Biospecimens

Under the Common Rule and IU HRPP Policy, IRB review is required for all human subjects research:

• Systematic investigation designed to contribute to generalizable knowledge
• that involves collection of information about a living individual through either interaction or intervention, with the individual or access to the individual's private information, including protected health information (PHI).

In addition, the FDA requires IRB review for the use of de-identified human specimens in clinical investigations of medical devices when the research may generate or collect data that may be submitted to the FDA for review.

Examples of biospecimen research requiring IRB review (exempt, expedited, or full board review):

• Prospective collection of biospecimens for a specific research study
• Prospective collection and storage of biospecimens for future research use
• Secondary use of identifiable biospecimens
  • Example: Obtaining blood/tissue samples along with identifiers from a biobank or repository
• Secondary use of coded biospecimens when the investigator collected the specimens him/herself for another research project
• Secondary use of coded biospecimens when the investigator has access to the code that would allow linkage of the specimens to identifiable information
• Secondary use of de-identified or coded biological specimens in a project that will generate or collect data that will or may be submitted to the FDA
  • Example: Testing the efficacy of a diagnostic device using de-identified specimens collected as standard of care and no longer needed for clinical diagnostic purposes

Examples of research NOT requiring IRB review (Application for Not Human Subjects Research is available if needed, but not required)

• Collection and/or use of de-identified biological specimens obtained through standard of care clinical procedures and that are not required for treatment or diagnostic purposes (waste or remnant specimens) provided the project will not generate or collect data that may be submitted to the FDA
• Secondary use of de-identified or coded biospecimens when the investigator will not have access to the code AND the data generated or collected will not be submitted to the FDA
• Use of biological specimens from deceased individuals in a project provided the project will not generate or collect data that may be submitted to the FDA

Some funding agencies may require IRB approval for research projects that are not regulated by the Common Rule or the FDA. In these cases, investigators are encouraged to speak directly with HRPP staff to determine the best course of action.

The federal regulations generally require subjects voluntarily consent to participate in research; however, the regulations also allow a waiver of this requirement for research that meets certain criteria. The decision regarding whether consent must be obtained is made on a case-by-case basis and is dependent on the type of research being conducted.

Biospecimen research can be categorized into three common groups:

• Prospective collection of biospecimens for research purposes
• Use of clinical samples in a research project
• Secondary use of previously-collected biospecimens

Prospective collection of biospecimens for research purposes

Prospective studies are those that ask a question and look forward, and are generally designed before any information is collected. Study subjects are identified (workers with low-back injury claims) and followed forward to see if the outcome of interest (return to work) happens over time. This outcome is assessed relative to the intervention factor (physiotherapy). Prospective research with biospecimens occurs when subjects are identified, and then a biospecimen is collected from the subjects as part of the research interventions.

For prospective research with biospecimens, the IU IRBs will generally require that consent be obtained from subjects prior to the collection of the biospecimen. Specifically, consent is likely to be required when the following are true:

• Subjects are identified prospectively prior to collection of the biospecimens
• At the time of collection, the investigators know and intend that the samples will be used for research purposes

Use of clinical samples in a research project

Biospecimens are often collected for clinical or diagnostic purposes, and then used for research purposes at a later time. For example, a remnant sample refers to the leftover biospecimen from a sample collected for clinical or diagnostic purposes. A waste sample is a biospecimen obtained during a clinical procedure that is not needed for a therapeutic or diagnostic purpose and will be otherwise discarded. Collection and use of these samples for research purposes may not require prospective consent if the investigators can provide justification that all of the following are true:

1. The research is no more than minimal risk, considering both research procedures and sensitivity of the information to be collected/analyzed
2. The research could not practicably be carried out if consent were required, considering the following:
   1. Scale—Is the scale of this research low, in terms of size of collection, sites, samples and study personnel?
   2. Collection procedure—Does the collection procedure vary from the standard of care procedure?
   3. Sample—Would the sample exist outside of clinical care?
3. If the research involves identifiable information or identifiable biospecimens, the research could not practicably be carried out without identifiers.
4. Waiving the informed consent requirement will not adversely affect rights and welfare of subjects.
5. When appropriate, subjects will be provided additional pertinent information about the research.

Secondary use of previously collected biospecimens

When an investigator uses previously-collected biospecimens for a secondary, new/different research project, it is likely that additional consent for the secondary use will not be required. Subjects may have provided consent for use of their biospecimens during the initial collection. The HRPP or IRB may need to determine whether the specimens were collected in accordance with an IRB approval and, if the secondary investigator has access to identifiers, whether the secondary use is consistent with the subjects' original consent and HIPAA authorization.

Informed consent documents for research with biospecimens must include all elements of a research consent required by the Common Rule as well as additional elements to address the specific considerations of research with biospecimens. If the research project is a stand-alone repository/banking protocol, a stand-alone consent is most appropriate. If, however, biospecimens are being collected as part of a larger research protocol, consent for collection may be incorporated into the main informed consent document.

The consent form should provide subjects with an understanding of how the biospecimens will be used and for what purpose, with as much specificity as possible given the investigator's research plan. Therefore, it is extremely important that investigators consider possible future uses of the biospecimens being collected. If the consent form describes uses of the specimens that are limited to a specific purpose or type of research, any future use of the biospecimens must be limited to research of that type or purpose. If the investigator envisions future unspecified research using the biospecimens, that possibility must be clearly stated.

Elements of consent for research with biospecimens

In addition to the elements of consent required by the IU HRPP Policy on Informed Consent, consent for collection and use of biospecimens should address all of the following topics:

1. Proposed use of biospecimens
2. Explanation that biospecimens will be stored for future research purposes, if applicable
3. Collection and storage procedures, including length of storage
4. Access to the biospecimens
   1. Whether the biospecimens will be discarded or given to someone in the same department if the investigator leaves the institution
   2. Whether third parties not part of the collection protocol will have access in the future and, if so, under what conditions
   3. Whether the subject can obtain future access to the stored biospecimens for information that may be of clinical relevance to him/her
   4. Information about possible secondary uses of the stored biospecimens, or the possible creation of an immortalized cell line based on the specimen, if applicable
5. Procedures to protect privacy and confidentiality of the information linked to the biospecimen and results obtained from analysis
   1. Whether the biospecimen will be de-identified per HIPAA standards
   2. Whether the biospecimen will be linked to other information and, if so, who controls that link
   3. Whether results of analyses will be linked back to the subject
   4. Whether results which may be clinically relevant to the individual subject will be reported to them
6. Procedures for withdrawal from the study, including:
   1. Whether investigators will continue to use data already collected up to the point of withdrawal
   2. Whether biospecimens will be destroyed upon withdrawal, or if biospecimens will be kept with all personal identifiers removed upon withdrawal
7. Whether the research will involve whole genome sequencing
8. Statement that the subject's biospecimens may be used for commercial profit and whether the subject will/will not share in those profits 

Further points to consider and sample informed consent language may also be found in the National Institutes of Health Guidance on Informed Consent for Secondary Research with Data and Biospecimens.

Biospecimens are often stored in repositories for future research uses, including unspecified future research. In these situations, investigators (who may or may not be part of the repository team) collect biospecimens per an IRB-approved protocol and consent, and submit them to the repository for storage and distribution to other investigators for future research. Repository teams should consider the following when accepting and distributing biospecimens.

Acceptance of samples from submitting-investigators

When a repository accepts biospecimens from submitting-investigators, the repository protocol to be reviewed by the IRB should include:

• a plan for ensuring that submitting-investigators have obtained appropriate IRB approval for collection of biospecimens; and
• a plan for ensuring collection of specimens is consistent with the repository protocol and consent.

There are several ways of ensuring that collection of specimens is consistent with the repository protocol and consent. The following are three examples but are not all-inclusive.

• The IRB-approved consent and authorization may be provided to the submitting-investigators for use in consenting subjects who wish to donate specimens. Submitting-investigators serve as part of the repository team and should be trained in obtaining consent and conducting study procedures.
• Submitting-investigators may receive IRB approval for a separate collection protocol that incorporates the consent and authorization for the repository into the submitting-investigator's protocol.
  • For example, Investigator B obtains IRB approval for a protocol studying the link between diabetes and diet. The research procedures include collection of two vials of blood each from 100 subjects with diabetes. She expects that, in most cases, she will use only one of the two collected vials of blood for her protocol, leaving her with an extra vial from each of the subjects. She wishes to allow the additional vials to be stored as part of Repository X for future use. To do so, she incorporates information about Repository X in her diabetes study consent form and asks subjects to opt-in to allowing any leftover blood to be submitted to Repository X. Repository X is also listed on the HIPAA authorization form. Copies of the consent form for all subjects who opt-in are provided to Repository X and Investigator B ensures that the originals are available to Repository X for as long as required.
• In some cases, investigators have leftover biospecimens from a completed protocol that they wish to submit to a repository even though subjects did not prospectively consent to the sharing of their biospecimens with the repository. In these situations, the repository team should review the consent and authorization under which the samples were collected and ensure that use by the repository would not conflict with the original consent. The repository team should then request a waiver of consent and/or authorization from the IRB allowing use of the samples by the repository without specific consent. The IRB must determine that all the elements of waiver of consent (listed above) have been met.

Before accepting biospecimens from submitting-investigators, the repository and the submitting-investigators should enter into a submittal agreement. This agreement, which may be a material transfer agreement, should include the following provisions:

• Collection of the biospecimens, and consent document for the collection, was approved by an IRB. Please note that review by the IU IRBs is not required, as review and approval from the local IRB where the collection took place may be acceptable. The HRPP will gladly provide counsel regarding acceptability of IRB approval from external institutions.
• Written informed consent was obtained from all donors, and that consent is not inconsistent with the repository protocol and consent.
• Submitting-investigators will provide access to identifiable information only if the repository confirms that the original consent signed by donors allowed such disclosure.

Distribution of samples to recipient-investigators

When a repository will distribute biospecimens to recipient-investigators for research purposes, the repository protocol to be reviewed by the IRB should include plans for the following:

• Evaluating requests for biospecimens
• Ensuring recipient-investigators have obtained appropriate IRB approval when required. Please note that review by the IU IRBs is not required, as review and approval from the local IRB where the collection took place may be acceptable. The HRPP will gladly provide counsel regarding acceptability of IRB approval from external institutions.
• Ensuring use of specimens is consistent with the original consent signed by the donor.

Repositories are encouraged to create an oversight committee to handle the above functions, including evaluating scientific validity of research projects, reviewing proposed use of the specimens, and determining whether the proposed use is consistent with the scope of the original consent form. A material transfer agreement between the repository and recipient-investigators should be signed prior to distribution of any samples.

Case studies for determining when IRB review is necessary

Case Study 1

Investigator is evaluating the efficacy of fluoride varnish. The study involves application of the fluoride to extracted teeth specimens to determine the effect of the varnish under various conditions. The teeth specimens are provided to IU by clinicians who have extracted the teeth for clinical purposes and would otherwise have been discarded. Instead, the samples are sent to IU without identifiers for use as needed (education, research, clinical comparison, etc.). Clinicians from all over the state of Indiana participate by donating these waste biospecimens.

Q. Is informed consent required for collection of the teeth specimens?

No—a waiver of consent is likely to be approved. Since there are no research procedures and no identifiers accompany the samples, the collection is minimal risk for the donors. The number of samples collected is extremely high, as is the number of collection sites. All biospecimens are collected per standard practice with no additional procedures to facilitate research. In addition, all samples exist due to a clinical procedure. Assuming the study team can justify that subjects' rights and welfare are not adversely affected by the collection and use of the teeth, the balance of the three practicability considerations (scale, standard practice, and clinical sample) indicate that the study could not practicably be conducted without the waiver.

Case Study 2

Investigators are collecting blood for use in studying diabetes. When potential subjects are seen by the diabetes clinic and a blood draw is ordered, staff will draw an extra vial of blood that will be provided to the study team for purposes of the research. Up to 100 subjects will be enrolled at this specific clinic.

Q. Is informed consent required for collection of the additional vial of blood?

Yes—a waiver of consent is unlikely to be approved. Blood draws are generally minimal risk; however, based on the practicability considerations (scale, standard practice, and clinical sample), it is unlikely that the investigator can justify that the study could not practicably be conducted without the waiver. Enrollment of 100 subjects is unlikely to be considered enough to justify an unreasonable burden. The sample is collected using common clinical procedures during a time when those procedures are already being conducted; however, the extra vial of blood is not a clinical sample because it is not necessary for clinical purposes.

The following is a specific scenario that has been addressed by the HRPP. Decisions regarding this scenario are provided below in order to provide additional guidance to investigators; however, decisions are extremely fact-specific. Investigators should not attempt to extrapolate these decisions to additional scenarios. Instead, investigators are encouraged to contact the HRPP with additional questions and scenarios.

Collection of cord blood

Collection of umbilical cord blood is not considered human subjects research as long as the study team cannot identify the donor and does not receive identifiable information about the donor. The research must be carefully designed to ensure the study team does not view or access any identifying information about the donor during the collection. Any screening for eligible subjects must be done by individuals who are not part of the study team.

• For example: Clinicians see that a patient scheduled for delivery meets the inclusion criteria for Dr. X's study. Upon delivery, the clinicians (who are not part of the study) take the placenta to another room (instead of discarding it as normal standard of care), where Dr. X's study team is waiting to collect the cord blood. In this example, the research design ensures that the study team does not see the patient donor and does not receive identifiable information.