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Studies Regulated by the FDA and Use of Investigational Articles (June 2012)

Operations Manual - Part 8

The United States Food and Drug Administration enforces the Food, Drug and Cosmetic Act and other laws and regulations governing the use of drugs, biologics, and devices for treatment and in research studies. This section describes when or under what circumstances an Investigational New Drug application or Investigational Device Exemption is needed; and describes investigator and IRB responsibilities with respect to protocols involving investigational articles.


[Operations Manual Table of Contents]

I. INVESTIGATOR RESPONSIBILITIES

An investigator must personally conduct or supervise the study as specified in the signed investigator statement, the investigational plan, any applicable sponsor agreement, and the IRB-approved protocol. Before initiating a study, the investigator must read and understand the information in the investigatorŐs brochure or similar documentation, including the risks and potential benefits of the investigational drug or device.

The investigator must ensure that a University IRB will be responsible for the initial and continuing review of the study. Changes may be made to a protocol only after notifying the sponsor and receiving approval from the IRB, except when necessary to eliminate apparent immediate hazards to subjects. Informed consent must be obtained from all prospective subjects prior to enrollment in the study, as further described in Section II (A) above.

During the study, the principal investigator is responsible for all aspects of protocol implementation. These include:

  • Proper receipt, storage, use and disposal of the investigational drug or device. The principal investigator is asked through eResearch for his or her plans to assure that test articles are used only in approved protocols and under the direction of approved investigators. Deviations from these plans are permitted only in emergency circumstances, consistent with FDA requirements and University policies on emergency use. An IRB may not approve a proposed project that does not include satisfactory plans for test article accountability. Additional information on emergency use is provided in Part 8 of this Operations Manual; at the IRBMED website (http://www.med.umich.edu/irbmed/guidance/emerguide.htm); and on the FDA website (http://www.fda.gov/oc/ohrt/irbs/drugsbiologics.html#emergency for drugs or biologics and http://www.fda.gov/oc/ohrt/irbs/irbreview/pdf_for_devices).
  • Timely reporting of adverse events and other unanticipated problems involving risks to subjects or others to the sponsor and the IRB. More information on adverse event and other reporting requirements is available in IRB Standard Operating Procedures, and on the IRBMED website http://www.med.umich.edu/irbmed/ae_orio/.
  • Creating and maintaining complete and accurate records, such as informed consent documents, case report forms, correspondence files, and other relevant information for recordkeeping purposes and possible inspection by institutional officials, outside sponsors, and regulatory agencies. Principal investigators must provide to the IRB promptly after receipt, copies of any audit or inspection reports, warning letters, debarment notices or similar documents generated internally or created by sponsors, government regulators (such as the FDA or NIH) or others with oversight responsibilities.

The principal investigator is responsible for ensuring that all co-investigators and other research team members assisting in the conduct of the study are informed about their obligations in meeting these commitments and are adequately trained to do so competently and appropriately.

Investigator responsibilities are described in further detail at 21 CFR ¤¤ 312.60-312.69 (drugs and biologics); and 21 CFR ¤¤ 812.100-812.110 (devices). See also http://www.fda.gov/cdrh/devadvice/ide/responsibilities.shtml (regarding investigational devices).

II. DETERMINATION THAT AN IND OR IDE IS REQUIRED

The Food, Drug, and Cosmetic Act ("FD&C Act") generally prohibits the manufacture, delivery, use, receipt or sale of any drug or device that is "adulterated" or "misbranded". New drugs and devices, and those used for a purpose or in a manner not approved by the FDA, may be either or both. To avoid civil and even criminal sanctions for adulteration or misbranding, an Investigational New Drug application (IND) or Investigational Device Exemption (IDE) may be required. (Note: The law applies only when there is some relationship between the activity in question and "interstate commerce". Thus, for example, if Drug X is manufactured locally and dispensed at a local clinic only to state residents, the FDA may not regulate it. Because the FDA views most drugs and devices as touching interstate commerce, however, investigators are encouraged to assume that the FD&C Act applies to their work unless they receive an explicit opinion from University counsel to the contrary.)

Whether an IND or IDE is required for the off-label use of an approved product depends largely on the intent and actions of the practitioner. Good medical practice and the best interests of the patient require that health care providers use legally available drugs, biologics and devices according to their best knowledge and judgment, regardless of approved labeling. A practitioner therefore may use a product for an indication not in the approved labeling, but in doing so must be well informed about the product, must base its use on firm scientific rationale and on sound medical evidence, and must maintain records of the product's use and effects. Use of a marketed product in this manner when the intent is the "practice of medicine" (e.g., diagnosis, cure, mitigation, treatment, or prevention of disease in humans) does not require the submission of an IND or IDE or review by an IRB. For additional guidance on whether an IND or IDE is required, an investigator may contact the individuals listed at http://www.fda.gov/oc/ohrt/irbs/offlabel.html. The investigator is encouraged to obtain written documentation of advice that an IND or IDE is not required or, if that is not forthcoming from the regulator, to write a letter to the regulator confirming the investigator's understanding of their conversation. See http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm073025.htm for information on CDRH and CBER procedures for responding to written requests for guidance.

If, however, the intent of the practitioner in using an approved product off-label is to develop information about the product's safety or efficacy, or for other non-diagnostic or therapeutic purposes, an IND or IDE may be required. If the product acts through metabolism, chemical reactions, or the like, it typically is regulated by FDA as a drug; if it is not metabolized, then it is regulated as a device; if it is or once was alive or came from a living being (e.g., cells, vaccines and the like), then it is generally regulated as a biologic. Devices include instruments apparatuses, implements, machines, contrivances, implants, in vitro reagents, and other similar or related articles that do not achieve their primary purposes through chemical action within or on the body and that are not dependent on being metabolized to do so. (See FD&C Act § 201(h).) An IND is the legal mechanism that allows one to clinically test a drug or biologic or otherwise use it for research involving human subjects; an IDE is the legal mechanism that allows one to clinically test a device or otherwise use it for research involving human subjects.

Investigators are responsible for determining whether research in which they are engaged requires an IND or IDE and, if so, for securing the necessary approvals. An investigator who is unsure whether IND or IDE requirements apply to his project may consult with the IRB, the Michigan Institute for Clinical and Health Research (MICHR), or the Health System Legal Office for assistance.

The guidance aids available at http://www.med.umich.edu/irbmed/guidance.html summarize the circumstances under which an IND or IDE may be required and the conditions and special requirements for early or expanded access to test articles.

A. Investigational Drugs and Biologics

The FD&C Act exempts from its adulteration and misbranding prohibitions research on new drugs, as well as "investigational use" of approved drugs, when the research or investigation is conducted in compliance with the FD&C Act and applicable FDA regulations. Physicians may prescribe approved and lawfully marketed drugs "off-label" for clinical purposes without an IND.

Human research on new drugs and biologics may proceed only under an IND. Investigational use of approved, lawfully marketed drugs generally requires an IND unless all of the following conditions are met:

  • It is not intended to be reported to the FDA in support of a new indication for use or to support any other significant change in the labeling for the drug;
  • It is not intended to support a significant change in the advertising for the product;
  • It does not involve a route of administration or dosage level, use in a subject population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;
  • It is conducted in compliance with FDA requirements for IRB review (see 21 CFR part 56) and informed consent (see 21 CFR part 50) respectively;
  • It is conducted in compliance with FDA requirements concerning the promotion and sale of drugs (see 21 CFR § 312.7); and
  • It does not intend to proceed under an exception to FDA's informed consent requirements for emergency research.

The following types of clinical investigations also are exempt from the IND requirement:

  • Those involving certain in vitro diagnostic biological products (blood grouping serum, reagent red blood cells, and anti-human globulin) if: (i) the products are intended to be used in diagnostic procedures that confirm a diagnosis made by another, medically established, diagnostic product or procedure; and (ii) the products are shipped according to specific FDA requirements (see 21 CFR § 312.60);
  • Those involving drugs intended solely for tests in vitro are exempt if shipped according to those same requirements; and
  • Those involving use of a placebo, if they do not otherwise require submission of an IND.

There are separate rules for bioavailability studies. These are described at 21 CFR § 320.31. An IND is required for a bioavailability study if: (i) the test product contains a "new chemical entity" (a drug that contains no active moiety approved by the FDA for marketing); (ii) the study involves a radioactively labeled drug product; or (iii) the study involves a cytotoxic drug product. An IND also is required for any bioavailability studies of approved, non-new chemical entities where the maximum single or total daily dose exceeds that specified in the FDA-approved labeling for the product; and for multiple-dose studies on extended release products on which no single-dose studies have been completed. Most other bioavailability studies are exempt from IND requirements if the researchers reserve samples of any test articles and reference standards used in the studies and release them to FDA on request, and comply with the FDA's regulations on prospective IRB review and informed consent.

Clinical investigations on new drugs and on non-exempt approved, lawfully marketed drugs are regulated by the FDA under 21 CFR part 312.

B. Investigational Devices

1. Generally

An investigational device is a medical device that is the subject of a clinical study designed to evaluate the effectiveness or safety of the device (or both), or a clinical evaluation of certain modifications or new intended uses of a legally marketed device. All clinical studies or evaluations of investigational devices, unless exempt according to the FDA rules, must have an approved IDE before they begin. If the study involves a non-significant risk device, the IDE must be approved by an IRB. If it involves a significant risk device, the FDA also must approve it.

Additional guidance regarding IDE requirements is available at http://www.fda.gov/cdrh/devadvice/ide/index.html.

2. Significant Risk (SR)/Non-significant Risk (NSR) Determinations

The significant risk (SR)/non-significant risk (NSR) determination is made initially by the sponsor (or sponsor-investigator) but must be confirmed by an IRB. If the sponsor believes the study is NSR, the sponsor provides the reviewing IRB with an explanation of its determination and any other information that may assist the IRB in evaluating the risk of the study. This includes, at a minimum, a description of the device, reports of prior investigations with the device, the proposed investigational plan, a description of patient selection criteria and monitoring procedures, as well as any other information that the IRB deems necessary to make its decision. The sponsor also should inform the IRB whether other IRBs have reviewed the proposed study and what determinations were made. The sponsor must inform the IRB of FDA's assessment of the device's risk if one has been made. The IRB also may consult directly with FDA for its opinion.

The IRB may agree or disagree with the sponsor's initial assessment. If the IRB agrees with an NSR assessment and approves the study, the study may begin without submission of an IDE application to FDA. If the IRB disagrees, the sponsor should notify FDA that an SR determination has been made. The study can be conducted as an SR investigation following FDA approval of an IDE application.

The IRB's SOPs or documented standard practice should require the determination to be based on the proposed use of the device in an investigation, and not on the device alone. The SOPs or documented practice also should require the IRB, in making its determination, to consider the nature of the harm that may result from use of the device. If the harm could be life threatening, result in permanent impairment, or necessitate medical or surgical intervention to preclude permanent impairment, the study must be treated as SR. If the subject must undergo a procedure as part of the study (e.g., surgery), the IRB must consider the potential harm that could be caused by the procedure in addition to the potential harm that could be caused by the device.

FDA has the ultimate authority to determine whether a device study is SR or NSR. If FDA disagrees with an IRB's NSR determination, an IDE application must be submitted to FDA. FDA may approve or disapprove an application, or it may require the sponsor to modify the protocol as a condition of approval. Alternatively, FDA may request additional information prior to acting on an application. A decision not to approve an application may be appealed to FDA. If FDA does not act within 30 days of its confirmed receipt of the IDE application, the study may proceed. Conversely, if a sponsor files an IDE with FDA because the study is presumed to be SR, but FDA classifies the study as NSR, FDA will return the IDE application to the sponsor and the study may be presented to IRBs as an NSR investigation.

An SR study is subject to all of the requirements of 21 CFR part 812. An NSR study does not, however, require submission of an IDE application to FDA. Instead, the sponsor must conduct the study as required by "abbreviated" IDE requirements, which address, among other items, requirements for IRB approval and informed consent, recordkeeping, labeling, promotion and study monitoring (see 21 CFR § 812.2(b)). Unless the sponsor is notified otherwise by FDA, an NSR study is considered to have an approved IDE if the sponsor fulfills these abbreviated requirements and it may begin immediately following final IRB approval.

Once a final SR/NSR decision is made by the IRB (or FDA), the IRB must consider whether the study should be approved, using the same criteria it would use in reviewing any other research involving FDA-regulated products.

3. Device Studies Exempt from IDE Requirements

In vitro diagnostic device studies are exempt from IDE requirements if: (i) the testing is non-invasive; (ii) the study does not require invasive sampling presenting significant risk; (iii) energy is not introduced into a subject; (iv) the information gained from the study is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic device or procedure; (v) a device undergoing consumer testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk; and (vi) a custom device as defined in 21 CFR part 812.3 (b), unless the device is being used to determine safety or effectiveness for commercial distribution. In vitro diagnostic devices exempt from IDE requirements still must comply with other related requirements including:

  • Following good scientific practice;
  • Complying with applicable informed consent and IRB oversight requirements;
  • Labeling, including a statement as applicable: "For Research Use Only. Not for use in Diagnostic procedures" or "For Investigational Use Only. The performance Characteristics of this product have not been established;"
  • Establishment and implementation of distribution controls;
  • Conducting inspections;
  • Ensuring adherence to investigational protocols; andMaking pertinent reports and keeping necessary records.

A study exempt from IDE requirements may or may not be exempt from continuing IRB oversight or the need to comply with informed consent requirements. See Part 4 of this Operations Manual.

III. WITHHOLDING FINAL APPROVAL PENDING VERIFICATION OF IND OR IDE ACQUISITION

Through eResearch, investigators are asked a series of questions designed to determine whether an IND or IDE may be required for an investigation. If it appears based on the investigator's responses that an IND or IDE may be required, the reviewing IRB must request the following information:

For Studies Involving Drugs or Biologics:

  • Documentation from the FDA that an IND has been granted (including the IND number), or that an existing IND has been amended as appropriate to cover the specific project in question; or
  • Documentation that the FDA's time for consideration of an application for the specific project in question has lapsed without a notice of disapproval or conditional approval and without a request for additional information (the investigator must still provide the IRB with the IND number assigned by FDA when FDA acknowledged receipt of the IND application); or
  • Documentation of FDA's determination that one is not required.

For Device Studies:

  • Documentation from the FDA that an IDE has been granted (including the IDE number), or that an existing IDE has been amended as appropriate to cover the specific project in question; or
  • Documentation that FDA's time for consideration has lapsed without a notice of disapproval or conditional approval and without a request for additional information (the investigator must still provide the IRB with the IDE number assigned by FDA when FDA acknowledged receipt of the IDE application); or
  • Documentation of FDA's determination that an IDE is not required.

Alternatively, for device studies, if the investigator demonstrates to the IRB that a study meets FDA's requirements for a non-significant risk ("NSR") study, IRB approval of the project and documentation of its NSR decision will suffice.

For additional guidance on whether an IND or IDE is required for off-label use of an approved drug, device, or biologic, an investigator or IRB representative may contact the Michigan Institute for Clinical and Health Research (MICHR) IND/IDE Investigator Assistance Program (MIAP) at http://www.michr.umich.edu/services/regulatorysupport/miap or the FDA at http://www.fda.gov/oc/ohrt/irbs/offlabel.html; for additional guidance on IND or IDE requirements more generally, FDA may be contacted as provided at http://www.fda.gov/AboutFDA/ContactFDA/default.htm.

If the investigator receives verbal advice from FDA that an IND or IDE is not required, the investigator may write a letter to the regulator confirming the conversation and provide a copy of that letter to the IRB. The IRB considers this adequate documentation for purposes of the requirements of this section. Note: an investigator's or sponsor's informal letter to FDA describing a study and reflecting the investigator's or sponsor's presumption that the study is exempt from IND or IDE requirements is not, in and of itself, adequate documentation.
The IRB may initially approve a study before receiving the necessary verification, but in this case will remind the investigator that an amendment containing the required documentation must be submitted and approved by the IRB prior to enrolling any subjects or performing any other activities requiring prior FDA permission.

All investigators who hold an IND or IDE are required to contact MICHR MIAP for guidance on understanding sponsor-investigator requirements and to develop a compliance plan for their studies (see section IV below).

IV. INSTITUTIONAL OR EMPLOYEE SPONSORSHIP OF INDs AND IDEs

The University generally does not "sponsor" (or "hold") INDs or IDEs in its own right and, without written approval of the Vice President for Research or his designee, a University researcher or staff member may not apply for an IND or IDE on behalf of the University. Researchers may, however act as "sponsor-investigators" and hold their own INDs or IDEs if they have adequate training, experience, and support to properly conduct and monitor the relevant investigations and are able and willing to comply with relevant regulatory and institutional requirements.

A. Sponsor-Investigator

A sponsor-investigator is a person who both initiates and conducts an FDA-regulated study; that is, an individual who (i) holds an IND or IDE; and (ii) serves as the principal investigator in one or more studies conducted under that IND or IDE. A sponsor-investigator is responsible for fulfilling all of the investigator obligations described above.

In addition to fulfilling the obligations of an investigator, the sponsor-investigator is responsible for drafting and submitting to the FDA all required documentation for a study, including the IND or IDE application, required amendments and progress reports, safety reports, annual reports, and so forth. The sponsor-investigator also is responsible for selecting other qualified investigators, as appropriate, providing them with the information they need to conduct the studies properly, ensuring proper monitoring of the studies, ensuring the studies are conducted in accordance with the general investigational plan and protocols contained in the IND or IDE application, maintaining an effective IND or IDE with respect to the investigations, and ensuring that FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the investigational agent. The FDA has published guidance on appropriate monitoring procedures. While compliance with this guidance is not mandatory, failure to implement similar procedures or alternative procedures approved by FDA may be deemed inadequate monitoring.

FDA regulations and an increasing number of peer reviewed publications mandate public registration of certain clinical trials. Failure to register may result in administrative sanctions and civil penalties, in addition to refusal by journals to publish. See Part 11 of this Operations Manual for additional information about clinical trials registries.

A sponsor may transfer some or all of these obligations to a contract research organization under a written agreement, but at all times remains ultimately accountable for their fulfillment.

Under FDA regulations, the responsibilities of a sponsor do not vary depending on the sponsorŐs affiliation. Thus, for example, a multinational pharmaceutical manufacturer has precisely the same obligations under the regulations, as does an academic sponsor-investigator. The responsibilities of a sponsor are described further at 21 CFR ¤¤ 312.50-312.59 and 812.40-812.47. See also FDA Guideline for Monitoring of Clinical Investigations; and FDA Responsibilities of Sponsors for Significant Risk Device Studies.

SPECIAL NOTE

When a University of Michigan faculty member applies to be the Sponsor-Investigator of an IND or IDE, the Sponsor-Investigator makes a personal commitment to the FDA to comply with a complex set of requirements (21 CFR 312, 812, and others) regarding the drug, biological, or device itself and the overall management of the research.

The Sponsor-Investigator has ultimate responsibility for fulfilling the FDA requirements; however, failure to comply can put research subjects, the integrity of the data, the University, and the investigator at risk. In particular, the FDA may disqualify the investigator from engaging in FDA-regulated research or impose other legal sanctions.

Any University of Michigan faculty member serving or seeking to serve as the Sponsor-Investigator of an IND or IDE in the course of his or her employment with the University must also:

  1. Register the intent to seek and IND or IDE with the University prior to submission of an application to the FDA.
  2. Participate in education about FDA Sponsor-Investigator requirements and document understanding of the key obligations of a Sponsor-Investigator.
  3. Seek expert consultation, as appropriate, or consider utilizing services available from the Michigan Institute for Clinical and Health Research (MICHR) IND/IDE Assistance Program (MIAP) for consultation, document preparation assistance, and application review and for maintaining and active IND or IDE.
  4. Authorize MIAP to receive FDA communications and include a MIAP contact in all correspondence with the FDA.
  5. Archive all documents related to the IND or IDE in the eResearch Regulatory Management project record.

Serious or continuing noncompliance with the obligations of a Sponsor-Investigator may lead to University restrictions on the ability of the faculty member to enter into these agreements with the FDA.

UM IRBs overseeing research involving a Sponsor-Investigator will develop standard operating procedures and guidance concerning these requirements.

B. Manufacturers

[Reserved]

V. EARLY AND EXPANDED ACCESS TO TEST ARTICLES

Ordinarily, FDA-regulated drugs, biologics, and devices may be used in research only in accord with an investigational plan previously approved by FDA and an IRB (FDA approval is not required for non-significant risk device studies, discussed above in section I(B)(2)). The principal investigator is responsible to assure adherence to the approved investigational plan and that the drug, biologic, or device is administered only by approved co-investigators. Exceptions to this rule are rare and generally apply only in emergency circumstances, describe in further detail below.

A. Investigational Drugs

FDA has developed special mechanisms to facilitate access to promising therapeutic agents where no satisfactory alternative treatments exist and standard IND requirements may result in unnecessary and counterproductive delays. These mechanisms are designed to ensure that human subjects protection and the scientific integrity of the product development process are not compromised.

1. Single Patient INDs for Emergency or Compassionate Use

Emergency use is the use of an investigational drug or biological product with a human subject in a life-threatening (or severely debilitating) situation in which no standard acceptable treatment is available and in which there is not sufficient time to obtain IRB approval. This exemption from prior IRB review and approval is limited to a single use. FDA regulations require that any subsequent use of the investigational product at the institution have prospective IRB review and approval. FDA acknowledges, however, that it would be inappropriate to deny emergency treatment to a second individual if the only obstacle is that the IRB has not had sufficient time to convene a meeting to review the issue.

IRBs may, but are not required to, establish procedures requiring notification prior to any emergency use. Notification does not substitute for approval and is used only to initiate tracking to ensure the investigator files a report within five days. Expedited approval is not permissible for emergency use; full board approval is required unless the requirements for an exemption as described above are met and it is not possible to convene a quorum within the time available (see http://www.fda.gov/oc/ohrt/irbs/drugsbiologics.html#emergency).

The emergency use of an unapproved investigational drug or biologic requires an IND. Instructions for completing a single patient IND for emergency or compassionate use are available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm107434.htm. Contact information for submission of an emergency use IND is available at http://www.fda.gov/oc/ohrt/irbs/drugsbiologicsNEW.html.

If the intended subject does not meet the criteria of an existing study protocol, or if an approved study protocol does not exist, the usual procedure is to contact the manufacturer and determine if the drug or biologic can be made available for the emergency use under the company's IND. However, 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 established by FDA.

2. Treatment INDs

A treatment IND may be granted only after sufficient data have been collected to show that the drug "may be effective" and does not have unreasonable risks. In addition, the following criteria must be met:

  • The drug must be 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; and
  • The trial sponsor is actively pursuing marketing approval.

An immediately life-threatening disease means a stage of a disease in which there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment. For example, advanced cases of AIDS, herpes simplex encephalitis, and subarachnoid hemorrhage are all considered to be immediately life-threatening diseases. Treatment INDs are made available to patients before general marketing begins, typically during Phase 3 studies. Treatment INDs also allow FDA to obtain additional data on the safety and effectiveness of the drugs in question.

Treatment INDs ordinarily do not obviate the requirement of prior IRB review and approval, and informed consent. A sponsor may, however, apply to the Vice President for Research and, with the VPR's approval, to FDA, for a waiver of local IRB review under a treatment IND if such a waiver would be in the best interest of subjects and a satisfactory alternative mechanism is available, such as review by a central IRB (see http://www.fda.gov/oc/ohrt/irbs/drugsbiologics.html#waiver and Part 5 of this Operations Manual for additional information). An IRB may still opt to review a study even if FDA has granted a waiver.

A special class of treatment IND has been established for the distribution of certain promising cancer drugs. The "Group C" treatment IND was established by agreement between FDA and the National Cancer Institute (NCI). The Group C program is a means for the distribution of investigational agents to oncologists for the treatment of cancer under protocols outside the controlled clinical trial. Group C drugs are generally Phase 3 study drugs that have shown evidence of relative and reproducible efficacy in a specific tumor type. Properly trained physicians can generally administer them without the need for specialized supportive care facilities. Group C drugs are distributed only by the National Institutes of Health under NCI protocols. Although treatment is the primary objective and patients treated under Group C guidelines are not part of a clinical trial, safety and effectiveness data are collected. Because administration of Group C drugs is not done with research intent, FDA has generally granted a waiver from the IRB review requirements. Even though FDA has granted a waiver for these drugs, an IRB may establish policies and procedures requiring approval in these cases. The use of a Group C drug is described in its accompanying "Guideline Protocol" document. The Guideline Protocol contains an FDA-approved informed consent document, which must be used if there has been no local IRB review.

3. Parallel Track Studies

The FDA has adopted a "Parallel Track" policy (see 57 Fed. Reg. 13250, May 21, 1990), which facilitates access to promising new drugs for AIDS/HIV related diseases under a separate protocol that "parallels" the controlled clinical trials that are essential to establish the safety and effectiveness of new drugs. It provides an administrative system that expands the availability of drugs for treating AIDS/HIV. These studies require prior IRB review and approval, and informed consent. FDA is responsible for assuring that the availability of a drug under the parallel track program does not interfere with the drug sponsor's ability to carry out well-controlled studies on the drug and does not encourage patients with other approved treatment alternatives to resort to untested investigational drugs.

4. Open Label Protocols or Open Protocol INDs

These are usually uncontrolled Phase 3 studies, carried out to obtain additional safety data. They typically are 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 prior IRB review and approval, and informed consent.

B. Investigational Devices

The FDA has described four ways providers may access investigational devices prior to FDA approval and outside the scope of a clinical trial. These are: (i) emergency use for life-threatening or serious diseases or conditions; (ii) compassionate use for patients who do not meet the criteria for inclusion in a trial but may benefit from use of the device; (iii) treatment use, to expand the number of subjects who may be permitted to participate in a trial that shows promise; and (iv) continued access to investigational devices for subjects participating in a trial after the trial is complete but prior to FDA approval. Additional guidance on early and expanded access to investigational devices is available at http://www.fda.gov/cdrh/devadvice/ide/early.html.

1. Emergency Use

FDA has recognized that emergency situations may arise in which there will be a need to use an investigational device in a manner inconsistent with the approved investigational plan or by a physician who is not part of the clinical study. Emergency use of an unapproved device may occur before an IDE is approved. To qualify for emergency use, the prospective patient must be suffering a life-threatening or serious disease or condition that requires immediate treatment; there must be no available, generally acceptable alternatives for treating the patient; and there must be no time to use existing procedures to obtain FDA approval.

Under very limited circumstances, the requirements for informed consent may be waived in an emergency situation. Guidance concerning waiver of consent for emergency research under FDA regulations is available at http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm118995.htm. Individual IRBs may, in their discretion, choose not to entertain applications for waiver of informed consent in emergency situations.

It is the treating physician's responsibility to determine whether these criteria have been met, to assess a patient's potential for benefits from the unapproved use, and to have substantial reason to believe that benefits will exist. Where emergencies are reasonably foreseeable, physicians should obtain FDA approval through standard IDE procedures or through the compassionate, treatment or continued use procedures described below. The FDA considers an emergency reasonably foreseeable if the device could be used in an emergency.

In the event an unapproved device is used in an emergency under this exception, the device developer must notify the FDA immediately after shipment. In addition, the physician employing the device should make every effort to protect subjects including, as applicable:
(i) obtaining an independent assessment by an uninvolved physician; (ii) obtaining informed consent from the patient or legally authorized representative; (iii) notifying the appropriate IRB as soon as practicable; and (iv) obtaining authorization from the IDE holder, if an approved IDE for the device exists.

After the emergency, the physician must: (i) report to the IRB within five days and otherwise comply with IRB requirements; (ii) evaluate the likelihood of a similar need occurring again and, if future use is likely, immediately initiate efforts to obtain IRB approval and an approved IDE for subsequent use; and (iii) if an IDE for the use already exists, notify the sponsor of the emergency use, or if an IDE does not exist, notify the FDA of the emergency use, and provide the FDA with a written summary of the conditions constituting the emergency, subject protection measures, and results. Subsequent emergency use may not occur unless the physician or another person obtains approval of an IDE for the device and its use. If one has been filed and disapproved by FDA, the device may not be used even in an emergency.

2. Compassionate Use

This provision allows access for patients who do not meet the requirements for participation in the clinical investigation but for whom the treating physician believes the device may provide a benefit in treating or diagnosing their disease or condition. The condition must be serious and there must be no available, generally acceptable alternatives for treatment. This provision is typically approved for single patients, but may be approved to treat a small group. Prior FDA approval is needed before compassionate use occurs. In order to obtain FDA approval, the sponsor should submit an IDE supplement requesting approval for a protocol deviation. The physician should not treat the patient (or patients) identified in the supplement until FDA and the appropriate IRB both approve the use of the device under the proposed circumstances. Additional requirements apply and are discussed at http://www.fda.gov/cdrh/devadvice/ide/early.shtml#compassionateuse.

3. Treatment Use

Approved IDEs specify the maximum number of clinical sites and the maximum number of human subjects that may be enrolled in a study. During the course of a clinical trial, if the data suggest that the device is effective, then the trial may be expanded to include additional patients with life-threatening or serious diseases. To qualify for a treatment use IDE, the disease or condition must be life threatening or serious, and patients must have no comparable or satisfactory alternatives to the investigational device. If the disease is immediately life-threatening (i.e., there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment), a device may be eligible for a treatment use IDE prior to completion of all clinical trials; if the disease is serious, a device ordinarily may be made available for treatment use only after all clinical trials have been completed. Thus, in summary, FDA will consider the use of an investigational device under a treatment IDE if all of the following criteria are met:

  • The device is intended to treat or diagnose a serious or immediately life-threatening disease or condition;
  • There is no comparable or satisfactory alternative device or other therapy to treat or diagnose that stage of the disease or condition in the intended patient population;
  • The device is under investigation in a controlled clinical trial for the same use under an approved IDE, or the clinical trials have been completed; and
  • The sponsor of the investigation is actively pursuing marketing approval/clearance of the investigational device with due diligence.

Specific requirements for a treatment IDE application are available at: http://www.fda.gov/cdrh/devadvice/ide/early.shtml#treatmentuse. Treatment use may begin 30 days after FDA receives the treatment IDE submission, unless FDA notifies the sponsor otherwise.

A licensed practitioner who receives an investigational device for treatment use under a treatment IDE is considered an "investigator" under FDA regulations and is responsible for meeting all applicable investigator responsibilities, including responsibilities to obtain prospective IRB approval and informed consent. See Part 6 for a description of investigator responsibilities for FDA-regulated research. The sponsor of a treatment IDE must meet all of the applicable sponsor responsibilities, including submission of progress reports.

C. Continued Access

FDA may allow continued enrollment of subjects after a controlled clinical trial under an IDE has been completed to allow access to the investigational device while a marketing application is being prepared by the sponsor or reviewed by the FDA and facilitate the collection of additional safety and effectiveness data to support the marketing application or to address new questions regarding the investigational device. This is referred to as an "extended investigation." FDA will approve an extended investigation only if it identifies a public health need or preliminary evidence is submitted that the device will be effective and no significant safety concerns have been identified for the proposed indication. See http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080260.htm for a description of the requirements for a continued access IDE application; see also http://www.fda.gov/cber/regsopp/8748.html (CBER guidance).

The difference between a treatment IDE and use of an investigational device under the continued access policy is that a treatment IDE can be submitted earlier in the IDE process (i.e., as soon as promising evidence of safety and effectiveness has been collected but while the clinical study is ongoing) but is intended only for patients with serious or immediately life-threatening diseases or conditions, whereas continued access generally is available only after completion of a clinical trial but for a broader range of patients.

D. Additional Exceptions

FDA from time to time approves additional exceptions to standard approval processes. For instance, guidance issued in June 2005 under the Project Bioshield Act of 2004 permits the FDA to allow the use of unapproved medical products or approved medical products for unapproved purposes during a declared emergency involving a heightened risk of attack on the public or U.S. military forces.

VI. CHARGING FOR TEST ARTICLES

When the sponsor or sponsor-investigator intends to charge subjects for investigational products or related treatment or services, he or she must comply with all IRB policies (e.g., to ensure that the charges are appropriate and equitable and to require disclosure of the charges in the informed consent document), institutional billing policies, and professional ethics, as well as the following FDA guidelines.

A. Investigational Medical Devices and Radiological Health Products

The IDE regulations allow sponsors to charge for an investigational device, however, the charge should not exceed an amount necessary to recover the costs of manufacture, research, development, and handling of the investigational device. A sponsor justifies the proposed charges for the device in the IDE application, states the amount to be charged, and explains why the charge does not constitute commercialization. FDA generally allows sponsors to charge investigators for investigational devices, and this cost usually is passed on to the subjects.

B. Charging for Investigational Drugs and Biologics

The IND regulations permit a sponsor to charge for an investigational drug or biologic that has not been approved for marketing, only as follows: the charge should not exceed an amount that is necessary to recover the costs associated with the manufacture, research, development, and handling of the investigational drug or biologic. FDA may withdraw authorization to charge if it finds that the conditions underlying the authorization are no longer satisfied.

1. Clinical Trials

The sponsor must obtain prior written approval from FDA to charge for the investigational drug or biologic. In requesting approval, the sponsor must explain why a charge is necessary (i.e., why providing the product without charge should not be considered part of the normal cost of conducting a clinical trial).

2. Treatment Protocols or Treatment INDs

The sponsor or investigator may charge for the product only if: (i) there is adequate enrollment in the ongoing clinical investigations under the authorized IND; (ii) charging does not constitute commercial marketing of a new drug for which a marketing application has not been approved; (iii) the drug or biologic is not being commercially promoted or advertised; and (iv) the sponsor is actively pursuing marketing approval with due diligence. Charges may begin 30 days after FDA receives a written notification, unless FDA notifies the sponsor otherwise.

VII. COMPLIANCE WITH 21 CFR PART 11, ELECTRONIC RECORDS AND ELECTRONIC SIGNATURES

The University has conducted a self-assessment of eResearch compliance with 21 CFR Part 11 (http://hrpp.umich.edu/policies/SelfAssessment.pdf) and has issued an electronic signature certification statement (http://hrpp.umich.edu/policies/Certification.pdf).