Chapter 16 - Considerations for FDA Regulated Research

IRB Review of Studies Utilizing Drugs, Biologics and Devices

The US Food and Drug Administration (FDA) regulates clinical studies conducted on drugs, biologics, devices, diagnostics, and in some cases dietary supplements and food additives. All such research studies must be conducted in accordance with FDA requirements for the protection of human subjects and IRBs, regardless of source of funding (21 CFR Parts 50 and 56).

When FDA regulated test articles are used in research conducted at the University of Pittsburgh and funded by another agency, more than one set of regulations may apply. For example, clinical trials involving FDA regulated test articles that are supported by the Department of Health and Human Services (DHHS) 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 participant regulations. Where regulations differ, the University of Pittsburgh IRB will apply the stricter regulation.

In addition to the other applicable requirements outlined in this document, for studies involving drugs, biologics or devices the IRB shall follow the procedures outlined below. As specified in Chapter 12, Meeting Materials, reviewers are provided with the sponsor protocol as well as other materials specific to the study, e.g. the investigator brochure and correspondence with the applicable regulatory agencies.

Drugs, Biological Products, and Dietary Supplements

Research Involving Drugs and Biological Products

For studies that involve FDA regulated drugs and biological products the UOP IRB will comply with the requirements of 21 CFR Parts 312 and 600.

Research Involving Unapproved / Investigational Drugs and Biological Products

In general, the submission of an Investigational New Drug (IND) application is required for any clinical research study that proposes the use (e.g., as a research tool to explore a biological phenomena or disease process) or evaluation (i.e. for safety and/or effectiveness) of an unapproved drug or biological product.

For studies that involve investigational drugs or biological products, the IRB shall require evidence that the FDA has issued an Investigational New Drug (IND) number. This confirmation will be made by determining if the IND number provided on the IRB coversheet or the OSIRIS submission matches that recorded on the sponsor protocol, communication from the sponsor, or communication from the FDA.

Research Involving Approved Drugs or Biological Products

For research using an approved drug or biologic, where the investigator has not provided a valid IND number, the IRB shall evaluate the protocol to determine if an IND is required. In general, the submission of an IND is not required for any clinical research study that proposes the use or evaluation (i.e., for safety and/or effectiveness) of an approved drug, provided that:

  • The results of the study are not intended to be reported to the FDA in support of a new indication for the use of the drug or to support any other significant change in the labeling of the product;
  • The results of the study are not intended to support a significant change in the advertising for the product;
  • The study does not involve a route of administration or dosage level, or use in a subject population or other factor that significantly increases the risks (or decreases the acceptability of risks) associated with the use of the product; and
  • The study is conducted in compliance with the requirements for IRB review and informed consent.

Dietary Supplements

Dietary supplements are exempt from FDA regulation as “drugs” provided that they are being evaluated and/or are labeled for intended use in affecting the structure or function of the body (i.e., a structure/function claim).1 However, the evaluation of a dietary supplement for the diagnosis, prevention, mitigation, treatment or cure of a specific disease or condition (i.e., a disease claim) requires the prior submission of an IND application.

1 Dietary Supplement Health and Education Act

Devices

A medical device is defined, in part, as any health care product that does not achieve its primary intended purpose by chemical action or by being metabolized. Examples of medical devices include, but are not limited to, surgical lasers, wheelchairs, sutures, pacemakers, vascular grafts or stents, intraocular lenses, orthopedic pins, and radiographic imaging equipment. Medical devices also include diagnostic aids such as reagents and test kits for in vitro diagnosis of disease or other medical conditions such as pregnancy.

For research involving medical devices, the UOP IRB will comply with the requirements set forth in 21 CFR Part 812. These regulations describe two types of investigational device studies, "significant risk" and "non-significant risk."

  • A "significant risk device study" is defined by FDA regulations as a study of a device that presents a potential for serious risk to the health, safety, or welfare of a subject and/or a) is intended as an implant (An “implant” is defined by the FDA as “a device that is placed into a surgically or naturally formed cavity of the human body and is intended to remain there for a period of 30 days or more”. The FDA may determine that devices placed into human subjects for shorter periods of time are also implants.); b) is used in supporting or sustaining human life; c) is of substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise preventing impairment of human health or d) otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.
     
  • A "non-significant risk device study" is a study of a device that does not meet the FDA’s definition for a "significant risk device study."

The determination that a device study presents a “significant risk” or a “non-significant risk” is initially made by the sponsor/investigator. If the sponsor/investigator considers the device study to be of “non-significant risk”, the sponsor/investigator must provide the IRB with an explanation of this determination and copies of the respective research protocol and informed consent document. The sponsor should inform the IRB of the FDA’s assessment of the risk status of the proposed device study, if such an assessment has been made. The IRB may question whether other IRBs have reviewed the proposed device study and what determination they made or the IRB may consult with the FDA for its opinion.

In making the risk determination, the IRB considers both the device as well as the nature of harm that may result from the use of the device. The IRB may agree or disagree with the determination of the sponsor/investigator.

If the IRB determines that the device study presents “non-significant risk”, and approves the research study and informed consent document(s), the study may proceed without further notification of the FDA.

If the IRB determines that the device study presents a “significant risk”, the sponsor must notify the FDA that the device study has been determined to be of “significant risk” and if electing to proceed with the study, must submit an IDE application. The device study may not commence until the FDA approves the IDE and the IRB approves the device risk designation, the study protocol and informed consent document(s).

The IRB will utilize the device checklist in making this determination and the determination will be recorded in the IRB meeting minutes.

Waiver of Consent for Planned Emergency Research

Criteria for Approval

In accordance with 21 CFR 50.24 or 45 CFR 46.101 (i), the IRB may approve planned research in an emergency setting without the informed consent of the participants or their legally authorized representatives in a limited class of emergency situations when the following criteria are met and documented:

  • Potential subjects are in a life-threatening situation, and
    • available treatments are unproven or unsatisfactory and
    • collection of scientific data is required to determine the safety and effectiveness of the experimental intervention
  • Obtaining informed consent is not feasible because:
    • the potential subject is not able to consent due to his/her medical condition
    • the intervention must be administered before consent from the potential subject’s authorized representative is feasible and
    • there is no reasonable way to prospectively identify potential eligible subjects
  • Participation in the research study holds out the prospect of direct benefit to the subjects because:
    • the subjects are facing a life-threatening situation
    • appropriate pre-clinical and prior clinical research studies support the potential for direct benefit and
    • the risks associated with the research are reasonable relative to the risks of the subjects’ condition and the risk/benefit ratio of standard therapy for the condition
  • The research could not be practicably carried out without the waiver.

Submission Requirements

The IRB recognizes the loss of the research subject’s autonomy when this waiver is granted and requires the following additional measures to be addressed by the Principal Investigator in the research protocol. These requirements include:

  • A defined therapeutic window, based on scientific evidence, of the maximum length of time for which the intervention(s) must be initiated.
  • A commitment to contact or attempt to contact, within this “therapeutic window”, a legally authorized representative for each subject and, if feasible, to ask this representative for consent for the subject’s participation. These efforts must be summarized by the investigator for all subjects enrolled at the time of continuing review.
  • In the event of the unavailability of a legally authorized representative of the subject, a description of what attempts will be made, if feasible, to contact, within this “therapeutic window”, a member of the subject’s family to determine whether s/he objects to the subject’s participation.
  • An informed consent document inclusive of the basic and applicable additional elements along with an outline of procedures to address subject enrollment with direct consent, if applicable, or with consent of the subject’s authorized representative, if available.
  • Procedures to inform, at the earliest feasible opportunity, the subject (i.e., if his/her condition improves), a legally authorized representative of the subject, or if such a representative is not reasonably available, a family member of the subject, of the subject’s inclusion in research, the details of the research, and the right to discontinue the subject’s participation at any time without penalty or a loss of entitled benefits.
  • Appropriate procedures and information to be used in providing an opportunity for a family member to object to a subject’s participation in the research.
  • Procedures to provide information about the research to the subject’s legally authorized representative or family member should a subject enrolled into the study without consent die before such individuals can be contacted.
  • An independent data monitoring committee to exercise oversight of the research. See guidance on data and safety monitoring plans or additional requirements related to data and safety monitoring committees/plans for additional requirements related to data and safety monitoring committees/plans.
  • Prior specific IND or IDE approval from the FDA for research involving investigational or approved drugs or devices for which the IND/IDE submission clearly indicates that the protocol(s) may include subjects who are unable to consent.
  • A plan for consultation with representatives of the community (communities) in which the research will be conducted and from which the subjects will be drawn. The University of Pittsburgh currently utilizes the Pittsburgh Human Relations Commission as its community consultation committee. A summary of comments/concerns raised by the community must be presented to the IRB prior to final approval being granted.
  • A plan, including draft copy, for public disclosure/notification of the research to the community (communities) in which the research will be conducted and from which the subjects will be drawn. This could include meetings with focus groups, church or community organizations, newspaper articles, etc.
  • A summary of comments/concerns raised during public disclosure/notification must be presented to the IRB prior to final approval being granted.

Note that public disclosure following the completion of the study to apprise the community and researchers of the study results is also required.

A licensed physician “who is a member of, or consultant to, the IRB and who is not otherwise participating in the clinical investigation” must concur that the waiver of consent is allowable.  Review of the above requirements is documented by the IRB on the checklist titled “Documentation of IRB Review and Approval: Emergency Acute Care Research Involving a Waiver of Informed Consent.” Please refer to the Forms, Templates, and Checklists in OSIRIS, Waiver of Emergency Research.

Special Additional Considerations

Research involving certain protected populations, including fetuses, pregnant women, prisoners and human in vitro fertilization, are explicitly excluded from eligibility for this waiver. If the research study does not involve an article regulated by the FDA and the IRB determines that it can approve an exception to the requirement for informed consent for emergency research as per the criteria addressed under 45 CFR 46.101 (i) (i.e., OHRP’s “Emergency Consent Waiver”), the IRB shall notify the OHRP of such approval.

If the IRB determines that the protocol does not meet the criteria outlined in 45 CFR 46.101 (i) [OHRP’s “Emergency Research Consent Waiver” to 45 CFR 46] or if applicable, 21 CFR 50.24, or because of other relevant ethical concerns disapproves the research, the IRB must promptly provide a summary of its findings to both the clinical investigator and the sponsor of the trial. The IRB recognizes that it is the sponsors’ responsibility to notify the FDA of the IRBs’ findings.

Investigators involved in the development or implementation of such research studies, wherein an exception to the requirement to obtain informed consent is an anticipated necessity, are advised to engage the assistance of the IRB Office as early as possible in the protocol development process. The Assistant Director of the IRB should be contacted for assistance with this matter.

Expanded Access to Unapproved Drugs, Biologics, or Devices

Expanded Access to Unapproved Drugs or Biologics

Under FDA regulations (21 CFR 312.300), expanded access allows for the use of unapproved drugs and biologics outside of a clinical trial for patients with serious diseases or conditions when there is no satisfactory alternative therapy to treat the patient’s disease or condition.  This is sometimes referred to as compassionate use or treatment use.  While expanded access is not considered a clinical investigation, FDA submission and IRB review are required.

Key Definitions:

Immediately life-threatening disease or condition means a stage of disease in which there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.

Serious disease or condition means a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible, provided it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.

Criteria for all expanded access uses for drugs and biologics:

The FDA must determine that:

(1) The patient or patients to be treated have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition;

(2) The potential patient benefit justifies the potential risks of the treatment use and those potential risks are not unreasonable in the context of the disease or condition to be treated; and

(3) Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.

Types of expanded access for drugs and biologics

Under FDA’s current regulations, there are three categories of expanded access as shown in the diagram below.

Single patient expanded access, non- emergency use

In addition to the criteria for all expanded access uses listed above, the following must also be met:

  1. The physician must determine that the probable risk to the person from the investigational drug is not greater than the probable risk from the disease or condition; and
  2.  FDA must determine that the patient cannot obtain the drug under another IND or protocol.

If the drug is the subject of an existing IND, the expanded access IND submission may be made by the sponsor or by a licensed physician.  Per the agreement between the University of Pittsburgh and UPMC, if the expanded access IND is industry sponsored, the expanded access protocol does not fall under the authority of the University of Pittsburgh IRB and must be processed through the UPMC OSPARS office.  If the expanded access IND is investigator initiated, it will be processed through the University of Pittsburgh IRB, and if there is an agreement for the provision of the drug, that agreement will be processed via UPMC OSPARS.

Procedures for IRB submission of single patient, non-emergency expanded access protocols

Single patient, non-emergency expanded access protocols must be submitted through OSIRIS and require IRB review and approval under FDA regulations.  The HRPO is cognizant of the need for timely review for these cases and will make every effort to assign these cases to the first available meeting with expertise.  Please see the Office for Investigator-Sponsored IND and IDE Support (O3IS) website (http://www.o3is.pitt.edu/) for information about preparing an IND submission to FDA.

Single Patient Expanded Access, emergency use

If there is an emergency that requires a patient to be treated before a written IND submission can be made to FDA, an emergency IND may be granted by FDA.  Under the emergency use provisions in the FDA regulations (21 CFR 56.104(c)), the emergency use of an unapproved drug is an exemption from prior review and approval by the IRB, but must be reported to the IRB.  According to FDA regulations (21 CFR 56.102(d), emergency use is the use of a test article on a human subject in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain IRB approval.  Life-threatening, for the purposes of section 56.102(d), includes the scope of both life-threatening and severely debilitating, as defined below.

  • Life-threatening means diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted and diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival. The criteria for life-threatening do not require the condition to be immediately life-threatening or to immediately result in death. Rather, the patients must be in a life-threatening situation requiring intervention before review at a convened meeting of the IRB is feasible.
  • Severely debilitating means diseases or conditions that cause major irreversible morbidity. Examples of severely debilitating conditions include blindness, loss of arm, leg, hand or foot, loss of hearing, paralysis or stroke.

The emergency exemption from prospective IRB review allows for one emergency use of a drug or biologic without prospective IRB review.  FDA regulations require that any subsequent use of the investigational product at the institution have prospective IRB review and approval.  However, in guidance documents, FDA acknowledges 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 protocol.

Procedures for IRB submission of single patient, emergency use protocols

The University of Pittsburgh HRPO requires that, when possible, the IRB be notified in advance of the proposed emergency use of an unapproved drug or biologic.  IRB notification is done through the Emergency Use pathway in OSIRIS.  The EU pathway provides a mechanism for verifying that the intended use meets criteria, for uploading documentation of correspondence with FDA, including the emergency IND approval, the treatment plan and the proposed consent form.  The IRB Chair or Vice Chair will review and acknowledge the emergency use.   The EU pathway also allows for submission of follow up information on the status of the patient.  Please note that acknowledgment of the emergency use by the IRB Chair or Vice Chair should not be construed as IRB approval. Only proposals that undergo full IRB review can receive IRB approval.   
In the event of a waiver of informed consent for an emergency use, the IRB Chair or Vice Chair will confirm that both the physician holding the emergency IND and a physician who is not otherwise participating in the emergency use have certified in writing all of the following:

  • the patient is confronted by a life-threatening situation necessitating use of the test article;informed consent cannot be obtained because of an inability to communicate with, or  obtain legally effective consent from, the patient;
  • time is not sufficient to obtain consent from the patient’s legal representative;
  • no alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the patient’s life;

If, in the physician’s opinion, there is not sufficient time to obtain an independent physician’s determination that the four criteria are met, the physician holding the emergency IND should make the determination and subsequently obtain (i.e., within five working days) a review of his/her determination by a physician not participating in the emergency treatment.

Expanded Access for Intermediate-size populations

FDA may permit an investigational drug to be used for treatment of a patient population smaller than that typical of a treatment IND or treatment protocol.  In cases where FDA has received a significant number of requests for individual patient expanded access for the same use, a sponsor may be asked to consolidate expanded access under this category.  

In addition to the criteria listed at the beginning of this section for all expanded access, the FDA must also determine that there is enough evidence that the drug is safe at the proposed dose and duration and there is at least preliminary evidence of effectiveness of the drug as a therapeutic option in the patient population.  For more information about FDA requirements, please see 21 CFR 312.315.

Procedures for IRB submission of expanded access protocols for intermediate –size populations

Intermediate size expanded access protocols must be submitted through usual procedures in OSIRIS and require full IRB review and approval under FDA regulations.  Please see the Office for Investigator-Sponsored IND and IDE Support (O3IS) website (http://www.o3is.pitt.edu/) for information about preparing an IND submission to FDA.

Expanded Access for Large Patient Populations

Expanded access protocols for large patient populations are also referred to as treatment IND or treatment protocols.  This category is used for widespread treatment use of an investigational drug.    In addition to the criteria listed at the beginning of this section for all expanded access, FDA must also determine that the drug is being investigated in a controlled trial under an IND to support a marketing application for the expanded access or all clinical trials of the drug have been completed, the sponsor is actively pursuing marketing for approval of the expanded access and there is sufficient data supporting safety and effectiveness of the drug for the expanded access.

Procedures for IRB submission of expanded access protocols for large patient populations

Expanded access protocols for large patient populations must be submitted per usual procedures through OSIRIS and require full IRB review and approval under FDA regulations.  Please see the Office for Investigator-Sponsored IND and IDE Support (O3IS) website (http://www.o3is.pitt.edu/) for information about preparing an IND submission to FDA.

Expanded Access to Unapproved Devices

According to FDA regulations, an unapproved medical device may normally only be used on human subjects through an approved clinical study in which the subjects meet certain criteria and the device is only used in accordance with the approved protocol by a clinical investigator participating in the clinical trial. However, FDA recognizes 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 or to help a patient suffering from a serious disease or condition for which there no other alternative therapy exists. Patients/physicians faced with these circumstances may request access to investigational devices under one of the following mechanisms by which FDA may make an unapproved device available:

Key Definitions: 
Unapproved medical device is a device that is utilized for a purpose, condition, or use for which the device requires, but does not have, an approved application for premarket approval under section 515 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360e)(the act) or an approved IDE under section 520(g) of the act (21 U.S.C. 360j(g)).
IDE  - An approved investigational device exemption permits a device that otherwise would be required to comply with a performance standard or to have premarket approval to be shipped lawfully for the purpose of conducting investigations of that device.

Emergency Use of an unapproved device

As mentioned above, an unapproved device should normally only be used in human subjects if it is approved for clinical testing under an IDE and if it is used by an investigator for the sponsor in accordance with the terms and conditions of the application. Emergency use of an unapproved device, however, may also occur when: (i) an IDE for the device does not exist, (ii) when a physician wants to use the device in a way not approved under the IDE, or (iii) when a physician is not an investigator under the IDE.  The sponsor must notify the FDA within 5 days through submission of an IDE report describing the case and the patient protection measures that were followed.

Life-threatening, for the purposes of section 56.102(d), includes the scope of both life-threatening and severely debilitating, as defined below.

  • Life-threatening means diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted and diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival. The criteria for life-threatening do not require the condition to be immediately life-threatening or to immediately result in death. Rather, the patients must be in a life-threatening situation requiring intervention before review at a convened meeting of the IRB is feasible.
  • Severely debilitating means diseases or conditions that cause major irreversible morbidity. Examples of severely debilitating conditions include blindness, loss of arm, leg, hand or foot, loss of hearing, paralysis or stroke.

Criteria: The physician who intends to use the device must determine that the following criteria are met

  • Life-threatening or serious disease or condition that needs immediate treatment
  • No generally acceptable alternative treatment for the condition exists
  • Because of the immediate need to use the device, there is no time to obtain FDA approval

FDA expects the physician to make the determination that the patient’s circumstances meet the above criteria, to assess the potential for benefit from the use of the unapproved device and to have substantial reason to believe that benefits will exist.

Under the emergency use provisions in the FDA regulations (21 CFR 56.104(c)), the emergency use of an unapproved test article is an exemption from prior review and approval by the IRB, but must be reported to the IRB within 5 working days.  FDA guidance indicates that the physician should follow as many patient protection procedures as possible, including:

  • Informed consent from the patient or a legal representative
  • Clearance from the institution as specified by their policies
  • Concurrence of the IRB Chairperson
  • An independent assessment from an uninvolved physician; and
  • Authorization from the IDE sponsor, if an approved IDE exists.
Procedures for IRB submission of protocols for emergency use of unapproved devices

The University of Pittsburgh HRPO requires that, when possible, the IRB be notified in advance of the proposed emergency use of an unapproved device.  IRB notification is done through the Emergency Use pathway in OSIRIS.  The EU pathway provides a mechanism for verifying that the intended use meets criteria, for uploading documentation of correspondence with FDA, the proposed treatment plan, and the proposed consent form.  The IRB Chair or Vice Chair will review and concur that the emergency use meets the criteria.   The EU pathway also allows for submission of follow up information on the status of the patient.  Please note that concurrence of the emergency use by the IRB Chair or Vice Chair should not be construed as IRB approval. Only proposals that undergo full IRB review can receive IRB approval. 
 
In the event of a waiver of informed consent for an emergency use, the IRB Chair or Vice Chair will confirm that both the investigator and a physician who is not otherwise participating in the clinical investigation have certified in writing all of the following:

  • the patient is confronted by a life-threatening situation necessitating use of the test article;
  • informed consent cannot be obtained because of an inability to communicate with, or  obtain legally effective consent from, the patient;
  • time is not sufficient to obtain consent from the patient’s legal representative;
  • no alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the patient’s life;

If, in the investigator’s opinion, there is not sufficient time to obtain an independent physician’s determination that the four criteria are met, the investigator should make the determination and subsequently obtain (i.e., within five working days) a review of his/her determination by a physician not participating in the investigation.

Compassionate Use (or Single Patient/Small Group Access)

FDA’s compassionate use provision is designed to provide access to an investigational device for patients who are not eligible for the clinical trial but for whom the treating physician believes the device may provide a benefit in treating and/or diagnosing their disease or condition.  Compassionate use may be used only during the clinical trial for which the device is being tested.  Compassionate use may be approved for a single patient or a small group of patients.

Criteria:  

  • The device is intended to  treat or diagnose a serious disease or condition
  • There is no comparable or satisfactory alternative device or therapy available

Prior FDA approval is required before compassionate use occurs.  The sponsor of the IDE is required to submit an IDE supplement requesting approval under 812.35(a) in order to treat the patient.    For further instructions about FDA requirements for the IDE supplement, please refer to the FDA website http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm051345.htm

The physician may not treat the patient identified in the IDE supplement until FDA approves the compassionate use for the intended patient.  FDA will consider preliminary evidence of safety and effectiveness as well as whether the compassionate use would interview with the conduct of a clinical trial to support marketing approval.  Once approved, the patient should be monitored for safety.   Follow up information on the use of the device should be submitted in an IDE Report after compassionate use has ended.

Procedures for IRB submission of protocols for compassionate use of unapproved devices

For investigator initiated IDEs, compassionate use protocols must be submitted through the usual procedures in OSIRIS.   Per the agreement between the University of Pittsburgh and UPMC, if the IDE is industry sponsored, the expanded access protocol does not fall under the authority of the University of Pittsburgh IRB and must be processed through the OSPARS office.  If the IDE is investigator initiated, it will be processed through the University of Pittsburgh IRB, and if there is an agreement for the provision of the device, that agreement will be processed via UPMC OSPARS.  

Treatment Use of Investigational Devices

These procedures are intended to facilitate that availability of devices that are not FDA approved for marketing, but are under clinical investigation for a serious or immediately life threatening disease or condition in patients for whom there is no comparable or satisfactory alternative device or treatment available.  During the trial or prior to final FDA action on the marketing approval, it may be appropriate to use the device to treat patients not in the trial under treatment IDE regulations (21 CFR 812.36).
For the purposes of treatment use, immediately life-threatening disease means a stage of a disease in which there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.

Criteria:

  • 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 available 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 such clinical trials have been completed; and
  • The sponsor of the investigation is actively pursuing marketing approval/clearance of the investigational device with due diligence.

A treatment IDE application must be submitted to FDA and approval must be obtained prospectively.  For information about FDA requirements for submission of a treatment IDE application, please see http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm051345.htm.

Procedures for IRB submission of protocols for treatment use of unapproved devices

For investigator initiated treatment IDEs, treatment use protocols must be submitted through the usual procedures in OSIRIS.   Per the agreement between the University of Pittsburgh and UPMC, if the treatment IDE is industry sponsored, the expanded access protocol does not fall under the authority of the University of Pittsburgh IRB and must be processed through the OSPARS office.  If the treatment IDE is investigator initiated, it will be processed through the University of Pittsburgh IRB, and if there is an agreement for the provision of the device, that agreement will be processed via UPMC OSPARS.

Continued Access

FDA may allow continued enrollment of subjects after the clinical trial under an IDE has been completed to allow access to the investigational medical device while the marketing application is being prepared by the sponsor or reviewed by FDA.  This is known as an “extended investigation”.

Criteria:

  • Public health need for the device, OR
  • Preliminary evidence that the device will be effective and there are no significant safety concerns

A sponsor’s request for an extended investigation should be submitted as an IDE supplement.  For information about FDA submission requirements for an extended investigation, please see  http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm051345.htm.

Procedures for IRB submission of protocols for continued access to unapproved devices

For investigator initiated IDE supplements for an extended investigation, continued access protocols must be submitted through the usual procedures in OSIRIS.  Per the agreement between the University of Pittsburgh and UPMC, if the IDE is industry sponsored, the continued access protocol does not fall under the authority of the University of Pittsburgh IRB and must be processed through the UPMC OSPARS office.  If the IDE is investigator initiated, it will be processed through the University of Pittsburgh IRB, and if there is an agreement for the provision of the device, that agreement will be processed via UPMC OSPARS.  

References

21CFR 312.300
21 CFR 56.102
21 CFR 812
FDA Guidance on IDE Policies and Procedures

   
 

 

 

 

 

 

 

 

 

Studies Using In Vitro Diagnostic Devices with Specimens that are NOT Individually Identifiable

In Vitro Diagnostics (IVDs) are reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, to cure, mitigate, treat, or prevent disease.  Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.

IVDs that are being tested for possible future marketing are devices, and may also be biological products.  They are test articles under Food and Drug Administration regulations and are subject to FDA regulations governing investigational devices (IDE regulations). When IVDs are used in research involving human subjects (or human samples), FDA’s regulations for the protection of human subjects (informed consent and IRB review) generally also apply.

IDE Exempt Studies

Studies may be exempt from FDA’s IDE regulations when the research meets all of the following criteria:

  • The sponsor has labeled the device properly;
  • The testing is non-invasive;
  • The testing does not require an invasive sampling procedure that presents significant risk;
  • The testing does not by design or intention introduce energy into a participant; and
  • The testing is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically-established diagnostic product or procedure.

IRB Review

Unlike DHHS regulations, FDA regulations do not provide for exemption from IRB review when research involves existing specimens and the investigator records information without identifiers or linking codes.  Nor do FDA regulations define “human subjects” with reference to the identifiability of the subject or of the subject’s private information (i.e., the donors of specimens/samples remain “human subjects” even when the specimens/samples are de-identified).  Current FDA guidance indicates that IRB review is required for any IVD study involving human specimens/samples, even when the research involves no identifiers and the biological materials cannot be linked to any identifying information.

Informed Consent

With a few narrow exceptions (emergency and some DOD research), FDA regulations do not permit waiver of consent, even when studies are minimal risk and would meet criteria for waiver of consent under DHHS regulations. Under FDA regulations, informed consent is required for IVD studies involving samples that are identifiable (i.e., are labeled with identifiers or accompanied by the patient’s identifiable clinical information), as well as for studies in which the samples are not identifiable but are coded or linked to identifiable information.
Current FDA guidance (4/25/06), however, indicates that under some circumstances, when samples taken from excess clinical or research specimens cannot be identified (e.g., all linking codes and identifiers have been removed, or the investigator has no access to the code keys or identifying information), the agency will exercise “enforcement discretion” and permit the IRB to approve the study without requiring informed consent of the sample sources.

To be eligible for approval without a requirement for informed consent, FDA indicates that IVD research must meet the following criteria:

  • The research must be conducted under an IRB-approved protocol;
  • The research must meet criteria for an IDE exemption (see above);
  • The research must use specimens left over from clinical care, specimen repositories, or other research (i.e., the specimens may not be collected specifically for the proposed research, and no additional specimen may be collected for the purpose of research);
  • Individuals caring for the patients are different from and do not share information about the patient with those conducting the investigation;
  • The specimens are provided for research without identifiers (codes are permissible only if neither the investigator nor anyone associated with the study has access to the code key or can identify the person who was the source of the specimen);
  • Any clinical information supplied with the specimen must not be individually identifiable;
  • No test results from the research may be reported to any subject or that subject’s health care provider; and
  • The supplier of the specimens must have established policies and procedures to prevent the release of identifying information.

FDA recommends that the IRB review the policies and procedures that are in place to determine (1) that identifiers will not be released to investigators, and (2) whether there is the potential for test results to be needed for clinical patient management (e.g., FDA suggests that if the research involves a public health threat such as anthrax, it may be necessary to report positive results; therefore informed consent might be required).

References

Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable http://www.fda.gov/RegulatoryInformation/Guidances/ucm078384.htm

John Hopkins University Organization on Review of In Vitro Diagnostic Device Protocols (with or without Commercial Sponsors) (Policy No. FDA 50.1) September 2006 http://irb.jhmi.edu/Policies/FDA50_1.html
 

Procedures for FDA Inspections of Investigator Sites

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

Responsibilities of Principal Investigator

Principal investigators conducting human subject research that is subject to FDA regulations are responsible for promptly notifying the Institutional Review Board (IRB) about inspections being conducted by the FDA for the purpose of either surveillance3 or compliance4 .
 
Investigators must also notify the IRB immediately of any FDA correspondence requesting that a clinical hold be placed on any human subject research.

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

Investigators should facilitate arrangements to ensure that a member of the RCCO is present for the FDA exit interview.
 
Investigators must provide the IRB with copies of any written correspondence received from the FDA as a result of the inspection, in particular any Form 483.

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

Responsibilities of the RCCO Staff

The Director of Regulatory Affairs of the IRB Office shall notify appropriate parties of the upcoming inspection.  This includes the IRB Chair, Co-Director of the Research Conduct and Compliance Office, University or UPMC Legal Counsel, the Authorized Institutional Official and the Education and Compliance Office for Human Subject Research. If applicable, O3IS will be notified as well.

On a case by case basis, the Education and Compliance Office will conduct a comprehensive review of the IRB file to ensure that the file is complete and in order. Any findings of non-compliance observed from this review will be reported to the Chair of the IRB, Director of Regulatory Affairs of the IRB and Co-Director of the RCCO, who will assess the findings and develop a plan of corrective actions as deemed appropriate.

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

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

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

Any Form 483 issued as a result of the inspection shall be reviewed by the IRB Committee F for determination of whether any observations contained therein constitute serious or continuing non-compliance with the federal regulations governing human subject research as outlined in Chapter 17 of this document.

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

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 3 A surveillance audit is a routine FDA inspection, concentrating on basic FDA requirements (i.e., good clinical practice compliance).
 4 A compliance inspection is based on a specific objective.

vesion 12.10.2015