DHHS-Regulated Research

Withdrawal of Subjects from Research Guidance

1. When a subject decides to withdraw from a clinical trial, the investigator conducting the clinical trial should ask the subject to clarify whether the subject wishes to withdraw from all components of the trial or only from the primary interventional component of the trial. If the latter, research activities involving other components of the clinical trial, such as follow-up data collection activities, for which the subject previously gave consent may continue. The investigator should explain to the subject who wishes to withdraw the importance of obtaining follow-up safety data about the subject.
2. Investigators are allowed to retain and analyze already collected data relating to any subject who chooses to withdraw from a research study or whose participation is terminated by an investigator without regard to the subject’s consent, provided such analysis falls within the scope of the analysis described in the IRB-approved protocol. This is the case even if that data includes identifiable private information about the subject.
3. For research not subject to regulation and review by FDA, investigators, in consultation with the funding agency, can choose to honor a research subject’s request that the investigator destroy the subject’s data or that the investigator exclude the subject’s data from any analysis.
4. When seeking the informed consent of subjects, investigators should explain whether already collected data about the subjects will be retained and analyzed even if the subjects choose to withdraw from the research.

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FDA-Regulated Research

Additional Requirements for FDA-Regulated Research

1. When a subject withdraws from a study:
   1. The data collected on the subject to the point of withdrawal remains part of the study database and may not be removed.
   2. An investigator may ask a subject who is withdrawing whether the subject wishes to provide continued follow-up and further data collection subsequent to their withdrawal from the interventional portion of the study. Under this circumstance, the discussion with the subject would distinguish between study-related interventions and continued follow-up of associated clinical outcome information, such as medical course or laboratory results obtained through non-invasive chart review, and address the maintenance of privacy and confidentiality of the subject’s information.
   3. If a subject withdraws from the interventional portion of the study, but agrees to continued follow-up of associated clinical outcome information as described in the previous bullet, the investigator must obtain the subject’s informed consent for this limited participation in the study (assuming such a situation was not described in the original informed consent form). IRB approval of informed consent documents is required.
   4. If a subject withdraws from the interventional portion of a study and does not consent to continued follow-up of associated clinical outcome information, the investigator must not access for purposes related to the study the subject’s medical record or other confidential records requiring the subject’s consent.
   5. An investigator may review study data related to the subject collected prior to the subject’s withdrawal from the study, and may consult public records, such as those establishing survival status.
2. For FDA-regulated research involving investigational drugs:
   1. Investigators must abide by FDA restrictions on promotion of investigational drugs:
      1. An investigator, or any person acting on behalf of an investigator, must not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug.
      2. This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution.
      3. An investigator must not commercially distribute or test market an investigational new drug.
   2. Follow FDA requirements for general responsibilities of investigators
      1. An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator’s care; and for the control of drugs under investigation.
      2. An investigator must, in accordance with the provisions of 21 CFR §50, obtain the informed consent of each human subject to whom the drug is administered, except as provided in 21 CFR §50.23 or §50.24 of this chapter.
      3. Additional specific responsibilities of clinical investigators are set forth in this part and in 21 CFR §50 and 21 CFR §56.
   3. Follow FDA requirements for control of the investigational drug
      1. An investigator must administer the drug only to subjects under the investigator’s personal supervision or under the supervision of a sub- investigator responsible to the investigator.
      2. The investigator must not supply the investigational drug to any person not authorized under this part to receive it.
   4. Follow FDA requirements for investigator record-keeping and record retention
      1. Disposition of drug:
         1. An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects.
         2. If the investigation is terminated, suspended, discontinued, or completed, the investigator must return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug under 21 CFR §312.59.
      2. Case histories.
         1. An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation.
         2. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual’s hospital charts, and the nurses’ notes. The case history for each individual must document that informed consent was obtained prior to participation in the study.
      3. Record retention: An investigator must retain required records for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified.
   5. Follow FDA requirements for investigator reports
      1. Progress reports: The investigator must furnish all reports to the sponsor of the drug who is responsible for collecting and evaluating the results obtained.
      2. Safety reports: An investigator must promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the investigator must report the adverse effect immediately.
      3. Final report: An investigator must provide the sponsor with an adequate report shortly after completion of the investigator’s participation in the investigation.
      4. Financial disclosure reports:
         1. The clinical investigator must provide the sponsor with sufficient accurate financial information to allow an applicant to submit complete and accurate certification or disclosure statements as required under 21 CFR §54.
         2. The clinical investigator must promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following the completion of the study.
      5. Follow FDA requirements for assurance of IRB review
         1. An investigator must assure that an IRB that complies with the requirements set forth in 21 CFR §56 will be responsible for the initial and continuing review and approval of the proposed clinical study.
         2. The investigator must also assure that they will promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others, and that he or she will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.
      6. Follow FDA requirements for inspection of investigator’s records and reports
         1. An investigator must upon request from any properly authorized officer or employee of FDA, at reasonable times, permit such officer or employee to have access to, and copy and verify any records or reports made by the investigator pursuant to 312.62.
         2. The investigator is not required to divulge subject names unless the records of particular individuals require a more detailed study of the cases, or unless there is reason to believe that the records do not represent actual case studies, or do not represent actual results obtained.
      7. Follow FDA requirements for handling of controlled substances
         1. If the investigational drug is subject to the Controlled Substances Act, the investigator must take adequate precautions, including storage of the investigational drug in a securely locked, substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is limited, to prevent theft or diversion of the substance into illegal channels of distribution.
3. For FDA-regulated research involving investigational devices:
   1. General responsibilities of investigators
      1. An investigator is responsible for ensuring that an investigation is conducted according to the signed agreement, the investigational plan and applicable FDA regulations, for protecting the rights, safety, and welfare of subjects under the investigator’s care, and for the control of devices under investigation. An investigator also is responsible for ensuring that informed consent is obtained in accordance with 21 CFR §50.
   2. Specific responsibilities of investigators
      1. Awaiting approval: An investigator may determine whether potential subjects would be interested in participating in an investigation, but must not request the written informed consent of any subject to participate, and must not allow any subject to participate before obtaining IRB and FDA approval.
      2. Compliance: An investigator must conduct an investigation in accordance with the signed agreement with the sponsor, the investigational plan, and other applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA.
      3. Supervising device use: An investigator must permit an investigational device to be used only with subjects under the investigator’s supervision. An investigator must not supply an investigational device to any person not authorized to receive it.
      4. Financial disclosure:
         1. A clinical investigator must disclose to the sponsor sufficient accurate financial information to allow the applicant to submit complete and accurate certification or disclosure statements required under 21 CFR §54.
         2. The investigator must promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following completion of the study.
      5. Disposing of device: Upon completion or termination of a clinical investigation or the investigator’s part of an investigation, or at the sponsor’s request, an investigator must return to the sponsor any remaining supply of the device or otherwise dispose of the device as the sponsor directs.
   3. Maintain the following accurate, complete, and current records relating to the investigator’s participation in an investigation:
      1. All correspondence with another investigator, an IRB, the sponsor, a monitor, or FDA, including required reports.
      2. Records of receipt, use or disposition of a device that relate to:
         1. The type and quantity of the device, the dates of its receipt, and the batch number or code mark.
         2. The names of all persons who received, used, or disposed of each device.
         3. Why and how many units of the device have been returned to the sponsor, repaired, or otherwise disposed of.
      3. Records of each subject’s case history and exposure to the device. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual’s hospital charts, and the nurses’ notes. Such records must include:
         1. Documents evidencing informed consent and, for any use of a device by the investigator without informed consent, any written concurrence of a licensed physician and a brief description of the circumstances justifying the failure to obtain informed consent.
         2. Documentation that informed consent was obtained prior to participation in the study.
         3. All relevant observations, including records concerning adverse device effects (whether anticipated or unanticipated), information and data on the condition of each subject upon entering, and during the course of, the investigation, including information about relevant previous medical history and the results of all diagnostic tests.
         4. A record of the exposure of each subject to the investigational device, including the date and time of each use, and any other therapy.
      4. The protocol, with documents showing the dates of and reasons for each deviation from the protocol.
      5. Any other records that FDA requires to be maintained by regulation or by specific requirement for a category of investigations or a particular investigation.
   4. Inspections
      1. Entry and inspection: A sponsor or an investigator who has authority to grant access must permit authorized FDA employees, at reasonable times and in a reasonable manner, to enter and inspect any establishment where devices are held (including any establishment where devices are manufactured, processed, packed, installed, used, or implanted or where records of results from use of devices are kept).
      2. Records inspection: A sponsor, IRB, or investigator, or any other person acting on behalf of such a person with respect to an investigation, must permit authorized FDA employees, at reasonable times and in a reasonable manner, to inspect and copy all records relating to an investigation.
      3. Records identifying subjects: An investigator must permit authorized FDA employees to inspect and copy records that identify subjects, upon notice that FDA has reason to suspect that adequate informed consent was not obtained, or that reports required to be submitted by the investigator to the sponsor or IRB have not been submitted or are incomplete, inaccurate, false, or misleading.
   5. Prepare and submit the following complete, accurate, and timely reports
      1. Unanticipated adverse device effects. An investigator must submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse device effect occurring during an investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect.
      2. Withdrawal of IRB approval. An investigator must report to the sponsor, within 5 working days, a withdrawal of approval by the reviewing IRB of the investigator’s part of an investigation.
      3. Progress. An investigator must submit progress reports on the investigation to the sponsor, the monitor, and the reviewing IRB at regular intervals, but in no event less often than yearly.
      4. Deviations from the investigational plan:
         1. An investigator must notify the sponsor and the reviewing IRB of any deviation from the investigational plan to protect the life or physical well-being of a subject in an emergency.
         2. Such notice must be given as soon as possible, but in no event later than 5 working days after the emergency occurred.
         3. Except in such an emergency, prior approval by the sponsor is required for changes in or deviations from a plan, and if these changes or deviations may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, FDA and IRB also is required.
      5. Informed consent. If an investigator uses a device without obtaining informed consent, the investigator must report such use to the sponsor and the reviewing IRB within 5 working days after the use occurs.
      6. Final report. An investigator must, within 3 months after termination or completion of the investigation or the investigator’s part of the investigation, submit a final report to the sponsor and the reviewing IRB.
      7. Other. An investigator must, upon request by a reviewing IRB or FDA, provide accurate, complete, and current information about any aspect of the investigation.

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Clinical Trials and ICH-GCP

Additional Requirements for Clinical Trials (ICH-GCP)

(Guidance on when and how to apply ICH-GCP or GCP as adopted by the FDA can be found here)

1. The clinical trial should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with good clinical practice (GCP) and the applicable regulatory requirements. The rights, safety and well-being of the participants are the most important considerations and should prevail over interests of science and society.
2. Clinical trials should be scientifically sound for their intended purpose and based on adequate and current scientific knowledge and approaches.
   • The available nonclinical and clinical information on an investigational product(s) should be adequate to support the proposed clinical trial.
   • Clinical trials should be scientifically sound and reflect the state of knowledge and experience with the investigational product(s), including, if applicable, the condition being treated, diagnosed or prevented; the current understanding of the underlying biological mechanism (of both the condition and the investigational product); and the population for which the investigational product is intended.
   • There should be periodic review of current scientific knowledge and approaches to determine whether modifications to the trial are needed, since new or unanticipated information may arise once the trial has begun.
3. Investigator’s Qualifications and Training
   • The investigator should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirements, and should provide evidence of such qualifications.
   • The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as described in the protocol, in the current Investigator’s Brochure, in the product information and/or in other information sources provided by the sponsor.
4. Resources
   • The investigator should be able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of eligible participants within the recruitment period as agreed with the sponsor.
   • The investigator should have sufficient time, an adequate number of available and qualified staff, and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.
5. Responsibilities
   • The investigator may delegate trial-specific activities to other persons or parties. The investigator may be supported by the sponsor in the identification of a suitable service provider(s); however, the investigator retains the final decision on whether the service provider intended to support the investigator is appropriate based on information provided to the sponsor. The investigator retains the ultimate responsibility and should maintain appropriate oversight of the persons or parties undertaking the activities delegated to ensure the rights, safety and well-being of the trial participants and reliability of the data. The level of investigator oversight of the delegated activities should depend on the nature of the delegated activities and be proportionate to the importance of the data being protected and the risks to trial participant safety and data reliability.
   • The investigator should ensure that all persons or parties to whom the investigator has delegated trial-related activities are appropriately qualified and are adequately informed about the relevant aspects of the protocol, the investigational product(s), and their assigned trial activities (including activities conducted by staff provided by other parties in accordance with local regulatory requirements). Trial-related training to persons assisting in the trial should correspond to what is necessary to enable them to fulfill their delegated trial activities that go beyond their usual training and experience.
   • The investigator should ensure a record is maintained of the persons and parties to whom the investigator has delegated trial-related activities. Documentation of delegation should be proportionate to the significance of the trial-related activities. In situations where the activities are performed as part of clinical practice, delegation documentation may not be required.
   • Agreements made by the investigator/institution with service providers for trial-related activities should de documented.
   • The investigator/institution should permit monitoring and auditing by the sponsor, inspection by the appropriate regulatory authority(ies) and, in accordance with applicable regulatory requirements, review by IRB(s).
6. Communication with IRB
   • Submission to the IRB may be made by the investigator/institution or sponsor in accordance with applicable regulatory requirements.
   • Before initiating a trial, the investigator/institution should have a documented and dated approval from the IRB for the trial protocol, informed consent materials, participant recruitment procedures (e.g., advertisements), and any other trial-related information to be provided to participants.
   • As part of the investigator’s/institution’s or sponsor’s (in accordance with applicable regulatory requirements) submission to the IRB, a current copy of the Investigator’s Brochure or basic product information brochure should be provided. If the Investigator’s Brochure or basic product information brochure is updated during the trial, the IRB should receive the current version in accordance with applicable regulatory requirements.
   • As the trial progresses, the investigator/institution or sponsor should provide any updates to the participant information to the IRB in accordance with applicable regulatory requirements.
   • The investigator or sponsor should submit documented summaries of the trial status to the IRB in accordance with local regulatory requirements or upon request.
   • The investigator or the sponsor should promptly communicate to the IRB and where applicable, to the institution any changes significantly affecting the conduct of the trial and/or increasing risk to participants.
7. Compliance with Protocol
   • The investigator/institution should sign the protocol, or an alternative contract, to confirm agreement with the sponsor.
   • The investigator/institution should comply with the protocol, GCP and applicable regulatory requirements.
   • The investigator should document all protocol deviations. In addition to those identified by the investigator themselves, protocol deviations related to their trial participants and their conduct of the trial may be communicated to them by the sponsor. In either case, the investigator should review the deviations, and for those deviations deemed important, the investigator should explain the deviation and implement appropriate measures to prevent a recurrence, when applicable.
   • The investigator should follow the protocol and deviate only where necessary to eliminate an immediate hazard(s) to trial participants. In case of deviations undertaken to eliminate immediate hazard to trial participants, the investigator should inform the sponsor promptly.
   • The investigator should report information on the immediate hazard, the implemented change and the subsequent proposed protocol amendment, if any, to the IRB and, where applicable, regulatory authorities.
8. Premature Termination or Suspension of a Trial
   • If the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly inform the trial participants and should assure appropriate therapy and follow-up for the participants.
   • Where the investigator terminates or suspends their involvement in a trial without prior agreement by the sponsors, the investigator should promptly inform the institution, where applicable, the sponsor, the IRB, and the regulatory authorities in accordance with applicable regulatory requirements and should provide a detailed explanation of the reasons.
   • If the sponsor terminates or suspends a trial, the investigator/institution, or the sponsor, in accordance with applicable regulatory requirement(s), should promptly inform the IRB and the regulatory authorities and should provide an appropriate explanation.
   • If the IRB terminates or suspends its approval of a trial, the investigator should inform the institution, where applicable, and the investigator/institution should promptly notify the sponsor.
9. Participant Medical Care and Safety Reporting
   • Medical Care of Trial Participants
     • A qualified physician or, where appropriate, a qualified dentist (or other qualified healthcare professionals in accordance with local regulatory requirements) who is an investigator or a sub-investigator for the trial, should have the responsibility for trial-related medical care and decisions.
     • Other appropriately qualified healthcare professionals may be involved in the medical care of trial participants, in line with their normal activities and in accordance with local regulatory requirements.
     • During and following participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a participant for any adverse events, including clinically significant laboratory values, related to the trial. The investigator/institution should inform a participant when medical care is needed for intercurrent illness(es) of which the investigator becomes aware.
     • The investigator should inform the participant’s primary physician about the participant’s involvement in the trial if the participant has a primary physician and agrees to the primary physician being informed.
   • Safety Reporting
     • Adverse events and/or abnormal test results required for safety evaluations (as outlined in the protocol) should be reported to the sponsor according to the reporting requirements and within the time periods specific in the protocol. Unfavorable medical events occurring in participants before investigational product administration (e.g., during screening) should be considered and reported to the sponsor if required by the protocol.
     • All serious adverse events (SAEs) should be reported immediately (after the investigator reasonably becomes aware of the event) to the sponsor. The investigator should also include an assessment of causality. In accordance with applicable regulatory requirements, the protocol may identify SAEs not requiring immediate reporting, for example, deaths or other events that are endpoints. Subsequent information should be submitted as a follow-up report, as necessary.
     • For reported deaths, the investigator should supply the sponsor, the IRB and, where applicable, the regulatory authority with any additional requested information (e.g., autopsy reports and terminal medical reports) when they become available.
     • The investigator may delegate activities for safety reporting to qualified investigator site staff but retains the overall responsibility for safety of participants under their responsibility and compliance with the reporting requirements.
10. Informed Consent of Trial Participants
    • In obtaining and documenting informed consent (paper or electronic format), the investigator should comply with the applicable regulatory requirements and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. The informed consent process should include the following:
      • Prior to consenting and enrolling participants, the investigator should have the IRB’s documented approval of the informed consent materials and process;
      • The information should be as clear and concise as possible, use simple language and avoid unnecessary volume and complexity. This is to ensure that the trial participants or their legally acceptable representatives have an adequate understanding of the objectives of the trial, alternative treatments, potential benefits and risks, burdens, their rights, and what is expected of the participants to be able to make an informed decision as to their participant in the trial.
      • Varied approaches (e.g., text, images, videos and other interactive methods), may be used in the informed consent process including for providing information to the participant. The characteristics of the potential trial population (e.g., participants may lack familiarity with computerized systems) and the suitability of the method of obtaining consent should be taken into consideration when developing the informed consent materials and process. When computerized systems are used to obtain informed consent, trial participants may be given the option to use a paper-based approach as an alternative.
      • Obtaining consent remotely may be considered where appropriate.
      • Whether the informed consent process takes place in person or remotely, the investigator should assure themselves of the identity of the participant (or legally acceptable representative) in accordance with applicable regulatory requirements.
    • The participant or the participant’s legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the participant’s willingness to continue trial participation. The communication of this information and confirmation of the willingness to continue trial participation should be documented. New information that could impact a participant’s willingness to continue participation should be assessed to determine if re-consent is needed (e.g., depending on the stage of the trial, consideration should be given to whether the new information is relevant only to new participants or to existing participants). If re-consent is needed (e.g., information on emerging safety concerns), new information should be clearly identified in the revised informed consent materials. Revised informed consent materials should receive the IRB’s approval in advance of use.
    • Neither the investigator, nor the investigator site staff, should coerce or unduly influence a participant to participate or to continue their participation in a trial.
    • None of the information provided to the participant or the participant’s legally acceptable representative during the informed consent process, should contain any language that causes the participant to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their service providers from liability for negligence.
    • The informed consent process should be conducted by the investigator or other investigator site staff delegated by the investigator, in accordance with applicable regulatory requirements. If the participant is unable to provide consent themselves (e.g., minors, patients with severely impaired decision making capacity), the participant’s legally acceptable representative should provide their consent on behalf of the participant.
    • The information provided during the informed consent process and translations should be relevant, clear, simple, concise and understandable to the participant or the participant’s legally acceptable representative and the impartial witness, where applicable.
    • Before informed consent may be obtained, the investigator, or investigator site staff delegated by the investigator, in accordance with the protocol and conditions of IRB approvals, should provide the participant or the participant’s legally acceptable representative ample time unless justified (e.g., in an emergency situation) and opportunity to inquire about trial details and to decide whether or not to participate in the trial. Questions about the trial should be answered to the satisfaction of the participant or the participant’s legally acceptable representative.
    • Prior to trial participation, the informed consent form should be signed and dated by the participant or by the participant’s legally acceptable representative, where appropriate, by an impartial witness and by the investigator or delegated investigator site staff who conducted the informed consent discussion. By signing the consent form, the investigator or delegated investigator site staff attests that the informed consent was freely given by the participant or the participant’s legally acceptable representative and the consent information was accurately explained to and apparently understood by the participant or the participant’s legally acceptable representative. The informed consent process may involve a physical or an electronic signature and date.
    • In emergency situations, when prior consent of the participant is not possible, the consent of the participant’s legally acceptable representative, if present, should be requested. When prior consent of the participant is not possible and the participant’s legally acceptable representative is not possible and the participant’s legally acceptable representative is not available, enrollment of the participant should require measures described in the protocol and/or elsewhere, with documented approval by the IRB, to protect the participant’s rights, safety and well-being and to ensure compliance with applicable regulatory requirements. The participant or the participant’s legally acceptable representative should be informed about the trial as soon as possible, and consent as appropriate should be requested.
    • If a participant or the legally acceptable representative is unable to read, an impartial witness should be present (remotely or in-person) during the entire informed consent discussion. After the informed consent form and any other information is read and explained to the participant or the participant’s legally acceptable representative, and they have orally consented to the participant’s trial participation, and if capable of doing so, have signed and dated the informed consent form, the witness should sign and date the consent form. By signing the consent form, the witness attests that the consent information was accurately explained to, and apparently understood by, the participant or the participant’s legally acceptable representative, and that informed consent was freely given by the participant or the participant’s legally acceptable representative.
    • The informed consent discussion and the informed consent materials to be provided to participant should explain the following as applicable:
      • The purpose of the trial;
      • That the trial involves research and summary of the experimental aspects of the trial;
      • The trial’s investigational product(s) and the probability for random assignment to the investigational product, if applicable;
      • The trial procedures to be followed, including all invasive procedures;
      • What is expected of the participants;
      • The reasonably foreseeable risks or inconveniences to the participant and, when applicable, the participant’s partner, to an embryo, fetus, or nursing infant;
      • The reasonably expected benefits. When there is no intended clinical benefit to the participant, the participant should be made aware of this;
      • The alternative procedure(s) or course(s) of treatment that may be available to the participant, and their important potential benefits and risks;
      • The compensation and/or treatment available to the participant in the event of trial related injury;
      • Any anticipated prorated compensation to the participant for trial participation;
      • Any anticipated expenses to the participant for trial participation;
      • That the participant’s trial participation is voluntary, and the participant may decide to stop taking the investigational product or withdraw from the trial, at any time, without penalty or loss of benefits to which the participant is otherwise entitled;
      • The follow-up procedure for participants who stopped taking the investigational product, withdrew from the trial or were discontinued from the trial;
      • The process by which the participant’s data will be handled, including in the event of the withdrawal or discontinuation of participation in accordance with applicable regulatory requirements;
      • That by agreeing to participant in the trial, the participant or their legally acceptable representative allows direct access to source records, based on the understanding that the confidentiality of the participant’s medical record will be safeguarded. This access is limited for the purpose of reviewing trial activities and/or reviewing or verifying data and records by the regulatory authority(ies) and the sponsor’s representatives, for example, monitor(s) or auditor(s), and in accordance with applicable regulatory requirements, IRB;
      • That records identifying the participant will be kept confidential and, to the extent permitted by the applicable regulatory requirements, will not be made publicly available. If the results of the trial are published, the participant’s identity will remain confidential. The trial may be registered on publicly accessible and recognized databases, per applicable regulatory requirements;
      • That the participant or the participant’s legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the participant’s willingness to continue trial participation;
      • The person(s) to contact for further trial information and the trial participant’s rights, and whom to contact in the event of suspected trial-related injury;
      • The foreseeable circumstances and/or reasons under which the participant’s trial participation may be terminated.
      • The expected duration of the participant’s trial participation;
      • The approximate number of participants involved in the trial;
      • That trial results and information on the participant’s actual treatment, if appropriate, will be made available to them should they desire it when this information is available from the sponsor.
    • Prior to participation, the participant or the participant’s legally acceptable representative should receive a copy (paper or electronic) of the signed informed consent form and any other informed consent materials provided, in accordance with applicable regulatory requirements. During trial participation, the participant or the participant’s legally acceptable representative should receive a copy of the consent form updates and any other updated informed consent materials provided.
    • When a minor is to be included as a participant, age-appropriate assent information should be provided and discussed with the minor as part of the consent process, and assent from the minor to enroll in the trial should be obtained as appropriate. As process for re-consent should be considered if, during the course of the trial, the minor reaches the age of legal consent, in accordance with applicable regulatory requirements.
    • When a clinical trial includes participant who may only be enrolled in the trial with the consent of the participant’s legally acceptable representative, the participants should be informed about the trial in a manner that facilitates their understanding and, if capable, the participant should sign and date the informed consent form or assent form as appropriate.
11. End of Participation in a Clinical Trial
    • When a participant decides to stop treatment with the investigational product, stop trial visits or completely withdraw from a trial; is discontinued from the trial; or reaches the routine end of the trial, the investigator should follow the protocol and other sponsor instructions to determine appropriate follow-up measures. This may include instructions to avoid unnecessary loss of already collected critical data in accordance with applicable regulatory requirements.
    • Although a participant is not obliged to provide a reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the participant’s rights. The investigator should consider if a discussion with the participant or the participant’s legally acceptable representative is appropriate. This discussion should focus on the reasons for withdrawal to determine if there are ways to address the concerns such that the participant could reconsider withdrawal without unduly influencing the participant’s decision. The investigator or delegated investigator site staff should consider explaining to the participant the value of continuing their participation to minimize trial participants withdrawal. In this process, the investigator should ensure that it does not interfere with the participant’s decision to refuse or withdraw participation at any time.
    • Where relevant, the investigator should inform the participant about the trial results and treatment received when this information is available from the sponsor after unblinding, with due respect to the participant’s preference to be informed.
12. Investigational Product Management
    • Responsibility for investigational product(s), including accountability, handling, dispensing, administration and return, rests with the investigator/institution. The sponsor may facilitate aspects of investigational product management (e.g., by providing forms and technical solutions, such as computerized systems, and arranging distribution of investigational product to trial participants).
    • When the investigator/institution delegates some or all of their activities for investigational product(s) management to a pharmacist or another individual in accordance with local regulatory requirements, the delegated individual should be under the oversight of the investigator/institution.
    • Where the investigator has delegated activities related to investigational product management or aspects of these activities have been facilitated by the sponsor, the level of investigator oversight will depend on a number of factors, including the characteristics of the investigational product, route and complexity of administration, level of existing knowledge about the investigational product’s safety and marketing status.
    • The investigator/institution and/or pharmacist or other appropriate individual, should maintain records of the product’s delivery, the inventory, the use by each participant (including documenting that the participants were provided the doses specified by the protocol), and the return to the sponsor and destruction or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial participants. For authorized medicinal products, alternative approaches to the aforementioned may be considered, in accordance with local regulatory requirements.
    • The investigational product(s) should be stored as specified by the sponsor and in accordance with applicable regulatory requirement(s).
    • The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol.
    • When applicable, the investigator or a person designated by the investigator/institution should explain the correct use of the investigational product(s) to each participant and should check, at intervals appropriate for the trial, that each participant is following the instructions properly.
    • The investigational product may be shipped to the participant’s location or supplied to/dispensed at a location closer to the participant (e.g., at a local pharmacy or local healthcare center). The investigational product may be administered at the participant’s location by investigator site staff, the participant themselves, or a caregiver or a healthcare professional.
    • Investigational product management should be arranged and conducted in accordance with applicable regulatory requirements, and safeguards should be in place to ensure product integrity, product use per protocol and participant safety.
13. Randomization Procedures and Unblinding
    • The investigator should follow the trial’s randomization procedures, if any, and in the case of an investigator-blinded trial, should ensure that the treatment randomization code is broken only in accordance with the protocol. In the case of an emergency, to protect participant safety, the investigator should be prepared and capable from the start of the trial to perform unblinding without undue delay and hinderance. The investigator should promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, emergency unblinding to protect trial participant, unblinding due to an SAE) of the investigational product(s).
14. Records
    • In generating, recording and reporting trial data, the investigator should ensure the integrity of data under their responsibility, irrespective of the media used.
    • The investigator/institution should maintain adequate source records that include pertinent observations on each of the trial participants under their responsibility. Source records should be attributable, legible, contemporaneous, original, accurate and complete. Changes to source records should be traceable, should not obscure the original entry and should be explained if necessary (via an audit trail). The investigator should define what is considered to be a source record(s), the methods of data capture and their location prior to starting the trial and should update this definition when needed. Unnecessary transcription steps in between the source record and the data acquisition tool should be avoided.
    • The investigator should be provided with timely access to data by the sponsor and be responsible for the timely review of data, including relevant data from external sources that can have an impact on, for example, participant eligibility, treatment or safety (e.g., central laboratory data, centrally read imaging data, other institution’s records and, if appropriate, electronic patient-reported outcome (ePRO) data. The protocol may provide exceptions for access, for instance, to protect blinding.
    • The investigator should ensure that data acquisition tools and other systems deployed by the sponsor are used as specified in the protocol or trial-related instructions.
    • The investigator should ensure the accuracy, completeness, legibility and timeliness of the data reported to the sponsor in the data acquisition tools completed by the investigator site (e.g., case report form (CRF)) and in any other required reports (e.g., SAE reports). The investigator should review and endorse the reported data at important milestones agreed upon with the sponsor (e.g., interim analysis).
    • Data reported to the sponsor should be consistent with the source records or the discrepancies explained. Changes or corrections in the reported data should be traceable, should be explained (if necessary) and should not obscure the original entry.
    • The investigator/institution should implement appropriate measures to protect the privacy and confidentiality of personal information or trial participants in accordance with applicable regulatory requirements on personal data protection.
    • Data reported to the sponsor should be identified by an unambiguous participant code that can be tracked back to the identity of the participant by the investigator/institution.
    • For systems deployed by the investigator/institution that maintain and retain trial data/information, the investigator/institution should ensure that such data are protected from unauthorized access, disclosure, dissemination or alteration and from inappropriate destruction or accidental loss.
    • When using computerized systems in a clinical trial, the investigator/institution should do the following:
      • For systems deployed by the investigator/institution, ensure that appropriate individuals have secure and attributable access;
      • For systems deployed by the sponsor, notify the sponsor when access permissions need to be changed or revoked from an individual;
      • For system deployed by the investigator/institution specifically for the purposes of clinical trials, ensure the requirements for computerized systems in section 4 of ICH GCP Annex 1 are addressed proportionate to the risks to participants and to the importance of the data;
      • Where equipment for data acquisition is provided to trial participants by the investigator, ensure that traceability is maintained and participants are provided with appropriate training;
      • Ensure that incidents in the use and operation of computerized systems, which in the investigator/institution’s judgment may have a significant and/or persistent impact on the trial data or system security, are reported to the sponsor and, where applicable, to the IRB.
    • The investigator/institution should maintain the trial records as specified in Appendix C of ICH GCP Annex 1 and as required by the applicable regulatory requirement(s). The investigator/institution should have control of all essential records generated by the investigator/institution before and during the conduct of the trial.
    • The investigator/institution should retain the essential records for the required retention period in accordance with applicable regulatory requirements or until the sponsor informs the investigator/institution that these records are no longer needed, whichever is the longest. The investigator/institution should take measures to ensure availability, accessibility and readability and to prevent unauthorized access and accidental or premature destruction of these records.
    • The investigator/institution should keep the sponsor informed of the name of the person responsible for maintaining the essential records during the retention period; for example, when the investigator site closes or an investigator leaves the site.
    • Upon request of the monitor, auditor, IRB, or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records.
15. Reports
    • Upon completion of the trial, the investigator, where applicable, should inform the institution. The investigator/institution should provide the IRB with a summary of the trial’s outcome, and, if applicable, the regulatory authorities with any required reports.

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DOD Research

Additional Requirements for Department of Defense Research

1. When appropriate, research protocols must be reviewed and approved by the IRB prior to the Department of Defense approval. Consult with the Department of Defense funding component to see whether this is a requirement.
   1. Modifications that significantly change the original protocol (i.e., new primary or secondary aim(s), elimination of safety procedures or addition of new procedures, the addition or removal of protected subject populations) will require that a new scientific review be performed and filed with the IRB before the study can be reapproved. Consult with the Department of Defense funding component to see whether this is a requirement.
2. Civilian researchers attempting to access military volunteers should seek collaboration with a military researcher familiar with service-specific requirements.
3. Employees of the Department of Defense (including temporary, part-time, and intermittent appointments) may not be able to legally accept payments to participate in research and should check with their supervisor before accepting such payments. Employees of the Department of Defense cannot be paid for conducting research while on active duty.
4. Service members must follow their command policies regarding the requirement to obtain command permission to participate in research involving human subjects while on-duty or off-duty.
5. Components of the Department of Defense might have stricter requirements for research-related injury than the DHHS regulations.
6. There may be specific educational requirements or certification required.
7. When assessing whether to support or collaborate with this institution for research involving human subjects, the Department of Defense may evaluate this institution’s education and training policies to ensure the personnel are qualified to perform the research.
8. When research involves U.S. military personnel, policies and procedures require limitations on dual compensation:
   1. Prohibit an individual from receiving pay of compensation for research during duty hours.
   2. An individual may be compensated for research if the participant is involved in the research when not on duty.
   3. Federal employees while on duty and non-Federal persons may be compensated for blood draws for research up to $50 for each blood draw.
   4. Non-Federal persons may be compensated for research participating other than blood draws in a reasonable amount as approved by the IRB according to local prevailing rates and the nature of the research.
9. Surveys performed on DOD personnel must be submitted, reviewed, and approved by the DOD Information Management Control Officer (IMCO) after the research protocol is reviewed and approved by the IRB. When a survey crosses DOD components, additional review is required. Consult with the Department of Defense funding component to coordinate this review.
10. When research involves large scale genomic data (LSGD) collected on DOD-affiliated personnel, additional protections are required:
    1. Additional administrative, technical, and physical safeguards to prevent disclosure of DoD-affiliated personnel’s genomic data commensurate with risk (including secondary use or sharing of de-identified data or specimens)
    2. Research will apply an HHS Certificate of Confidentiality
    3. DoD Component security review
11. Data or information sent to a DOD component under a pledge of confidentiality for exclusively statistical purposes must be used exclusively for statistical purposes and may not be disclosed in identifiable form for any other purpose, except with the informed consent of the respondent.
12. When conducting multi-site research, a formal agreement between institutions is required to specify the roles and responsibilities of each party.
13. The following must be reported to the applicable DOD Component Office of Human Research Protections within 30 days:
    1. When significant changes to the research protocol are approved by the IRB or EC:
       1. Changes to key investigators or institutions.
       2. Decreased benefit or increased risk to participants in greater than minimal risk research.
       3. Addition of vulnerable populations as participants.
       4. Addition of DOD-affiliated personnel as participants.
       5. Change of reviewing IRB.
    2. When the organization is notified by any federal body, state agency, official governing body of a Native American or Alaskan native tribe, other entity, or foreign government that any part of an HRPP is under investigation for cause involving a DOD-supported research protocol.
    3. Any problems involving risks to participants or others, suspension or termination of IRB approval, or any serious or continuing noncompliance pertaining to DOD-supported human participant research.
    4. The results of the IRB’s continuing review, if required.
    5. Change in status when a previously enrolled participant becomes pregnant, or when the researcher learns that a previously enrolled participant is pregnant, and the protocol was not reviewed and approved by the IRB in accordance with 45 CFR 46, Subpart B.
    6. Change in status when a previously enrolled participant becomes a prisoner, and the protocol was not reviewed and approved by the IRB in accordance with 32 CFR 219, Subpart C.
    7. Closure of a DOD-supported study.
14. For human participant research that would not otherwise be approved but presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of pregnant participants, fetuses, or neonates, written approval from the DOD Office for Human Research Protections must be obtained through the DOD Component Office of Human Research Protections prior to research starting.
15. Other specific requirements of the Department of Defense research be found in the “Additional Requirements for Department of Defense (DOD) Research” section in the IRB’s HRP-318 – WORKSHEET – Additional Federal Agency Criteria.

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DOJ Research

Additional Requirements for Department of Justice (DOJ)
Research

Additional Requirements for DOJ Research conducted in the Federal Bureau of Prisons

1. Implementation of Bureau programmatic or operational initiatives made through pilot projects is not considered to be research.
2. The project must not involve medical experimentation, cosmetic research, or pharmaceutical testing.
3. The research design must be compatible with both the operation of prison facilities and protection of human subjects.
4. Investigators must observe the rules of the institution or office in which the research is conducted.
5. Any investigator who is a non-employee of the Bureau of Prisoners must sign a statement in which the investigator agrees to adhere to the requirements of 28 CFR §512.
6. The research must be reviewed and approved by the Bureau Research Review Board.
7. Incentives cannot be offered to help persuade inmate subjects to participate. However, soft drinks and snacks to be consumed at the test setting may be offered. Reasonable accommodations such as nominal monetary recompense for time and effort may be offered to non-confined research subjects who are both: No longer in Bureau of Prisons custody. Participating in authorized research being conducted by Bureau employees or contractors.
8. A non-employee of the Bureau may receive records in a form not individually identifiable when advance adequate written assurance that the record will be used solely as a statistical research or reporting record is provided to the agency.
9. Except as noted in the consent statement to the subject, you must not provide research information that identifies a subject to any person without that subject’s prior written consent to release the information. For example, research information identifiable to a particular individual cannot be admitted as evidence or used for any purpose in any action, suit, or other judicial, administrative, or legislative proceeding without the written consent of the individual to whom the data pertain.
10. Except for computerized data records maintained at an official Department of Justice site, records that contain non-disclosable information directly traceable to a specific person may not be stored in, or introduced into, an electronic retrieval system.
11. If you are conducting a study of special interest to the Office of Research and Evaluation but the study is not a joint project involving Office of Research and Evaluation, you may be asked to provide Office of Research and Evaluation with the computerized research data, not identifiable to individual subjects, accompanied by detailed documentation. These arrangements must be negotiated prior to the beginning of the data collection phase of the project.
12. Required elements of disclosure additionally include:
    1. Identification of the investigators.
    2. Anticipated uses of the results of the research.
    3. A statement that participation is completely voluntary and that the subject may withdraw consent and end participation in the project at any time without penalty or prejudice (the inmate will be returned to regular assignment or activity by staff as soon as practicable).
    4. A statement regarding the confidentiality of the research information and exceptions to any guarantees of confidentiality required by federal or state law. For example, an investigator may not guarantee confidentiality when the subject indicates intent to commit future criminal conduct or harm themselves or someone else, or, if the subject is an inmate, indicates intent to leave the facility without authorization.
    5. A statement that participation in the research project will have no effect on the inmate subject’s release date or parole eligibility.
13. You must have academic preparation or experience in the area of study of the proposed research.
14. The IRB application must include a summary statement, which includes:
    1. Names and current affiliations of the investigators
    2. Title of the study
    3. Purpose of the study
    4. Location of the study
    5. Methods to be employed
    6. Anticipated results
    7. Duration of the study
    8. Number of subjects (staff or inmates) required and amount of time required from each.
    9. Indication of risk or discomfort involved as a result of participation
15. The IRB application must include a comprehensive statement, which includes:
    1. Review of related literature
    2. Detailed description of the research method
    3. Significance of anticipated results and their contribution to the advancement of knowledge
    4. Specific resources required from the Bureau of Prisons
    5. Description of all possible risks, discomforts, and benefits to individual subjects or a class of subjects, and a discussion of the likelihood that the risks and discomforts will actually occur
    6. Description of steps taken to minimize any risks
    7. Description of physical or administrative procedures to be followed to: Ensure the security of any individually identifiable data that are being collected for the study
    8. Destroy research records or remove individual identifiers from those records when the research has been completed
    9. Description of any anticipated effects of the research study on institutional programs and operations
    10. Relevant research materials such as vitae, endorsements, sample consent statements, questionnaires, and interview schedules
16. The IRB application must include a statement regarding assurances and certification required by federal regulations, if applicable.
17. You must assume responsibility for actions of any person engaged to participate in the research project as an associate, assistant, or subcontractor.
18. At least once a year, you must provide the Chief, Office of Research and Evaluation, with a report on the progress of the research.
19. At least 12 working days before any report of findings is to be released, you must distribute one copy of the report to each of the following: the chairperson of the Bureau Research Review Board, the regional director, and the warden of each institution that provided data or assistance.
20. You must include an abstract in the report of findings.
21. In any publication of results, you must acknowledge the Bureau’s participation in the research project.
22. You must expressly disclaim approval or endorsement of the published material as an expression of the policies or views of the Bureau.
23. Prior to submitting for publication, the results of a research project conducted under this subpart, you must provide two copies of the material, for informational purposes only, to the Chief, Office of Research and Evaluation, Central Office, Bureau of Prisons.
24. Other specific requirements of the Department of Justice (DOJ) Research Conducted within the Federal Bureau of Prisons (BOP) can be found in the “Additional Requirements for Department of Justice (DOJ) Research Conducted within the Federal Bureau of Prisons (BOP)” section in the IRB’s HRP-318 – WORKSHEET – Additional Federal Agency Criteria

Additional Requirements for DOJ Research Funded by the National Institute of Justice

1. The project must have a privacy certificate approved by the National Institute of Justice Human Subjects Protection Officer.
2. All investigators and research staff are required to sign employee confidentiality statements, which are maintained by the responsible investigator.
3. The confidentiality statement on the consent document must state that confidentiality can only be broken if the subject reports immediate harm to subjects or others.
4. Under a privacy certificate, investigators and research staff do not have to report child abuse unless the subject signs another consent document to allow child abuse reporting.
5. A copy of all data must be de-identified and sent to the National Archive of Criminal Justice Data, including copies of the informed consent document, data collection instruments, surveys, or other relevant research materials.
   1. At least once a year, the researcher shall provide the Chief, Office of Research and Evaluation, with a report of the progress of the research.
   2. At least 12 working days before any report of findings is to be released, the researcher shall distribute one copy of the report to each of the following: the chairperson of the Bureau Research Review Board, the regional director, and the warden of each institution that provided data or assistance. The researcher shall include an abstract in the report of findings.
   3. In any publication of results, the researcher shall acknowledge the Bureau’s participation in the research project.
   4. The research shall expressly disclaim approval or endorsement of the published material as an expression of the policies or views of the Bureau.
   5. Prior to submitting for publication, the results of a research project conducted under this subpart, the researcher shall provide two copies of the material, for informational purposes only, to the Chief, Office of Research and Evaluation, Central Office, Bureau of Prisons

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ED Research

Additional Requirements for Department of Education (ED) Research

1. Each school at which the research is conducted must provide an assurance that they comply with the Family Educational Rights and Privacy Act (FERPA) and the Protection of Pupil Rights Amendment (PPRA).
2. Provide a copy of all surveys and instructional material used in the research. Upon request parents of children* involved in the research* must be able to inspect these materials.
3. The school in which the research is being conducted must have policies regarding the administration of physical examinations or screenings that the school may administer to students.

* Children are persons enrolled in research not above the elementary or secondary education level, who have not reached the age or majority as determined under state law.

* Research or experimentation program or project means any program or project in any research that is designed to explore or develop new or unproven teaching methods or techniques.

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EPA Research

Additional Requirements for Environmental Protection Agency (EPA) Research

1. Research conducted, supported, or intended to be submitted to EPA is subject to Environmental Protection Agency Regulations.
2. Intentional exposure of pregnant persons or children to any substance is prohibited.
3. Observational research involving pregnant persons and fetuses are subject to additional DHHS requirements for research involving pregnant persons (45 CFR §46 Subpart B) and additional DHHS requirements for research involving children (45 CFR §46 Subpart D.)
4. Research involving children must meet category #1 or #2.

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Single IRB Basics

The National Institutes of Health expects that all sites participating in multi-site studies involving non-exempt human subjects research funded by the NIH will use a single Institutional Review Board (sIRB) to conduct the ethical review required by the Department of Health and Human Services regulations for the Protection of Human Subjects at 45 CFR Part 46.

• This policy applies to the domestic sites of NIH-funded multi-site studies where each site will conduct the same protocol involving non-exempt human subjects research, whether supported through grants, cooperative agreements, contracts, or the NIH Intramural Research Program. It does not apply to career development, research training or fellowship awards.
• This policy applies to domestic awardees and participating domestic sites. Foreign sites participating in NIH-funded, multi-site studies will not be expected to follow this policy.
• Exceptions to the NIH policy will be made where review by the proposed sIRB would be prohibited by a federal, tribal, or state law, regulation, or policy. Requests for exceptions that are not based on a legal, regulatory, or policy requirement will be considered if there is a compelling justification for the exception. The NIH will determine whether to grant an exception following an assessment of the need.

The Office for Human Research Protections expects that all sites located in the United States participating in cooperative research must rely upon approval by a single IRB for that portion of the research that is conducted in the United States. The reviewing IRB will be identified by the Federal department or agency supporting or conducting the research or proposed by the lead institution subject to the acceptance of the Federal department or agency supporting the research.

The following research is not subject to this provision:

1. Cooperative research for which more than single IRB review is required by law (including tribal law passed by the official governing body of an American Indian or Alaska Native tribe); or
2. Research for which any Federal department or agency supporting or conducting the research determines and documents that the use of a single IRB is not appropriate for the particular context.
3. For research not subject to paragraph (b) of this section, an institution participating in a cooperative project may enter into a joint review arrangement, rely on the review of another IRB, or make similar arrangements for avoiding duplication of effort.

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