Stanford University Office of the Dean of Research

Human Research Protection Program (HRPP)

DOMAIN I: ORGANIZATION

Chapter 5: Investigational or Unlicensed Test Articles

STANFORD* has the following written policies and procedures that state use of any investigational or unlicensed test articles complies with all federal, state, or local regulations. (AAHRPP Standard I-5) The process that the IRBs use to comply with this policy is to request that the primary reviewer complete the Presenter Checklist (Document F.5.b.), present the findings to the IRB, and ask whether the IRB agrees with the findings.

The Food and Drug Administration (FDA) regulates clinical investigations (research) conducted on drugs, biologics, devices, diagnostics, infant formulas and, in some cases, dietary supplements and food additives, hereinafter referred to as “FDA regulated test articles.” All such investigations must be conducted in accordance with FDA requirements for informed consent and IRB review, regardless of funding source or sponsor.

5.1 Regulatory Requirements

When an FDA regulated test article is used in research being done at STANFORD or funded by another federal agency, more than one set of regulations may apply. For example, clinical trials involving FDA regulated test articles that are supported by the U.S. Department of Health and Human Services (DHHS), e.g., the National Institutes of Health (NIH), fall under the jurisdiction of both the FDA and the DHHS Office for Human Research Protections (OHRP). Such trials must comply with the FDA and the DHHS human subject regulations. Where regulations differ, the IRBs apply the stricter one.

FDA Requirements Compared to DHHS (the Common Rule) Requirements

The human subject protection requirements found in FDA regulations are substantially the same as the Common Rule requirements. However, there are important differences:

1. The FDA has different definitions for “human subject” and “clinical investigation (research)”

2. FDA regulations contain no Assurance requirement

3. Conditions for exemption, exception, and waiver of IRB review and informed consent requirements differ

4. FDA regulations require specific determinations for the IRB review of device studies

5. FDA regulations include specific requirements for reporting adverse events that are not found in the Common Rule or DHHS regulations.

The Common Rule includes specific additional protections for pregnant women, human fetuses, and neonates (Subpart B); prisoners (Subpart C); and children (Subpart D). In April 2004, FDA issued revised regulations to protect children in research (21 CFR 50 Subpart D).

In addition to regulations governing human subject protection, the FDA also has regulations governing the investigational use of drugs and biological drugs (21 CFR 312) and devices (21 CFR 812).

Additional Veterans Affairs (VA) Requirements

VA policy (M-3, Part 1, Chapter 9) requires that all research comply with the VA human subject regulations, as well as with all applicable regulations and requirements regarding storage and security procedures for investigational agents.

A VA Investigational Drug Information Record (VA Form 10-9012) must be completed by the Protocol Director (PD), submitted to Pharmacy Service, and monitored by the Research and Development (R&D) Committee (M-3, Part 1, Chapter 9.15(3)).

Upon approval of the research by the IRB and R&D Committee, a Report of Subcommittee on Human Studies (VA Form 10-1223) must be forwarded to the PD and the Chief of Pharmacy Service.

Research Involving Investigational FDA Regulated Test Articles

New medical products that have not yet been approved for marketing by the FDA require a special status so they can be legally shipped for the purpose of conducting clinical investigations to establish safety and efficacy.

IND refers to an investigational new drug application and is synonymous with “Notice of Claimed Investigational Exemption for a New Drug.” Investigational new drug means a new drug or biological drug used in a clinical investigation. An investigational drug must have an IND before it can be shipped, unless one of the exemptions outlined in 21 CFR 312.2 is met.

An approved investigational device exemption (IDE) permits a device not approved by FDA to be shipped to conduct clinical investigations of that device. Not all investigational devices need an IDE, if they satisfy the FDA criteria for non-significant risk devices (Document D.5.f.).

With only a few exceptions, most clinical research being done on FDA-regulated test articles with either an IND or IDE will need initial and continuing review at convened IRB meetings.

Research involving FDA-regulated test articles will be approved only after the IRB:

·Has received documentation that the research will be conducted under an applicable Investigational New Drug Application (IND) or Investigational Device Exemption (IDE); or

·Has formally determined that satisfactory justification has been provided by the investigator as to why an IND or IDE is not required; or

·Has formally determined and documented that the proposed use of any unapproved device satisfies the FDA criteria for non-significant risk devices.

5.2 Requirements of the Sponsor and the Investigator as a Sponsor

STANFORD secures assurances from the sponsor or the investigator-sponsor* that the manufacture and formulation of investigational or unlicensed test articles conform to federal regulations. (AAHRPP Element I.5.A) * Note: Investigator-sponsor refers to a situation in which the individual investigator is a STANFORD investigator and is the holder of the IND or IDE and therefore assumes the duties of the sponsor of the clinical investigation under the applicable FDA regulations.

5.2.1 Sponsors

Sponsors will provide such assurances through the sponsored research agreements, i.e., the Stanford University Clinical Study Agreement template (Document C.4.b.i.) and the PAIRE Research Agreement template (Document B.4.a.).

Under FDA regulations and guidance, investigators (and investigator-sponsor) are responsible for the conduct of the study and for leading the team of individuals conducting the study. Their responsibilities include the following:

· Ensuring informed consent of each subject is obtained

· Ensuring the investigation is conducted according to the investigational plan

· Personally conducting or supervising the investigation

· Protecting the rights, safety, and welfare of participants

· Preparing and maintaining adequate, current, and complete case histories or records

· Retaining records for two years following the date the marketing application is approved or withdrawn

· Furnishing the required reports to the sponsor, including reports of adverse events and study completion

· Providing timely reports to the IRB, including reports of changes in the research activity needed to avoid immediate hazards to participants, unanticipated problems involving risks to participants or others, including adverse events to the extent required by the IRB

· Ensuring that changes are not implemented without prospective IRB approval, unless required to eliminate immediate hazard to participants

· Complying with the requirements of the Controlled Substances Act

· Complying with all FDA test article requirements

· Adequately maintaining control of test articles, including appropriate tracking documentation for test articles to the extent that such control and documentation are not centrally administered

· Supervising the use and disposition of the test article

· Disclosing relevant financial information

· Ensuring that all associates, colleagues, and employees assisting in the conduct of the investigation(s) are informed about their obligations in meeting the above commitments.

The sponsor takes responsibility for initiating the clinical investigation, and holding the IND or IDE, but does not usually conduct the investigation. Although the sponsor is usually a pharmaceutical, biotech, or medical device company, an individual or group of individuals or medical center can also be considered a sponsor for an investigation. The sponsors’ responsibilities include the following:

· Selecting qualified investigators

· Providing investigators with the information they need to conduct the investigation properly

· Ensuring proper monitoring of the investigation

· Ensuring that the FDA and (for devices) any reviewing IRBs or (for drugs) all participating investigators are promptly informed of significant new information about an investigation.

5.2.2 Investigator-Sponsors

In reviewing research involving FDA regulated articles, the IRB determines if the study involves an investigator-sponsor. If so, the IRB informs the investigator that sponsor responsibilities, including reporting requirements to the FDA, (as well as the investigator responsibilities) are his/her responsibility as required by this Section 5.2.2.

Investigator-sponsors who submit protocols to the IRB involving FDA test articles must include all supporting FDA documentation for their IND or IDE and any STANFORD required approvals for applying for an IND or IDE. Additionally, if the IND or IDE product will be manufactured at STANFORD, the Protocol Director must submit documentation that:

· The product preparation and manufacture meets the standards for current Good Manufacturing Practice (GMP), or any modification to those standards approved by the FDA in issuing the IND or IDE.

· The GMP plan has been approved by the applicable STANFORD official, appointed by the Sr. Assoc. Dean of Research in the School of Medicine.

· If a Stanford University investigator-sponsor, the GMP plan has been reviewed and accepted by Risk Management.

The IND or IDE product must be stored, secured, dispensed, and documented in accordance with the policies of the STANFORD institution in which it will be used, i.e., Stanford Hospital and Clinics (see Section 5.7, Internal Handling of Test Articles), Lucile Packard Children’s Hospital at Stanford (see Section 5.7, Internal Handling of Test Articles), or the Veterans Affairs Palo Alto Health Care System.

An investigator-sponsor for an IDE protocol must follow the FDA regulations in 21 CFR 812 applicable to sponsor responsibilities, particularly Subpart C. This includes:

· the record keeping requirements of 21 CFR 812.140(b), and

· the required notification under 21 CFR 812.150(b)(1) to the FDA and all participating investigators of any evaluation of an unanticipated device effect within ten (10) working days of first receiving notice of the effect.

An investigator-sponsor for an IND protocol must follow the FDA regulations in 21 CFR 312 applicable to sponsor responsibilities, particularly Subpart D. This includes:

· the record keeping requirements of 21 CFR 312.57, and

· promptly 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.

Education concerning these responsibilities will be provided by: (i) SPCTRM, the unit in the Stanford University School of Medicine providing administrative support for clinical trials, to investigator-sponsors who are faculty and conducting such clinical trials at Stanford Hospital and Clinics and the Lucile Packard Children’s Hospital at Stanford, and (ii) the Palo Alto Veterans Affairs Health Care System for its employees who are investigator-sponsors.

STANFORD auditors must site visit the investigator-sponsor before initiation of the research to determine compliance with these FDA regulatory requirements. If compliance has been demonstrated, the investigator-sponsor may begin the research. The audit must be repeated at the time of, and prior to the renewal, of the protocol by the IRB.

5.3 IRB Review of Medical Devices

The FDA Center for Devices and Radiological Health (CDRH) device regulations differentiate between significant risk (SR) and non-significant risk (NSR) devices. A significant risk device must have an IDE, whereas a non-significant risk device does not.

Protocol Directors (PD) are instructed to review the laminated sheet on SR/NSR found on the RCO website. If a clinical investigation is submitted to the IRB for a device that has an IDE, the device is considered a SR device. If not submitted with an IDE, the PD must address specific SR/NSR determinations and rationale in the New Protocol Application Form for Regular or Expedited Review - Medical (Document F.1.a.(Section 4.b)). IRB members and staff refer to the laminated sheet on SR/NSR (Document D.5.f.) for guidance and the review of protocols that involve the use of such devices.

The primary reviewer documents in the Presenter Checklist and presents to the IRB information regarding SR or NSR devices, whether a device is a SR or NSR device, whether an IDE# is required, whether a device meets SR device criteria, and whether the IRB agreed with the PD’s rationale regarding SR/NSR. The primary reviewer documents in the Presenter Checklist the rationale for the IRB’s determination.

If the PD or sponsor states that the device is a “NSR device” but the IRB determines that the research involves a “SR device,” the IRB will notify the PD of that determination, and require the PD to notify the sponsor.

5.4 Radiology Devices and Radioactive Materials

The FDA is responsible for regulating radiology devices and radioactive materials used in healthcare and research. Oversight at STANFORD is handled by the Administrative Panel on Radiological Safety (APRS) which is chartered as a Radioactive Drug Research Committee (RDRC) by the FDA under 21 CFR 361.1. Their review covers only a very small portion of investigational drug studies involving radiation (only those regarded to be “generally recognized as safe”). Most research involving radiation is covered by an IND, in the case of radioactive drug products or an IDE, in the case of devices that impart radiation to the subjects.

As defined in 21 CFR 361.1 the APRS has no oversight responsibility or authority over an investigation carried out under an IND exemption. This authority is retained by the FDA.

The APRS (Document C.2.d.iii.) must determine if the radiopharmaceutical in a particular research project has the following characteristics:

A. The protocol meets the following seven aspects of the definition of “generally recognized as safe and effective:”

1. The amount of active ingredient or combination of active ingredients to be administered is known not to cause any clinically detectable pharmacological effect in human beings

2. Under no circumstances does the radiation dose to an adult research subject (either from a single study or cumulatively from a number of studies conducted within 1 year) exceed limits specified by 21 CFR 361.1

3. The amount of radioactive material to be administered is the smallest radiation dose the subject can practically receive to perform the study without jeopardizing the benefits to be obtained from the study

4. All radioactive material included in the drug, either as essential material or as a significant contaminant or impurity, was included when total radiation doses and dose commitments were determined

5. Radiation doses from x-ray procedures that are part of the research study (i.e., would not have occurred but for the study) and the possibility of follow-up studies were included in the dose calculations

6. Numerical definitions of dose were based on an absorbed fraction method of radiation absorbed dose calculation, such as the system set forth by the Medical Internal Radiation Dose Committee of the Society of Nuclear Medicine, or the system set forth by the International Commission on Radiological Protection

7. The radiation exposure is justified by the quality of the study and the importance of the information it seeks to obtain.

B. The protocol is only intended to obtain basic information regarding the metabolism (including kinetics, distribution, and localization) or human physiology, pathophysiology, or biochemistry of a radioactively labeled drug.

If all the above determinations cannot be made and documented, the radiopharmaceutical may not be classified as “generally recognized as safe and effective,” so the APRS may not review and approve the research. An IND may be needed.

If the protocol is approved, serious adverse events (SAEs) are reported to the IRB. The APRS submits reports to the FDA at least yearly, in the format specified by the regulation.

In assessing research involving radiology devices or radioactive materials, the New Protocol Application Form (Document F.1.a.) addresses the necessary radiological safety questions which are reviewed by both the IRB and a member(s) of APRS (Document F.4.x.).

Only applications from the faculty of the Stanford University School of Medicine or senior medical staff at the Veterans Affairs Palo Alto Health Care System will be accepted. In general the PD must be a licensed clinician; however, in the unusual circumstance that the PD is not a physician, collaboration and appropriate assistance by such a physician is mandatory and both names must appear.

Each applicant or user must have previously filed with Health Physics a complete statement of training and experience. (A user is a radiation clinician, perhaps listed as a co-investigator, who is providing radiation support services to an applicant who does not personally provide radiation medicine).

See http://www.stanford.edu/dept/EHS and click Health Physics, or telephone the Radiation Safety Office at (650) 725-1413 for assistance.

For radioisotope projects, investigators provide to Health Physics the following radiation- and safety-related information:

· Identify the radionuclide, chemical form, FDA status, and route of administration

· For each dosage, provide the amount in millicuries received, the amount administered, and the method of measurement

· Describe the pharmacokinetics sufficiently to allow internal dosimetry calculations. (Alternatively, dosimetry published by United States Pharmacopeial Forum Society of Nuclear Medicine, in a package insert, or in another peer-reviewed format may be submitted.)

· Describe preparation, handling, storage, administration, and waste disposal in sufficient detail to permit a radiological hazards evaluation of the proposal, including potential for radiation dose to other health care providers from external radiation or contamination

· Describe safety measures and safety equipment that will be used

· Identify the rooms where radioactivity will be handled and where research subjects will be used.

For radiation machine projects, investigators provide the following information about diagnostic and therapeutic procedures:

· For well-established radiographic procedures, identify the radiographic procedures and the number of times each will be performed on a single research subject. State whether the procedures are performed as a normal part of clinical management for the medical condition that is under study or whether they are being performed because the research subject is participating in this project

· For each radiographic procedure, provide the setup and technique sufficient to permit dose modeling. The chief technologist can usually provide this information

· For radiographic procedures that are not well-established, provide the FDA status of the machine, and information sufficient to permit dose modeling

· For a well-established therapeutic procedure, identify the area treated, the dose per fraction, and the number of fractions. State whether the therapeutic procedure is being performed as a normal part of clinical management for the research subject’s medical condition or whether it is being performed because the research subject is participating in this project

· For a therapeutic procedure that is not well-established, provide the FDA status of the machine, basis for dosimetry, area treated, dose per fraction and number of fractions.

5.5 “Off-label” (Unapproved) Use of FDA-Regulated Products

In Medical Practice

The FDA approves the sale, use, and labeling of a product for specific indications (the reason the product is being used – a disease, condition, as a diagnostic tool, etc.). “Off-label” or unapproved use is when the product is used in medical practice in a way or on a population different from that for which it was approved. The IND regulations do not apply to the use of marketed drugs for unlabeled indications in the practice of medicine (21 CFR 312.2(d)).

In Research

Good medical practice and the best interests of the patient require that physicians use legally available, marketed drugs, biologics and devices according to their best knowledge and judgment. If physicians use a product for an indication not included in the approved labeling (i.e., off-label), they have the responsibility to be well-informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects.

The FDA definition of research in the IND regulations is as follows: “Clinical investigation” means any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR 312.3(a)). Thus, under the FDA IND regulations, it is possible for one drug given to one person to be considered research.

The off-label use of a marketed drug or biologic in research does require IRB review, informed consent and, under some circumstances, may require an IND. To be exempt from the requirements of the IND regulations, all of the following conditions must apply (that includes the requirement of IRB review and informed consent):

·The drug is lawfully marketed in the United States

· The investigation is not intended to support a new indication for use nor any other significant change in the labeling for the drug

· The investigation is not intended to support a significant change in the advertising for the product

· 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

· The investigation is conducted in compliance with the requirement for institutional review board review and informed consent, and

· The investigation is conducted in compliance with the FDA regulations on promoting and charging for investigational drugs (21 CFR 312.7).

Use of a marketed product in research intended to support a new indication for use, change in labeling, or advertising requires IRB review, informed consent, and submission of an IND.

Using a marketed product in research involving 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 its use requires IRB review, informed consent, and may also require submission of an IND.

The IRB solicits information from the PD in the New Protocol Application Form in order to determine, in part, whether submission of an IND would be required.

5.6 Other Unique Situations

Expanded Access to Investigational Drugs

Investigational products are sometimes used for treatment of serious or life-threatening conditions either for a single subject or for a group of subjects. The procedures that have evolved for an investigational new drug (IND) used for these purposes reflect the recognition by the FDA that, when no satisfactory alternative treatment exists, subjects are generally willing to accept greater risks from test articles that may treat life-threatening and debilitating illnesses. The following mechanisms expand access to promising therapeutic agents without compromising the protection afforded to human research participants or the thoroughness and scientific integrity of product development and marketing approval (21 CFR 312.34, 312.35, and 312.83).

Open Label Protocol or Open Protocol IND

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

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. Four requirements must be satisfied before a treatment IND can be issued:

1. The drug must be intended to treat a serious or immediately life threatening disease.

2. There must be no satisfactory alternative treatment available.

3. The drug must already be under investigation or the drug trials must have been completed.

4. The trial sponsor must be actively pursuing marketing approval.

Treatment IND studies require prospective IRB review and informed consent.

Parallel-Track Studies

FDA also permits wider access to promising new drugs for HIV/AIDS related diseases under a “separate access” protocol that “parallels” the controlled clinical trials that are essential to establish the safety and effectiveness of new drugs. These so-called “parallel track” studies require prospective IRB review and informed consent.

Expanded Access to Investigational Devices

According to statute and FDA regulations, an unapproved medical device may normally only be used in human subjects when the device is under clinical investigation and when used by investigators participating in the clinical trial. The FDA recognizes, however, that there may be circumstances under which a health care provider may wish to use an unapproved device to save the life of a patient, to prevent irreversible morbidity, or to help a patient suffering from a serious disease or condition for which there exists no alternative therapy.

Four main mechanisms are utilized by FDA to make unapproved devices available to patients/physicians faced with circumstances such as those described above. These mechanisms are consistent with the Expanded Access provisions of the FDA Modernization Act of 1997 (Section 561 of the Federal Food, Drug, and Cosmetic Act). The sponsor must agree and FDA must approve the use. Under most circumstances, such studies require IRB review and informed consent.

The four mechanisms are as follows:

1. Single Patient/Small Group Access to Investigational Devices. Allows access to a device where patient is not eligible for an ongoing clinical trial. The subject must have a serious condition/disease, with no alternative intervention available. Under some conditions, the FDA may grant permission, even if there is no pre-existing IDE

2. Treatment Use/IDE (21 CFR 812.36). Allows wider access to a device during the clinical trial or prior to final action on marketing application. Again, the subject must have a serious condition/disease, with no alternative intervention available

3. Continued Access to Investigational Devices. Allows access to a device while a marketing application is being prepared and reviewed, and can be used to collect additional evidence of safety and effectiveness, as well as to address new questions regarding the investigational device, such as labeling claims. There must be a public health need for the device, as well as preliminary evidence that the device is effective

4. Access under a Formal Protocol. Access in a controlled rate of enrollment and with no significant safety concerns identified for the proposed indication.

Gene Transfer Research

Gene transfer involves the administration of genetic material to alter the biological properties of living cells for therapeutic use. Gene-transfer activities in humans are investigational and are regulated by the both the FDA and the National Institutes of Health (NIH) Office of Biotechnology Activities (OBA).

FDA regulations require the submission of an IND for human gene-transfer research through the FDA Center for Biologics.

DHHS regulations specify that no individual may be enrolled in human gene-transfer research until review has been completed by the NIH Recombinant DNA Advisory Committee (RAC), local Institutional Biosafety Committee (IBC) approval has been obtained, local IRB approval has been obtained, and the investigator has obtained all other regulatory authorizations from the subject (65 FR 60328, October 10, 2000).

While the RAC is advisory to the Director of the NIH, compliance with its guidelines is mandatory for all investigators at institutions that apply for NIH funds for research involving recombinant DNA.

For gene-transfer research, review and approval by the Biosafety Panel is required prior to IRB approval. A combined Protocol Application Form for Human Subjects Investigation Using Biological Agents or Recombinant DNA Vectors (Document F.1.c.) must be filled out and submitted by the investigator.

5.7 Internal Handling of Test Articles

STANFORD has policies and procedures to ensure that the handling of investigational or unlicensed test articles meets organizational standards relating to pharmacy, inventory control, and documentation. (AAHRPP Element I.5.B) These policies and procedures are found in the Stanford Hospital and Clinics (SHC) Administrative Guide and in the Lucile Packard Children’s Hospital (LPCH) Formulary. Both are available in the online Clinical Reference Library (CRL) at http://www.crlonline.com by typing in investigational drugs.

The policies for SHC and for LPCH spell out the standards relating to both drugs and devices for pharmacy practices, inventory control and documentation.

See:

· SHC policy “Investigational New Devices”

· SHC policy “Investigational Drugs and Biologics”

· LPCH policy “Investigational New Devices”

· LPCH policy “Investigational Drugs and Biologics”

5.8 Emergency Use of a Test Article

STANFORD has and follows written policies and procedures for compliance with federal regulations governing emergency use of an investigational or unlicensed test article. (AAHRPP Element I.5.C)

See guidance