The US Food and Drug Administration (FDA) on Friday released new draft guidance intended to help improve the quality, consistency and transparency of clinical data on the performance of devices for particular patients in various age, race and ethnic groups.
The 38-page draft document highlights three specific objectives:
1) To encourage the collection and consideration during the study design stage of relevant age, race, ethnicity and associated covariates (e.g., body size, biomarkers, bone density, etc.), for devices for which safety, effectiveness or benefit-risk profile is expected to vary;
2) To outline the types of analyses of study subgroup data that should be performed, with a framework for considering demographic data when interpreting overall outcomes; and
3) To specify FDA’s expectations for reporting age, race, and ethnicity-specific information in summaries and labeling of approved devices.
“In general, to achieve an unbiased estimate of treatment effect in the general population, sponsors should develop a strategy to enroll diverse populations including representative proportions of relevant age, race, and ethnicity subgroups, which are consistent with the intended use population of the device,” FDA says.
The draft guidance comes as Section 907 of the Food and Drug Administration Safety and Innovation Act (FDASIA) directed FDA to publish and provide to Congress a report describing how clinical trial participation and safety and effectiveness data varies across demographic subgroups, including sex, age, race and ethnicity.
In addition, FDA was directed to publish and provide to Congress an action plan with recommendations for improving the completeness and quality of analyses of data on demographic subgroups in summaries of product safety and effectiveness data and in labeling; on the inclusion of such data, or the lack of availability of such data, in labeling; and on improving the public availability of such data.
When finalized, this guidance will extend the policy set forth in the FDA’s Evaluation of Sex-Specific Data in Medical Device Clinical Studies Guidance to additional demographic subgroups of age, race and ethnicity. FDA intends to integrate the final content into one final guidance document, which, when finalized, will also extend and complement FDA’s Collection of Race and Ethnicity Data in Clinical Trials Guidance.
Why It’s Necessary
In a 2013 FDASIA report, FDA disclosed that of the 310 approved pre-market approval applications (PMAs) evaluated, only 40% publicly reported an age based analysis of outcomes data.
Similarly, only 27% of the studies reviewed contained a race or ethnicity subgroup analysis and only 16% had public statements regarding a race or ethnicity analysis.
In terms of age, FDA notes these findings are worrisome as the proper study of device use in both older and pediatric populations is important when the device is likely to be used for these subgroups.
“For example, the use of cochlear implants in certain pediatric subgroups may not be advisable due to the size of the implant, or may be inappropriate due to the stage of the neurological development of the child. In the case of intraocular lenses used to treat vision loss, device use may also improve future visual development in a young child,” FDA adds.
And as for race and ethnicity data for medical devices, FDA notes several devices where differences in effect were observed that were correlated with race and ethnicity, including “differences in skin structure and physiology can affect response to dermatologic and topically applied products. Mortality rates of patients on dialysis have been shown to differ across race and ethnicity groups.”
The main obstacles that lead to a lack of participation in trials among different age, race and ethnic groups in clinical research can include:
- Inclusion/exclusion criteria which unintentionally exclude different age, race, or ethnic groups (e.g., creatinine levels for African Americans);
- Lack of understanding about differences in disease etiology and pathophysiology may lead to under-diagnosis and under-referral of specific demographic subgroups;
- Patient concerns related to treatment group, randomization, possible side effects, privacy and historical mistrust of clinical trial ethics;
- Language, cultural, and health literacy gaps between investigators and patients;
- Investigator and sponsor avoidance of specific age, race, or ethnic groups of patients due to the perception that it is more difficult and potentially more expensive to recruit and maintain participation;
- Pressure on investigators to quickly enroll patients regardless of demographic characteristics;
- Perceived ethical concerns among investigators regarding enrollment of certain demographic groups in clinical trials;
- Trial logistics (e.g., transportation, childcare) may disproportionately affect specific age, race and ethnic groups’ ability to complete study follow-up visits;
- Disproportionate drop out and lost-to-follow-up rates.
Recommendations for Achieving Appropriate Enrollment
To understand potential age, race, and ethnicity differences relevant to a clinical evaluation of a device, FDA recommends sponsors identify and consider: age, race, and ethnicity-specific prevalence, if known; age, race, and ethnicity-specific diagnosis and treatment patterns, if known; proportions of age, race, and ethnicity subgroups included in past studies for the target indication, if known; and any known clinically meaningful age, race and ethnicity-specific differences in outcomes related to either safety or effectiveness (or probable benefit for humanitarian device exemptions (HDEs)).
If information demonstrating age, race and ethnicity differences in these areas is available, sponsors should include it in their study protocol and submission documents, FDA says.
Sponsors should also consider: Developing a follow-up plan with goals, frequency of upcoming scheduled follow-up visits, proxy contact information, and number and type of contacts for patients missing such a visit; Demonstrating continued interest in the subjects (e.g., send newsletter to participants to maintain interest); Monitoring follow-up rates closely; Reporting subject accountability data as part of the study report.
Intrinsic and extrinsic biological differences across age, race, and ethnic groups (e.g. gonad development, skin texture, skin color, hormone levels, metabolism, degenerative disease, bone density, cell receptors, etc.) exist that may influence the safety and effectiveness (or probable benefit for HDEs) of a device, FDA notes.
For example, FDA says that "ionizing radiation exposure to pediatric patients from medical imaging procedures is of particular concern because pediatric patients are more radiosensitive than adults (i.e., the cancer risk per unit dose of ionizing radiation is higher).
Additionally, age, race, and ethnicity may play a role in an individual’s interaction with his/her environment, which in turn could affect an individual’s health. For example, FDA notes that intermittent exposures to intense UV radiation (e.g., tanning beds) leading to sunburns, especially in childhood and teen years, increase the risk of melanoma.
Investigators also should consider participating in cultural competency training, counseling subjects about the importance of returning to follow-up during informed consent and follow-up visits; Reminding subjects of upcoming scheduled follow-up visits; Attempting to locate/return patients who miss scheduled clinic visits; Obtaining proxy information to use when unable to contact a study subject; Asking subjects who withdraw during the study to provide the reason for withdrawal and ask them whether the investigator may contact them once more at the end of the study follow-up to assess the experience with a device, FDA adds.
Study Design, Analysis and Interpretation of Study Results
"Due to the potential impact on safety and effectiveness (or probable benefit for HDEs), unless the investigational device is intended for use in only one age, race or ethnic group (e.g., neonatal devices), it is important that the variation in data across age, race, and ethnic groups be accounted for both in study design and analysis of results, as appropriate," FDA says.
If any clinically meaningful demographic subgroup differences are found, either based on pre-specified or exploratory post-hoc analyses, FDA says companies should discuss whether additional data are needed to address any remaining subgroup-specific questions: “You should describe how any clinically meaningful differences across subgroups may contribute to differences in benefit-risk profile in certain subpopulations.”
If results of an analysis suggest that there is insufficient data to assess whether age, race or ethnicity is associated with clinically meaningful differences in outcome, FDA says it may determine that clinical data from additional subjects in one or several of demographic subgroups may be needed pre- or postmarket to address potential questions related to safety or effectiveness in any or all of those subgroups.
And although it’s expected to be rare, in cases where clinically meaningful differences among the age, race, or ethnic groups are observed in safety or effectiveness, FDA may request additional confirmatory studies, implement specific pre- or post-approval study conditions and/or recommend modifications to the design of subsequent studies.
“FDA will consider such requests in the context of a benefit-risk framework. Sponsors should describe how any observed clinically meaningful differences across subgroups may affect overall benefit-risk profile in certain subpopulations,” the draft notes. “There are limitations to interpreting clinically meaningful differences in small data sets or in larger studies in which certain subgroups are underrepresented. Mean differences could exist among demographic subgroups due to small sample sizes, and interpretation about whether they are clinically meaningful may be premature in many cases. Alternatively, sample sizes may not be large enough to detect clinically meaningful differences in device safety or effectiveness (or probable benefit for HDEs). Consultation with FDA is recommended in these cases."
When there is a hypothesis for a clinically meaningful difference, FDA offers four decision trees provide a framework in deciding when various age-, race-, or ethnicity-specific statistical recommendations apply for different clinical study designs. Here are the two decision trees presented at the outset of the guidance: