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Appendix A-2 Additional Requirements for USFDA-Regulated Research

  1. The FDA defines a human subject as: An individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient. A human subject includes an individual on whose specimen an investigational medical device is used. When medical device research involves in vitro diagnostics and unidentified tissue specimens, the FDA defines the unidentified tissue specimens as human subjects.
  2. When a subject withdraws from a study:[1]
    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 participant who is withdrawing whether the participant 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 participant 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 participant’s information.
    3. If a participant 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 participant’s medical record or other confidential records requiring the participant’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.
  3. For USFDA-regulated research involving investigational drugs:
    1. Investigators must abide by USFDA restrictions on promotion of investigational drugs:[2]
      1. For clinical investigations requiring an Investigational New Drug (IND), the IRB will not approve the investigation until one of the following are satisfied:
        1. The IRB receives evidence that an IND has been approved (e.g. including an IND number on the protocol or other sponsor document); or
        2. The IRB receives evidence that an IND application was received by the USFDA and 30 calendars days have elapsed with no communication(s) from the USFDA. (Note: The IND goes into effect 30 days after the USFDA receives the IND application, unless the sponsor receives earlier notice from the USFDA).
      2. 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.
      3. 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.
      4. An investigator must not commercially distribute or test market an investigational new drug.
    2. Follow USFDA requirements for general responsibilities of investigators[3]
      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.
      3. Additional specific responsibilities of clinical investigators are set forth in this part and in 21 CFR §50 and 21 CFR §56.
    3. Follow USFDA requirements for control of the investigational drug[4]
      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 USFDA requirements for investigator recordkeeping and record retention[5]
      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 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 USFDA requirements for Expanded Access to Investigational Drugs for Treatment Use per 21 CFR 312.300 (Subpart I). This is often referred to as “compassionate use”. The aim of this subpart is to facilitate the availability of investigational new drugs and approved drugs to patients with serious diseases or conditions when there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the patient’s disease or condition. Expanded access to investigational drugs requires prior IRB review and approval (with the exception of Emergency Use).
    6. Follow USFDA requirements for investigator reports[6]
      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 possibly 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 the 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.
    7. Follow USFDA requirements for assurance of IRB review[7]
      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 they will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.
    8. Follow USFDA requirements for inspection of investigator's records and reports[8]
      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, 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.
    9. Follow USFDA requirements for handling of controlled substances[9]
      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.
  4. For USFDA-regulated research involving investigational devices:
    1. General responsibilities of investigators.[10]
      1. An investigator is responsible for ensuring that an investigation is conducted according to the signed agreement, the investigational plan and applicable USFDA 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[11]
      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 USFDA approval.
        1. When the IRB determines an Investigational Device Exemption (IDE) is required for a clinical investigation, the IRB will not approve the investigation until one of the following are satisfied:
          1. The IRB receives a copy of a letter from the USFDA indicating that an IDE has been approved; or
          2. The IRB receives evidence that an IDE application was received by the USFDA and 30 days have elapsed with no communication(s) from the USFDA. (Note: The IDE goes into effect 30 days after the USFDA receives the IDE application, unless the sponsor receives earlier notice from the USFDA).
      2. Compliance: An investigator must conduct an investigation in accordance with the signed agreement with the sponsor, the investigational plan, and other applicable USFDA regulations, and any conditions of approval imposed by an IRB or USFDA.
      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:[12]
      1. All correspondence with another investigator, an IRB, the sponsor, a monitor, or USFDA, 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 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 USFDA requires to be maintained by regulation or by specific requirement for a category of investigations or a particular investigation.
    4. Inspections[13]
      1. Entry and inspection: A sponsor or an investigator who has authority to grant access must permit authorized USFDA 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 USFDA 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 USFDA employees to inspect and copy records that identify subjects, upon notice that USFDA 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:[14]
      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, USFDA and IRB in accordance with § 812.35(a) is also is required.
        4. 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.
        5. 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.
        6. Other. An investigator must, upon request by a reviewing IRB or USFDA, provide accurate, complete, and current information about any aspect of the investigation.

[1] http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126489.pdf

[2] http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.7

[3] http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.60

[4] http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.61

[5] http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.62

[6] http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.64

[7] http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.66

[8] http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.68

[9] http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.69

[10] http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=812.100

[11] http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=812.110

[12] http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=812.140

[13] http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=812.145

[14] http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=812.150