This section of the Investigator Manual outlines additional regulatory requirements that may apply to research. Other specific requirements can be found in the IRB’s HRP-318 – WORKSHEET – Additional Federal Agency Criteria.


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.

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 he or she 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.

Clinical Trials and ICH-GCP

Additional Requirements for Clinical Trials obligated to follow ICH-GCP through contract/funding agreement commitments

(Investigator decision guidance here)

  1. Investigator’s Qualifications and Agreements
    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 and the applicable regulatory requirements.
    2. 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 through up-to-date curriculum vitae and/or other relevant documentation requested by the sponsor, the IRB, and/or the regulatory authorities.
    3. The investigator should be thoroughly familiar with the appropriate use of the investigational product, as described in the protocol, in the current Investigator’s Brochure, in the product information and in other information sources provided by the sponsor.
    4. The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.
    5. The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authorities.
    6. The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.
  2. Adequate Resources
    1. The investigator should be able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of suitable subjects within the agreed recruitment period.
    2. The investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period.
    3. The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.
    4. The investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product, and their trial-related duties and functions.
  3. Medical Care of Trial Subjects
    1. A qualified physician (or dentist, when appropriate), who is an investigator or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.
    2. During and following a subject’s participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial. The investigator/institution should inform a subject when medical care is needed for intercurrent illnesses of which the investigator becomes aware.
    3. It is recommended that the investigator inform the subject’s primary physician about the subject’s participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.
    4. Although a subject is not obliged to give his/her reasons for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reasons, while fully respecting the subject’s rights.
  4. Communication with IRB
    1. Before initiating a trial, the investigator/institution should have written and dated approval opinion from the IRB for the trial protocol, written informed consent form, consent form updates, subject recruitment procedures (e.g., advertisements), and any other written information to be provided to subjects.
    2. As part of the investigator’s/institution’s written application to the IRB, the investigator/institution should provide the IRB with a current copy of the Investigator’s Brochure. If the Investigator’s Brochure is updated during the trial, the investigator/institution should supply a copy of the updated Investigator’s Brochure to the IRB.
    3. During the trial the investigator/institution should provide to the IRB all documents subject to review.
  5. Compliance with Protocol
    1. The investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authorities and which was given approval opinion by the IRB. The investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm agreement.
    2. The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval opinion from the IRB of a modification, except where necessary to eliminate an immediate hazards to trial subjects, or when the changes involves only logistical or administrative aspects of the trial (e.g., change in monitors, change of telephone numbers).
    3. The investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol.
    4. The investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard to trial subjects without prior IRB approval opinion. As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol modifications should be submitted: a) to the IRB for review and approval opinion, b) to the sponsor for agreement and, if required, c) to the regulatory authorities.
  6. Investigational Product
    1. Responsibility for investigational product accountability at the trial site rests with the investigator/institution.
    2. Where allowed/required, the investigator/institution may/should assign some or all of the investigator’s/institution’s duties for investigational product accountability at the trial site to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution.
    3. The investigator/institution and/or a pharmacist or other appropriate individual, who is designated by the investigator/institution, should maintain records of the product’s delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product. These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product and trial subjects. Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product received from the sponsor.
    4. The investigational product should be stored as specified by the sponsor and in accordance with applicable regulatory requirements.
    5. The investigator should ensure that the investigational product is used only in accordance with the approved protocol.
    6. The investigator, or a person designated by the investigator/institution, should explain the correct use of the investigational product to each subject and should check, at intervals appropriate for the trial, that each subject is following the instructions properly.
    7. Randomization Procedures and Unblinding: The investigator should follow the trial’s randomization procedures, if any, and should ensure that the code is broken only in accordance with the protocol. If the trial is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational product.
  7. Informed Consent of Trial Subjects
    1. In obtaining and documenting informed consent, 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. Prior to the beginning of the trial, the investigator should have the IRB’s written approval opinion of the written informed consent form and any other written information to be provided to subjects.
    2. The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised written informed consent form, and written information should receive the IRB’s approval opinion in advance of use. The subject or the subject’s legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject’s willingness to continue participation in the trial. The communication of this information should be documented.
    3. Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial.
    4. None of the oral and written information concerning the trial, including the written informed consent form, should contain any language that causes the subject or the subject’s legally acceptable representative 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 agents from liability for negligence.
    5. The investigator, or a person designated by the investigator, should fully inform the subject or, if the subject is unable to provide informed consent, the subject’s legally acceptable representative, of all pertinent aspects of the trial including the written information and the approval opinion by the IRB.
    6. The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to the subject or the subject’s legally acceptable representative and the impartial witness, where applicable.
    7. Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the subject or the subject’s legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the trial should be answered to the satisfaction of the subject or the subject’s legally acceptable representative.
    8. Prior to a subject’s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject’s legally acceptable representative, and by the person who conducted the informed consent discussion.
    9. If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. After the written informed consent form and any other written information to be provided to subjects, is read and explained to the subject or the subject’s legally acceptable representative, and after the subject or the subject’s legally acceptable representative has orally consented to the subject’s participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject’s legally acceptable representative, and that informed consent was freely given by the subject or the subject’s legally acceptable representative.
    10. Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of the following:
      1. That the trial involves research.
      2. The purpose of the trial.
      3. The trial treatments and the probability for random assignment to each treatment.
      4. The trial procedures to be followed, including all invasive procedures.
      5. The subject’s responsibilities.
      6. Those aspects of the trial that are experimental.
      7. The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant.
      8. The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this.
      9. The alternative procedures or courses of treatment that may be available to the subject, and their important potential benefits and risks.
      10. The compensation and/or treatment available to the subject in the event of trial related injury.
      11. The anticipated prorated payment, if any, to the subject for participating in the trial.
      12. The anticipated expenses, if any, to the subject for participating in the trial.
      13. That the subject’s participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled.
      14. That the monitors, the auditors, the IRB, and the regulatory authorities will be granted direct access to the subject’s original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject’s legally acceptable representative is authorizing such access.
      15. That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the subject’s identity will remain confidential.
      16. That the subject or the subject’s legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject’s willingness to continue participation in the trial.
      17. The persons to contact for further information regarding the trial and the rights of trial subjects, and whom to contact in the event of trial-related injury.
      18. The foreseeable circumstances and/or reasons under which the subject’s participation in the trial may be terminated.
      19. The expected duration of the subject’s participation in the trial.
      20. The approximate number of subjects involved in the trial.
    11. Prior to participation in the trial, the subject or the subject’s legally acceptable representative should receive a copy of the signed and dated written informed consent form and any other written information provided to the subjects. During a subject’s participation in the trial, the subject or the subject’s legally acceptable representative should receive a copy of the signed and dated consent form updates and a copy of any modifications to the written information provided to subjects.
    12. When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject’s legally acceptable representative (e.g., minors, or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject’s understanding and, if capable, the subject should sign and personally date the written informed consent.
    13. Except as described above, a non-therapeutic trial (i.e. a trial in which there is no anticipated direct clinical benefit to the subject), should be conducted in subjects who personally give consent and who sign and date the written informed consent form.
    14. Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled: a) The objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally. b) The foreseeable risks to the subjects are low. c) The negative impact on the subject’s well-being is minimized and low. d) The trial is not prohibited by law. e) The approval opinion of the IRB is expressly sought on the inclusion of such subjects, and the written approval opinion covers this aspect. Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.
    15. In emergency situations, when prior consent of the subject is not possible, the consent of the subject’s legally acceptable representative, if present, should be requested. When prior consent of the subject is not possible, and the subject’s legally acceptable representative is not available, enrolment of the subject should require measures described in the protocol and/or elsewhere, with documented approval opinion by the IRB, to protect the rights, safety and well- being of the subject and to ensure compliance with applicable regulatory requirements. The subject or the subject’s legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate should be requested.
  8. Records and Reports
    1. The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports.
    2. Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained.
    3. Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry (i.e. an audit trail should be maintained); this applies to both written and electronic changes or corrections. Sponsors should provide guidance to investigators and/or the investigators’ designated representatives on making such corrections. Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor’s designated representatives are documented, are necessary, and are endorsed by the investigator. The investigator should retain records of the changes and corrections.
    4. The investigator/institution should maintain the trial documents as specified in Essential Documents for the Conduct of a Clinical Trial and as required by the applicable regulatory requirements. The investigator/institution should take measures to prevent accidental or premature destruction of these documents.
    5. Essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained.
    6. The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.
    7. Upon request of the monitor, auditor, IRB, or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records.
  9. Progress Reports
    1. The investigator should submit written summaries of the trial status to the IRB annually, or more frequently, if requested by the IRB.
    2. The investigator should promptly provide written reports to the sponsor, the IRB and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or increasing the risk to subjects.
  10. Safety Reporting
    1. All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator’s Brochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects’ names, personal identification numbers, and/or addresses. The investigator should also comply with the applicable regulatory requirements related to the reporting of unexpected serious adverse drug reactions to the regulatory authorities and the IRB.
    2. Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol.
    3. For reported deaths, the investigator should supply the sponsor and the IRB with any additional requested information (e.g., autopsy reports and terminal medical reports).
    4. 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 subjects, should assure appropriate therapy and follow-up for the subjects, and, where required by the applicable regulatory requirements, should inform the regulatory authorities. In addition:
      1. If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the IRB, and should provide the sponsor and the IRB a detailed written explanation of the termination or suspension.
      2. If the sponsor terminates or suspends a trial, the investigator should promptly inform the institution where applicable and the investigator/institution should promptly inform the IRB and provide the IRB a detailed written explanation of the termination or suspension.
      3. If the IRB terminates or suspends its approval opinion of a trial, the investigator should inform the institution where applicable and the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.
  11. Final Reports by Investigator: 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 the regulatory authorities with any reports required.

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. 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
  10. DoD Component security review
  11. When conducting multi-site research, a formal agreement between institutions is required to specify the roles and responsibilities of each party.

DOE Research

Additional Requirements for Department of Energy (DOE) Research

(See DOE Order 443.1C)

  1. Research that involves one or more of the following must be submitted to the appropriate IRB for human subjects research review and determination:
    1. Study of humans in a systematically modified environment. These studies include but are not limited to intentional modification of the human environment:
      1. Study of human environments that use tracer chemicals, particles or other materials to characterize airflow.
      2. Study in occupied homes or offices that:
        1. Manipulate the environment to achieve research aims.
        2. Test new materials.
        3. Involve collecting information on occupants’ views of appliances, materials, or devices installed in their homes or their energy-saving behaviors through surveys and focus groups.
    2. Use of social media data.
    3. Human Terrain Mapping (HTM).
    4. All exempt HSR determinations must be made by the appropriate IRB and/or IRB office.
  2. Personally identifiable information collected and/or used during HSR projects must be protected in accordance with the requirements of DOE Order 206.1, Department of Energy Privacy Program, current version. The Central DOE IRBs require submission of DOE’s HRP- 490- CHECKLIST-Reviewing Protocols that use Personally Identifiable Information (PII) if your research includes PII.
  3. You must report the following to the DOE human subjects research Program Manager (and, when an NNSA element is involved, the NNSA HSP Program Manager) prior to initiation of any new human subjects research project, even if it meets the regulatory definition of exempt human subjects research as outlined in 10 CFR Part 745.104, involving:
    1. An institution without an established Institutional Review Board (IRB);
    2. A foreign country;
    3. The potential for significant controversy (e.g., negative press or reaction from stakeholder or oversight groups);
    4. Research subjects in a protected class (prisoners, children, individuals with impaired decision making capability, or DOE/NNSA federal or DOE/NNSA contractor employees as human subjects, who may be more vulnerable to coercion and undue influence to participate) that is outside of the reviewing IRB’s typical range/scope; or
    5. The generation or use of classified information.
  4. The IRB must be notified immediately and the DOE HSP Program Manager (and, when an NNSA element is involved, the NNSA HSP Program Manager) must be notified within 48 hours and consulted regarding planned corrective actions if any of the following occur:
    1. Adverse events. Notify the IRB for all adverse events and the DOE/NNSA HSP Program Manager if the IRB determines them to be significant, as defined in DOE Order 443.1C.
    2. Unanticipated problems and complaints about the research.
    3. Any suspension or termination of IRB approval of research.
    4. Any significant noncompliance with HSP Program procedures or other requirements.
    5. Any finding of a suspected or confirmed data breach involving PII in printed or electronic form. Report immediately to the IRB, the DOE/NNSA HSP Program Manager(s), and the DOE-Cyber Incident Response Capability, in accordance with the requirements of the CRD associated with DOE O 206.1.
    6. Serious adverse events and corrective actions taken must be reported immediately to the IRB and the DOE/NNSA HSP Program Manager(s). The time frame for “immediately” is defined as upon discovery.
  5. Requirements for human participant protections for classified research apply to all classified research conducted or supported by the DOE and its national laboratories, including contracts, and including Human Terrain Mapping research.
  6. Researchers conducting human subjects research in any other country or on citizens or other individuals residing in that country must be cognizant of country-specific human subjects research requirements and consult the IRB regarding applicability of such requirements.
  7. No human subjects research conducted with DOE funding, at DOE institutions (regardless of funding source), or by DOE or DOE contractor personnel (regardless of funding source or location conducted), whether done domestically or in an international environment, including classified and proprietary research, may be initiated without both a Federalwide Assurance (FWA) or comparable assurance (e.g., Department of Defense assurance) of compliance and approval by the cognizant Institutional Review Board (IRB) in accordance with 10 CFR §745.103. Human subjects research involving multiple DOE sites (e.g., members of the research team from more than one DOE site and/or data or human subjects from more than one DOE site) must be reviewed and approved by one of the Central DOE IRBs prior to initiation, or if authorized by the DOE and/or NNSA HSP Program Manager, other appropriate IRB of record. In all cases, an IRB Authorization Agreement (IAA) or Memorandum of Understanding (MOU) must be in place between the organization(s) conducting the HSR and the organization responsible for IRB review.
  8. Human subjects research that involves DOE Federal and/or contractor employees must first be reviewed and approved by the appropriate DOE IRB (the DOE site IRB or one of the Central DOE IRBs), or if deemed more fitting by the Federally assured DOE site or Headquarters, other appropriate IRB of record, in accordance with an IAA or MOU negotiated between the DOE site or Headquarters and the organization responsible for IRB review.
  9. Classified and unclassified human subjects research that is funded through the Strategic Intelligence Partnership Program (SIPP) must be reviewed and approved by the Central DOE IRB- Classified.
  10. If applicable, federally funded HSR must comply with the requirements of the Paperwork Reduction Act.

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 himself or herself 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

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.

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.

Single IRB Basics

  • That 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.

EU GDPR

Additional Requirements for Research Subject to EU General Data Protection Regulations (GDPR)

  1. Human Research involving personal data about individuals located in (but not necessarily citizens of) European Union member states, Norway, Iceland, Liechtenstein, and Switzerland is subject to EU General Data Protection Regulations.
  2. For all prospective Human Research subject to EU GDPR, contact the IRB Office or institutional legal counsel to ensure that the following elements of the research are consistent with institutional policies and interpretations of EU GDPR:
    1. Any applicable study design elements related to data security measures.
    2. Any applicable procedures related to the rights to access, rectification, and erasure of data.
    3. Procedures related to broad/unspecified future use consent for the storage, maintenance, and secondary research use of identifiable private information or identifiable biospecimens.
  3. Where FDA or DHHS regulations apply in addition to EU GDPR regulations, ensure that procedures related to withdrawal from the research, as well as procedures for managing data and biospecimens associated with the research remain consistent with the DHHS and FDA appendix sections.