January 1, 1996

11 Min Read

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published January 1996

David Casal

In recent years, the process of receiving approval from FDA to distribute a medical device commercially has become increasingly long and perilous. Review times for premarket notifications (510(k)s) and premarket approval (PMA) applications have lengthened dramatically, and FDA has not taken the steps (e.g., third-party review, major device reclassifications) necessary to slow or reverse this trend.

Although larger device manufacturers with more-established product lines can normally withstand the unpredictability of this regulatory process, the survival of start-up companies, particularly those with novel technologies, often hinges on how FDA reviews their products. Survival can be made easier, however, by developing a comprehensive strategy beforehand for dealing with the agency. This strategy should incorporate a set of guidelines focusing on the regulatory process; clinical trials, if they are necessary; and corporate expectations. Although the guidelines I lay out below reflect my background in the in vitro diagnostics (IVD) segment of the medical device industry, for the most part they apply to the entire industry.


There are two key factors in developing a regulatory strategy: the classification of the proposed device and the establishment of regulatory milestones.

Device Classification. A logical first step toward developing a regulatory strategy is determining the classification of the device, which ultimately dictates whether the submission will be in the form of a 510(k) or PMA. At one time, this decision was relatively simple and straightforward. The situation has changed, however, with the advent of FDA's tier system for 510(k)s. These range from tier I submissions, which involve fairly simple reviews of general-purpose devices, to the more rigorous and PMA-like tier III submissions, which are intended for unusual analytes or technologies.

Four issues weigh heavily in determining the classification of a device:

*Does the proposed device have a clear predicate?

*Is the proposed device intended for use in a high-profile disorder or one with significant public health implications?

*Does the intended use of the proposed device raise new safety and effectiveness issues?

*Will the device change the "standard of care"?

If there is no predicate device, the 510(k) route should not be taken simply because it appears more expedient or more attractive to investors and management. Choosing an inappropriate submission route only ends up costing more money and taking more time when the initial application is rejected and a more extensive 510(k) or a PMA has to be prepared. It may even damage a company's relationship with FDA. If the intended use of the proposed device involves a high-profile medical problem, promises to affect the public significantly, or raises new issues of safety and effectiveness-- especially if the device potentially changes the standard of care--then a PMA will most likely be required.

When a company is uncertain about whether to submit a PMA or a 510(k), it has several options. The first is to seek the advice of an attorney or consultant specializing in regulatory affairs. Armed with the facts about the device, about the manufacturer, and about the intended use, an experienced consultant can help develop an effective regulatory strategy, including an effective negotiating stance for interacting with FDA.

Another option is to contact FDA directly. The risk of this strategy has diminished in recent years and, in the current political and regulatory environment, FDA may be more willing to allow a tier III 510(k) review rather than a PMA, particularly if it is confident that the scientific review can be completed via the 510(k) process. A device manufacturer that chooses to contact FDA directly should have its strategy prepared beforehand. FDA will not recommend a strategy, but it will provide feedback to help develop one.

Regulatory Milestones. Once the classification issue has been resolved, regulatory milestones for completing the project should be set. The key is to be realistic and plan for likely outcomes. If the average review time for a PMA is 500 days, a company should not expect to be the exception to the rule. This is particularly true if the company is making its first major submission, since FDA reviewers will probably spend additional time becoming familiar with the company and the device.

It is also important to interact with FDA as soon as possible in the submission process, even as early as the pilot clinical trial phase. Such meetings not only make the agency a partner in the process, which can generate valuable feedback, but they also allow it to better understand the analytical and clinical nature of the device.

Another useful strategy-- particularly if the intended clinical use of the device is unique--is to organize a seminar for FDA, at which the submitting company's experts describe the device's technological characteristics and clinical utility.

Companies with novel devices that target significant public health problems should also consider asking FDA for an expedited PMA review. Over the last year, the agency's Division of Clinical Laboratory Devices has granted at least three such reviews for PMA applications in the areas of prematurity, breast cancer, and tuberculosis.

Finally, companies should prepare their submissions with care, making certain that all sections are complete and well written. It is essential to deliver what has been promised.


Establishing a sound clinical trial strategy is integral to developing an effective regulatory strategy, and consists of several key elements: the intended-use statement, the clinical trial design, and the clinical utility of the device.

Intended-Use Statement. The most critical portion of any regulatory submission is the intended-use statement. In a well-designed clinical trial, this statement, which reflects both the hypothesis to be tested and the end point of the study, must be established before the trial begins. The first questions an FDA reviewer will ask during the review process are: Is the clinical trial design adequate? Do the results support the intended-use statement? To have an application approved, the manufacturer must provide sound scientific evidence in support of the intended-use statement. If the results support the statement, FDA will continue the review. If the clinical support is equivocal, however, FDA will appropriately challenge the manufacturer. And if the results clearly do not support the statement, FDA will reject the submission.

Clinical Trial Design. In the past five years, FDA has placed increasing emphasis on the performance of more rigorous clinical evaluations, particularly for IVD devices. FDA has described many issues relating to the conduct of clinical trials and the collection of data in guidance documents, and the following list encapsulates some of the critical issues that are evaluated during the review process.1,2

*Clinical trials must be designed rationally using appropriate epidemiological methods. The study design must be suitable and a specific hypothesis must be tested.

*The trial must be prospectively conducted in a defined population of sufficient sample size to test the hypothesis. Keep in mind that a prospective trial can be conducted retrospectively by using samples that have been collected beforehand and then "banked." This is particularly useful for screening trials when the prevalence of the disorder is small, e.g., in the case of some cancers or neural tube defects.

*The primary and secondary outcomes associated with the device result must be established before the study is performed.

*The analysis must be planned. When possible, the data should be "blinded" until the study is completed.

*All elements of the trial should be described in the protocol, which is used by each of the trial sites. Using a single protocol is essential when conducting multicenter clinical trials because it allows data to be pooled from all sites.

While these requirements may sound somewhat daunting, they are relatively straightforward and can be easily achieved using some combination of internal resources and assistance from clinical investigators or a clinical research organization. Protocols for investigational IVD devices, which are not subject to review through the investigational device exemption process, should be reviewed informally by the appropriate FDA branch.

In planning and executing a clinical trial strategy, it is also imperative to have experienced individuals monitor the trial. This is necessary to ensure the accuracy and integrity of the data included in the submission, as well as to ensure the safety and rights of all human subjects participating in the trial. When a clinical site is audited, FDA investigators will cite any deficiencies they observe, including deviations from the protocol, inaccurate or incomplete patient information, and incomplete administrative documentation (e.g., institutional review board approvals, correspondence, protocol). Significant deficiencies may jeopardize a submission even if it has cleared other regulatory hurdles, so it is essential that clinical sites be monitored carefully. FDA has prepared a guideline that provides additional information regarding the elements of proper clinical trial monitoring.3

Clinical Utility. The term clinical utility encompasses a variety of issues concerning the device's relationship to the disease, patient management, and patient outcome. The clinical utility of a device is integral to FDA's evaluation of safety and effectiveness, and clearly establishing it should lead to acceptance not only from regulators, but from the medical and reimbursement communities as well.4 A good approach to defining clinical utility is to provide FDA with a clear definition of the medical problem or public health need addressed by the device. (This definition should be supported by references to medical literature.) Once it has a basic understanding of the medical problem, FDA will likely ask a number of questions related to the clinical utility of the device, such as:

* How does the device add to the existing armamentarium of diagnostic tools?

*How will physicians use the results to improve patient outcome (i.e., does the device change and improve the standard of care)?

*What are the risks associated with a false-positive or false- negative test result?

The clinical performance of the device must be well understood for these questions to be answered, and this may require the manufacturer to perform additional pilot clinical evaluations. Although this consumes additional time and money, it may save both in the long run. Moreover, information from these trials can provide the basis for articles in peer-reviewed publications. This can help promote FDA's understanding of the device's performance characteristics, which should in turn assist the review process.


As they formulate strategies and set goals, investors in and managers of device companies are devoting more attention than ever to clinical and regulatory requirements. As a result, the clinical and regulatory strategies being developed--particularly for novel devices--are increasingly sophisticated, expensive, and, oftentimes, risky. It is important that these strategies be realistic, and companies can ensure this by focusing on several areas related to regulatory issues.

For investors and managers to establish appropriate, realistic objectives, it is imperative that they understand the strengths, weaknesses, and likely outcomes of different regulatory strategies. In anticipation of the longer lead times to FDA approval now prevalent, strategic planning should accommodate increased investment in clinical and regulatory processes. It is easier to react to the good news of a shorter-than-expected regulatory review than to the bad news of an overly long one.

Forecasting the human and financial resources necessary for a particular regulatory submission is an important consideration. For unique devices, most manufacturers would be best served by having in-house experts manage the submission. For common devices with well-understood applications, a consultant or contract research organization might be a better alternative. The goal is to allocate resources to maximize the probability of regulatory approval.

To generate the revenues necessary to sustain a company through a potentially lengthy FDA review process, management may feel compelled to develop a strategy for marketing a new product offshore first. This is particularly tempting for companies that lack other commer- cially available products. If this route is pursued, management must understand what the likely outcomes will be under various regulatory strategies. It should also understand the regulatory processes in non-U.S. markets and become familiar with section 801(e) of the Federal Food, Drug, and Cosmetic Act, under which unapproved devices can be exported.

Management and investors must also realize that clinical trials in support of regulatory approval do not always satisfy marketing needs. A comprehensive clinical trial strategy should therefore generate data to support sales and marketing as well as regulatory affairs. To the extent that funding allows, clinical trials should be designed to encourage the development of other indications for the device. Customer awareness can be further increased by publishing peer- reviewed studies that support both the intended use and other potential indications.

Finally, it is essential that a company be aggressive in reporting regulatory progress to management and investors, regardless of the clinical strategy employed. A helpful tool is a timeline that describes milestones and anticipated dates of completion. The tracking system should also include monthly or even weekly progress reports. These do not need to be elaborate, complicated charts; even a simple tracking system can provide valuable information. Most important, the use of tracking instruments provides evidence of a well-managed, controlled process in which the manufacturer is accountable for all of the elements of the submission.


1."Medical Device Clinical Study Guidance," draft, Rockville, MD, FDA, Center for Devices and Radiological Health (CDRH), 1993.

2."Points to Consider for Collection of Data in Support of In Vitro Device Submissions for 510(k) Clearance," draft, Rockville, MD, FDA, CDRH, 1994.

3."Guidelines for the Monitoring of Clinical Investigations," Rockville, MD, FDA, CDRH, 1988.

4."Clinical Utility and Premarket Approval," Rockville, MD, FDA, CDRH, Office of Device Evaluation, 1991.

David Casal is vice president for clinical and regulatory affairs at Adeza Biomedical (Sunnyvale, CA).

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