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Research Using FDA Test Articles

September 2011

I. Definition

The term “test article” is found in the FDA regulations on Protection of Human Subjects (21 CFR 50.3, Definitions (j)).  The term includes drugs (including botanicals, biologicals, and gene therapy, and genetically derived products that meet the definition of a “drug”), and medical devices for human use.  The FDA has statutory authority to regulate the development and marketing of these products.

II. What kind of review process will the IRB conduct if the intent of the research in humans is to develop information about safety and efficacy of drugs or devices for submission to, or inspection by, the FDA?

1.      Type of IRB Review

If a test article does not meet the criteria for an expedited review procedure, the study must be reviewed at a convened IRB meeting.

2.      Drugs, Botanicals, Biologicals, or Other Substances

JHM IRB review of research involving unlicensed or unapproved drugs, botanicals, biologicals, or other substances (e.g., food additives, food derivatives, vitamins, minerals, extracts, etc.) must be conducted at a convened meeting.  The review must include the presence of a P&T IRB member who will make a recommendation concerning the risks and proposed benefits of each product to be used in the study.  The IRB review will address the need for submission of an FDA Investigational New Drug Application (IND) prior to the use of the test article in the research study.  The IRB may determine that an IND is not required if all the conditions set forth in 21 CFR 312.2(b) have been met.  The IRB will determine whether to require submission of an IND, or if appropriate, to require the Primary Investigator (PI) to seek clarification from the FDA about the need for obtaining an IND before the IRB completes its review, and before the research may begin (See: "Investigator Inquiry to the FDA About the Need for an Investigational New Drug Application (IND)").  Consent forms for IND studies must clearly state that the “test article” is investigational or experimental.

For all studies that involve a drug product, the PI must complete the eIRB section on Drugs.  The PI must clarify for the IRB whether or not there is an FDA issued IND number for the use of the test article in the protocol, and if not, why not.  Appropriate documentation (investigator drug brochure, package insert, FDA issued IND letter when the PI or other study team member holds the IND, etc.) should be included in the eIRB application.

3.      Medical Devices

When the test article is a medical device, the JHM IRB reviewing the investigational medical device study will determine if the application will involve: a device approved by the FDA for marketing, or an investigational use of an unapproved device. 

For unapproved devices, the IRB will determine:

A.     Whether the test article requires an Investigational Device Exemption (IDE) from the FDA or is exempt from the IDE requirements. 

1.    The JHM IRB may consult the FDA or ask the Principal Investigator (PI) to consult the FDA for an opinion for difficult device assessments.

B.     Whether the device poses a “Significant Risk” (SR) to the participants in the study.

1.    The risk determination made by the IRB will be based upon both the nature of the device AND the proposed use of the device in the study as outlined in 21 CFR 812(3)(m)(1-4). 

2.    If the device is SR, the investigator must provide documentation from the FDA that the device either:

a. Has a 510(k) designation or an Investigational Device Exemption (IDE) before the IRB may take final action to approve a protocol; or 

b.If the JHM IRB believes that a device is SR, and the sponsor believes it to be NSR, the JHM IRB will require the PI to notify the sponsor of the JHM IRB determination.  The sponsor may then consult with the FDA for an agency opinion.  The FDA opinion must be provided to the IRB.  If the sponsor chooses not to consult with the FDA and/or not to submit an IDE application to the FDA, the protocol will not be approved at JHM. 

C.     Whether the device poses a “Non-Significant Risk” (NSR) to the participants in the study.

1.      In the case of an NSR claim, the initial assessment of whether or not the device study is NSR is made by the sponsor/investigator and the justification for this assessment is submitted in the eIRB application.  The IRB then determines whether that assessment is appropriate.  If it agrees, the IRB will record the rationale for its NSR assessment on the review sheet for determinations and in the minutes for a convened meeting.  All NSR devices under 21 CFR 812.2(b) are “considered to have approved applications for IDEs”.

2.     The IRB will consider whether some NSR devices meet the criteria for exempt classification as a diagnostic device under 21 CFR 812(c)(3).  If an investigational device meets those criteria, the IRB will document that it is exempt from the IDE requirements.

Consent forms for IDE studies must clearly state that the “test article” is investigational or experimental.

Institutional Requirement for Use of Medical Devices at Some JH Locations

Devices that are either electrical or battery powered and would be used at the East Baltimore JH Hospital and/or JH Bayview Medical Center must be reviewed and approved by Clinical Engineering at that location prior to use.  Documentation of Clinical Engineering approval must be uploaded into the application and submitted to the JHM IRB for review.  If the electrical or battery operated device would be used at both locations, then approval documents from both Clinical Engineering Departments must be uploaded into the application and submitted to the JHM IRB for review.

III. What are the responsibilities of investigators who are also the sponsor of IND or IDE clinical investigations?

JHM investigators who submit protocols involving FDA test articles and for which they hold the IND or IDE are sponsor-investigators must adhere to the same regulatory responsibilities as any other sponsor.  The application must include all supporting FDA documentation.  

Additionally, in cases where an IND product will be manufactured at Hopkins, the PI must submit documentation that the proposed drug preparation meets standards for current Good Manufacturing Practice.

Institutional Requirement for Sponsor-Investigators:

1.    IND Studies:  

a.  All research studies for which an investigator holds an IND must comply with the Drug Use for Clinical Investigation (DUCI) policy "Organization Policy on Drug Use and Control in Clinical Investigations (Policy No. 103.19(a)) ".  The Investigational Drug Service (IDS) will monitor the study for compliance with sponsor-investigator requirements.

2.    IDE Studies:

a.  The Organization requires a monitoring process for receipt, dispensing, and record keeping concerning devices that are studied using an IDE granted by FDA.  The monitoring process shall be performed by the Compliance Monitoring Specialists of the OHSR. 

b. Researchers who serve as a sponsor-investigator for an IDE research study are required by the Organization to follow FDA regulations 21 CFR 812 Subpart C applicable to sponsor responsibilities.  Compliance Monitoring Specialists of the OHSR will conduct a monitoring visit for investigators holding an IDE to determine compliance with FDA sponsor requirements in 21 CFR 812 before initiation of the research. 

FDA Reporting and Record Keeping Requirements for IND and IDE Research Studies

Sponsor-investigators must comply with the record-keeping and reporting requirements provided in the Federal Regulations for INDs and for IDEs.  In addition, the sponsor-investigator must comply with institutional record-keeping requirements and unanticipated problem reporting.  See: JHM IRB Guidance on Data Retention; and the "Organization Policy on Reports of Unanticipated Problems Involving Risks to Participants or Others (Policy No. 103.6(b))".   (For annual reporting requirements, see below.)

A.     A sponsor-investigator holding an IDE must report to the FDA and all reviewing IRBs and participating investigators any evaluation of an unanticipated device effect within ten (10) working days of first receiving notice of the effect (see, 21 CFR 812.150 (b)(1)). 

B.     A sponsor-investigator holding an IND must satisfy the requirement to ensure that the FDA “and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug” (see, 21 CFR 312.50). 

FDA Annual Reports Required for Sponsor-Investigators of INDs: 

Each year, within 60 days of the anniversary date that the IND went into effect, the sponsor-investigator must submit to the FDA a brief progress report that includes the following information for each protocol actively under the IND.

A.     Individual Study Information:

1.      the title of the study, its purpose, a statement identifying the patient population, and a statement as to whether the study is completed;

2.      the total number of subjects initially planned for inclusion; the number entered into the study to date tabulated by age group, gender and race; the number whose participation in the study was completed as planned; and the number of subjects who dropped out of the study for any reason; and

3.      If the study has been completed, or if interim results are known, a brief description of available study results.

B.     Summary Information:

1.      a narrative or tabular summary showing the most frequent and most serious adverse experiences by body system;

2.      a summary of all IND safety reports submitted during the past year;

3.      a list of subjects who died during participation in the study, with the cause of death for each subject;

4.      a list of subjects who dropped out during the course of the investigation in association with any adverse experience, whether or not drug related;

5.      a brief description of what, if anything, was obtained that is pertinent to an understanding of the drug’s actions, including for example, information about dose response, information about controlled trials, and information about bioavailability;

6.      a list of preclinical studies (including animal studies) completed or in progress during the past year and a summary of the major preclinical findings; and

7.      a summary of any significant manufacturing or microbiological changes made during the past year.

C.     General Investigational Plan

A description of the general plan for the upcoming year to replace that which was submitted in the previous year.  This plan should include all information required in 21 CFR 312.23(a)(3)(iv). 

D.     Revised investigator brochure and description of the revision, if applicable.

E.      Description of any Phase 1 protocol modifications made during the year and not previously reported to the IND in a protocol amendment.

F.      Brief summary of significant foreign marketing developments with the drug during the past year, if applicable.

G.     If desired, a log of any outstanding business with respect to the IND for which the sponsor/investigator requests or expects a reply, comment, or meeting.

FDA Required Reports for Sponsor-Investigators of IDEs: 

A sponsor-investigator of an IDE must submit the following reports:

A.     Progress Reports

a.       A sponsor-investigator shall submit progress reports on the investigation at regular intervals, and at least yearly, to all reviewing IRBs. 

b.      In the case of a significant risk (SR) device, the sponsor shall also submit progress reports to the FDA. 

c.       A sponsor of a treatment IDE shall submit semi-annual progress reports to all reviewing IRBs and FDA in accordance with 21 CFR 812.36(f). 

B.     Recall and Device Disposition

A sponsor shall notify FDA and all reviewing IRBs of any request that an investigator return, repair, or otherwise dispose of any units of a device.  Such notice shall occur within 30 working days after the request is made, and shall state why the request was made. 

C.     Final Report

a.       In the case of an SR device, the sponsor shall notify FDA within 30 working days of the completion or termination of the investigation and shall submit a final report to FDA and all reviewing IRBs and participating investigators within 6 months of the completion or termination. 

b.      In the case of a device that is not significant risk (NSR), the sponsor shall submit a final report to all reviewing IRBs within 6 months after termination or completion.

D.     Unanticipated Adverse Events and Withdrawal of Approval

a.       The sponsor-investigator of an IDE must submit reports of unanticipated adverse device effects to the FDA and all reviewing IRBs.

b.      The sponsor-investigator of an IDE must submit reports regarding withdrawal of FDA approval to all reviewing IRBs.

c.       The sponsor-investigator of an IDE must submit reports regarding withdrawal of approval of any reviewing IRB to all reviewing IRBs and the FDA.

IV. What are the requirements for “emergency treatment use” of FDA test articles in clinical care situations without prior convened JHM IRB review?

See FDA Information Sheet updated 2011 - "Emergency Use of an Investigational Drug or Biologic"

The JHM IRB may allow for “emergency treatment use” of a test article with an IND or IDE in accordance with FDA regulations. 

  • For drugs, the situation must meet the definition of “Emergency Use” as stated in 21 CFR 56.102(d):  “Emergency use means 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.” 
  • For devices, in the case of serious disease, a device may ordinarily be made available for treatment use after all clinical trials are completed; in the case of an immediately life-threatening condition, the device may be made available before completion of clinical trials (21 CFR 812.36).  

The JHM IRB prefers notification of an IRB Chairperson prior to the emergency use when time permits. 

A.     Emergency Use With Prior Notification or Approval by JHM IRB

Requests for emergency off-protocol use of FDA IND or IDE test articles outside of an IRB approved protocol must come from the JHH attending physician.  

1)      The JHH attending physician must submit either a new eIRB application or if there is an existing eIRB application, a Further Study Action, Emergency Use request and must include a written statement the necessity for JHM IRB approval of an emergency use request.

a)            If the test article being used were not associated with a current research study, then the prescribing physician would need to submit a new eIRB application for the emergency use of the test article.

b)            If the test article is being used in a current study the prescribing physician must contact the PI of the current study and ask the PI to submit a Further Study Action activity in eIRB and advise the JHM IRB of the emergency use by submitting an Emergency Use Request.   

2)      The new eIRB application for the emergency use or the Emergency Use Request would be reviewed by the JHM IRB at a convened meeting.

3)      The JHM IRB will not accept requests from non-attending physicians or staff. 

4)      If time does not permit a JHM IRB convened review of the new eIRB application or Emergency Use Request, a JHM IRB Chairperson, Co-Chairperson and/or P & T representative may review the request for compliance with FDA regulations. 

a)      If necessary, the reviewer will provide a written response to the investigator with notification whether the emergency use is “cleared” to proceed.  The response could be in the form of an email to the PI.

b)      If the use does not meet regulatory requirements, the reviewer will inform the PI that the emergency use may not take place. 

c)      The eIRB application will be reviewed by the JHM IRB at a convened meeting whether or not the reviewer “clears” the use of the test article.

5)      If the PI receives clearance from the JHM IRB, the response will include a reminder that she/he must submit safety reports or adverse event reports to either the sponsor who holds the IND/IDE for the test article, or if the PI holds the IND/IDE, to the FDA as required by regulation.  A copy of such reports should be uploaded into the eIRB application.

B.     Emergency Use Without Prior Notification to or Approval by JHM IRB

Although the JHM IRB prefers to be notified before a test article is used in an emergency clinical care situation, there may be cases for which there is no time to notify the JHM IRB.  In such cases, the physician may proceed with the emergency use in accord with 21 CFR 56.104(c). 

1)      The prescribing physician must notify the JHM IRB of the emergency use within 5 working days after use of the test article. 

a)      If the test article being used were not associated with a current research study, then the prescribing physician would need to submit a new eIRB application for the emergency use of the test article.

b)      If the test article is being used in a current study the prescribing physician must contact the PI of the current study and ask the PI to submit a Further Study Action activity in eIRB and advise the JHM IRB of the emergency use by submitting an Emergency Use Request.   

2)      The new eIRB application for the emergency use or the Emergency Use Request would be reviewed by the JHM IRB at a convened meeting.

3)      Consent for emergency use of a test article must be obtained from the subject or their legally authorized representative (LAR) using a research consent formA Johns Hopkins Hospital consent form may not be used to obtain such consent.  

a)      A research consent document provided either by a sponsor or by the physician must contain all of the FDA required elements. 

b)      The research consent form must be reviewed and signed by the subject or subject’s legally authorized representative even in emergency use cases. 

c)      In the rare case where the test article is administered or used prior to consent, the treating physician must still obtain a research consent post administration or use.  

4)      The JHM IRB will provide a written response acknowledging the physician’s submission of the emergency request information.  The acknowledgement will remind the physician that she/he must submit safety reports or adverse event reports to either the sponsor who holds the IND/IDE for the test article, or if the PI holds the emergency IND, to the FDA as required by regulation.  A copy of such reports should be uploaded into the eIRB application.

C.     What are the limits on use of data obtained from emergency use of a test article under the FDA Exemption

To be exempt from the FDA requirement (21 CFR 56.104) for IRB review for the emergency use of a test article in a life threatening situation, an investigator must not use the data in a systematic investigation designed to develop or contribute to generalizable knowledge or else the exemption no longer applies.  To comply with this limitation, investigators must follow these rules:

1.      If the emergency use of the test article occurred without prior IRB notification and approval, the prescribing physician must notify the JHM IRB of the emergency use within 5 working days after use of the test article;  

2.      Do not use the FDA emergency use exemption from IRB review to circumvent the general requirement for prior IRB review;

3.      Do not use data from an emergency use of a test article in a prospective research study; and

4.      Do not report data from an emergency use of a test article in a retrospective research study, unless the PI obtains specific approval from the IRB.

V.  What are the requirements for “compassionate use” of FDA test articles in clinical care situations?

A.     “Compassionate use” is not an official FDA term.  Compassionate use generally implies the use of non-FDA approved test articles for a single patient or a small group of seriously ill patients, where no other available treatments are satisfactory. 

1.      A compassionate use of a test article may be needed if:

a)      there are no other FDA approved test articles available for the disease or condition; 

b)      the patient does not meet the inclusion criteria of a study using an IDE; or

c)      there are no alternative treatments.

B.     IRB and FDA review and approval of compassionate use of test articles must be obtained before the test article can be used.

C.     The PI may use a non-FDA approved, compassionate use test article in order to treat, diagnose, or monitor a patient with a serious disease or condition.  However, the PI must justify that the probable risk of using the compassionate use test article to the patient is not greater than the probable risk from the disease.

D.     The PI will be required to submit an eIRB application or a Further Study Action, Change in Research activity, and request the compassionate use of a test article.  The PI would have to upload the following documents:

1.      Sponsor approval;

2.      FDA approval;

3.      Independent assessment from an independent attending physician describing the need for the compassionate use of the test article.

E.         Consent for compassionate use of a test article must be obtained from the subject or their authorized representative using a research consent form.  

F.         Consent for compassionate use of a humanitarian use device or HUD must be obtained from the participant or LAR using the standard hospital consent form, and does not require the use of a research consent form.

VI.  What are the requirements for “humanitarian use device” in clinical care situations?

A.     A humanitarian use device (HUD) is commercially approved under the Humanitarian Use Exemption (HDE).  (See, 21 CFR 814 Subpart H – Humanitarian Use Devices.)

B.     The HUD is not considered “investigational” nor is the use of the device considered “research.”  However, the federal regulations require IRB review and approval before a HUD is used.

C.     The PI is required to submit an eIRB application in order for the IRB to review and approve the use a HUD. 

1.      The IRB does not need to review and approve each individual use of a HUD, as long as the HUD is used within the FDA approved indication. 

2.      However, if the IRB desires, it may require approval of the device on a case-by-case basis.

D.     If the HUD is to be used in an emergency situation and the PI does not have time to obtain IRB approval before the use of the HUD, the PI is required to submit an eIRB application for IRB review within 5 days after the emergent use of the HUD.  The PI must include an explanation as to why prior IRB approval was not obtained.

E.         Consent for the use of a HUD (with prior IRB approval or in an emergency situation) must be obtained from the participant or LAR using the standard hospital consent form, and does not require the use of a research consent form.




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