SOP 022: Research Involving Investigational Drugs and Biologics

1. Purpose

This SOP describes the requirements for research involving investigational drugs or biologics, including the responsibilities of Principal Investigators (PIs), IRBs, and sponsors.

2. Overview

PIs and IRBs must ensure that research (i.e., clinical investigation) involving investigational drugs or biologics is conducted in accordance with applicable federal regulations. These regulations describe, among other things, requirements for Investigational New Drug Applications (INDs), drug accountability and record retention, and responsibilities of PIs, IRBs, and sponsors when research is conducted with investigational drugs.

3. General Information

3.1. When human subjects research involves the use of drugs or biological products, FDA regulations apply. Investigators must provide sufficient information about the drug or biologic for the IRB to evaluate its associated risks and benefits, including the FDA approval status of the product (i.e., approved for marketing or investigational).

3.2. An Investigational New Drug Application (IND) must be filed with FDA to test the safety and efficacy of a new (i.e., investigational) drug for marketing approval. Studies involving the “investigational/research use” of an approved drug also require an IND if the intent of the research is to generate data that will lead to a new clinical indication, formulation, or advertising claim, or the research includes a new dose, population, or other factor that significantly increases risk (or decreases acceptability of the risk).

3.3. As described above, an IND is required for some research uses of a marketed drug or biologic; however, certain exemptions apply to the FDA requirements. For information about FDA exemptions from the requirements for an IND for studies involving marketed drugs, see Addendum A.

3.4. When an IND is required for the proposed use of a marketed drug or biologic in research, investigators must submit an application (Form FDA 1571) to FDA. An IND number will be assigned by FDA upon receipt of the application. Unless earlier notification is received, studies may be initiated 30 days after FDA’s receipt of the application. For more information about obtaining an IND and forms and instructions, see 21 CFR 312 Subpart B – Investigational New Drug Application and Information for Sponsor- Investigators Submitting Investigational New Drug Applications (INDs). Final IRB approval will not be given until a valid IND number is provided.

3.5. An investigator obtaining an IND for the proposed use of a drug or biologic in research becomes a “sponsor-investigator” and additional institutional resources are available to assist investigators in complying with applicable FDA regulations.

3.6. The “off-label” use of an FDA-approved, marketed drug (i.e., a use other than the indication(s) approved by FDA) by a physician for treatment purposes does not require an IND or IRB approval. When such uses meet the regulatory definitions of research or clinical investigation, IRB approval is required. An IND may also be required, unless the conditions for exemption (described in Addendum A) are met.

3.7. In certain non-emergency situations, an investigational drug intended to treat a serious or immediately life-threatening condition may be used outside of a clinical investigation, as part of an “expanded access” program. Such “treatment use” of an investigational drug requires an IND and IRB review and approval. For more information, see the Expanded Access section below.

3.8. Additional requirements apply to the emergency use of an investigational drug or biologic and planned emergency research involving investigational drugs or biologics subject to FDA regulations. (See SOP 053: Emergency Use of Investigational Drugs, Biologics, or Devices and SOP 054: Planned Emergency Research.)

4. Submission and Pre-Review Procedures

4.1. To describe proposed uses of drugs or biologics in human subject research, PIs will indicate in their WVU electronic protocol submission that they will be using drugs or biologics (including dietary supplements/ingredients) in their proposed research.

4.2. During the pre-review process, WVU OHRP staff are responsible for making an initial determination about whether a PI’s proposed use of a drug or biologic involves the use of a marketed drug in the course of medical practice, requires an IND, or meets one of the FDA exemptions from the IND requirements. The IRB committee will make the final determination. Note: For assistance in determining whether an IND is required in a specific situation, FDA may be contacted directly. (For contact information, see FDA guidance “Off-label” and Investigational Use of Marketed Drugs, Biologics, and Medical Devices.)

4.3. When the research involves a drug or biologic with an IND, WVU OHRP staff will verify that the IND number provided by the PI is valid. Protocol-specific confirmation (e.g., sponsor’s protocol cover sheet, FDA or sponsor correspondence, etc.) will be obtained. The investigator’s drug brochure is NOT a protocol-specific document and cannot be used to validate an IND number.

5. IRB Review

5.1. The convened IRB committees will review proposed research involving investigational drugs or biologics considering the criteria for approval as described in SOP 007: IRB Approval Criteria. Note: Research involving a drug for which an IND is required is not eligible for expedited review.

5.2. When research involves the use of an investigational drug or biologic, to approve the research the IRBs committees will also require the following:

• Available clinical and non-clinical information on the investigational product that is adequate to support the proposed research.
• Documentation of a valid IND unless the proposed use of the drug or biologic represents the use of a marketed product in the course of medical practice or meets one of the FDA exemptions from the IND requirements.
• An adequate plan for monitoring data to ensure the safety of subjects and for reporting adverse events and unanticipated problems involving risks to subjects or others.
• A plan for control, accountability, and storage of the investigational drug or biologic that ensures that the product will be used only in the approved research under the direction of the approved investigator(s); and
• For sponsor-investigators, that they are knowledgeable about and will comply with additional FDA requirements associated with conducting research for which an IND has been obtained.

6. Expanded Access

6.1. Expanded access, sometimes called “compassionate use,” is the use outside of a clinical trial of an investigational medical product (i.e., one that has not been approved by the FDA). Expanded access refers to the use of an investigational drug when the primary purpose is to diagnose, monitor, or treat a patient’s disease or condition rather than to obtain the kind of information about the drug that is generally derived from clinical trials. Except for emergency expanded access use when there is not sufficient time to secure prospective IRB review, an investigator treating a patient with an investigational drug under expanded access is responsible for obtaining IRB review and approval before treatment with the investigational drug may begin.

Under FDA’s current regulations for investigational drugs and biologics, there are three areas of expanded access:

• Expanded access for individual patients, including for emergency use.
• Expanded access for intermediate-size patient populations (generally smaller than those typical of a treatment IND or treatment protocol – a treatment protocol is submitted as a protocol to an existing IND by the sponsor of the existing IND); and
• Expanded access for widespread treatment use through a treatment IND or treatment protocol (designed for use in larger patient populations).

For more information, see FDA guidance Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers and Charging for Investigational Drugs under an IND – Questions and Answers, or contact WVU OHRP at irb@mail.wvu.edu.

7. Investigational Drug Control, Accountability, and Record Retention

7.1. Investigational drugs used at WVU must be appropriately controlled, administered, and stored in compliance with the IRB and FDA requirements, and applicable university policies. Such requirements include processes to ensure that investigational products are manufactured, handled, and stored in compliance with applicable good manufacturing practices; inventory and accountability records are maintained for investigational drug receipt, dispensing, and disposition; and investigational drugs are used only in accordance with available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information and the approved protocol.

7.2. Investigators may delegate accountability, storage, and recordkeeping responsibilities to the WVU Hospitals Department of Pharmaceutical Services, who have a Pharmacy Coordinated Investigational Drug Service. For more information, please contact the WVUH Department of Pharmaceutical Services. Alternatively, an investigator may provide a plan to ensure that the investigational drug or biologic will be used according to the IRB-approved protocol, under the direction of the approved investigator(s), and in compliance with FDA and university requirements.

8. Additional Responsibilities of Sponsor-Investigators

8.1. Investigators obtaining an IND to initiate and conduct research must also fulfill the federal requirements of sponsors. These requirements include (but are not limited to) additional FDA reporting (e.g., annual progress reports), data monitoring, and recordkeeping obligations. Additional institutional assistance may be available when a WVU investigator wishes to obtain an IND to perform human subjects research. Sponsor-investigators may be referred to any number of institutional groups who can assist with IND requirements related to being a sponsor-investigator.

8.2. In addition to FDA regulations for the protection of human subjects, (21 CFR Parts 50 and 56), and the use of investigational drugs (21 CFR 312), additional regulations may apply to sponsor-investigators, depending on the nature of the research. It is the responsibility of the investigator to become familiar with these regulations and requirements if he or she becomes a sponsor-investigator for FDA-regulated research. These regulations could include:

• Electronic Records/Signatures (21 CFR 11).
• Financial Disclosure by Clinical Investigators (21 CFR 54).
• Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs (21 CFR 210).
• Applications for FDA approval to Market a New Drug (21 CFR 314).
• Bioavailability and Bioequivalence Requirements (21 CFR 320).
• Over-the-counter Human Drugs which are Generally Recognized as Safe and Effectie and Not Misbranded (21 CFR 330); or
• Applications for FDA Approval of a Biologic License (21 CFR 601).

8.3. Additional Human Subject Protection (HSP) training (see WVU’s CITI training page) for first-time sponsor-investigators may be required prior to protocol approval and activation of the FDA-regulated research.

For more information describing the FDA requirements for sponsor-investigators when research is initiated and conducted with investigational drugs or biologics, see FDA’s Investigational New Drug Application (21 CFR 312) Subpart D – Responsibilities of Investigators and Sponsors. Additional guidance describing the international standards for good clinical practices in human subjects research (ICH/GCP) is available at ICH E6(R2): Good Clinical Practice Industry Guidance.

9. References

WVU Policies:
SOP 007: IRB Approval Criteria
SOP 053: Emergency Use of Investigational Drugs, Biologics, or Devices

Federal Regulations:
21 CFR 50
21 CFR 56
21 CFR 312
21 CFR 600

AAHRPP:
Standard I.7

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Addendum A: IND Subpart (21 CFR 312)

Applicability

Except as provided in this section, this part applies to all clinical investigations of products that are subject to section 505 of the Federal Food, Drug, and Cosmetic Act or to the licensing provisions of the Public Health Service Act (58 Stat. 632, as amended (42 U.S.C. 201et seq.)).

Exemptions

1. The clinical investigation of a drug product that is lawfully marketed in the United States is exempt from the requirements of this part if all of the following apply:
1. The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug;
2. If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product;
3. The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;
4. The investigation is conducted in compliance with the requirements for institutional review set forth in 21 CFR 56 and with the requirements for informed consent set forth in 21 CFR 50; and
5. The investigation is conducted in compliance with the requirements of 21 CFR 312.7.
2. 
   
1. A clinical investigation involving an in vitro diagnostic biological product listed in
   paragraph (ii) of this section is exempt from the requirements of this part if:
1. It is intended to be used in a diagnostic procedure that confirms the diagnosis made
   by another, medically established, diagnostic product or procedure and
2. It is shipped in compliance with 312.160.
2. In accordance with paragraph (i) of this section, the following products are exempt from the requirements of this part
1. Blood grouping serum;
2. Reagent red blood cells; and
3. Anti-human globulin
3. A drug intended solely for tests in vitro or in laboratory research animals is exempt from the requirements of this part
   if shipped in accordance with 312.160.
4. FDA will not accept an application for an investigation that is exempt under the provisions of paragrah of (1) of this section.
5. A clinical investigation involving the use of a placebo is exempt from the requirements of this part if the investigation does not otherwise require the submission of an IND.
6. A clinical investigation involving an exception from informed consent under 21 CFR 50.24 of this hcapter is not exempt from the requirements of this part.