II. Individuals and organizations interested in attending may submit written materials by February 6, 2012; those interested in making oral presentations at the meeting should notify the agency by January 27, 2012.

The FDA’s contact person for the meeting is Avena Russell; she may be reached via email at avena [dot] russell [at] fda [dot] hhs [dot] gov.

Markets: USATags: 510(k), 510k, CES, cranial electrotherapy stimulator, FDA, premarket approval

Author: Stewart EisenhartDate: November 18, 2011

US Consumer Group Urges Stronger Role for FDA

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.

Markets: USATags: 510(k), 510k, Consumers Union, FDA, post-market surveillance, premarket approval

Author: Stewart EisenhartDate: November 17, 2011

FDA Clarifies IDE Approval Process

Through new guidance published this month, the US Food and Drug Administration has clarified its review and approval process for its Investigational Device Exemption (IDE) regulations, and has also proposed steps to allow clinical investigations of high-risk medical devices in some instances where IDE approvals have not been finalized.

Approval of an IDE submission must occur before a manufacturer can begin clinical investigations of its device. The guidance explains four outcomes of its IDE review process: approval, approval with conditions, staged approval with or without conditions, and disapproval.

IDE Approval

If a manufacturer’s IDE application obtains FDA approval without conditions, the firm may begin clinical investigation efforts according to the terms set forth in the agency’s approval letter.

IDE Approval with Conditions

In instances where the FDA approves an IDE application with conditions, manufacturers may begin clinical investigations provided that they submit data to address outstanding issues within 45 days. If the agency takes issue with sponsors’ informed consent documents, however, those issues must be resolved before clinical investigations begin.

Issues often garnering approvals with conditions by the FDA include proposed study data analysis methods; late-stage follow-up procedures and assessments; divergences from appropriate study endpoints; and requests for additional information related to non-clinical testing issues.

Failure to submit supplements to the FDA within the 45-day timeframe will result in disapproval of an IDE application.

Staged Approval with or without Conditions

The new FDA guidance introduces staged approval and staged approval with conditions to the IDE approval process. Under these scenarios, manufacturers may begin limited subject enrollments for their investigations while simultaneously addressing issues raised by the regulatory about their IDE applications. (Once outstanding questions have been resolved, sponsors could then expand their study enrollments.)

Staged clinical investigations are warranted, according to the guidance, in instances where obtaining clinical data of a device’s safety characteristics is deemed necessary, requiring review of data from subjects in early stages of a clinical investigation before allowing a wider pool of subjects to be added to the investigation.

Staged investigations are also valuable when existing data supports enrolling a limited number of subjects in a clinical investigation while also conducting long-term non-clinical testing. The FDA would require validation of non-clinical testing results before allowing full enrollment in the sponsor’s clinical investigation.

IDE Disapproval

If the FDA disapproves an IDE application, the sponsor must submit an amendment to its IDE to address deficiencies; only following subsequent approval or approval with conditions by the agency may that sponsor proceed with its clinical investigation.

The guidance identifies five common factors for IDE disapproval:

Failure to comply with any relevant FDA requirement
IDE application contains false information or omits required information
Request for additional information is not addressed within required timeframe
Device’s health benefits do not outweigh the risk its use poses to patients, or it is ineffective
Inadequacies in the sponsor’s report of prior investigations, manufacturing processes or monitoring process of its investigation

Key Factors for Consideration

The FDA’s guidance also lists some of the major factors its reviewers evaluate in order to determine approval status of IDE applications. These include:

Non-clinical testing data, reviewed to see whether it supports a device’s safety and performance
Category of clinical investigation—feasibility or pivotal—can affect which elements of an IDE application FDA reviewers will examine most carefully
Risk assessment—are the expected risks of a clinical investigation acceptable?
Sudy design elements such as subject safety, enrollment criteria and clinical methodology for feasibility studies, and primary safety and effectiveness endpoints, assessment methodologies and statistical analysis plans for pivotal studies
Informed consent documents must meet requirements of 21 CFR Part 50
Least burdensome approaches to address premarket regulatory issues to ensure appropriate timeframes, efforts and cost-effectiveness for industry participants and FDA personnel

Markets: USATags: clinical investigation, FDA, IDE, investigational device exemption, premarket approval

Author: Stewart EisenhartDate: November 14, 2011

PMA Summary Review Database Now Available from CDRH

The US Food and Drug Administration’s Center for Devices and Radiological Health (CDRH) has launched a new searchable database of premarket approval (PMA) summary review memos.

The CDRH defines 180-day supplements as requests for significant changes in components, materials, design or other factors to a previously approved premarket application or report. The new database specifically provides information on PMA summary review memos for 180-day design changes.

The database is part of the CDRH Transparency Initiative, a pilot program launched by the FDA. Updates to the database will occur every Sunday, according to the agency.

Markets: USATags: CDRH, FDA, medical device, PMA, premarket approval

Author: Stewart EisenhartDate: November 1, 2011

FDA Plans Reclassifying External Pacemaker Pulse Generators to Class II

The US Food and Drug Administration may reclassify external pacemaker pulse generators from Class III to Class II, contending that the 510(k) premarket notification process is sufficient to address risks associated with these devices.

External pacemaker pulse generators serve as temporary substitutes for cardiac pacing systems prior to implanting permanent pacemakers in patients as well as for controlling irregular heartbeats. The FDA has issued Class II special controls guidance specifically for devices with product code DTE. The guidance does not cover devices indicated for use in cardiac resynchronization therapy, pacemaker electrode function testers or temporary pacemaker electrodes.

The guidance lists several special controls that, if reclassification of external pacemaker pulse generators goes into effect, would have to be followed by manufacturers as part of their 510(k) review process. These include pre-510(k) risk analysis, through device description and software validation.

Devices should also be evaluated for electrical safety according to FDA-recognized standards such as IEC 60601, as well as for electromagnetic compatibility in terms of both emissions and immunity. Performance testing and labeling instructions are also included.

Importantly, clinical studies will not be required for most new external pacemaker pulse generators if their Class II designation is finalized. FDA reviewers may require clinical study data, however, for devices with new features; new technology; different indications for use; or for questionable results from bench or animal testing.

Markets: USATags: 510(k), External pacemaker pulse generator, FDA, IEC 60601, premarket approval, premarket notification

Author: Stewart EisenhartDate: October 18, 2011

FDA Panel: ECT Devices Require Further Testing

The US Food and Drug Administration’s Neurological Devices Advisory Committee came out last week in support of further testing of devices used in electroconvulsive therapy (ECT).

ECT devices used in perennially controversial “shock therapy” would retain their Class III status based on the 18-member committee’s recommendations, but also submit to expensive and data-intensive premarket approvals (PMAs); such products had heretofore not had to undergo PMA submissions, and new ECT products have been cleared via the FDA 510(k) process, according to MedPage Today and The Washington Post.

Prompted by the Government Accountability Office (GAO) in 2009 to address Class III high-risk devices being cleared through the less stringent 510(k) process, the FDA is now considering whether to move ECT products into the Class II category—a move favored obviously by ECT device manufacturers as well as some mental health professionals advocating ECT as a viable option for disorders such as severe depression—or keep them categorized as Class III and require PMAs for both existing and new products. If the latter approach is taken, as it probably will, ECT device manufacturers will have to provide clinical evidence demonstrating their wares’ safety and efficacy, potentially via new clinical studies.

The FDA recently deliberated similar issues with automatic external defibrillator devices, and appears poised to begin requiring more in-depth testing of those products, as well, indicating that the regulator is making good on the Class III-related recommendations it received from the GAO in 2009.