Chapter 16: FDA-Regulated Research

An Investigational New Drug (IND) application is the FDA regulatory mechanism by which a sponsor can ship an unapproved drug or biologic to study sites and initiate clinical research on the drug. The FDA assigns an IND number and allows the investigation to begin after it determines that research participants will not be exposed to unreasonable risk. An IND application is required for:

• • Testing of unapproved drugs

• • Testing of approved drugs that involves new indications or significant labeling changes

IND regulations are found at 21 CFR 312.

Investigators must describe the regulatory status of each study drug in the iStar application as well as rationale for determining whether or not an IND is required for the study. If a drug is covered by an IND, the IND number and documentation of the IND number must be provided. Documentation may include FDA correspondence to the sponsor that provides the IND number, or a clinical protocol or investigator’s brochure that identifies the IND number. The IRB staff verifies that there is an IND number and that the number provided in the iStar application is correct. The study will not be approved until the IND number is verified.

Certain drug investigations may be exempt from the requirement for an IND. A clinical investigation of a marketed drug is exempt from the IND requirements if all of the criteria are met:

• • The drug product is lawfully marketed in the United States

• • The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication and there is no intent to use it to support any other significant change in the labeling of the drug

• • In the case of a prescription drug, the investigation is not intended to support a significant change in the advertising for the drug

• • The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product

• • The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR 56) and with the requirements for informed consent (21 CFR 50)

• • The investigation is conducted in compliance with the requirements of 21 CFR 312.7 (the investigation is not intended to promote or commercialize the drug product)

Investigations of marketed drugs or biologics must have an IND if none of the exemptions described above apply. When the principal intent of the investigation is to develop information about an approved product’s safety or efficacy, IRB approval and an IND are required.

Additional information about exemptions from IND requirements is found in the FDA guidance document “Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND.”

The IRB will determine if the IND exemption proposed in the iStar application is consistent with FDA regulations and guidance. The committee determination will be recorded in the meeting minutes. If there is no IND and the study does not meet any of the FDA exemption categories, the IRB will not approve the study. The investigator may re-submit the iStar application after obtaining an IND number from the FDA or obtaining a written determination from the FDA that no IND is needed.

When there is a question as to whether the use of a marketed drug or biologic for an unapproved indication requires an IND, the investigator should contact the FDA directly for a determination. The IRB may require that an investigator contact the FDA, if this has not been done, at the time of IRB review. If the FDA indicates that an IND is not required, documentation of contact with the FDA is required. This may be either a written notification from the FDA, or documentation of contact with the FDA, including who was contacted, the phone number, the time of the call, and a summary of the information provided by the FDA.

Off-Label Use

An IND is not required when a health care provider prescribes a marketed drug to treat an individual patient for an unlabeled indication. This is referred to as “off-label”, meaning the treatment is being used in a manner not specified in the FDA’s approved packaging label or insert. An IND is not required because this use falls within the scope of medical practice and it is not research.

Expanded Access of Investigational Drugs

The use of investigational drugs and biologics is usually limited to subjects enrolled in clinical trials under an IND. However, investigational products may show some promise before the trials are completed. When there is no satisfactory standard treatment for a serious, life-threatening, or debilitating condition, the FDA has a mechanism that allows expanded access to investigational drugs before the clinical trials are complete. When no satisfactory alternative treatment exists, subjects are generally willing to accept greater risks from investigational drugs that have potential benefits.

Expanded access to investigational drugs requires an IND and prospective IRB approval. In some cases, the sponsor will have an expanded access protocol under an existing IND. In other cases, an investigator may have to obtain a new IND for expanded access to an investigational drug. A new IND is needed if there is no existing IND or if the sponsor does not want to amend an existing IND to include expanded access. The following mechanisms expand access to promising therapeutic agents without compromising the protection afforded to human subjects or the thoroughness and scientific integrity of product development and marketing approval.

Individual Expanded Access Involving Investigational New Drugs

Individual Expanded Access allows physicians access to investigational drugs and biologics for the treatment of a single patient (21 CFR 56.111). The Individual Patient Expanded Access Investigational New Drug Application – Form FDA 3926, may be completed to request access to investigational treatments for patients when there is no other option to treat their serious disease or condition. Still available for use are Form 1571 and Form 1572 for single patient expanded access submissions; however, Form 3926 is developed specifically for these requests and is easier to complete. When submitting an expanded access IND for single patient using Form 3926 a check box (10.b.) is available to request a waiver of full board IRB review. The waiver may be granted by the IRB chairperson or another designated IRB member before treatment use begins. The USC IRB submission must include the:

• • Investigator Brochure or other source of information to determine risks and potential benefits

• • Draft Informed Consent document

• • Form FDA 3926
    Completed FDA Form 3926

Expanded access for intermediate-size patient populations and widespread use of a treatment IND require USC IRB submission with Form 1571 or Form 1572. Information describing expanded access categories can be found on the FDA website.

The IRB will determine whether the criteria for approval have been met based on the applicable regulations (21 CFR 56, 21 CFR 312.305 and 312.310).

When the patient is a child provisions of 21 CFR 50.52 must be met to assure that the anticipated benefit to risk is at least as favorable to the child as available alternative treatment.

If the patient is considered vulnerable to coercion or undue influence additional safeguards should be included in the treatment plan to protect the rights and welfare of the patient.

The following links provide additional information:

• • For Physicians: A Guide to Non-emergency Single Patient Expanded Access Submissions
  • Expanded Access (Compassionate Use)
  • Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers Guide for Industry

Right to Try Act (S. 204)

In May 2018, the Federal Right to Try Act was signed into law, creating a federal framework for patients to access new investigational drugs and biological products outside of clinical trials and outside of the U.S. Food and Drug Administration’s (FDA) expanded access program. The federal law enables manufacturers and physicians to provide investigational drugs to eligible patients without risk of liability. It follows California’s passage of the State’s Right to Try Act, signed into law in 2016. Similar to the federal law, the California law enables manufacturers and physicians to provide investigational products to eligible patients without risk of liability under state law.

Both the federal and state right to try laws enable patients meeting certain criteria under each law to receive access to investigational products without FDA oversight. However, the laws differ in fundamental ways that should be considered before providing an investigational product to a patient without FDA authorization. 

USC IRB will abide by:

• The requirement for IRB review and approval for all Right to Try uses at USC.
• The stricter California Right to Try law requirements.
• The federal law and does not allow treatments using investigational devices under the Right to Try Act. USC will abide by the limits imposed by the federal law. If the treating physician wishes to pursue use of a device, refer to FDA Expanded Access.

Physician’s Responsibilities

Treating physicians must comply with the following:

• Seek permission from the product manufacturer to provide the investigational drugs or biologics. Note, there is no law that requires a manufacturer to make its product available outside of clinical trials.
• Provide the proposed treatment plan, including total cost of treatment and care, provisions for safety, monitoring, and collecting data.
• Obtain a concurrence in writing from an uninvolved physician with the use of the test article.
• Attest that the patient has an “Immediately life-threatening disease or condition” meaning a stage of disease in which there is a reasonable likelihood that death will occur within a matter of months.
• Attest that the patient has not been accepted to participate in the nearest clinical trial to their home for the immediately life-threatening disease or condition within one week of completion of the clinical trial application process, or, in the treating physician’s medical judgment, it is unreasonable for the patient to participate in that clinical trial due to the patient’s current condition and stage of disease.
• The “Investigational drug or biological product” is a drug or biological product that has successfully completed phase one of a clinical trial approved by the United States Food and Drug Administration (FDA), but has not been approved for general use by the FDA and remains under investigation in a clinical trial approved by the FDA.
• Obtain written informed consent from the eligible patient or their legally authorized representative. Consent provided by a patient’s legally authorized representative must meet the requirement and conditions under the Protection of Human Subjects in Medical Experimentation Act.
• All other FDA approved treatment options have been exhausted/considered.
• The treating physician is in good standing with the physician’s licensing organization or board
• The treating physician will not be compensated directly by the manufacturer.
• Ensure patient understands financial and health care considerations outlined in consent form.
• The treating physician must provide the following in a biannually report to the IRB:
• Duration of patient treatment
• Cost of treatment paid
• The success or failure of the investigational drug or biological product, in treating the immediately life-threatening disease or condition from which the patient suffers.
• Any adverse event during treatment

Other Local Responsibilities

Necessary collaboration with the following entities will depend upon the individual sponsor and requirements for the drug or biologic.

• Consult with USC Clinical Trials Office (CTO) to determine whether an agreement is necessary with the sponsor/manufacturer and determine if any billing implications exist.
• Consult with USC Stevens Center for Innovation to determine the need for a Materials Transfer Agreement.
• Contact Investigational Drug Services pharmacy regarding receipt and storage of product.

Treating physicians should not confuse Right to Try, with the FDA’s Expanded Access program for drugs, biologics, or medical devices.

IRB Responsibilities

The USC IRB will evaluate the following for each Right to Try application received:

• The proposed treatment plan is for the use of a drug or biological product that has successfully completed phase one of a clinical trial approved by the FDA, but has not been approved for general use by the FDA and remains under investigation in a clinical trial approved by the FDA.
• The treating physician’s treatment plan makes adequate provisions for ensuring the safety of the patient, including monitoring (e.g., types of tests/exams, etc.) and appropriate plans for collecting reporting data.
• The treating physician has attested that the patient meets the eligibility criteria.
• The treating physician has attested that a consulting physician has concurred in writing with the use of the test article for the patient.
• Ensure that the treating physician will follow standard medical practice to protect the privacy interests of the patient.
• The written informed consent to ensure it is consistent with the informed consent requirements of the Protection of Human Subjects in Medical Experimentation Act.

Please contact the USC IRB with questions with regard to submitting a Right to Try application at hrpp@usc.edu or (323) 442-0114. 

Right to Try applications will receive appropriate IRB chair/designee review and concurrence with full IRB review prior to IRB acknowledgment.

 Right to Try Informed Consent Requirements

The USC Right to Try informed consent template is available on the HRPP website.

The USC consent form must contain the following information:

• The patient, or when the patient lacks the capacity to consent their legally authorized representative (LAR), must attest that they concur with the treating physician in believing that all currently approved and conventionally recognized treatments are unlikely to prolong the patient’s life.
• Clearly identifies the specific proposed investigational drug or biological product that the patient is seeking to use.
• Describes the potentially best and worst outcomes of using the investigational drug or biological product and describes the most likely outcome. This description shall include the possibility that new, unanticipated, different, or worse symptoms might result, and that death could be hastened by the proposed treatment. The description shall be based on the treating physician’s knowledge of the proposed treatment in conjunction with an awareness of the patient’s condition.
• Clearly states that the patient’s health benefit plan, if any, and health care provider are not obligated to pay for the investigational drug or biological product or any care or treatments consequent to use of the investigational drug or biological product.
• States that the patient understands that he or she is liable for all expenses consequent to the use of the investigational drug or biological product and that this liability extends to the patient’s estate, except as otherwise provided in the patient’s health benefit plan or a contract between the patient and the manufacturer of the drug or biological product.
• Clearly states that the patient’s eligibility for hospice care may be withdrawn if the patient begins curative treatment and that care may be reinstated if the curative treatment ends and the patient meets hospice eligibility requirements.
• Clearly states that in-home health care may be denied if treatment begins.

The USC HIPAA Authorization to Use Health Information for Research form is not required to be signed by patients, or their LAR, unless non-covered components of USC will have access to Protected Health Information (PHI). 

Treatment IND

A treatment protocol added to an existing IND is called a “treatment IND.” The treatment IND 21 CFR 312.34 and 312.35 is a mechanism for providing eligible subjects with investigational drugs for the treatment of serious and life-threatening illnesses for which there are no satisfactory alternative treatments. A treatment IND may be granted after sufficient data have been collected to show that the drug may be effective and does not have unreasonable risks. Because data related to safety and side effects are collected, treatment INDs also serve to expand the body of knowledge about the drug.

There are four requirements that must be met before a treatment IND can be issued:

• • The drug is intended to treat a serious or immediately life-threatening disease

• • There is no satisfactory alternative treatment available

• • The drug is already under investigation, or trials have been completed

• • The trial sponsor is actively pursuing marketing approval

Treatment IND studies require prospective IRB review and informed consent.

Open Label Protocol or Open Protocol IND

These protocols are usually uncontrolled studies, carried out to obtain additional safety data (Phase 3 studies). They are typically used when the controlled trial has ended, and treatment is continued to enable the subjects and the controls to continue to receive the benefits of the investigational drug until marketing approval is obtained. These studies require prospective IRB review of the protocol and informed consent.

Open Label Protocol or Open Protocol IND

These protocols are usually uncontrolled studies, carried out to obtain additional safety data (Phase 3 studies). They are typically used when the controlled trial has ended, and treatment is continued to enable the subjects and the controls to continue to receive the benefits of the investigational drug until marketing approval is obtained. These studies require prospective IRB review of the protocol and informed consent.

Parallel Track

The FDA’s Parallel Track policy 57 FR 13250 permits wider access to promising new drugs for AIDS/HIV-related diseases under a separate “expanded access” protocol that “parallels” the controlled clinical trials that are essential to establishing the safety and effectiveness of new drugs. It does so by providing an administrative system that expands the availability of drugs for treating AIDS/HIV. These studies require prospective IRB review and informed consent.

USC investigators who initiate and submit IND or IDE applications to the FDA assume the responsibilities of both the investigator and the sponsor. Sponsor-Investigators must provide FDA documentation of their IND or IDE in the iStar application.

Sponsor-Investigators are required to complete and sign the USC Sponsor-Investigator Agreement Form and upload to the iStar application. This agreement serves as an assurance that the investigator will review, be cognizant of, and comply with regulatory requirements of sponsor-investigators. The IRB may require the PI to receive training / education from the IRB Chair, an experienced IRB member, or other designee before beginning the research. FDA requirements and application links for an IDE and IND are listed below.

IDE

A sponsor-investigator for an IDE protocol needs to submit an FDA IDE Application and must follow the FDA regulations in 21 CFR 812 applicable to sponsor responsibilities. This includes:

• • The record keeping requirements of 21 CFR 812.140(b)

• • The reporting requirements of 21 CFR 812.150(b) including annual IDE progress report to the IRB (and annual progress report to FDA if the IDE is for a significant risk device)

• • The required notification under 21 CFR 812.150(b)(1) to the FDA and all participating investigators of any evaluation of an unanticipated adverse device effect within 10 working days of first receiving notice of the effect. Unanticipated adverse device effects are described in Section 6.12 Reportable Events.

IND

A sponsor-investigator for an IND protocol needs to submit an FDA Form 1571 and must follow the FDA regulations in 21 CFR 312 applicable to sponsor responsibilities, particularly Subpart D. This includes:

• • The recordkeeping and record retention requirements of 21 CFR 312.57

• • The annual report requirements of 21 CFR 312.33 and safety reporting of 312.32
    and

• • Prompt reporting as required in 21 CFR 312.55(b) to the FDA and all participating investigators of significant new adverse effects or risks with respect to the drug or biologic

The IND or IDE product must be stored, secured, dispensed, and documented in accordance with policies of the Institution where the test article will be used, such as Keck Hospital of USC, USC Norris Comprehensive Cancer Center and Hospital, Keck Medicine clinics, LAC+USC Medical Center, and other USC locations.

If the sponsor-investigator holding the IND or IDE leaves USC or transfers to USC, the sponsor-investigator is responsible for notifying FDA about the change in Institution and address.

For additional information, refer to:

Section 12.2 – Investigator-Initiated Research and Sponsor-Investigators.

HRPP – Drugs and Devices

The FDA Expanded Access (Compassionate Use) provision allows patients who do not meet eligibility criteria for a clinical trial to have access to an investigational device. This provision applies to an individual patient or a small number of patients for whom the treating physician believes the device may provide a benefit in treating and/or diagnosing their disease or condition. Patients must have a serious disease or condition and have no acceptable alternatives for treatment.

Both FDA approval and IRB approval are needed before expanded access use occurs. Submission for Compassionate Use is located in the Emergency Use application (iStar Item 1.6) The Compassionate Use provision differs from the Emergency Use of Test Article or Humanitarian Use Devices (HUD). Prior to treatment the sponsor must submit an IDE supplement and request approval for a compassionate use under section §812.35(a) in order to treat the patient(s). The IDE supplement should include:

• • A description of the patient’s condition and the circumstances requiring treatment

• • A discussion of why alternatives therapies are unsatisfactory and why the probable risk of using the investigational device is no greater than the probable risk from the disease or condition

• • An identification of any deviations in the approved clinical protocol that may be needed in order to treat the patient

• • The patient protection measures that will be followed (including informed consent, concurrence of IRB Chair, clearance from the Institution, independent assessment from uninvolved physician, and authorization from IDE sponsor)

• • The number of patients to be treated (when use is of Small Group)

Physicians Responsibilities

The physician should not treat the patient until FDA and the manufacturer approves the specific compassionate use of the device and the USC IRB Chair has approved the iStar application.

Reporting and Monitoring Requirements

The attending physician should devise an appropriate schedule for monitoring the patient(s), considering the investigational nature of the device and specific patient needs. The patient(s) should be monitored to detect any possible problems arising from the use of the device.

Following the compassionate use of the device:

• • A follow-up report should be submitted to FDA as an IDE supplement in which summary information regarding patient outcome is presented

• • Any problems which occurred as a result of device use should be discussed in the supplement and reported to the IRB as soon as possible.

• • Follow-up information on the use of the device should be submitted in an IDE supplement after all compassionate use patients have been treated.

IRB Responsibilities

The IRB will acknowledge and evaluate the submission to determine whether the compassionate use met the eligibility criteria and complied with the regulatory requirements. Compassionate use is a clinical care activity, not research. Data obtained from compassionate use cannot be used for research purposes.

Compassionate Use for Multiple Patients

Compassionate use is typically approved by the FDA for individual patients but may be approved to treat a small group. Clinician may treat multiple patients rather than an individual patient suffering from a serious disease or condition for which no adequate alternative therapy meets the medical need. In this case, the clinician should request access to the investigational device through the IDE sponsor. The sponsor should submit to the FDA an IDE supplement that includes the information identified above and indicates the number of patients to be treated. Such a supplement should include the protocol to be followed or identify deviations from the approved clinical protocol. As with single patient compassionate use, a monitoring schedule should be designed to meet the needs of the patients while recognizing the investigational nature of the device. Follow-up information on the use of the device should be submitted to the FDA in an IDE supplement after all compassionate use patients have been treated.

More information can be found on the FDA website.

The treating physician must notify the IRB of any intended emergency use of a test article before the use occurs. This is done through the “New Emergency Use Application” activity in iStar. The physician must provide assurances that the proposed use of the test article meets the emergency use criteria and that an IND, IDE, or HDE will be obtained. The physician must submit the first part of the application to the IRB as notification of the intended use. If the physician proceeds with emergency use of the test article, the physician is required to notify the IRB within 5 working days of the use. This is done by completing and submitting the second part of the Emergency Use Application to the IRB. The IRB will acknowledge the emergency use at the next convened meeting. In the acknowledgment letter, the physician is reminded that subsequent uses of the test article require prior IRB approval.

Some manufacturers will not ship the test article to the physician without written agreement from the IRB. The physician will receive an acknowledgement notice from the IRB when the emergency use application is submitted. If this acknowledgement notice is not sufficient documentation for the sponsor to ship the test article, the physician should contact the IRB immediately for additional documentation.

Emergency Use of an Investigational Drug or Biologic

The emergency use of an unapproved investigational drug or biologic requires an IND. The treating physician must contact the manufacturer to find out if the manufacturer will ship the drug or biologic for emergency use under the manufacturer’s IND.

The need for an investigational drug or biologic may arise in an emergency situation that does not allow time for submission of an IND. In such a case, FDA may authorize shipment of the test article in advance of the IND submission. Requests for such authorization may be made by telephone or other rapid communication means. Refer to “Individual Expanded Access Involving Investigational New Drug”.

Informed Consent

The treating physician is required to obtain informed consent of the subject or the subject’s legally authorized representative for emergency use of a drug or biologic, unless both the treating physician and a physician who is not otherwise participating in the clinical investigation certify in writing all of the following:

• • The subject is confronted by a life-threatening situation necessitating the use of the test article

• • Informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from the subject

• • Time is not sufficient to obtain consent from the subject’s legal representative

• • No alternative method of approved or generally recognized therapy is available
    that provides an equal or greater likelihood of saving the subject’s life

If the treating physician believes that immediate use of the test article is required to preserve the subject’s life and if time is not sufficient to obtain an independent physician’s assessment, the treating physician should make the determination and, within 5 working days after the use of the article, have the determination reviewed and evaluated in writing by a physician who is not participating in the clinical investigation.

Emergency Use of an Investigational Device

Unapproved devices are normally used only in approved clinical studies conducted under an IDE. Emergency situations may arise in which there is a need to use an investigational device in a manner inconsistent with the clinical study or by a treating physician who is not part of the clinical study.

Emergency use of an unapproved device may occur before an IDE is approved if all the following criteria are met:

• • The subject has a life-threatening disease or serious condition requiring immediate use

• • There are no generally accepted alternative treatments

• • There is no time to obtain FDA approval of an IDE

If an IDE exists, authorization from the IDE sponsor should be obtained. The sponsor is responsible for reporting the emergency use to the FDA within 5 working days. If no IDE exists, the treating physician is responsible for reporting the emergency use to the FDA.

The treating physician has the following responsibilities:

• • Obtain an independent assessment by a physician who is not participating in the investigation

• • Obtain institutional clearance according to institutional policy (if required by the healthcare facility)

• • Obtain concurrence from the IRB Chair

• • Obtain authorization from the sponsor if an IDE exists

• • Obtain informed consent for the emergency use

Informed Consent

The treating physician is required to obtain informed consent of the subject or the subject’s legally authorized representative unless both the treating physician and a physician who is not otherwise participating in the clinical investigation certify in writing all of the following (21 CFR 50.23):

• • The subject is confronted by a life-threatening situation necessitating the use of the device

• • Informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from, the subject

• • Time is not sufficient to obtain consent from the subject’s legal representative

• • No alternative method of approved or generally recognized therapy is available
    that provides an equal or greater likelihood of saving the subject’s life

Independent Physician Assessment

Planned emergency research is a rare type of research that allows participants to be enrolled without prior informed consent. It differs from emergency use of a test article described above. Investigators who wish to conduct planned emergency research should consult with IRB staff prior to submission of the protocol to the IRB. All of the following conditions must be present for emergency research with an exception from informed consent requirements, as described in 21 CFR 50.24:

• • The human subjects are in a life-threatening situation that necessitates urgent intervention

• • Available treatments are unproven or unsatisfactory

• • Collection of valid scientific evidence is necessary to determine the safety and
    effectiveness of the intervention

• • Obtaining informed consent is not feasible because the subjects are not able to give their informed consent as a result of their medical condition

• • The intervention must be administered before consent can be obtained from the subject’s legally authorized representative
  • There is no reasonable way to identify prospectively individuals likely to become eligible for participation
  • Participation in the research holds out the prospect of direct benefit to the subjects
  • The clinical investigation could not practicably be carried out without the waiver

Planned emergency research is a rare type of research that allows participants to be enrolled without prior informed consent. It differs from emergency use of a test article described above.  Investigators who wish to conduct planned emergency research should consult with IRB staff prior to submission of the protocol to the IRB. All of the following conditions must be present for emergency research with an exception from informed consent requirements, as described in 21 CFR 50.24:

• The human subjects are in a life-threatening situation that necessitates urgent intervention
• Available treatments are unproven or unsatisfactory
• Collection of valid scientific evidence is necessary to determine the safety and effectiveness of the intervention
• Obtaining informed consent is not feasible because the subjects are not able to give their informed consent as a result of their medical condition
• The intervention must be administered before consent can be obtained from the subject’s legally authorized representative
• There is no reasonable way to identify prospectively individuals likely to become eligible for participation
• Participation in the research holds out the prospect of direct benefit to the subjects
• The clinical investigation could not practicably be carried out without the waiver

Planned emergency research refers to research planned to occur in emergency settings, and it requires prospective IRB approval. Studies meeting the criteria for an exception from informed consent for emergency research must be approved by the FDA and have a separate IND or IDE.

Before the research is approved, investigators must consult with representatives of the communities where the research will be conducted and from which participants will be drawn and publicly disclose the research plan and potential risks and benefits to the communities. Investigators must also publicly disclose the results of the trial to the community after the trial is completed. An independent data monitoring committee must be established to exercise oversight of the research.

The IRB must ensure that there are appropriate procedures in place to inform subjects, their legally authorized representative, or their family members of their inclusion in the study, details about the study, the subject’s right to discontinue participation, and other information contained in the informed consent form. This must be done at the earliest feasible opportunity.

The IRB evaluates the responses provided in all corresponding subject sections of the iStar submission application to determine that the study will be conducted in accordance with applicable regulations and requirements.

The IRB and/or the investigator will only provide advance notice of these protocols to the Office for Human Research Protections (OHRP) when the research is not subject to FDA regulations. Information about OHRP’s Informed Consent Requirements in Emergency Research can be found at https://www.hhs.gov/ohrp/regulations-and-policy/guidance/emergency-research-informed-consent-requirements/index.html.

Additional responsibilities of investigators, the IRBs, and the sponsors are described in the FDA’s Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors – Exception from Informed Consent Requirements for Emergency Research.

Research Supported by the Department of Defense (DOD)

Research supported by or in collaboration with the Department of Defense (DOD) is subject to additional regulations. The USC IRBs do not approve exceptions from consent in emergency medicine research funded by DOD unless a waiver is approved by the Secretary of Defense.

Dietary supplements are regulated by the FDA under the Dietary Supplement Health and Education Act of 1994 (DSHEA). Dietary supplements include vitamins, minerals, herbs, botanicals, amino acids, and other dietary substances intended to supplement the diet.

Investigators who wish to use dietary supplements in clinical studies will be asked to add information about each dietary supplement product to the iStar application. This should include the composition of the product and whenever possible, information about previous human use, testing, and safety.

Although dietary supplements are not subject to the same FDA regulations as drugs, clinical testing of a dietary supplement may still require an Investigational New Drug (IND) application. If the intent of the study is to evaluate a dietary supplement’s effects on the normal structure or function of the body, no IND is required. If the intent of the study is to evaluate the dietary supplement’s ability to diagnose, cure, mitigate, treat, or prevent a disease, an IND is required before the IRB will approve the study. Investigators should review the FDA guidance document “Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND” when planning a clinical study using a dietary supplement. The IRB may ask investigators to contact the FDA for a written opinion about the need for an IND for clinical studies of dietary supplements. Additional information is available in the FDA guidance: What is a Botanical Drug?

The following is excerpted from the FDA Information Sheet “Screening Tests Prior to Study Enrollment”: 

In general, for some studies, the use of screening tests to assess whether prospective subjects are appropriate candidates for inclusion in studies is an appropriate pre-entry activity. While an investigator may discuss availability of studies and the possibility of entry into a study with a prospective subject without first obtaining consent, informed consent must be obtained prior to initiation of any screening procedures that are performed solely for the purpose of determining eligibility for FDA regulated research.

Screening may qualify as a minimal risk procedure [21 CFR 56.102(i)] and the IRB may choose to use expedited review procedures [21 CFR 56.110] to approve such screening. The IRB should receive a written outline of the screening procedure to be followed and how consent for screening will be obtained. The IRB may find it appropriate to limit the scope of the screening consent to a description of the screening tests and to the reasons for performing the tests including a brief summary description of the study in which they may be asked to participate.

Unless the screening tests involve more than minimal risk or involve a procedure for which written consent is normally required outside the research context, the IRB may decide that prospective study subjects need not sign a screening consent document [21 CFR 56.109(c)]. If the screening indicates that the prospective subject is eligible, the informed consent procedures for the study, as approved by the IRB, would be followed.

HIPAA Waiver for Screening Medical Records

HIPAA regulations apply to the screening process if it involves review of medical records. Investigators must obtain prospective HIPAA authorization from participants or apply for a partial waiver of HIPAA authorization for recruitment and screening. Refer to Section 11 – Health Insurance Portability and Accountability Act (HIPAA) for additional information.

In FDA-regulated research, specific data retention requirements and disclosure to subjects apply, as described below:

• • When a participant withdraws from a study, the data collected on the participant to the point of withdrawal remains part of the study database and may not be removed. The consent document cannot give the participant the option of having data removed.

• • A researcher 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 distinguishes 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.

• • The researcher must obtain the participant’s consent for this limited participation in the study (assuming such a situation was not described in the original consent document). The IRB must approve the consent document.

• • If a participant withdraws from the interventional portion of a study and does not consent to continued follow-up of associated clinical outcome information, the researcher must not access for purposes related to the study the participant’s medical record or other confidential records requiring the participant’s consent. However, a researcher may review study data related to the participant collected prior to the participant’s withdrawal from the study, and may consult public records, such as those establishing survival status.

USC researchers are expected to comply FDA, NIH, and ICJME requirements to register clinical trials in clinicaltrials.gov. FDA regulations require that all “applicable clinical trials” be registered in the ClinicalTrials.gov clinical trials data bank (FDAAA 801). NIH requires that all clinical trials meeting the NIH definition of “clinical trial” must be registered to clinicaltrials.gov. Studies that are intended to be published in an ICMJE must also be registered in clinicaltrials.gov prior to subject enrollment.

ClinicalTrials.gov is a public registry and results database of clinical trials supported by public or private funds.

The “Responsible Party” (the sponsor or the principal investigator designated by the sponsor) must register and report results of applicable clinical trials involving:

• • Drugs and Biologics: controlled, clinical investigations, other than Phase 1 investigations, of a product subject to FDA regulation or

• • Devices: controlled trials with health outcomes, other than small feasibility studies, and pediatric post market surveillance

“Applicable clinical trials” generally include interventional studies (with one or more arms) of FDA-regulated drugs, biological products, or devices that meet one of the following conditions:

• • Have one or more sites in the U.S

• • Involve a drug, biologic, or device that is manufactured in the US (or its
    territories) and is exported for research

• • Be conducted under an investigational new drug application (IND) or investigational device exemption (IDE).

For more information on definitions of terms, refer to FDAAA 801 Requirements It is important to note that FDA and HHS regulations are inconsistent in the use of the terms “clinical trials” and “clinical investigation”. For more information, refer to 21 CFR 50, 56, 312 and 812.

Registration and results reporting are required for applicable clinical trials; however, ClinicalTrials.gov allows voluntary reporting of other studies that:

• • Are in conformance with any applicable human subject or ethics review regulations (or equivalent) and

• • Are in conformance with any applicable regulations of the national (or regional) health authority (or equivalent)

Investigators may choose to register a study that is not an applicable clinical trial as a condition to publish study results in a journal.

FDA regulations require reporting of results from registered trials. The Responsible Party must generally report results no later than 12 months after the trial completion date. Results must include participant baseline characteristics, participant flow diagram, outcomes, and adverse events. Instructions for submitting results are available at ClinicalTrials.gov. FDA also requires sponsors or investigators to certify compliance with ClinicalTrials.gov registration when submitting certain applications to the FDA. FDA 3674 is used to certify compliance. Guidance for FDA 3674 is available online – the form itself is difficult to retrieve.

Public Posting of Informed Consent Form

Any clinical trial that is conducted or supported by a Common Rule department or agency must post one consent form on a publicly available federal website. It must be a consent used to enroll participants, and posted after the study is closed to enrollment, and no later than 60 days after the last study participant visit. Two websites are available to satisfy this requirement:

• • ClinicalTrials.gov, and a docket folder on

• • Regulations.gov (Docket Folder ID: (HHS-OPHS-2018-0021)

The responsibility for posting is the awardee or the federal department or agency component conducting the study.

Mandatory Informed Consent Language

FDA regulations require that informed consent forms contain specific language about clinical trial registration. Informed consent documents for applicable clinical trials or any study that will be registered in Clinicaltrials.gov must contain the following language in the Confidentiality section:

“A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This web site will not include information that can identify you. At most, the web site will include a summary of the results. You can search this web site at any time.”

Federal Enforcement

Investigators who fail to comply with registration or reporting of results on ClinicalTrials.gov can be penalized. Penalties include civil monetary fines and withholding of grant funds if the study is federally funded.

Other Registration Requirements

National Institutes of Health

NIH requires all grantees, regardless of whether or not they are the Responsible Party, to certify that they are complying with FDAAA 801 in grant applications and progress reports. Grantees must certify that the responsible party has made all required submissions to ClinicalTrials.gov for applicable clinical trials funded in whole or in part by the NIH. Click here for more details about Certifying Compliance with FDAAA in NIH Applications and Progress Reports. NIH certification is different from the FDA certification described above.

Centers for Medicare & Medicaid Services (CMS)

CMS now requires providers and suppliers to report an 8-digit clinical trial number (NCT number) assigned by ClinicalTrials.gov on claims for items/services furnished pursuant to clinical trials that qualify for coverage as set forth in the Medicare National Coverage Determination Manual. This requirement became effective 1/1/2014. Any qualifying clinical trial that bills tests and procedures to Medicare must be registered to receive payments from CMS. Claims submitted without the NCT number will be returned to providers for reprocessing and addition of the NCT trial number.

Journals

Journals may require registration of clinical trials and other types of health-related interventions in order to publish manuscripts. The International Committee of Medical Journal Editors (ICMJE) policy requires, and recommends that all medical journal editors require, registration of clinical trials in a public trials registry prior to enrollment of the first subject. Investigators should carefully review registration requirements at ICMJE Clinical Trials Registration.

How to Register a USC Study

For industry-sponsored research:

The industry sponsor is responsible for registration of the research on ClinicalTrials.gov. USC Clinical Trials Office (CTO) will verify that the sponsor has registered the trial and provided the NCT number.

For investigator-initiated research:

Investigators in the Cancer Center should contact the Clinical Investigations Support Office (CISO) for assistance in registering their research on ClinicalTrials.gov.

Investigators who are not in the Cancer Center should contact the Associate Director of HSC Department of Contracts and Grants to request a user account for ClinicalTrials.gov:

Email: jeanbcha@usc.edu

Telephone: 323-442-2825

Webpage: https://hrpp.usc.edu/research/starting-a-research-trial-the-basics/

For more information on registration of research go to: ClinicalTrials.gov

Helpful Information

• • FDA “Guidance for Industry: Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions”

• • Clinicaltrials.Gov Protocol Registration System

• • ICMJE List of Journals Following the ICMJE Recommendations

This policy applies to all principal investigators who conduct clinical investigations that are regulated by the FDA and clinical investigations that support applications for research or marketing permits for products regulated by the FDA.  The purpose of this policy is to outline the specific procedures that should be followed when principal investigators conducting human subject research that is subject to FDA regulations are notified of an FDA inspection.

Responsibilities of Principal Investigator

Principal investigators conducting human subject research that is subject to FDA regulations are responsible for promptly notifying the Institutional Review Board (IRB) about inspections being conducted by the FDA for the purpose of either surveillance or compliance.

Investigators must also notify the IRB immediately of any FDA correspondence requesting that a clinical hold be placed on any human subject research.

Notifications must be made in writing and sent to the IRB.  The notice should include reference to the IRB protocol number, the date and location of the planned inspection, and any information available as to whether the inspection is for surveillance or compliance.

Investigators should facilitate arrangements to ensure that a member of the HRPP or IRB is present for the FDA exit interview.

Investigators must provide the IRB with copies of any written correspondence received from the FDA as a result of the inspection, in particular any Form 483.

Investigators must submit all written responses prepared as a result of the FDA Inspection to the IRB for review and comment PRIOR to sending the final response to the FDA. The Final FDA report shall be forwarded to the IRB within 10 working days of receipt by the investigator.

Responsibilities of the IRB

The IRB shall notify appropriate parties of the upcoming inspection.  This includes the IRB Chair, IRB Associate Directors, the Director of HRPP, the Office of Research Integrity and the Office of Compliance.

On a case by case basis, the HRPP or the Office of Research Integrity will conduct a comprehensive review of the IRB file to ensure that the file is complete and in order. Any findings of non-compliance observed from this review will be reported to the Chair of the IRB, Director of IRB, the Director of HRPP, [ Office of Research Integrity]. A plan of corrective actions will be developed as deemed appropriate.

The HRPP or the Office of Research Integrity shall contact the Principal Investigator and make arrangements (if time permits) to conduct a review of the research subject records and regulatory files in advance of the FDA inspection to ensure compliance with IRB policies, FDA regulations and Good Clinical Practices.

All requests for information surrounding the FDA inspection shall be treated as a priority by all involved parties.

The Authorized Institutional Official and/or his/her designee must be included in the exit interview.

Any Form 483 issued as a result of the inspection shall be reviewed by an IRB full board committee for determination of whether any observations contained therein constitute serious or continuing non-compliance with the federal regulations governing human subject research.

In the event that an IRB full board committee meeting is not scheduled within 5 working days of receipt of the investigator’s response, a special committee of IRB members may be convened for purposes of reviewing the response.