On November 29, 2017, CDRH issued two draft guidances regarding CLIA Waiver requests: “Select Updates for Recommendations for Clinical Laboratory Improvement Amendments of 1998 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices” (CLIA Waiver Guidance) and “Recommendations for Dual 510(k) and CLIA Waiver by Application Studies” (Dual Submission Guidance). These guidances can be found here and here, respectively. These guidances are based, in part, on Section 3057 of the 21st Century Cures Act (the Cures Act) and MDUFA IV Commitment Letter.
The Cures Act required that FDA allow manufacturers of in vitro diagnostic devices submitting CLIA waiver by application requests to demonstrate accuracy through comparable performance between a waived user and a moderately complex laboratory user. This approach replaces the requirement to demonstrate accuracy based upon a gold standard. The Cures Act required the Agency to revise its guidance on CLIA waiver by application requests within one year of the statute becoming law. The CLIA Waiver Guidance incorporates this statutory change. Once finalized, this guidance will replace Section V of FDA’s 2008 Guidance “Recommendations for Clinical Laboratory Improvement Amendments of 1998 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices.”
The CLIA Waiver Guidance provides significant detail regarding considerations for studies to demonstrate Accuracy. The guidance provides specific study design, results reporting, and statistical guidance for qualitative, quantitative, and semi-quantitative tests. The guidance also provides general design considerations regarding testing sites, study participants, subjects/samples, financial disclosures, and clinical study reports. FDA suggests providing the following details in these clinical study reports.
- Protocol description;
- Number of subjects (i.e., patients) studied
- Procedures for subject inclusion and exclusion
- Description of the subject population
- Description of how specimens were collected and stored
- Masking techniques
- Complaints, device failures, and replacements
- Any invalid results and how these were handled
- Information about QC procedures that were performed by untrained operators
- Pertinent tabulations
- Annotated line listings of results (including electronic versions
- Clear descriptions and presentations of the statistical analyses
- An explanation for data that are incomplete or missing (Note: You should not remove “outliers”)
You should also report the following for each untrained operator:
- Total number of performed candidate tests
- Number of initial invalid results
- Number of retested results
- Number of final invalid results
The document further states, “You should calculate and report the percentage of initial and final (if applicable) invalid results with a 95% two-sided confidence interval and then exclude invalid results from calculations of the test performance characteristics. You should provide a rationale as to why the observed percentage of invalid results is clinically acceptable.”
These topics appear to be generally applicable to all IVD clinical study reports, not just CLIA Waiver by Application requests. Manufacturers should consider including these topics in other IVD clinical study reports. It is also worth noting that the last four bullets (details for each untrained operators) and requirement for analysis of invalid results are new requirements that were not included in Section V of the 2008 guidance.
The Dual Submission Guidance is intended to aid manufacturers in designing clinical studies to meet the requirements for demonstrating substantial equivalence in a 510(k) and demonstrating that a device is sufficiently simple to meet the requirements for a CLIA waiver. The guidance provides specific recommendations for information in a dual 510(k) and CLIA waiver application, including:
- Device description, including determination that the device is “simple;”
- Risk analysis;
- Failure-alert and fail-safe mechanisms;
- Flex studies;
- Analytical studies, including analytical sensitivity, measuring interval, analytical specificity, linearity, precision, carry-over, reagent stability, and sample stability;
- Comparison study;
- Reproducibility study; and
While this information generally aligns with the 510(k) requirements (e.g., analytical studies, device description, labeling), if a manufacturer simply follows FDA’s 510(k) Refuse-to-Accept (RTA) checklist, it would fail to fulfill all of these requirements. For example, the RTA checklist does not require submission of a risk analysis, failure-alerts and fail-safe mechanisms, or Flex studies. Therefore, manufacturers submitting this type of application should be aware of these additional requirements.
One of the negotiated terms of the MDUFA IV Commitment Letter requires that manufacturers notify FDA of its intent to submit a Dual 510(k) and CLIA Waiver by Application through the pre-submission process. This is a new requirement that manufacturers should ensure to follow. While most “requirements” in guidance documents are really only recommendations, this was a negotiated term of the user fee commitment, and therefore a company would disregard it at its own peril.
We suspect that nearly all applicants will make a pre-submission prior to such a submission, regardless of this requirement, because the guidance lacks specificity with regard to certain study elements. For example, the guidance says that actual patient samples “provide the best assessment of a device.” However, the guidance also says that “in certain situations” alternative samples types might be appropriate (e.g., for rare samples). Similarly for tests intended for both waived and non-waived point-of-care (POC) sites, if the waived users group does not adequately represent the non-waived POC sites, FDA recommends including “one or a few POC non-waived sites” in the study. It is unclear from such an ambiguous statement whether one or more sites will be required to support a non-waived POC intended user group. Thus, we anticipate manufacturers will have questions regarding their study design if they choose to use alternative sample types or need to include non-waived sites (for example) on which it will want FDA’s feedback prior to executing a study to support a dual submission.
The Dual Submission Guidance includes the same clinical study report guidance as the CLIA Waiver Guidance. It also provides much of the same study design guidance as the CLIA Waiver Guidance. It appears, accordingly, that whether an applicant submits a dual application or a waiver by application request, the data requirements will be very similar.
The commitment letter also significantly reduced the review time goal for these applications from 210 days to 180 days. FDA updated its guidance “Administrative Procedures for CLIA Categorization” to update the MDUFA IVA negotiated review times for these applications (as well as CLIA waiver by application requests) in early October. We will be curious to see if the number of dual submissions increases in the future now that we have both updated guidance and shorter time frames.