IVD developers sometimes find it surprising that it is not enough to demonstrate the analytic validity of a test – the ability of the test to determine whether what it is designed to detect is present or absent. IVD developers may expect existing scientific knowledge and a series of informed inferences to connect the dots between the test result and a clinical outcome.
The reality is that regulatory approval and market success for an IVD intended to support treatment decisions very often do require demonstrating clinical utility by testing in the intended-use setting. FDA classifies such IVDs as Significant Risk devices and therefore requires evidence of clinical utility. Reimbursement for clinical use of a new IVD is far from automatic. Some reviews have questioned the adequacy of evidence for clinical utility of certain LDTs, including LDTs used for treatment decisions in oncology. In the absence of such evidence, reimbursement for tests is uncertain at best. The reimbursement environment is especially complex for some molecular diagnostics.
When a Retrospective Study Is Sufficient for Marketing Approval
To be sure, it may sometimes be possible to demonstrate the clinical performance of a new IVD with a retrospective study that takes advantage of banked samples. However, the requirements for a retrospective study to demonstrate clinical utility are substantial. Such a retrospective study will likely be acceptable to regulators only if all of the following conditions are met:
- Archived specimens are available that are representative of the intended-use population, including specimens representative of any known variability in the indication rather than just the most common cases.
- The specimens are drawn from a large enough population of subjects to reflect random sampling.
- There is adequate data on the clinical status of the patients who provided the archived samples.
- The archived samples are known to be stable enough over time to provide valid test results with the investigational IVD.
- It is possible to show that the sample collection process for the archived sample was unbiased or involved minimal bias.
Unless specimens are available that meet the requirements above, providing evidence that use of the IVD improves clinical outcomes will require a prospective trial. This means collecting samples in the intended-use setting and very likely collecting data on clinical outcomes. There may be a possibility that there is already such a well-established link between the test result and clinical outcomes that collecting additional outcomes data is not considered necessary. However, it is usually necessary for a trial to follow patients and collect outcomes data.
Advantages of a Prospective Trial to Demonstrate Clinical Utility
While a prospective trial involves greater effort and expense, it provides substantial value to the IVD developer. First, it presents an opportunity to develop a study design that provides strong evidence of clinical utility – evidence that healthcare payers are more likely to accept. IVD developers can work with partners who can design every aspect of the trial to provide the strongest possible evidence of clinical utility and address potential healthcare payer objections in the most cost-effective way. Healthcare payers will have fewer opportunities to question evidence of clinical utility as with a retrospective study, which by definition did not start out with the intention of collecting evidence in the intended use setting to demonstrate that the new IVD is safe and effective and will in fact support treatment decisions that lead to improved clinical outcomes in the intended-use population. Second, prospective IVD trials increase the likelihood that an IVD will generate revenue earlier and experience market success. Such trials also give IVD developers greater control over their fate.
For additional information on studies to demonstrate clinical utility, see the Global Harmonization Task Force publication, Clinical Performance Studies for IVD Medical Devices. A Health Decisions white paper, 10 Tips for Establishing the Clinical Utility of Molecular Diagnostics, may also assist IVD companies in identifying a successful pathway to approval and reimbursement for new products.