Medical Device Link.

REGULATIONS AND STANDARDS

Thomas M. Tsakeris is president of Devices and Diagnostic Consulting Group Inc. (Rockville, MD) and a member of IVD Technology’s editorial advisory board. He can be reached at ddcgi@comcast.net.

Four years ago, IVD Technology magazine published a series of articles on managing premarket approvals (PMA) for IVDs.^1–3 As an update, this article describes how to manage postmarket PMA activities involving additional FDA approvals for product modifications following initial PMAs, and managing postmarket clinical studies if they are required as a condition for granting a PMA.

IVD Product Modifications

Given the competitive nature of the IVD market, the shelf life of new IVD products can be short. Accordingly, IVD manufacturers are compelled to continually update and improve their product portfolios to stay competitive. This is particularly challenging for small IVD companies with limited financial resources and for small start-ups launching their first IVDs.

FDA requires all validation testing to be performed on the commercial version of an IVD product. Given the considerable cost of time and capital needed to secure a PMA, IVD sponsors must be able to recover such costs quickly following market introduction of their products if they want to be self-sustaining. However, the reality for most IVD companies is that the product represented in a PMA may not be preferred for market introduction because additional modifications and enhancements will be ongoing while the PMA is being processed at FDA. On average, PMA processing time at FDA takes about one year from the filing date. By the time the product’s PMA is finalized, a newer, more marketable assay may be developed, and must be returned to FDA for a follow-up review as a PMA supplement application.

PMA Supplement Process

In March, FDA issued a new draft guidance regarding the PMA supplement process.⁴ That detailed guidance covers topics such as when to submit a PMA supplement, the types of supplements corresponding to the types of product modifications with examples, and the information and formatting required for each application. This article reviews aspects of the guidance of particular interest to IVD sponsors of PMAs.

Types of PMA Supplement Submissions

FDA has identified six types of PMA supplement submissions: an original PMA, a panel track supplement, a 180-day supplement, a real-time supplement, a special supplement, and a 30-day and 135-day notice supplement.

Original PMA. The criterion that FDA applies to determine the type of PMA supplement required is based on whether the preclinical (or analytical validation) data and clinical data submitted for the original PMA can support the IVD product modifications. If the design and indications for use of the modified IVD product cannot be supported by the original PMA data, a brand new PMA will be required. An IVD example in the guidance is a new prostate specific antigen (PSA) test that involves a new analyte (free serum PSA), a new indication for use (differentiates prostate cancer from benign prostate disease), and a more selective patient population (defined PSA levels and specific digital rectal exam results).

Panel Track Supplements. A panel track supplement is required when the IVD product modifications involve a substantial new indication or condition for use that relates to a new disease or patient population, thus requiring new clinical data. One IVD example in the guidance is a glucose monitoring device intended for pediatric use in which only new clinical data would be required, but not preclinical data. A panel track supplement may require a formal review of the clinical data by an FDA advisory panel but may not require another FDA audit of the manufacturing facilities. However, FDA will still likely perform a good clinical practices (GCP) or bioresearch monitoring (BIMO) audit of the clinical test sites.

180-Day Supplements. A 180-day supplement is the most commonly submitted supplement and is required when IVD product changes are limited to those that affect the device’s principle of operation, the control mechanism, product design or performance specifications, labeling (but not significant changes in the indications for use), and new testing requirements or acceptance criteria. An IVD example in the guidance relates to a significant change in an instrument analyzer for a PSA test in which new analytical data were required, but not clinical validation data.

Real-Time Supplements. Real-time supplements are used for minor changes to the IVD product design, labeling, or software. The real-time feature of this PMA supplement provides that PMA sponsors and FDA should meet face-to-face to review the data supporting the supplement.⁵ The following criteria are applied to determine eligibility for real-time supplement status:

• An accepted test method, or an FDA-recognized standard or guidance document can address the safety or effectiveness of the change.
• The change is adequately supported by bench or animal testing, with no new clinical data needed.
• An inspection of the manufacturing facility is not required.
• A review of the application would involve a single scientific discipline, and it would not be subject to a multidisciplinary review.
• The review may be achieved in a real-time setting.

Although no specific IVD example is given, a real-time supplement could apply to an assay in which there is a change in storage temperature for a test kit containing a labile reagent.

Special Supplements. A special supplement is intended for certain labeling and manufacturing changes that enhance the safety of the device itself or in its use. IVD manufacturers may initiate such changes prior to FDA approval of the supplement under the following conditions: the manufacturer has newly acquired safetyrelated information; the information in question was not previously considered by FDA; and valid scientific evidence exists for the modification. Moreover, FDA requires a special supplement to include the following information:

• The supplement and its mailing cover are plainly marked “Special PMA Supplement—Changes Being Effected.”
• A full explanation of the basis for the changes.
• Acknowledgment from FDA of receipt of the supplement.
• The date that such changes are being effected.

FDA advises that any change being effected under a special supplement should be considered temporary until it either approves the supplement or determines that a 180-day supplement should be filed instead. Any changes must also have a sound scientific basis rather than be made merely to avoid liability under state tort law. In addition, FDA expects that most special supplements will address labeling issues or minor manufacturing changes related to process controls. In fact, most manufacturing changes should be more appropriately considered under the 30-day notice supplement.

30-Day and 135-Day Notice Supplements. The 30-day notice supplement is similar to the special supplements with two important exceptions: the 30-day notice is limited to manufacturing changes only, and the product can only be distributed 30 days after filing the supplement with FDA. However, after reviewing the 30-day notice supplement, if FDA determines that additional information is required, the 30-day notice may be converted to a 135-day notice supplement, and the manufacturing changes cannot be made before FDA approval. PMA sponsors should consult the FDA guidances for 30-day and 135-day notice supplements before filing them.⁶ For example, a 30-day notice involves information related to qualifying a new supplier of primary test reagents.

PMA Annual Reports

Although not the same as PMA supplements, IVD manufacturers are required to submit PMA annual reports to FDA for each PMA device.⁷ In general, any changes or modifications to the device, its manufacturing, or its labeling, including those that were the subject of PMA supplements or reports required for PMA postapproval studies, should be identified and summarized in the annual report unless FDA advises to submit the postapproval reports separately. Such annual reports should include information regarding any changes made to the device as a result of complaints, recalls, and adverse-event reports, or as part of any corrective action taken. Any risk analyses performed to support device changes should also be summarized in the annual report.

Postapproval Studies

As part of the initial PMA review, FDA may determine that postapproval studies are necessary to demonstrate an IVD product’s safety and effectiveness over a longer period of time if such cannot be established from the clinical studies submitted for the initial PMA. For example, a novel test for a biomarker associated with a particular disease or condition may also be reactive for other related but very rare and slowly developing diseases that do not occur frequently enough to be adequately studied in a reasonable period of time (e.g., certain neurodegenerative diseases). In such instances, FDA may require PMA sponsors to design and execute postapproval studies to evaluate longer-term test performance in patients undergoing differential diagnosis and how the test performs if and when such other conditions occur.

In the vast majority of cases, the decision to require postapproval studies is determined based on a review of the PMA application by an outside FDA advisory panel as a recommended condition for granting a PMA. Prior to final approval of the original PMA, the PMA sponsor and FDA are required to agree to a postapproval study design and establish periodic data analysis and reporting requirements in follow-up submissions to FDA.

In the past, most PMA sponsors were receptive to performing postapproval studies given the critical nature of obtaining initial FDA approval to market their tests. Moreover, FDA had a spotty track record in enforcing the completion of postapproval studies. However, in 2005, FDA conducted a meticulous internal review of its postmarket processing practices and discovered many serious shortcomings. As part of a corrective action plan, FDA has undertaken several decisive steps to tighten its management control over required postapproval studies. Some of the salient FDA initiatives include the following:

• Setting up a separate postmarket staff in the Office of Surveillance and Biometrics (OSB) at the Center for Devices and Radiological Health (CDRH), which deploys a new electronic system for monitoring and tracking reported adverse events that may occur during postapproval studies.
• Discussing the status of ongoing studies at the postapproval staff members advisory panel meetings and provide guidance to the panels regarding the criteria that should be applied in deciding the appropriateness for postapproval studies.
• Issuing an industry and staff guidance on procedures for administering postapproval PMA studies.⁸
• Setting up a publicly accessible Web page that provides a database of ongoing postapproval studies and their status.⁹

In short, FDA has gone to great lengths to ensure that postapproval study requirements are complied with and the studies are completed. Failure by PMA sponsors to comply with the postapproval study requirements could lead FDA to withdraw approval of the PMA or initiate a civil money penalties action if FDA believes that such failure to comply constitutes a significant public health risk.

Managing the Postapproval Study Process

The administration of postapproval studies has been transferred from CDRH’s Office of Device Evaluation (ODE) and Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) to OSB. This action has substantial implications for IVD sponsors since up to this point the PMA process has been primarily administered by OIVD, whose review staff had intimate knowledge of a PMA’s contents and where salient review issues arise. While OSB staff statisticians and epidemiologists have significantly contributed to PMA reviews, their role was consultative, and nearly all interactions with PMA sponsors were through or cleared by OIVD. However, in the postapproval study process, the offices’ responsibilities have been switched, with OSB taking the lead and OIVD’s role being consultative.

While theoretically this division of administration between the preapproval and postapproval processes should be seamless, the reality for IVD sponsors of PMAs is that the two processes are far from transparent. PMA sponsors will have to establish a working rapport with a new team of OSB staff who may not be as knowledgeable as the OIVD review staff about specific technical and clinical issues related to a given IVD device’s safety and effectiveness. If not carefully managed, this situation can sometimes lead to postapproval study deliberations marked by an emergence of study design elements intended to address new safety and effectiveness issues that either were not raised during the initial PMA review (including panel deliberations) or are tangentially related. The risk to IVD sponsors of PMAs may be having to agree to postapproval studies that could be more onerous than the one required to secure initial approval.

Since safety and effectiveness issues that require postapproval studies are raised during panel deliberations, IVD manufacturers should start managing the postapproval process during the late phase of the panel meetings. In these meetings, individual panel members respond to FDA’s request to identify any conditions to their recommendations for approving a PMA by suggesting additional studies the IVD sponsors should perform. FDA attempts to provide guidance to the panel by stressing the need to differentiate between preapproval and postapproval safety and effectiveness considerations that require additional studies. Nevertheless, panel recommendations may sometimes be general, vague, or otherwise lack specificity, with the panel preferring FDA staff and the PMA sponsors to work out the details. However, if it is not clear to the IVD sponsors of PMAs exactly what specific safety and effectiveness issues are being identified for postapproval studies or, more importantly, if the issues identified are being raised for the first time or were not specifically discussed during the preceding panel deliberations, they should request clarification from FDA and the panel.

The next step is to begin drafting a postapproval study protocol while holding postpanel meeting discussions with FDA staff. It is imperative to discern as quickly as possible what the salient questions are that the postapproval studies are intended to address. Accordingly, PMA sponsors should set up a meeting with FDA at the earliest opportunity and engage in collaborative discussions toward defining the design elements of the postapproval studies. Final approval of a PMA application cannot occur until FDA agrees on what type of study it will accept.

Conclusion

For IVD companies that must file for a PMA, the postapproval process can be as complex and challenging as the preapproval process discussed in previous IVD Technology articles. Fortunately, the overwhelming majority of new IVD devices are evaluated by FDA via the 510(k) process since the agency recognizes that only the highest-risk IVDs should be subject to the PMA process. However, if a company’s device happens to be one of the approximately 1% of new IVDs subject to the PMA process, careful planning will be required to make the return on investment of cost and time to manage the process worthwhile.

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