Access to human biologic material is essential for biomedical research and discovery. Rapidly expanding research in the human genome, gene therapy, AIDS, stem cells, cloning and other areas have sensitized the public to the benefits and risks of participating in biomedical research in general and to tissue repositories or banks in particular. There is a consensus that the major risk in using human tissues and cells is the harm that can occur when private information about present or future health is revealed. It is therefore necessary to develop a system of protections to ensure that risks are minimized and the interests of sample sources protected. The President’s National Bioethics Advisory Commission (NBAC) was appointed to review the practices and policies regarding use of human biologic material in research and to make recommendations for improvement. Recommendations for policy on the use of human biologic material for research were published in August, 1999. The CHS, as outlined below, will review proposed studies involving collection and storage of human biologic material in accordance with these standards.
Before human biologic material may be used by UH affiliated investigators for research purposes, researchers must submit an application to the CHS; or they must request, in writing, an exemption from CHS IRB review and oversight. Deviations from the guidelines will be considered by CHS on a protocol-by-protocol basis. Genetic testing research protocols do not qualify for Expedited Review.
A repository is a common site for storage of collections of human biologic specimens available for study. This may be one geographic location or may be a virtual aggregation of biologic specimens from many locations. Repositories are also referred to as tissue banks, collections, resources, inventories, or by other terms.
When used with reference to a human biological repository, specimen refers to the quantity of material stored in the repository, whereas the term sample refers to an aliquot of the specimen supplied to investigators.
In the context of this policy, a sample refers to any human biological material. This includes, but is not limited to, molecular material such as DNA, cells, tissues (blood, bone, muscle, etc.), organs (liver, bladder, heart, etc.), gametes, embryos, fetal tissue, waste (hair, nail clippings, urine, feces, etc.) and other materials of human origin.
Four levels of identification of research samples are recognized. These are differentiated by the amount of information that is available about the subject from whom the sample was obtained. The levels include
1. Unidentified Samples (Anonymous): These samples are/were obtained and stored without any identification that may link the specimen to a specific individual.
3. Coded Samples: Coded samples are those from which the source of the specimen can be identified by reference to a code rather than a name or other personal identifier. When such samples are obtained from a tissue repository, the repository retains information linking the code to a particular human specimen. Information is sufficient such that the investigator, repository or third party could link the biological sample or information derived from the research using the sample with a particular person or small group of identifiable individuals.
4. Identified Samples: These samples are collected or supplied to investigators with personal identifiers sufficient to allow identification of the donor of the material.
Identifiers are information that can be used to link a sample or scientific result with a specific person or group of people. Examples of identifiers include name, social security number, hospital number or other unique identifier. It should also be noted that using current information technology, a combination of descriptive data may be sufficient to allow identification of the donor and thereby collectively may be considered identifiers (e.g., zip code, birth date or profession may be sufficient to identify a specific individual).
There are two conditions under which use of human biologic material for research becomes an IRB issue: retrospective use of previously stored tissue and prospective studies requesting the use or storage of tissue for current and/or future research. Similarly, there are two categories of specimens: those obtained initially for clinical diagnostic purposes only, and those obtained for research purposes. In all cases, a protocol describing the proposed research use of the specimens must be submitted to and approved by the CHS before the tissue is used.
Retrospective studies of already stored specimens must obtain IRB approval. The level of review and issues of informed consent may depend on the following:
a. If samples are to be used anonymously (without linkage to subject identifiers), an investigator may request an Exemption from full board review of a research protocol (see §3.1);
b. If samples can be linked to identifiers either by the principal investigator or a third party, then such protocols will require full board review or may be Expedited (see §3.2). Depending on the nature of the protocol, the investigator may be required to obtain informed consent from the subjects for the new use.
If prospectively collected specimens are to be used for research purposes that are described in a current protocol, then the protocol must have CHS approval before they are collected and used. Some studies may qualify for Expedited review (see §3.2) but most will require full board review. If the PI plans to store specimens from this protocol for future research use, the use must be specified and justified and be included in the consent form. If the future use cannot be specified, or is significantly different from the original plan, then the specimens’ use in future protocols must be approved by the IRB before the specimens are used. The PI may be required to re-contact all of the subjects before their specimens can be used in this or any subsequent study.
If prospectively collected specimens obtained for clinical or diagnostic purposes are to be used for research purposes, then the specimens’ use in future protocols must be approved by the CHS before the specimens are used. Biological waste and left over specimens are included in this category. None of these studies will qualify for Exempt status, but will require either Expedited or full board review. Depending on the nature of the protocol, the investigator may be required to obtain informed consent from the patients for the new use.
1. Justification for Research Design:
Indicate the importance of the research and the rationale for the testing. Indicate the general nature of tests that will be done on the samples. Identify any significant risks to the subject incurred by the testing. Physiological harm during sample procurement is considered as a risk. However, other risks may be more important. These include psychological, social or fiscal risks to the donor. Consideration must be given to the risks to individual dignity, invasion of privacy, violation of confidentiality, stigmatization of a subject or group, discrimination in insurance or employment, psychological harm, generation of conflict within a family, harm to relatives, inappropriate commercialization of findings, or use of samples in projects objectionable to the subject.
2. Source of Samples:
Indicate how samples have been or will be obtained. Are samples to be obtained directly from a) subjects or b) from a repository (existing samples)? Will the samples have codes or identifiers that could link the samples to the subject’s identity or will they be unlinked or anonymous? If identifiable or coded samples will be obtained from a repository, the investigator should include a copy of the consent form used to collect the original samples in the application. With regard to new uses of stored samples, the guidelines state clearly the CHS’s policy that stored DNA may be studied for new markers only if the samples are anonymous. Samples are anonymous only if there is no possibility that individuals identified as positive for the marker could be identified or located. Anonymous means that an investigator may not hold a code to the samples, which could allow a sample to be linked to the individual who donated it.
3. Minimization of Risk:
Describe procedures to minimize risks to subjects. Specifically indicate the method of identifying samples (unidentified, unlinked, coded or identified). Specify the general process for coding, identifying or anonymizing material. Indicate any security measures to be used to assure the continued anonymity of the donor. Indicate which individuals will have access to identifiers. If identified material is to be anonymized for use, indicate what consideration has been given to the fact that anonymization may deny the donor or the donor’s descendants of assured or implied access to results of research.
4. Contact with Subjects:
Indicate if access to existing medical records or contacting subjects is required for the project. Indicate under what circumstances it is anticipated that subjects may be contacted. If subjects are to be contacted, indicate what steps will be used to minimize their risks summarized in the Justification for the Research Design. For genetic studies, if the research investigator wishes to contact relatives of an index case, the index case or proband must be asked whether this contact is acceptable. If the index case declines to allow contact of relatives, the project may not proceed. If permission is granted for contact, the investigator must design a consent form to address the issue of information that may be forthcoming from the research project. The relatives should be given the option to decide whether they are willing to contribute samples. If they are willing to donate, they must be given the option of accepting or declining information derived from the research study.
5. Consent Issues
a. The consent process and documentation (form) must be approved by the IRB. Elements of the consent process may be waived or modified by the IRB. In general, prospective collection of coded or identified samples must be done using written consent. In minimal risk situations, identified or linked samples may qualify for consideration of waiver of consent or verbal consent. General consent statements given in conjunction with consent for a clinical or surgical procedure may not be presumed to cover research use of specimens.
i. Purpose: The consent form should describe the proposed research uses of the samples. If storage and future use of samples is planned, the consent form should inform subjects that their samples will be stored and it should provide the subjects with a meaningful description of the possible uses. In general, a subject cannot meaningfully consent to an unspecified use of the donated specimen. List any specific restrictions to use. Subjects should be given options as to whether and how their samples could be used for future use without reconsent.
ii. Procedures: The consent form should explain the procedures for collecting and identifying specimens submitted to a repository or samples taken from the repository. Indicate who, in general, can use the repository. Indicate if the subjects are identified in the repository or to users of samples from the repository. Subjects should be told whether their samples would be given to other investigators and how their identities will be protected. Stored DNA may not be studied if the samples contain any subject identifiers, unless specific, current informed consent is obtained before the DNA is studied. If consent is given for genomic screening using a particular set of probes identified for a particular disease under study, probes identified with other diseases may not be used unless further consent is obtained for the study of the individual’s DNA with those new probes. Investigators must seek an opinion from the IRB regarding the appropriateness of the risk/benefit ratio and possible impact of test results on subjects before they may recontact individuals who agreed either to be contacted for future testing or whose samples are stored and consent for future testing was not discussed. Testing new probes in samples that are anonymous is acceptable. Indicate whether there is the possibility of future contact. The consent process should include an option for the subject to be told or not told the results of the screening.
iii. Benefits: Indicate whether the subjects will derive any personal benefit. Explain whether results will be provided to subjects or their physicians.
iv. Risks: The risks information should include not only the physical risk of sample acquisition, but also the potential fiscal, psychological, and social risks of disclosure of test results. Risks of participating in genetic studies potentially include the effects of the knowledge that one is the carrier of a disease gene that might affect their life course, employability or insurability. If subjects want to be told, precautions must be taken to minimize the potential harm of receiving bad news and to preserve the confidentiality of the results. The precautions needed in conveying genetic screening results depend upon the age of onset of the disorder, the burden of illness, and the availability of treatment or prevention. The communication of genetic information carries with it the responsibility to interpret the results and provide care for the individual; and thus, it is ideally done in the setting of a clinical rather than research relationship with the subject.
v. Alternatives to participation. Indicate whether subjects can limit future uses of their samples.
c. Waiver of written consent: Federal regulations permit the IRB to waive the requirement to obtain prospective informed consent, if the following four criteria are met:
1. the research involves no more than minimal risk;
2. the waiver does not adversely affect the rights and welfare of the subjects;
3. the research could not be practically carried out without the waiver; and
4. when appropriate, subjects will be provided information after participation.
A waiver of the requirement to obtain informed consent can be requested for a research application that falls into the category of minimal risk research. For existing coded or identifiable samples (those already collected and stored), the IRB may consider research to be of minimal risk if the study adequately protects the confidentiality of the personally identifiable information associated with the sample. The application must justify the category of minimal risk and contain information to address the following issues:
i. Would disclosure of results involve more than minimal risks to subjects?
The major risk associated with the study of existing samples is from the release of information. In identifying minimal risk, for identifiable or coded samples, the investigator should indicate how confidentiality of personally identifiable information will be maintained, verify that no information will be released to third parties with an interest in the employment or insurability of the subject, and explain that there is no need to reveal findings to the subjects or their physicians.
ii. Would waiver of consent adversely affect the subject’s rights or welfare?
The investigator should ascertain that the waiver would not violate any State or Federal statute or customary practice regarding entitlement to privacy. The application should provide an assessment of the potential effects of studies that examine traits commonly considered to have political, cultural or economic significance to the community to which the sample source belongs.
iii. Demonstrate that research could not practically be carried out without the waiver of consent.
The IRB will generally not require reconsent for research using existing, identifiable samples where the research is considered to fall into the minimal risk category.
iv. If appropriate, define when subjects will be provided with pertinent information after participation in the project. (This is usually construed to cover disclosure of necessary deception in psychological studies.) This need not necessarily be a requirement for minimal risk studies. Consent should not be waived when release of information to the subject or their physician is considered likely.
Linkage of consent to specimens is not possible in anonymized or anonymous collections. For identifiable specimens, consent forms should be retained in the event it is necessary to verify that consent was obtained; however, storage of consent forms should be in a manner whereby the identity of a subject cannot be linked to a specific sample.
A repository that conducts human subjects research should have procedures for the storage of samples, determining who will have access to samples, and how confidentiality of personally identifiable information related to the sample will be protected. These procedures should be submitted to the CHS for review and approval.
Specimens maintained in a repository controlled by an individual investigator, or in a multi-user repository, may only be released to collaborators knowledgeable in the legal and ethical issues involved in confidentiality and consent in human research. In addition, investigators should have demonstrable expertise to maximize the chance that the subject’s sample will be used to produce valid data.
Use of samples from a repository must be restricted to the stipulations indicated in the original consent form used to procure the specimen, unless the sample is studied without identifiers or the IRB waives the requirement for consent. When identifiable samples are to be used, the investigator should submit to the IRB a copy of the consent that was originally used to collect the sample. Samples should not be provided to other investigators without written documentation of IRB approval or documentation that the protocol is exempt from IRB review.
Investigators receiving identifiable samples from, or supplying identifiable samples to, other investigators (coded or identified) must have IRB review and approval before samples are obtained or released for use. Investigators must obtain review from the CHS when UH faculty are co-investigators.
Investigators and repositories should maintain records to assure compliance with any specified restrictions of sample use. Investigators receiving samples with identifiers or codes are legally and ethically responsible for maintaining the confidentiality of the subjects.
Specimens collected, tested and/or stored for clinical care of a specific patient are not considered part of research and are not covered by this policy. Such clinical testing is not limited to licensed clinical tests.
Per NBAC recommendations, when research is contemplated using existing materials, the expressed wishes of the individuals who provided the materials must be respected. Where consent documents exist, they may indicate whether individuals wanted their samples to be used in future research, and in some instances they may specify the type of research. CHS IRBs will use the following criteria to evaluate the applicability of such documents to the proposed research:
In some cases, the IRB may determine that an existing consent form permitting unspecified future uses is sufficient. When the IRB determines existing consent documents are inadequate and when the existing sample is identifiable, the individual should be contacted, offered the option of consenting to the specific proposed protocol, and further offered the option of deciding how the sample may be used in the future.
Existing collections of human biologic material may have been developed over a period of time without use of written consent from subjects, or a limited consent from subjects may have been obtained. Recontact of donors may be difficult or impossible. In such situations, investigators should submit an application to the CHS for continued use of the collection or may adopt a policy to anonymize their collection. Procedures to anonymize a collection should be approved by an IRB.
For all UH related research involving FDA sponsorship or FDA regulated products, the IRB must make special note to abide by FDA regulations where they differ from those of the DHHS. The specific FDA regulations for the protection of human subjects and for institutional review boards can be found at 21 CFR 50 and 56 (appendices A.2 and A.3) respectively.
All research involving the use of unapproved drugs must be reviewed and approved by the CHS. All protocols that fall under this category are reviewed by the full IRB; this research never qualifies for Expedited Review and must always have a written consent form. In addition, investigators or their study sponsors must have an Investigational New Drug (IND) application on file with the FDA and must have received an IND number. FDA IND applications may be obtained directly from the FDA.
Investigators proposing to do IND research must indicate such on the protocol submission form and include a form with the drug name, IND #, and company name. The consent form must identify the drug as “experimental.” The investigator’s brochure, provided by the company sponsor, and any other background information must be included as part of the original protocol submission.
All research involving the use of unapproved investigational devices (devices exempt for FDA requirements, significant risk devices or non-significant risk devices) must be reviewed by the full IRB; this research never qualifies for Expedited Review and must always have a written consent form. With the exception of devices exempt from FDA requirements and non-significant risk devices, investigators must have an Investigational Device Exemption (IDE) application on file with the FDA and have received an IDE number. FDA IDE applications may be obtained directly from the FDA.
Investigators proposing to do IDE research must indicate such on the protocol submission form and include a form with the device name, IDE #, and company name. If the FDA has granted an exemption, a copy of the letter of exemption must be included in the protocol submission packet.
The consent form must identify the device as “experimental.” It is important that the investigator’s brochure, provided by the company sponsor, or any other background information be included as part of the original protocol submission. These are required for all device studies and are particularly important for research with devices considered to present a non-significant risk. The CHS is charged by the FDA with the responsibility of confirming a device study as non-significant risk.
While clinically, physicians may use approved drugs for unapproved purposes with no special permissions, research on approved agents for unapproved purposes requires
1. either a new IND number from the FDA or a specific exemption and
2. approval of the IRB.
Generally, a new IND number will be needed when
a. an FDA-approved drug is to be used repeatedly or systematically for new (unapproved) indications,
b. the investigator or sponsor is seeking to change or expand the current FDA-approved labeling of the drug, or
Experimental combinations of approved drugs do not require an IND if both drugs are being used in accordance with their FDA-approved indication.
Federal regulations allow physicians to use investigational drugs and/or devices in the provision of emergency medical care for patients who need such care. Per 21 CFR 56.102(d), “Emergency use is defined as the use of an investigational drug or investigational device with a human subject in a life-threatening situation in which no standard acceptable treatment is available and in which there is not sufficient time to obtain IRB prior approval.” This use of the investigational drug or device does not, however, constitute research.
In cases where a physician wishes to use an investigational drug or device for emergency care, it is advisable to contact the CHS prior to use of the test article. Post-event notification of emergency uses of investigational drugs and devices should be sent to the CHS, as well as to the study sponsor. Notification should include the following information: the drug or device name, provider/sponsor of the drug or device, IND/IDE number, subject’s initials, details about the subject’s disease or condition, copy of the consent form and justification or rationale for the emergency use. Such notification should be provided within five working days after any emergency use of a test article. The CHS will send a written statement to the investigator acknowledging that the IRB is aware of the use and (if appropriate) considers it to meet the requirements of 45 CFR 46.116(f) or 21 CFR Part 56.104(c).
Although prior approval to use an investigational drug or device in an emergency is often difficult to obtain from the CHS, the IRB Chair can provide an acknowledgment letter in advance of administration of the test article. Again, PIs must supply a letter which includes the following information: the drug or device name, provider/sponsor of the drug or device, IND/IDE number, subject’s initials, details about the subject’s disease or condition, and justification or rationale for the emergency use and include a copy of the consent form. If the proposed use meets the requirements of either 45 CFR 46.116 (f) or 21 CFR 56.104 (c), the IRB will provide an acknowledgment letter. Although this is not an “IRB approval,” the acknowledgment letter may be acceptable to manufacturers and may allow the shipment of drug or device to proceed.
Subsequent use of this drug or device in similar circumstances should be handled by a formal protocol submission to the CHS and review through the normal CHS mechanisms. However, the FDA acknowledges that it would be inappropriate to deny emergency treatment to a second individual if the only obstacle is that the IRB has not had sufficient time to convene a meeting to review the issue. Again, in these cases, the IRB must be notified within five working days after any emergency use of a test article.
Note: DHHS regulations for the protection of human subjects do not permit research activities to be started, even in emergencies, without prior IRB review and approval of a research protocol and applicable consent forms. Thus, if a patient is treated via this emergency use mechanism, then the patient, and any data derived from the treatment of that patient, may not be used for the evaluation of the product unless there was prior IRB review and approval of the project.
Research practica (usually in the form of course-related research projects and/or directed studies) are designed to provide students an opportunity to practice various research methods such as interview, observation and survey techniques, measurement of behavior (e.g., reaction time, speech, problem solving) as well as data analysis. Typically such projects are quite limited in scope, do not lead to generalizable knowledge and are not undertaken with that goal in mind. For example, a student may interview a peer when the interview does not involve any sensitive, personal information.
Such projects should not put the subjects at more than minimal risk, and the data must be recorded anonymously by the students (i.e., with no names, social security numbers, or any other codes that can be linked to a list of names). These projects are considered “classroom exercises” and are not subject to review by the CHS. They do not require review unless the student researcher anticipates publishing the results or presenting at a professional meeting.
While practica are not under the purview of the CHS, the CHS staff is available for consultation with students and for class presentation regarding issues of the protection of the rights and welfare of human subjects. It is important to note that data collected as practica cannot at a later date be used for presentation at conferences, publications, or doctoral dissertations.
Any research conducted by students, graduate or undergraduate, that does not fall under the definition of a research practicum, which uses human beings as subjects, and which is intended to contribute to generalizable knowledge, must be reviewed and approved by the CHS. This includes, but is not limited to, all independent undergraduate research projects and honors theses, masters’ theses and dissertations.
Faculty advisors of both undergraduate and graduate students should be certified to conduct research with human subjects, even if they are not currently conducting research with human subjects. One way of receiving certification is to complete one of the web-based modules on human subjects protections provided by the OHRP at <http://188.8.131.52/cbttng_ohrp/cbts/assurance/login.asp>, the NIH at <http://ohsr.od.nih.gov/extramural/extramural_training.html> and elsewhere.
Another method is to attend one of the 4 hour seminars on The Protection of Human Research Subjects for Research Investigators presented by the CHS throughout the year. Certificates of Completion are given for these seminars and can be used to verify fulfillment of the certification requirement.
It is the responsibility of faculty advisors to determine when an undergraduate or graduate student project does not meet the definition of a practicum and must be reviewed by the IRB. However, the advisor must be certified as having completed at least the CHS sponsored Protection of Human Research Subjects for Research Investigators seminar or its equivalent to be authorized to make this decision.
It is the responsibility of faculty advisors to ensure that research practica and exempt research activities are conducted according to the ethical standards of the relevant discipline.
When student research activities are not practica, it is the responsibility of faculty advisors to assist students in preparing review materials for the IRB and to ensure that the research is conducted in accordance with the UH’s agreement with the federal government (the FWA) and with applicable UH and CHS policies.
Many professional organizations, such as the American Psychological Association, consider deception undesirable except in the rarest of cases. Strong justification must be provided for procedures calling for either concealment or deception, and participants should be fully informed at the conclusion of the activities, preferably with an opportunity to withdraw their data if they are bothered by the concealment or deception.
APA Code of Ethics (2002) <http://www.apa.org/ethics/code2002.html>
8.07 Deception in Research
(a) Psychologists do not conduct a study involving deception unless they have determined that the use of deceptive techniques is justified by the study's significant prospective scientific, educational, or applied value and that effective nondeceptive alternative procedures are not feasible.
(b) Psychologists do not deceive prospective participants about research that is reasonably expected to cause physical pain or severe emotional distress.
(c) Psychologists explain any deception that is an integral feature of the design and conduct of an experiment to participants as early as is feasible, preferably at the conclusion of their participation, but no later than at the conclusion of the data collection, and permit participants to withdraw their data. (See also Standard 8.08 Debriefing)
(a) Psychologists provide a prompt opportunity for participants to obtain appropriate information about the nature, results, and conclusions of the research, and they take reasonable steps to correct any misconceptions that participants may have of which the psychologists are aware.
(b) If scientific or humane values justify delaying or withholding this information, psychologists take reasonable measures to reduce the risk of harm.
(c) When psychologists become aware that research procedures have harmed a participant, they take reasonable steps to minimize the harm.
The CHS finds deception acceptable when, and to the extent which, it is unavoidably required by the research to be done, and when the benefits outweigh the risks.
In most investigations the subject should be made aware of the major purposes of the research. In some investigations, however, there is some degree of deception involved. Usually deception consists of merely failing to tell the subject what the specific points of interest are in an attempt to prevent biasing the results. Deception of this kind may be deemed reasonable and acceptable by the IRB (on a case by case basis) as long as the investigator provides justification for its use, and —at the discretion of the IRB— debriefs the subjects after their participation, as appropriate.
Withholding information cannot be used as a means to secure the participation of subjects in research.
The use of deception imposes special responsibilities on the investigator. One of these responsibilities is to provide appropriate debriefing to the subjects. In each case, the IRB will require information sufficient to understand why deception is needed, how the potential benefits justify its use, and how debriefing will be done.
Debriefing usually has two components. One is a debriefing protocol; the other is an accompanying written debriefing statement.
The debriefing protocol constitutes an explanation to the IRB of the in-person interaction between subjects and investigators. It should
The written debriefing statement constitutes a guideline for in-person interaction between subjects and investigators. It should
The written debriefing statement should present the same information in summary form, and should include a contact telephone number and name for subjects to call if they should have further questions or concerns.
The participants should also be provided with the opportunity to not have their data used.