September 1, 2006 (Vol. 26, No. 15)

More Lenient Guidelines May Inadvertently Lead to a Scarcity of Consented Samples

Recently, no area has contributed more and increasingly complex layers to the bioethics debate than research employing human genetic material. One such layer involves the use of patient samples for in vitro diagnostic (IVD) device studies and informed consent requirements, as evidenced by a recent document issued by the FDA, entitled “Guidance on Informed Consent for In Vitro Diagnostic Device Using Leftover Human Specimens that Are Not Individually Identifiable.”

The FDA document suggests that informed consent requirements have “created confusion and difficulty for persons developing IVDs.” In an effort to eliminate unnecessary hurdles to medical product development, the FDA has announced that it will exercise enforcement discretion concerning the requirements for informed consent.

It is important to note that the U.S. demand for IVD products is estimated to grow 6.1% annually through 2009. According to a report published by The Freedonia Group, clinical chemistry and immunoassay will remain the top two IVD sciences, while nucleic acid products are expected to grow the fastest. This trend has led to a heightened demand for patient samples and, consequently, added new steam to the debate over the cost and difficulty of obtaining informed consent.

The informed consent process is widely considered a crucial component of any research study requiring patient samples. Its chief purposes are to inform subjects of any potential risks of participation and to explain how the investigator intends to use the sample, how long the sample will be kept, and what mechanisms will be employed to protect the subject’s personal information.

The new FDA guidance document contends that such concerns are adequately addressed by stripping leftover samples of any identifiers that might reveal their source. Leftover patient samples are defined as remnants of specimens that were collected for routine clinical testing. An area where leftover samples are especially useful is IVD device investigation of new nucleic acid products.

DNA in its purified form is very stable and not likely to degrade like most specimens used for routine clinical testing. Because IVD studies often require the use of specimens with specific laboratory characteristics, routine testing can provide information that allows investigators to quickly check whether the specimen will meet study inclusion criteria.

Ethical Concerns

The FDA document suggests that as long as these samples are not individually identifiable, obtaining informed consent from the subjects is not required. Despite the emphasis on anonymity, these guidelines obfuscate many of the other ethical implications of using leftover samples without obtaining informed consent.

While stripping identifiers may indeed be enough to insulate a subject’s personal information in some cases, there are a few noteworthy exceptions to this rule. One involves samples obtained from previous genetic-based research studies.

For instance, if an IVD study investigator were to obtain controls for a CYP2D6 genotyping assay (a gene encoding a well-known drug metabolism enzyme) from specimens left over from a cardiovascular drug trial, the probability of identifying the specimen’s source would be fairly high. Any participant who experienced adverse reactions to the cardiovascular drug would exhibit a specific mutation of their CYP2D6 gene, indicative of altered drug response. This genetic signature would reveal a great deal more about the sample source and could lead to indirect identification of the subject.

By allowing the use of patients’ DNA samples as controls in the research community without obtaining informed consent, the new FDA guidelines may inadvertently lead to a future scarcity of consented samples. As the general public becomes more aware of the many hidden purposes their samples are serving, they are likely to become more suspicious and less willing to collaborate in future studies. Learning of such activities is precisely what contributed to patients’ hesitation to allow free access to their genome in the first place.

Transparency is an extremely important benefit of informed consent. A 1995 national poll, cited in the preamble to the Health Insurance Portability and Accountability Act of 1996, revealed that 85% of respondents were concerned that employers and insurers might have access to their genetic information. Therefore, they were hesitant to engage in any form of genetic testing.

Bypassing the need for informed consent in an effort to facilitate access to leftover genetic material is likely to contribute to the public’s fear and mistrust.

Moreover, a key ethical issue has been overlooked. When a doctor asks a patient for a blood sample, there is an implied consent on the part of the patient to allow the doctor to use the sample for specific testing, such as a complete blood cell count (CBC). Because DNA is very stable, there is likely to be more material left than there would be with other clinical tests where the sample might be compromised or destroyed by the testing procedure.

Should the implied consent given by the patient to use his blood sample to perform a CBC be extrapolated to mean a consent to use his leftover DNA in an IVD study?

IVD sponsors often argue that the challenge of prospectively collecting consented specimens for research can be cost prohibitive. However, approximately 90% of the final cost of a leftover sample comes from the resources expended by the clinic to obtain, process, and ship the sample to the research sponsor. Ensuring that a sample is properly consented upfront would not significantly impact the price IVD sponsors pay for a sample.

One effective way of navigating the challenges of potentially collecting specimens that exhibit specific characteristics would be for pharmaceutical companies conducting drug trials to work in tandem with IVD investigators. Patients enrolled in clinical trials for new drugs that may require an IVD companion test would then be asked to consent to the use of their specimens for both purposes.

Another issue that arises from the use of leftover samples that were not consented is the fact that companies are deriving a commercial benefit from these specimens. While many believe the sample’s sole purpose is to further research that will lead to the development of a new medical device, the fact remains that any approved device will be sold for profit. One of the ways to address this matter would be to offer patients a stipend in exchange for the right to use their genetic material as part of the informed consent procedure.

The FDA’s new guidance document on informed consent for IVD studies using leftover human specimens will positively impact industry with regards to facilitating the development of new technologies. The document fails to address the instances in which study sponsors do have access to reliable and consistent commercial sources of DNA controls that were obtained with informed consent. Due to the many ethical issues that surround the use of leftover specimens, selecting alternative sample sources that have been procured with the proper informed consent should be a priority that guides both the FDA’s and sponsors’ decisions.

Michael Murphy is the president and CEO of Gentris. Web: E-mail: [email protected]. For more information regarding informed consent requirements for IVD trials:

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