March 30 , 2006

In This Issue . . .

Using Leftover Specimens for Diagnostic Clinical Trials
FDA looking at exceptions to informed consent regulations
Julie L McDowell

In January, the Food and Drug Administration (FDA) announced plans to develop a draft guidance on using leftover specimens to conduct clinical studies necessary to bring in vitro diagnostic (IVD) devices through the regulatory approval process. News of the planned guidance is receiving a warm reception in the clinical laboratory community, where restrictions on using these specimens have been blamed for hindering diagnostic research and development. This issue of Strategies examines the subject of informed consent involving leftover specimens, and what these potential regulatory changes mean for clinical laboratorians.

Under federal law, scientists who want to use human subjects in their research must first seek the approval of an Institutional Review Board (IRB) and obtain informed consent from the study participants. Furthermore, under FDA regulations, the definition of human subjects includes individuals on whose specimens an investigational device is used. As a result of both this law and regulation, there are FDA requirements in place indicating that consent is needed to use human samples in any type of clinical study, even if the subject will be neither harmed nor helped by the study, according to Steven Gutman, MD, Director of FDA's Office of In Vitro Diagnostic Device Evaluation and Safety, Center for Devices and Radiological Health (CDRH). An IRB is a review body established to ensure the safety of human subjects participating in biomedical or behavioral research.

In clinical studies of in vitro diagnostic tests, many laboratorians use leftover specimens or residual samples that are banked and will likely be discarded. While this practice avoids the additional expense of obtaining fresh specimens, following the letter of existing law, laboratorians could be cited by the FDA if they cannot show informed consent, shutting down programs in many labs that perform clinical trials for IVD manufacturers.

“Using leftover and banked residual specimens has been the heart's blood of research in the clinical diagnostic arena,” explained Carolyn Jones, JD, Associate Vice President for Technology and Regulatory Affairs for the Advanced Medical Technology Association (AdvaMed). “There are a lot of clinical researchers that have said that they will not do studies for companies if they need to show proof of informed consent,” said Jones. “Since this regulation has been in place, there has been a great deal of difficulty trying to get people involved in certain studies because of this regulation. At AdvaMed, we do not feel that these specimens are ‘patients', however, an FDA reading of its regulation implies that these specimens are patients and therefore fall under the FDA regulations for protection of human subjects.” AdvaMed has been pressing the FDA to deal with this issue, and the association would like to see that the agency adopt a policy similar to the Dept. of Health and Human Services (HHS), which does not consider leftover specimens as patient samples, making them exempt from informed consent requirements.

One of the arguments for informed consent is that it gives the FDA a way to verify data in a clinical study. Researchers need to confirm to the agency that they haven't fabricated their data; therefore, then the agency can trace the specimen back to a patient. “In order to make this confirmation, you have to be able to go back and look at patient records and the FDA is saying that in order for them to go back and look at these patient records, there has to be informed consent,” said Jones. “If that is the case, we would propose that there be some sort of ‘delinking” similar to what is required under HIPAA [the Health Insurance Portability and Accountability Act of 1996], although HIPAA delinkage still poses a problem somewhat for the diagnostic industry. Some information is needed in order to characterize the specimen.” HHS's HIPAA regulations enforce the privacy protections of medical information, including patient records.

Clinical laboratorians, many of whom conduct the clinical studies for the manufacturers, are also pleased that FDA is confronting this issue. “I think this is an absolutely terrific development in that we'll be able to use leftover samples,” said Robert H. Christenson, PhD, DABCC, FACB, Professor of Pathology and Medical and Research Technology, and Director, Rapid Response Laboratories at the University of Maryland School of Medicine in Baltimore . “Without the use of a real specimen matrix, tests cannot be properly validated, and in order to use the right matrix, the FDA has required informed consent. This process is very expensive, inconvenient, and introduces a bias. Consider, for example, if the patients were discharged from the hospital because they were not as ill or in a better (or worse) socioeconomic situation. Only the inpatients could be included in studies, and then there is a patient spectrum bias built in to the process that compromises the science. That FDA is reexamining this issue must be considered promising. Having said that, however, the devil is in the details and we don't know what the guidance looks like yet.”

Reducing Regulatory Barriers

The National Institutes of Health (NIH) also has a different understanding of patient samples, according to CDRH's Gutman. NIH has a detailed, risk-based approach to human subject research, which is explained in algorithms and flow charts as defined by the Institutes' Office of Human Research Protection ( ). “Under FDA law, the sample of a human subject is in essence a human subject; therefore, that sample, in order to be used, would require IRB and informed consent,” he explained. “But that requirement appears not to exist, at least in a parallel form, in the regulations and the guidance in place for NIH-directed research.”

Gutman acknowledges that these FDA regulations for leftover specimens is slowing down the research pipeline for diagnostics, and running counter to the agency's Critical Path Initiative (CPI), which is focused on speeding the path of new medical technologies from development to the marketplace by reducing barriers. “Perhaps requiring informed consent is not actually important if these specimens are legitimately delinked if there is no possibility of either helping or hurting the patient, and if they are going to be just thrown out,” he added. FDA has made the issue of this guidance document providing easier access to patient samples under well defined circumstances a high priority item and expects it to be published in the near future.

As the CPI projects move beyond the planning phase, it's clear that this leftover specimen issue needs to be resolved before the FDA regulatory process for diagnostics is going to improve. Last week, the agency released its initial listing of CPI priority research projects, and biomarker development and streamlining clinical trials ranked high on the list. If the leftover specimens regulation remains in place, it will adversely impact any efforts to speed up biomarker development, according to AdvaMed's Jones. “You don't have specific informed consent for the use of those specimens to develop a diagnostic,” she said. “There is a whole host of ways that this rigid application of informed consent will have on diagnostic test development.”

For more information:

Update on “Medically Unbelievable Edits”

The March 9th issue of Strategies highlighted the controversies surrounding the Centers for Medicare and Medicaid Services' (CMS) efforts to curb coding errors by denying reimbursement claims for “medically unbelievable edits” or MUEs. The comment period for the MUE codes was originally set for March 20, with the implementation date scheduled for July 1, although CMS had postponed that date. Last week, CMS announced the comment period would be extended by at least 60 days, and the implementation date will now be January 1, 2007.

Julie McDowell is the Editor of Strategies. She can be reached by email.

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