Human Research Protection Program
(HRPP)
DOMAIN I:
ORGANIZATION
Chapter 5: Investigational or Unlicensed Test Articles - Research with Drugs, Devices or Biologics
STANFORD has and follows
written policies and procedures which specify that use of any investigational
or unlicensed test article complies with all federal, state, or local
regulations (AAHRPP Standard I-5).
This chapter outlines policy
for
FDA
regulates clinical investigations (research) “that support applications for
research or marketing permits for products regulated by the Food and Drug
Administration, including foods, dietary supplements that bear a nutrient
content claim or a health claim, infant formulas, food and color additives,
drugs for human use, medical devices for human use, biological products for
human use, and electronic products.” (21 CFR 56.101) See http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=56.101.
All
such investigations must be conducted in accordance with FDA requirements for
informed consent and IRB review, regardless of funding source or sponsor.
FDA’s document Comparison of FDA and HHS Human
Subject Protection Regulations outlines
differences between FDA regulations and OHRP’s 45 CFR 46 regulations for the
protection of human subjects. See http://www.fda.gov/oc/gcp/comparison.html. Where
regulations differ, the IRB applies the stricter one.
5.1
Research with Test Articles
STANFORD
secures assurances from the sponsor that the manufacture and formulation of
investigational or unlicensed test articles conform to federal regulations
(AAHRPP Element I.5.A)
Research with FDA-regulated test articles will be approved only after the IRB:
·receives documentation that the research will be conducted under an applicable Investigational New Drug Application (IND) or Investigational Device Exemption (IDE); or
·formally determines and documents that the proposed use of any investigational device satisfies the FDA criteria for non-significant risk devices; or
·formally
determines that satisfactory justification has been provided by the
investigator as to why an
The IRB collaborates with SPCTRM, CCTO and the Office of the Dean of Research to support STANFORD clinical investigators who conduct FDA-regulated research.
Biologic means a
biological or related product, regulated by the FDA, including blood, vaccines,
allergenics, tissues, and cellular and gene therapies. Biologics, in contrast to drugs that are
chemically synthesized, are derived from living sources (such as humans,
animals, and microorganisms). Studies of
unlicensed biologics are regulated according to the
See http://www.fda.gov/opacom/laws/phsvcact/sec262.htm.
Clinical investigation
means any experiment that involves a test article and one or more human
subjects, and that either must meet the requirements for prior submission to
the Food and Drug Administration under section 505(i) or 520(g) of the act,
(see http://www.fda.gov/opacom/laws/fdcact/fdctoc.htm) or need not meet the requirements for prior
submission to the Food and Drug Administration under these sections of the act,
but the results of which are intended to be later submitted to, or held for
inspection by, the Food and Drug Administration as part of an application for a
research or marketing permit. The term
does not include experiments that must meet the provisions of part 58,
regarding nonclinical laboratory studies.
The terms research, clinical research, clinical study, study, and
clinical investigation are deemed to be synonymous for purposes of this
part. 21 CFR 56.102. See http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=56.102.
Combination product means a product containing a combination of a
drug, a device, or a
biological product. Studies of
combination products are regulated according to the
Human subject means an
individual who is or becomes a participant in research, either as a recipient
of the test article or as a control. A
subject may be either a healthy individual or a patient. 21 CFR 56.102. See
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=56.102.
Off-Label means use of an approved drug, an approved or
cleared device, or a licensed biologic for an indication not in the approved
labeling. Most research involving
off-label uses requires
Test article means any drug for human use, biological product for
human use, medical device for human use, human food additive, color additive,
electronic product, or any other article subject to regulation under the act or
under sections 351 or 354-360F of the Public Health Service Act. 21 CFR 56.102. See
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=56.102.
Clinical investigations of
drugs are subject to the Investigational New Drug Application (IND)
regulations, 21 CFR 312. See
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312.
An investigational new drug
application (
Applications for research on
the use of a drug, unless that research is exempt from the
As
stated in 21 CFR 312.2, clinical investigation of a drug is exempt from the
(i) The investigation is
not intended to be reported to FDA as a well-controlled study in support of a
new indication for use nor intended to be used to support any other significant
change in the labeling for the drug;
(ii) If the drug that is
undergoing investigation is lawfully marketed as a prescription drug product,
the investigation is not intended to support a significant change in the
advertising for the product;
(iii) The investigation
does not involve a route of administration or dosage level or use in a patient
population or other factor that significantly increases the risks (or decreases
the acceptability of the risks) associated with the use of the drug product;
(iv) The investigation
is conducted in compliance with the requirements for institutional review set
forth in part 56 and with the requirements for informed consent set forth in
part 50; and
(v) The investigation is
conducted in compliance with the requirements of 312.7 (Promotion and charging
for investigational drugs).
Additionally, a clinical investigation
involving use of a placebo is exempt from the requirements of 21 CFR 312 if the
investigation does not otherwise require submission of an IND. Clinical investigations that are exempt from
Even when there is no immediate intent to
change product labeling or advertising, investigators who are planning
rigorous, carefully controlled clinical investigations of off-label uses of
approved drugs or biologics should contact the FDA regarding obtaining an IND
before submitting a protocol to the IRB.
See the FDA guidance for FDA’s current
thinking on exemptions from
Studies involving potentially addicting
drugs have additional informed consent requirements. See Research Policy Handbook RPH 7.6.
Clinical investigations of
devices are subject to the Investigational Device Exemptions (IDE) regulations,
21 CFR 812. See
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=812.
An approved investigational
device exemption (IDE) permits a device that is not approved (via premarket
authorization, PMA) or cleared to market (via 510(k)) by the FDA to be shipped
to conduct clinical investigations of that device. Significant risk investigational devices must
have an IDE issued by FDA before they can be shipped. Nonsignificant risk devices are considered to
have an approved IDE when the IRB agrees with the sponsor that the device meets
the criteria for a nonsignificant risk device.
Research with devices falls
into three categories:
FDA provides two guidances
to help investigators and sponsors understand significant and nonsignificant
risk device studies.
Studies that include medical
device use in an incidental way, where the device or the use of the device is
not the focus of the research, are generally not considered to be FDA-regulated
research or subject to 21 CFR 812, and in some instances are eligible for IRB
review according to the expedited procedure.
Applications for research on
the use of a significant risk device must be accompanied by documentation from
the FDA that includes a valid IDE number.
The IDE number must either match the number on the sponsor protocol with
the same title as the proposed research, or be listed on communication from the
sponsor specific to the proposed research, or on communication with the
FDA. IDE numbers may not be validated
with a device manual (which may serve multiple IDEs).
When research is conducted
to determine the safety or effectiveness of a device, the organization confirms
that the device fulfills the requirements for an abbreviated IDE (21 CFR 812.2(b)(1)):
·
The device is
not a banned device;
·
The sponsor
labels the device in accordance with 21 CFR 812.5;
·
The sponsor
obtains IRB approval of the investigation after presenting the reviewing IRB
with a brief explanation of why the device is not a significant risk device,
and maintains such approval;
·
The sponsor
ensures that each investigator participating in an investigation of the device
obtains from each subject under the investigator’s care, consent under 21 CFR
50 and documents it, unless documentation is waived;
·
The sponsor
complies with the requirements of 21 CFR 812.46 with respect to monitoring
investigations;
·
The sponsor maintains the records
required under 21 CFR 812.140(b) (4) and (5) and makes the reports required
under 21 CFR 812.150(b) (1) through (3) and (5) through (10);
·
The sponsor ensures that
participating investigators maintain the records required by 21 CFR
812.140(a)(3)(i) and make the reports required under 21 CFR 812.150(a) (1),
(2), (5), and (7); and
·
The sponsor complies with the
prohibitions in 21 CFR 812.7 against promotion and other practices.
If the investigator applies
to the IRB for a nonsignificant risk determination for a device study, but the
IRB determines that the device is significant risk, the IRB shall notify the
investigator and the sponsor, if appropriate.
Clinical investigations that
are exempt from IDE regulations still require IRB review and approval. An investigation of a medical device in human
subjects research that is exempt from the IDE regulations must fall into one of
the following categories (Criteria in 21 CFR 812.2(c)):
·
A device legally
marketed in the
·
A diagnostic
device (that is, an in vitro diagnostic device) if the testing:
o Is noninvasive
o Does not require an invasive sampling procedure that
presents significant risk,
o Does not by design or intention introduce energy into
a subject, and
o Is not used as a diagnostic procedure without
confirmation of the diagnosis by another, medically established diagnostic
product or procedure.
·
A device
undergoing consumer preference 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.
·
A custom device
as defined in 21 CFR 812.3(b), unless the device is being used to determine
safety or effectiveness for commercial distribution.
In
vitro diagnostic (IVD) device investigations may be exempt from the IDE
requirements of 21 CFR 812 if the devices are properly labeled and meet the
criteria set forth in 21 CFR 812.2(c)(3). However, such studies are still
subject to the FDA regulations and IRB review requirements if the research is
to support an application for research or marketing of the device (see 21 CFR
50.1). This is true regardless of
whether the samples to be used are individually identifiable or not. The
FDA regulations define a subject to include a human on whose specimens
an investigational device is used (21 CFR 812.3(p)). Thus, an IVD study
to support a premarket submission to the FDA is considered a human subject
investigation and is subject to IRB review under 21 CFR parts 50 and 56. IVD research may be eligible for expedited
review and waiver of informed consent, when appropriate.
In addition to the above, FDA guidance makes clear that IRB review is one of
several criteria for IVD studies using left-over specimens that are not
individually identifiable. See http://www.fda.gov/cdrh/oivd/guidance/1588.html.
The FDA regulates radiology devices and radioactive materials
used in research. Oversight at STANFORD
is handled by the Administrative Panel on Radiological Safety (APRS) which is
chartered as a Radioactive Drug Research Committee (RDRC) by the FDA under 21
CFR 361.1. Most research involving
radiation is covered by an
As defined in 21 CFR 361.1 the APRS has no oversight
responsibility or authority over an investigation carried out under an
The Protocol Application includes the
necessary radiological safety questions which are reviewed by both the IRB and
a member(s) of APRS. In addition, Health
Physics provides assistance for protocol directors designing studies with
radiation. See http://www.stanford.edu/dept/EHS/prod/researchlab/radlaser/Human_use_guide.pdf.
Clinical investigations of
biologics are regulated in the same way as clinical investigations for drugs,
and require an
Generally, protocols
using biological agents or recombinant DNA vectors are reviewed by IRB
1. The
Research Policy Handbook RPH 6.9 provides more information about research with
biohazardous agents and human subjects. See Chapter 6.9.
In reviewing research
involving test articles, the IRB determines if a STANFORD investigator holds
his or her own
Sponsor-investigators who
submit protocols to the IRB involving FDA test articles must include all
supporting FDA documentation for their IND or IDE and any STANFORD required
approvals for applying for an IND or IDE. Additionally, if the
· The product preparation and manufacture meets the
standards for current Good Manufacturing Practice (GMP), or any modification to
those standards approved by the FDA in issuing the IND or IDE.
·
The GMP plan has been approved by the
applicable STANFORD official, appointed by the Sr. Assoc. Dean of Research in
the
· The GMP plan has been reviewed and accepted by Risk
Management, if the sponsor-investigator is a STANFORD investigator.
The IND or IDE product must be
stored, secured, dispensed, and documented in accordance with the policies of
the STANFORD institution in which it will be used, i.e., SHC/LPCH (see Section
5.6, Internal Handling of Test Articles), or the Veterans Affairs Palo Alto
Health Care System.
In coordination with the
Research Compliance Office, education covering these responsibilities will be
provided by: (i) SPCTRM, the unit in the Stanford University School of
Medicine providing administrative support for clinical trials, to investigator-sponsors
who are faculty and conducting clinical trials at SHC and LPCH, and (ii) the
Palo Alto Veterans Affairs Health Care System for its employees who are
sponsor-investigators.
Prior to approving a protocol that involves a sponsor-investigator, the IRB must be satisfied that the sponsor-investigator is knowledgeable about his/her responsibilities and has adequate policies and procedures in place to comply with the FDA regulatory requirements. The IRB may rely on feedback from the STANFORD entity providing the education in its determination of proficiency, but may also contact or site visit the sponsor-investigator as deemed necessary. An on-site compliance audit, designed to evaluate compliance with the FDA regulatory requirements, must be conducted on at least an annual basis as a condition for renewal of the protocol by the IRB.
A sponsor-investigator for
an
A sponsor-investigator for
an IDE protocol must follow the FDA regulations in 21 CFR 812. See guidance, Sponsor-Investigator Research
when the STANFORD investigator holds the IDE.
Investigators studying
nonsignificant devices, regulated by the abbreviated IDE regulations, have
abbreviated sponsor responsibilities when there is no industry sponsor.
STANFORD has policies and
procedures to ensure that the handling of investigational or unlicensed test
articles meets organizational standards relating to pharmacy, inventory
control, and documentation. (AAHRPP
Element I.5.B) These policies and
procedures are found in the
The policies for SHC and for LPCH outline the standards relating to drugs and devices for pharmacy practices, inventory control and documentation.
See:
· SHC policy “Investigational New Devices”
· SHC policy “Investigational Drugs and Biologics”
· LPCH policy “Investigational New Devices”
· LPCH policy “Investigational Drugs and Biologics”
Veterans Affairs (VA) Requirements
VA policy (M-3, Part 1, Chapter 9) requires that all research comply with the VA human subject regulations, as well as with all applicable regulations and requirements regarding storage and security procedures for investigational agents.
A VA Investigational Drug Information Record (VA Form 10-9012) must be completed by the Protocol Director (PD), submitted to Pharmacy Service, and monitored by the Research and Development (R&D) Committee (M-3, Part 1, Chapter 9.15(3)).
Upon approval of the research by the IRB and R&D Committee, a Report of Subcommittee on Human Studies (VA Form 10-1223) must be forwarded to the PD and the Chief of Pharmacy Service.
5.8 Emergency Use of a Test Article
STANFORD has and follows written policies and procedures for compliance with federal regulations governing emergency use of an investigational or unlicensed test article. (AAHRPP Element I.5.C)
See guidance Emergency Use of a Test Article, and the Human Subjects Research web page Emergency Use.
Emergency use is defined as use of a test article on a human participant 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 (21 CFR 56.102(d)). The emergency use provision in the FDA regulations (21 CFR 56.104(c)) allows for one emergency use of a test article without prior review and approval by the IRB review. FDA regulations require any subsequent use of the investigational product at the institution have prospective IRB review and approval. However, the 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 issue ["Emergency Use of an Investigational Drug or Biologic," FDA Information Sheet, 1998 Update at http://www.fda.gov/oc/ohrt/irbs/drugsbiologics.html#emergency].
Prior Notification to the IRB of Emergency
Use
Prior notification to the IRB of an impending emergency use of a test article by a protocol director is permissible. However, such notification should not be construed as, and does not, evidence prior IRB approval of the emergency use. Prior notice of an impending emergency use of a test article will be used by the IRB only to initiate tracking to ensure the protocol director submits a report to the IRB within the five day time frame required by 21 CFR 56.104(c). The IRB may choose to request additional information.
When investigators provide prior notifications of their intent to use a test article in an emergency or their intent to invoke the exception to the requirement to obtain consent, a senior staff member in the Research Compliance Office will review the notification to determine whether the circumstances follow FDA regulations.
Informed Consent
Requirement
The protocol director must obtain the informed consent of the participant (or the participant’s legally authorized representative), unless the requirements of an exception from the informed consent requirement (21 CFR 50.23(a)) are satisfied. In addition to obtaining informed consent, the protocol director must obtain the HIPAA authorization from the participant (or the participant’s legally authorized representative). Exception from the informed consent requirement is discussed below.
Exception from Informed Consent
Requirement
An exception under FDA regulations at 21 CFR 50.23 permits the emergency use of an investigational drug, device, or biologic without informed consent where the protocol director and an independent physician, who is not otherwise participating in the clinical investigation, certify in writing all of the following (see below for required forms):
1. The patient is confronted by a life-threatening or severely debilitating situation, necessitating the use of the test article
2. Informed consent cannot be obtained from the patient (because the patient cannot communicate or is incompetent to give consent)
3. Time is not sufficient to obtain consent from the patient’s legally authorized representative
4. 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 protocol director’s opinion, immediate use of the test article is required because the patient is confronted by a life-threatening or severely debilitating situation and if time is not sufficient to obtain the independent physician determination that the four conditions above apply, the protocol director should make the determination and, within five working days after the use of the article, have the determination reviewed and evaluated in writing by an independent physician, and submit that evaluation to the IRB.
Submission and Reporting Requirements - IRB and FDA
Written
documentation of the emergency use must be submitted to the IRB within
5 working days after the use of the test article. [21 CFR 56.104(c)]. The protocol
director must submit the following
documents to the IRB:
For Drugs and
Biologics:
If the company declines permission or cannot be
reached, the protocol director should contact the FDA for authorization of the
shipment of the drug in advance of the
The IRB may request that the protocol director contact
the FDA to obtain an IND.
For Devices:
If the company declines permission or cannot be
reached or an IDE does not exist, the FDA expects the protocol director to:
In addition, if the device is used and there
is no IDE:
o
The use must be reported to the FDA within 5 working days
(to CDRH or CBER). This report should contain a summary of the conditions
constituting the emergency, patient outcome information, and the patient
protection measures that were followed.
IRB Review (Retrospective) of an Emergency
Use of a Test Article
The Chair of a medical IRB or designated IRB member will review the documentation submitted in support of an emergency use of a test article. IRB review includes an assessment of whether or not the conditions for the emergency use were satisfied. The reviewer completes the Exemption from IRB Review: Emergency Use of a Test Article. A copy of this form is sent to the protocol director. If the emergency use did not meet the criteria allowing an exemption from prior IRB review and approval, the action will be handled according to the non-compliance policy. (See Chapter 3.9.)
The Research
Compliance Office (RCO) is responsible for
maintaining all documentation on emergency uses of test articles in the IRB
records.
5.9 “Compassionate” Use of a Test Article
The term “compassionate use” does not appear in FDA regulations
(it does appear in a guidance issued by the
However, “compassionate use” is often used when referring to the provision of investigational products to patients outside of an ongoing clinical trial.
There are specific access programs for the use of investigational articles outside of formal clinical trials. The following are some examples of such “compassionate uses” of unapproved drugs and devices, all of which require prospective IRB approval and informed consent:
Treatment
Single-Patient Treatment
Orphan
Drugs: Refers to drugs that treat rare diseases
affecting fewer than 200,000 individuals. See the FDA Office of Orphan Products
Development at http://www.fda.gov/orphan/.
Treatment IDE: Treatment for desperately ill patient with investigational devices before general marketing of the device has begun when (1) the patient has a serious or life threatening condition; (2) there is no comparable alterative available; (3) the device is under investigation or has undergone investigation for the same use; (4) the sponsor is pursuing marketing approval; and (5) the device has an approved IDE.
5.10 “Humanitarian” Use of a Device
A Humanitarian Use Device (HUD) is a device that is intended to benefit patients by treating or diagnosing a disease or condition that affects fewer than 4,000 individuals. The FDA developed this regulation to promote the development of devices for diseases affecting these populations. The HUD regulations provide for Humanitarian Device Exemptions (HDE) by the FDA for the marketing of the HUD. Prior IRB approval of a HUD is required before use. For research under a HDE, the scope of the IRB approval is to confirm the planned use is consistent with the HDE’s FDA-approved indication.
See guidance Compassionate and Humanitarian Use [FDA].
5.11 Planned Emergency Research
Planned research in
life-threatening emergent situations where obtaining prospective informed
consent has been waived is permitted by 21 CFR 50.24. The research plan must be approved in advance
by the FDA and IRB. The research plan
must also be disclosed to the communities where the research will be conducted and
from where participants will be drawn, including presentation of the risks and
expected benefits of the research. An
independent data monitoring committee must be established to exercise oversight
of the research. Such planned emergency research is usually not
eligible for emergency use approvals (see Chapter 5.8
above). Advance notice of these
protocols will be provided to the Office for Human Research Protections
pursuant to federal regulation 45 CFR 46.101(i). PDs who wish to conduct planned emergency research
should consult with IRB staff prior to submission of the protocol to the IRB.