Originally Published IVD Technology June 2002
Regulations & Standards
New perspectives on informed consent in IVD clinical trials
Katie M. Smith
 |
|
Katie
M. Smith, PhD, is senior director for diagnostics clinical research and
regulatory affairs at Prometheus Laboratories Inc.
(San Diego). She is also a member of the IVD Technology editorial advisory board. She can be reached at ksmith@prometheus-labs.com. |
In recent times, the development and clinical investigation of IVDs employing nucleic acid detection technologies has necessitated a reexamination of the patient-risk and privacy issues related to informed consent. The emergence of nucleic acid detection technologies has spawned a number of highly specific and sensitive tests and methodologies, which are today most often used to assist in the rapid and accurate diagnosis of pathogen infection or for DNA or RNA sequence identification.
Perceived subject
risks can be generated by early detection of infectious disease using a nucleic
acid–based test because such a result may not be easily confirmed by other
lab tests or by clinical signs and symptoms, yet may be an accurate indicator
of the presence of a pathogen. Similarly, genetic identification testing or
genetic screening using nucleic acid detection technology may reveal a predisposition
to an inherited disease that may or may not have clinical manifestations within
a study subject's lifetime. In addition, the descendant of an individual
thus identified with disease-associated genes may run some risk of inheriting
those genes, which may or may not manifest disease in that person's lifetime.
While nucleic acid technologies are leading to potentially exciting medical advances in disease detection, such tests and technologies are also raising new issues for the subjects who provide biological samples, and for the clinical investigators who seek investigational review board (IRB) approval of IVD clinical trial protocols.
Using Stored
Specimens
One key issue for
study subjects, IRBs, and clinical investigators revolves around the fact that
many past IVD studies have been conducted using stored biological specimens.
After collecting and testing biological samples for an initial study in real
time, clinical study sites and investigators have commonly archived the specimens
for use in studies to be described or designed at a later time. With the sequencing
of the human genome still freshly completed, and the vast potential of human
genomics and proteomics still under eager exploration, such an archive of well-pedigreed
study specimens could be a valuable resource for use in validating newly developed
genetic tests as they enter the clinical development phase.
However, full clinical
validation of such genetic tests may require the gathering of prior clinical
and laboratory information about the study subject who provided the test sample,
necessitating an exploration of that individual's clinical history and
medical records. In today's environment, such a patient record review would
likely elicit concerns about patient (i.e., study subject) privacy.
As a result, it seems probable that newly designed studies involving the collection and storage of biological specimens for possible use in a later trial of a genetic test may be required to include more-stringent informed consent language. In this scenario, the informed consent would have to explicitly define a possible study risk brought about if the individual's specimen were used in a later trial to identify and validate disease-associated genes. Equally important, the informed consent form may need to offer the study subject an option to disallow the use of his or her sample in any or all future, yet-to-be-defined clinical studies—especially if those studies involve disease-associated gene identification.
Emerging views
and guidance from the U.S. Department of Health and Human Services (HHS), FDA,
and other government entities all lean in the direction of adding further requirements
for informed consent statements. The institutional intent of such enhanced requirements
is to further protect patient privacy and ensure greater definition of the risks
to potential study subjects—including the possible use of their biological
specimens in future studies—while also ensuring that important new medical
research continues through clinical trials.
Such recent pronouncements and subsequent discussions have led many in the IVD industry to express concern over the possible inadequacy of study subjects and samples for conducting timely and cost-effective clinical trials for future IVDs—especially those involving nucleic acid tests and technologies. The following sections examine this topic further by providing a summary of FDA, international, and HHS pronouncements related to the scope of informed consent and patient privacy.
FDA and International
Regulations
FDA regulations
on informed consent are intended to embody and further define the intent of
the Nuremberg Code, which addresses the safety and rights of human subjects
in clinical research.1,2 With only narrow exceptions, no subject may be enrolled
in a study unless he or she, or his or her legal representative, has had sufficient
opportunity to consider whether to participate in the trial, and gives informed
consent without coercion or undue influence.
Federal regulations
specify the content of informed consent statements, which must be approved by
each study site's IRB along with the study protocol. A recent IVD Technology
article has described the basic elements of informed consent in light of FDA
regulations.3 In addition to basic conceptual elements, an informed consent
statement is only sufficient when the potential study subject, or his or her
representative, can readily understand it. The use of simple, direct language
is of prime importance for informed consent statements.
In addition, the
informed consent statement must indicate that participation may involve risks
that cannot currently be foreseen; identify alternative forms of diagnosis or
treatment, as applicable; and describe the extent to which confidentiality of
subject records will be preserved. These latter provisions are especially important
in cases in which stored biological specimens obtained in an initial study may
be used in a later study involving nucleic acid–based or genetic testing,
and may therefore require a review of the study subject's records.
International regulations agree with those of FDA in stressing the importance of identifying risks to clinical trial subjects and obtaining their informed consent. In concordance with FDA, these regulations stipulate that obtaining subjects' voluntary consent is essential to the conduct of clinical trials.2,4,5
HHS and OHSR
Requirements for Informed Consent
Other U.S. government agencies offer directives that are even more specific on the subjects of privacy and patient risk. Some of the most recent directives constitute implementing regulations related to the Health Insurance Portability and Accountability Act of 1996 (HIPAA).6
Chief among these
new patient-privacy rules is the HHS regulation "Standards for Privacy
of Individually Identifiable Health Information," with which most covered
entities must comply by April 2003.7 The HIPAA privacy rule emphasizes not only
the need to protect subjects' privacy, but also to inform them about how
study data will be used.
The general thrust
of the HIPAA privacy rule is to impose strict limitations on the gathering and
use of health-related information about an individual. As originally published,
the rule would have required healthcare providers (including investigators)
having a direct relationship with patients (including study subjects) to obtain
consent to use and disclose protected health information for healthcare operations
(including future uses of stored biological samples). The original form of the
rule would also have permitted patients (and study subjects) to specify the
permitted uses of such data.
This March, HHS
relented somewhat in its stringency, proposing modifications to make the privacy
rule more workable for healthcare professionals and clinical researchers.8 The
original rule would have required researchers to provide a notice detailing
the study site's health information practices with every informed consent
statement. The consent statement would have had to reference the notice, and
would have been required to inform the subjects of their right to request restrictions
on how information about them might be used or disclosed.
Under the proposed
modifications, researchers are permitted to use a single form that combines
informed consent and notice of the study site's health information practices.
Study subjects are still required to provide informed consent for their participation
in the study, but need only authorize the use and disclosure of their personal
health information. In the case of nucleic acid testing, such information could
include data from the current study as well as any data associated with future
studies using the subject's stored biological samples.
These provisions
are consistent with the guidelines of the Office of Human Subjects Research
(OHSR), which regulates clinical research conducted by the intramural research
program of the National Institutes of Health (NIH). In its guidelines for the
preparation of clinical research protocols and informed consent statements,
OHSR stipulates that risks to subjects must be reasonable and balanced in relation
to anticipated benefits and to the importance of the knowledge gained from the
study. All precautions should be taken to respect subjects' privacy, and
informed consent statements should indicate that subjects' confidentiality
will be maintained.
OHSR has specifically identified a number of points that researchers should consider when preparing informed consent statements for subjects who provide biological materials to be stored for research.9 According to the OHSR guidance, such statements should thoroughly discuss the storage and intended short- and long-term use of the samples. If long-term use of samples is planned or contemplated, subjects should know whether they will be informed of the interim or final results of future studies, and whether study samples are likely to be shared among investigators.
Privacy and
Informed Consent Considerations in Genetic Testing
In the recent past
and foreseeable future, the use of stored samples for a new IVD clinical study
is a key issue driving informed consent statements to include new disclosures
that address study-subject risks and patient privacy. Unless the patient consent
form initially describes sample use in future studies—or the study sponsor
makes provisions to contact the original study subject and obtain a new informed
consent—study subjects and IRBs are likely to limit or even prohibit access
to archived or stored sample banks. This is particularly true for linked samples—biological
specimens that can be matched to the patient or donor through a review of that
person's medical record.
In a recent publication, the National Bioethics Advisory Commission (NBAC) addresses this issue by stressing that it is appropriate for researchers to ask study subjects for their consent to future use of their samples, and to be as explicit as possible about the nature of the future study or research.10 This guidance document further recommends that study subjects be given a variety of options to help them understand the nature of their consent to the future use of their specimens. Suggested options range from refusing use of their samples for future research to permitting use of the samples for any kind of future study.
Pressure on
Industry
Taken together,
such directives compiled by various government agencies are putting pressure
on the IVD industry in relation to the continued use of stored specimens for
IVD clinical trials. IVD manufacturers seeking to conduct such trials as efficiently
as possible are faced with several specific concerns, including the reluctance
of individuals to become study subjects, the cost and duration of IVD clinical
trials, and industry incentive to continue developing new IVD markers or tests.
Reluctance of
Study Subjects. Informed consent documents that contain language added to
address the use of subjects' samples in future research projects or in
studies involving genetic testing may lead many potential subjects to decline
study participation.
According to the
preamble to the HIPAA privacy rule, lack of privacy protection for health information
has led many people to distrust genetic testing.7 The preamble states that more
than 85% of respondents in a 1995 national poll expressed concern that insurers
and employers might obtain and use genetic information. A total of 630 of the
1000 respondents in a 1997 survey indicated that they would not undergo genetic
tests if the results would be available to insurers and employers. And in studies
at NIH, 32% of eligible individuals who were offered a genetic test for breast
cancer risk did not consent to testing, saying they were concerned about loss
of privacy and possible health insurance discrimination.
Prospective study
subjects who worry that genetic test results might be made available without
their knowledge and used for nonmedical purposes may not consent to providing
samples for clinical studies evaluating nucleic acid tests. Consequently a key
element for IVD trials—the actual study subject—may become increasingly
scarce.
Study Cost and Duration. Potential study subject suspicions of genetic testing may lead to lower subject and sample accrual rates. Study sponsors may then need to recruit additional sites to achieve required subject accruals and accrual rates, or prolong study duration to obtain the number of subjects and biological samples required by the protocol.
In turn, the need
to include additional study sites could also drive up study costs. Even if each
study site is paid for its participation on an equal cost-per-patient basis,
each will have added administrative, investigator, and institutional overhead
fees that will increase total study costs in proportion to the number of sites.
In turn, if additional sites are needed to achieve a target patient accrual,
the cost of a prospective IVD clinical study could increase by 75–100%
over the cost of a study using stored specimens.
An additional impact
on the duration of a study may be realized when subjects or IRBs are unwilling
to consent to long-term storage and use of study subjects' biological samples—particularly
for investigations unspecified at the time of the initial study. In such a situation,
study sponsors may have no choice but to conduct prospective IVD clinical trials.
Again, such studies will be more expensive and much more time-consuming than
trials using stored specimens and retrospective data analysis, since each new
study will require enrolling new subjects and collecting new samples in real
time.
Incentives to Develop New Tests. The measures described above could result in some IVD clinical trials requiring time and resources commensurate with trials of therapeutic devices or pharmaceuticals—and well beyond the means of most IVD companies. Making the clinical trials process more cumbersome and potentially more costly would almost certainly slow the emergence of important new diagnostic tests from all IVD companies, regardless of their size or history in the medical device marketplace. Such changes could have an even harsher effect on small IVD companies, at least discouraging them from pursuing certain types of new test development, but making it especially undesirable for them to take a new IVD test—especially a genetic test—into a possibly protracted and costly clinical trial development program.
Informed Consent for Nucleic Acid–Based IVD Trials
It is reasonable
that study subjects be provided with detailed information about the risks associated
with their participation in an IVD clinical trial. And it is just as important
that explicit language in the informed consent document address the inclusion
of IVD genetic tests among current or future studies.
The informed consent
process must provide the study subject with full and precise information about
nucleic acid–based genetic tests and test results, the use of study specimens
or leftover specimen aliquots in future studies of known or unknown intent,
and the study site's health information practices. The use of study specimens
should be specifically defined as including the gathering of information from
subject records required to support studies conducted with materials left over
from the initial sample collection.11
The inspection
of study records by representatives of the study sponsor or FDA should also
be explained. Subjects should receive a description of the means of disclosing
study data, including publications, entry in medical records, or transmission
from the investigator to other physicians.9 Ensuring that a subject's genetic
test results will not be disclosed to any insurance company is critical to bolstering
an individual's confidence to join as a clinical study participant.
IVD study sponsors
should include these recommended items as part of their clinical trial planning,
and should discuss them thoroughly with prospective investigators. Study investigators
should take the time to educate the IRB chair and members on the value of stored
specimens to support the development of new IVD studies. Clinical trial investigators
and IRB chairs should ensure that their institutions have a clear policy that
supports the use of stored samples in IVD clinical trials and disallows poststudy
destruction of leftover specimens—even when their immediate use is not
evident.
Finally, IRBs should exercise some foresight by instituting an annual review of their informed consent forms, offering past patients an opportunity to sign an updated informed consent that would permit their specimens to be part of a new, future clinical trial. Such a practice would ensure that prospective study subjects have a chance to reconsider the risks and benefits of allowing their previously collected specimens to be used in future investigations, the nature and goals of which may be unknown.
Conclusion
The IVD industry
should play an active role in developing new informed consent language to address
study-subject risks and concern for patient privacy. In doing so, IVD manufacturers
should seek to ensure that industry-sponsored IVD trials are not delayed or
financially burdened unduly because of intimidating informed consent language
or the elimination of storable study specimens for current or future IVD studies.
As the primary
sponsor of IVD clinical studies, the IVD industry should actively deal with
current issues surrounding informed consent content in order to minimize concerns
that have been expressed by government agencies and study subjects. Such industry
efforts should be directed toward reducing public fears surrounding the unknown
impact of new genetic tests, and concern over the potential for test information
to be leaked from clinical study sites, while continuing to manage patient-risk
and privacy issues.
Adoption of such
recommendations will improve the overall protection of subjects and institutions
participating in nucleic acid–based IVD studies, and will facilitate the
timely and cost-effective conduct of those studies by IVD manufacturers.
References
1. "Protection of Human Subjects," Code of Federal Regulations, 21 CFR 50 (revised April 1, 2000).
2. "The Nuremberg Code," in Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, vol. 2 (Washington, DC: U.S. Government Printing Office, 1949), 181–182.
3. JN Gibbs, "Informed Consent for IVD Studies: The Manufacturer's Role," IVD Technology 7, no. 9 (2001): 22–25.
4. Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects (Helsinki, Finland: World Medical Association, 1964; rev. ed. 1989).
5. Guideline for Good Clinical Practice (Geneva: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2000).
6. Health Insurance Portability and Accountability Act of 1996, PL 104-191 (August 21, 1996).
7. "Standards for Privacy of Individually Identifiable Health Information; Final Rule," Code of Federal Regulations, 45 CFR 160 and 164; Federal Register, 65 FR 250: 82462–82829 (December 28, 2000).
8. "Standards for Privacy of Individually Identifiable Health Information; Proposed Rule, Modification," Code of Federal Regulations, 45 CFR 160 and 164; Federal Register, 67 FR 59:14776–14815 (March 27, 2002).
9. "Points to Consider in Development of Informed Consent Documents That Include the Collection and Research Use of Human Biological Materials," information sheet 15 (Bethesda, MD: Office of Human Subjects Research, National Institutes of Health, 2000).
10. Biological Materials: Ethical Issues and Policy Guidance, vol. I (Washington, DC: National Bioethics Advisory Commission, 1999), i–viii.
11. FA Sedor, American Association for Clinical Chemistry. Correspondence to V. Sellman, Chief, Program Enforcement Branch II, Division of Bioresearch Monitoring, Office of Compliance, Center for Devices and Radiological Health, Food and Drug Administration, October 12, 2000.
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