Professional Documents
Culture Documents
Research Compliance Handbook
Research Compliance Handbook
Professional’s Handbook
The Practical Guide to Building
and Maintaining a Clinical Research Second
Compliance & Ethics Program Edition
Copyright © 2013 by the Health Care Compliance Association. All rights reserved.
No part of this publication may be reproduced or transmitted by any means,
electronic or mechanical, including photocopying and transmittal by fax, without
prior written permission of the Health Care Compliance Association.
ISBN: 978-0-9910783-0-1
1 Research Compliance 101.................................................................................................. 1
6 Oversight of Clinical Trials: The Role of OHRP, FDA and the IRB...........................50
12 Grant Management.........................................................................................................120
Endnotes...........................................................................................................................164
1
consent are outlined in 45 CFR Part 46.116 and
50 CFR Parts20-27. The rules state that informed
consent must contain the following elements:
Clinical research compliance has become a major • Potential risks or discomforts of participation
focus area of compliance professionals in recent • Potential benefits of participation—although
years. Clinical research is highly regulated and as many institutions include a statement that
such, the role of a compliance professional is vital makes it clear that the individual will be treated
to maintaining compliance with NIH, FDA, ORI appropriately regardless of whether they partici-
and OMB requirements. The laws and regulations pate in the research study
related to human subject protections, grant and
• Alternatives—other courses of treatment and/or
trial accounting, effort reporting, scientific mis-
other research studies that might be appropriate
conduct, privacy and security and clinical trial
to the disease condition of the patient (if any)
billing are highly complex and always evolving.
This chapter will outline some of the key compli- • Confidentiality of records—this statement
ance issues important in research today. may include HIPAA language after the HIPAA
Privacy Rule Compliance Date (April 14, 2003)
Informed Consent and Human • Compensation for injury statement (for greater
Subject Protections than minimal risk studies)
Informed consent is one of the most coveted rights • Contact persons—individuals involved with
in healthcare today. Informed consent for treat- the study including the name of the Principal
ment by a provider of healthcare services is well Investigator and key study staff
known and understood by most people. Informed
• Statement of voluntary participation—it must
consent in a research context has been a topic of
be clear that the subject has the right NOT to
much debate and reasonable academic minds have
participate
differed with regard to how informed consent for
research should be administered to a prospec- • Unforeseen risks
tive research participant. Informed consent for • Reasons for involuntary termination of
research is defined in the Belmont Report (www. participation
hhs.gov/ohrp/humansubjects/guidance/belmont.
htm) and is required to be: informed, understood • Additional costs to participate or withdrawal—
and voluntary. The federal rules for informed are there likely clinical outcomes if the protocol
is interrupted?
Many study sites have incorporated research The monitor could begin by assessing the nature
compliance programs into their repertoire of of the recruitment of the potential subjects. The
compliance activities. These programs include a “monitor” would document the time and circum-
regimen of training, periodic reporting, anony- stances of obtaining the informed consent (i.e. it is
mous ways of reporting issues, discipline, and being obtained while the patient is being admitted
prompt follow up, and auditing and monitor- to the Emergency Department with a life threat-
ing. In the past, the areas that were typically ening illness or injury or otherwise potentially
monitored in research were simply issues related under “duress”). To the extent that the potential
to funding of federal grants, time and effort subject speaks a language other than English, the
reporting and the like. Given some of the federal monitor would ensure that the form document
investigations and lawsuits in prestigious institu- used is translated into the language of the patient
tions around the country, auditing and monitoring and/or a translator is available. To the extent that
of human subject protections is a necessary part of the patient or his/her family members ask ques-
the compliance process. In fact, representatives of tions, the monitor would document not only the
the Federal Office for Human Subject Protections questions but the answers as well. As a final step,
(OHRP) have publicly stated that investigators and the monitor may ask the subject certain follow-up
study sites should be proactive in monitoring the questions designed to test the subject’s under-
area of human subject protections. standing of the material delivered to them.
Implementing an informed consent monitoring While monitoring the informed consent process
process is an easy and low cost way to evaluate is not foolproof in making sure that the subjects
how the investigators and study coordinators are truly understand what will happen if they par-
doing. The “monitor” could be the compliance ticipate in the research and what will happen if
officer, an internal auditor, a peer investigator or they do not participate in the research, it certainly
peer study coordinator, or frankly almost any would demonstrate and document diligence taken
individual who is independent of the research by the investigator/study site. The costs for imple-
study. That individual would begin by reviewing menting this process could be borne by either
the form used to deliver the informed consent to the study site, or could be built into the study
ensure that it contains all the necessary elements costs/budget. As for the number of studies to be
as required by the federal rules. Presumably, reviewed and the number of subjects to be moni-
this will already have been done in detail by the tored, that would be a factor of what resources are
Institutional Review Board as part of the review available to the study site/investigator. There is no
of the protocol, but it does not hurt to double right or wrong answer—any monitoring is better
check. In the spirit of full disclosure, the potential than no monitoring.
subject should be queried as to whether he/she
will allow a “monitor” to sit in on the informed Scientific Misconduct
consent discussion. Confidential information as
Over the course of the last fifteen years, we
well as “protected health information” as defined
have witnessed a number of prominent enforce-
by HIPAA will be discussed, and you will want
ment initiatives pursued by the DHHS Office of
to make sure that the subject is comfortable
Inspector General (OIG) and the Department of
with having a “third party” involved in those
Justice (DOJ). These initiatives have ranged from
Medicare Advantage billing is also quite compli- a. with an authorization signed by the partici-
cated. The rules require that protocol-scheduled pant or his/her legal representative; or
services be billed to Medicare prime as opposed
to the Advantage “plan” and any services that b. with a waiver of authorization from an IRB or
are unrelated to the research protocol be billed Privacy Board; or
to Medicare Advantage. In large part this is done
c. with a limited data set and a data use
so that CMS can track the amount it is paying
agreement; or
to support research and because many Medicare
Advantage plans do not have the claims process- d. if the data is fully de-identified; or
ing capability to handle required modifiers used
to denote “research,” such as a V 70.7 code placed e. if the data is on a decedent.
in the secondary diagnosis position or a Q1 or
Q0 modifier to denote either a standard of care Much like the other research risk issues described
service (e.g. Q__) or a research related service herein, compliance with the HIPAA Privacy,
(e.g. Q__). HITECH and Security Rules is critical for ongo-
ing compliance and is likely to be the subject of
Research Privacy and Security enforcement issues in the coming years.
The primary laws and regulations that cover Oversight of Clinical Research
research privacy and security are found in the
Health Insurance Portability and Accountability The myriad regulatory schema, oversight agencies
Act (“HIPAA) and the HITECH provisions deal- and enforcement all reinforce the importance of
ing with data breaches. The final HIPAA Omnibus an effective clinical research compliance program.
Rule was published in January 2013 and in A strong clinical research compliance program
research-related issues, it essentially modified the should be multifaceted. To be effective, it must
• Identify others who may be involved with the “An inquiry’s purpose is to decide if an allega-
challenged conduct; tion warrants an investigation. An investigation
• Identify others who may “be aware” of the is warranted if there is—(1) A reasonable basis
situation; for concluding that the allegation falls within
the definition of research misconduct … and
• Review relevant grant proposals, protocols, (2) Preliminary information-gathering and pre-
monitoring/ audit records, journal articles; liminary fact-finding from the inquiry indicates
• Assess the course the complainant wishes to that the allegation may have substance” (42
follow—review concepts of anonymity and con- CFR §93.307).
fidentiality as well as institutional policies on
research integrity and nonretaliation. The institution is required to prepare an “inquiry
report” to which the respondent is entitled to
Steps that must be taken to protect the records respond. The respondent’s comments should be
and evidence over which the (now) respondent attached to the report and be made part of the
has physical control, for example, in the labora- inquiry record. The regulation directs that the
tory, will likely produce turmoil and anxiety. inquiry should be completed within sixty days of
Section §93.307 provides substantial detail its initiation. Upon completion of the inquiry, the
regarding the kinds of evidence that should be respondent must be notified whether an investiga-
protected, as well as provision of notice to the tion will be undertaken and provided with a copy
The NIH Guidelines for Research Involving • Provide laboratory research staff with protocols
Recombinant and Synthetic Nucleic Acid Molecules describing potential biohazards and necessary
(NIH Guidelines) detail procedures and practices precautions.
for the containment and safe conduct of vari- • Instruct and train laboratory staff in: (i) the
ous forms of recombinant and synthetic DNA practices and techniques required to ensure
research, including research involving genetically safety, and (ii) the procedures for dealing with
modified plants and animals, and human gene accidents.
transfer.
• Inform the laboratory staff of the reasons and
When the NIH Guidelines Apply: provisions for any precautionary medical prac-
tices advised or requested (e.g., vaccinations or
All institutions that receive NIH funding for serum collection).
recombinant or synthetic DNA research must
comply with the NIH Guidelines. Researchers at • Supervise laboratory staff to ensure that the
institutions that are subject to the NIH Guidelines required safety practices and techniques
must comply with the requirements even if their are employed.
individual projects are not funded by NIH. • Correct work errors and conditions that may
result in the release of recombinant DNA
The Institutional Biosafety Committee materials.
Institutional Biosafety Committees (IBCs) provide • Ensure the integrity of physical containment
local review and oversight of nearly all forms of (e.g., biological safety cabinets) and biological
research utilizing recombinant DNA. They ensure containment (e.g., purity and genotypic and
that recombinant DNA research conducted at or phenotypic characteristics).
sponsored by the institution is in compliance with
the NIH Guidelines. A requirement of the NIH • Comply with permit and shipping requirements
Guidelines is that an IBC must review and approve for recombinant DNA molecules.
all research subject to the NIH Guidelines. • Adhere to IBC-approved emergency plans
for handling accidental spills and personnel
NIH Office of Biotechnology Activities contamination.
The NIH Office of Biotechnology Activities (OBA)
promotes science, safety, and ethics in biotech-
nology through the advancement of knowledge,
enhancement of public understanding, and
development of sound public policies. A core
responsibility of OBA is to foster awareness of, and
adherence to, the standards and practices set forth
in the NIH Guidelines.
1 •• Not known to consis- •• Standard microbiologi- •• No primary barrier required •• Laboratory bench and sink required
tently cause diseases cal practices •• PPE: Laboratory coats and
in health adults gloves; eye, face protec-
tion as needed
that all research animal receive adequate veteri- •• 1 practicing scientist with expe-
rience in animal research
nary care. The attending veterinarian must have •• 1 non-scientist
appropriate training and experience in the vet- Quorum consists of 50% of Quorum consists of 50% of the
erinary oversight of animal research programs, the IACUC membership +1. IACUC membership +1. Individuals
Individuals with specific quali- with specific qualifications are not
and he/she must have extensive knowledge of the fications are not necessary to necessary to constitute quorum,
requirements of the AWA, PHS Policy, and most constitute quorum, but if these but if these individuals do not
individuals do not regularly regularly attend IACUC meetings,
especially, the Guide. Like the institutional official, attend IACUC meetings, the the IACUC will not be considered
the attending veterinarian must have appropriate IACUC will not be considered properly constituted.
properly constituted.
lines of authority within the institution to ensure
that the health and welfare of research animals
is always protected. As a part of this authority,
the attending veterinarian must have the power
3. To promote and coordinate the development Under the requirements of 45 Code of Federal
of regulations, policies, and procedures for the Regulations 46.111, institutional review boards are
protection of human subjects. specifically charged with determining that:
4. To establish criteria for approval of assur- 1. risks to subjects are minimized and reasonable
ances of compliance for domestic and foreign in relation to anticipated benefits;
institutions engaged in Health and Human
Services conducted or supported human sub- 2. selection of subjects is equitable;
ject research.
Oversight of Clinical Trials: The Role of OHRP, FDA and the IRB 51
3. privacy and confidentiality of subjects are Food and Drug Administration (FDA)
protected;
Any research involving a drug, a biologic, or
4. appropriate safeguards are in place to protect a medical device is subject to FDA regulation.
vulnerable subjects. FDA regulations establish direct authority over
all investigators, sponsors, monitors, contract
To determine the applicability of the DHHS regu- research organizations, and IRBs/institutions
lations6, four key questions must be answered: conducting research under a U.S. investigational
new drug (IND)/investigational device exemp-
1. Is it research? [Research: A systematic inves- tion (IDE).7
tigation, including research development,
testing and evaluation, designed to develop or The FDA expects sponsors to understand when
contribute to generalizable knowledge (45 CFR an application to FDA is required. In general, an
46.102(d)]; IND/IDE is required when an unapproved drug
(biologic or significant risk device) is used in a
2. Are human subjects involved? [A living indi- clinical investigation. An IND may be required
vidual about whom an investigator conducting when an approved product is used in a clinical
research obtains: data through intervention investigation based on use of the study informa-
or interaction with the individual, or identifi- tion (e.g., to support a new indication, change in
able private information (45 CFR 46.102(f)]; labeling, or change in advertising) or based on
increased risk. Even when exempt from an IND,
3. Is it exempt? [There are six categories of
an informed consent and IRB review are required.
research that are “exempt” from federal regu-
Furthermore, the FDA expects sponsors to select
lations. OHRP recommends that institutions
qualified sites and investigators and to provide
(not investigators) determine whether pro-
investigators with the information they need to
posed research qualifies as “exempt” under
conduct the investigation properly. The sponsor
DHHS regulations. DHHS regulations apply to
should monitor the conduct of the investigation,
all non-exempt human subject research sup-
and to carry out safety monitoring and timely
ported by DHHS]; and
reporting to the FDA and investigators.
4. Is the institution engaged? [An institution is
The FDA expects the IRB to understand its impor-
considered engaged if its employees or agents:
tance, authority, and responsibility under the
interact or intervene with subjects for research
regulations. In addition, the IRB should under-
purposes, or obtain identifiable private infor-
stand its fundamental roles: protection of research
mation about subjects for research purposes.]
subjects; ethical review of protocols; assurance
In summary, OHRP oversees the function and of informed consent; and ensuring through con-
performance of individual IRBs and the process of tinuing review that the study remains ethical to
informed consent, and it investigates when there continue and that informed consent is current.
is reason to believe that procedures with respect Moreover, investigators must understand the pro-
to the protection of human subjects from risks tocol and take full responsibility for the conduct
associated with research have not been appropri- of the research. FDA Form 1572 is a key document
ately followed. and an indication of investigator qualifications
and official commitment to the study. Moreover,
the FDA expects all parties to respect the ethical
principles promulgated by the Belmont Report.
Oversight of Clinical Trials: The Role of OHRP, FDA and the IRB 53
7
• 21 C.F.R. Part 50 (Protection of Human
Subjects) and Part 56 (Institutional Review
Boards), which correspond substantially with
the provisions of the Common Rule5
FDA-Regulated • 21 C.F.R. Part 54 (Financial Disclosures by
Clinical Research Clinical Investigators)6
• 21 C.F.R. Part 312 (Investigational New Drug
Application (IND))
Neil F. O’Flaherty, Esq.
• 21 C.F.R. Part 812 (Investigational Device
Nancy W. Mathewson, Esq.
Exemptions (IDE))
• The type of product being tested I have read and understand the information in the
• The complexity of the study investigator’s brochure, including the potential
risks and side effects of the drug.
• The nature of the disease or condition
being studied I agree to ensure that all associates, colleagues, and
employees assisting in the conduct of the study(ies)
Sponsors (or their appropriately authorized are informed about their obligations in meeting
designees) must monitor clinical investigations the above commitments.
periodically to ensure investigator compliance I agree to maintain adequate and accurate records
with the requirements of the study and applicable in accordance with 21 C.F.R. § 212.62 and to make
regulations. If an investigator does not comply, those records available for inspection in accor-
the sponsor must implement effective and timely dance with 21 C.F.R. § 312.68.
remedial action to correct the non-compliance.
I will ensure that an IRB that complies with the
Sponsors also must evaluate data regarding safety
requirements of 21 C.F.R. Part 56 will be respon-
and effectiveness as it is gathered, make all appro- sible for the initial and continuing review and
priate reports to FDA and suspend or terminate approval of the clinical investigation. I also agree
the study as required.14 to promptly report to the IRB all changes in the
research activity and all unanticipated problems
also are exempt from IND requirements: 3 Expanded controlled and uncontrolled trials,
performed after preliminary evidence suggesting
• Investigations of drugs intended solely for in effectiveness has been obtained. Phase 3 trials
are intended to gather the additional information
vitro tests or for use in laboratory research ani- about effectiveness and safety that is needed to
mals, if they are shipped in accordance with evaluate the overall benefit-risk relationship of the
drug and to provide an adequate basis for physi-
21 C.F.R. § 312.160, “Drugs for Investigational cian labeling.
Use in Laboratory Research Animals or 4 Studies performed after FDA grants marketing
In-Vitro Tests” approval, also referred to as “post-marketing stud-
ies” or “post-market surveillance studies.” FDA
may ask or require sponsors to perform certain
• Investigations involving use of a placebo if they post-marketing studies to gather additional infor-
do not otherwise require submission of an IND mation about a drug’s risks, potential benefits, and
optimal use concurrent with marketing approval.
• Certain in vivo bioavailability studies20
As with drug studies, FDA generally requires • Certain adverse events and unanticipated prob-
advance approval of changes to investigational lems affecting risks to subjects and others
plans that are likely to have a significant effect on • Deviations from the investigational plan for
scientific soundness of trial design and/or validity any reason
of data resulting from the trial such as a change
• Withdrawal of IRB or FDA approval
in indication, or a change in type or nature of the
study control.32 Approval must be granted by FDA • Final report
and the IRB in SR studies and by the IRB only
in NSR studies. There are exceptions, however, A complete listing of all the required reports may
including for emergency use, certain developmen- be found at 21 C.F.R. § 812.150.
tal changes to the device, and other minor changes
to the clinical protocol. Notice of these types of 4. Early and Expanded Access
changes must be provided to FDA within five (5) FDA has described four ways providers may access
working days. investigational devices prior to FDA approval and
outside the scope of an approved clinical trial.
FDA and IRB approval also is required for each
These are: (i) emergency use for life-threatening or
site that will participate in a device investigation.
serious diseases or conditions; (ii) compassionate
FDA will consider IDE applications that do not
use for patients who do not meet the criteria for
contain a certification of IRB approval for each
inclusion in a trial but may benefit from use of the
site, but the sponsor must submit that certifica-
device; (iii) treatment use, to expand the number
tion in an IDE supplement when that approval
of subjects who may be permitted to participate
is secured and to open any new study sites to
in a trial that shows promise; and (iv) continued
enrollment.
access to investigational devices for subjects par-
A sponsor may report minor changes in the ticipating in a trial after the trial is complete but
following areas as part of its annual progress prior to FDA approval.33
report: study purpose, risk analysis, monitoring
In the event an unapproved investigational Prior FDA approval is needed before compas-
device is used in an emergency under this sionate use occurs. In order to obtain FDA
exception, the device developer must notify approval, the sponsor should submit an IDE
the FDA immediately after shipment. In addi- supplement requesting approval for a protocol
tion, the physician employing the device should deviation. The physician should not treat the
make every effort to protect subjects includ- patient (or patients) identified in the supple-
ing, as applicable: (i) obtaining an independent ment until FDA and the appropriate IRB both
assessment by an uninvolved physician; (ii) approve the use of the device under the pro-
obtaining informed consent from the patient posed circumstances.35
or legally authorized representative; (iii) notify-
• Treatment Use
ing the appropriate IRB as soon as practicable;
Approved IDEs specify the maximum number
and (iv) obtaining authorization from the IDE
of clinical sites and the maximum number of
holder, if an approved IDE for the device exists.
human subjects that may be enrolled in a study.
After the emergency, the physician must: (i) During the course of a clinical trial, if the data
report to the IRB within five days and otherwise suggest that the device is effective, then the trial
comply with IRB requirements; (ii) evaluate the may be expanded to include additional patients
likelihood of a similar need occurring again with life-threatening or serious diseases. To
and, if future use is likely, immediately initiate qualify for a treatment use IDE, the disease or
efforts to obtain IRB approval and an approved condition must be life threatening or serious,
IDE for subsequent use; and (iii) if an IDE for and patients must have no comparable or satis-
the use already exists, notify the sponsor of factory alternatives to the investigational device.
the emergency use, or if an IDE does not exist, If the disease is life-threatening (i.e., there is
notify the FDA of the emergency use, and pro- a reasonable likelihood that death will occur
vide the FDA with a written summary of the within a matter of months or premature death is
While marketing or promoting investigational As with drugs, sponsors may request FDA to
drugs or devices is prohibited, FDA recognizes waive any requirement of 21 C.F.R. Part 812.43
the practical need to recruit clinical investiga- A waiver request, with supporting documenta-
tors and study subjects through dissemination tion, may be submitted separately or as part of an
of information on investigational products. An IDE application. FDA may grant a waiver of any
FDA guidance entitled “Guidance for Industry requirement it deems not required by the act, nor
and FDA Staff: Preparing Notices of Availability of necessary to protect the rights, safety or welfare of
Investigational Medical Devices and for Recruiting the study subjects. It is important to understand,
Study Subjects” (March 19, 1999)40 defines the however, that each requirement applies unless and
recommendations and restrictions regarding until FDA expressly waives it.
such information dissemination for devices. See
The Privacy Rule permits use or disclosure of Research on decedents’ information.27 A covered
PHI without an individual’s written authoriza- entity may use or disclose PHI to the researcher,
tion for “treatment,” “payment,” and “healthcare if the researcher provides: (1) a representation that
operations” (collectively “TPO”). These terms the use or disclosure sought is solely for research
are defined narrowly and do not include most on the PHI of decedents; (2) documentation, at the
research activities.22 HIPAA also permits use or covered entity’s request, of the death of the speci-
disclosure to law enforcement and public health fied individuals; and (3) a representation that the
authorities, subject to specified limitations.23 PHI for which use or disclosure is sought is neces-
sary for the research purposes.
HIPAA includes five additional exceptions to the
written authorization requirement relevant to De-identified data sets. Section 164.514(a) of the
research activities, which are described below: HIPAA Privacy Rule provides the standard for
de-identification of protected health information.
Waiver of authorization.24 Under this standard, health information is not
The Privacy Rule empowers an institutional
individually identifiable if it does not identify an
review board (“IRB”) functioning under a federal-
individual and if the covered entity has no reason-
wide assurance, or a properly constituted privacy
able basis to believe it can be used to identify an
board, to grant a waiver or alteration of written
individual.
authorization if the proposed use or disclo-
sure will pose minimal risk to participants and A covered entity may use or disclose de-identified
other specified criteria are met. A comparison of health information for any purpose without
Common Rule and HIPAA waivers and detailed restriction (although other laws may apply). The
discussion of the role of a privacy board under Privacy Rule designates two ways by which a
HIPAA is discussed later in this chapter. covered entity can determine that health informa-
tion is de-identified. The first is the “Safe Harbor”
• Administrative burden. In hybrid covered Like HIPAA, the Common Rule recognizes cir-
entities, such as large research universities, cumstances where securing informed consent
imposition of a requirement that consents is unreasonable and unnecessary for the ethical
and authorizations be integrated can result in conduct of a research project. Though similar, the
noncovered components using overly complex Privacy Rule and Common Rule requirements
forms and, in some cases, inadvertently imply- are not identical because of the different concerns
ing that they are subject to HIPAA. addressed by each. The regulatory standards are
summarized as follows in the table below:
2. Research and Quality Improvement HIPAA Common Rule
Both the Common Rule and HIPAA define The use or disclosure involves Research poses no more than
no more than minimal risk minimal risk to prospective
research as a: “systematic investigation. . . to the privacy of individuals participants
designed to develop or contribute to generalizable because there’s an adequate
plan to protect identifiers
knowledge.”46 The Common Rule equally regulates from improper use and dis-
activities undertaken solely for research purposes closure; to destroy identifiers
consistent with the conduct
and those undertaken primarily for other reasons of the research; and to not
(e.g., quality improvement, program evaluation) if reuse or re-disclose the data
except as required by law, for
there is also a research component, no matter how oversight of the study, or for
insignificant. HIPAA, by contrast, treats the fol- other permitted research
lowing activities as “healthcare operations” rather N/A The waiver or alteration will not
adversely affect participants’
than research. rights and welfare
• Conducting quality assessment and improve- The research could not prac- The research could not practi-
ticably be conducted without cably be carried out without the
ment activities, including outcomes evaluation the waiver or alteration; waiver or alteration
and development of clinical guidelines, if the nor without access and use
of the PHI
obtaining of generalizable knowledge is not the
N/A Whenever appropriate, the
primary purpose of studies resulting from the subjects will be provided with
activities additional pertinent information
after participation
• Population-based activities relating to improv- Documentation of the waiver Documentation of the waiver
reflecting that it was properly must be maintained by the IRB
ing health or reducing healthcare costs awarded must be maintained for at least 3 years.
by the covered entity for at
• [Clinical] protocol development, case manage- least 6 years.
ment and care coordination.
The Privacy Rule empowers IRBs acting under a
Thus, while the Common Rule requires individual Federal Wide Assurance (“FWA”) to grant autho-
consent (or IRB-approved waiver of consent) to rization waivers.47 The regulation’s drafters also
conduct quality improvement activities even if recognized, however, that while not all covered
primarily undertaken for non-research purposes,
Privacy advocates have advanced additional Who May Authorize Use or Disclosure of
proposals to further protect health information Health Information
privacy, including laws restricting access to and
use of genetic testing and results information or to In addition to the laws that govern sensitive infor-
limit use of social security numbers. The Genetic mation, state laws also govern who is empowered
Information Nondiscrimination Act (GINA) to determine whether a person’s health informa-
became law in 2008. The Final Rule, effective tion can be used in research (where authorization
in 2013, provides for implementation of GINA. is required). For example, minors (usually, but
DHHS includes “genetic information” as a type not always, individuals under age 18)62 may have
of health information subject to HIPAA Rules, the right to control certain health information.
including the imposition of restrictions that pro- HIPAA provides that a minor who is empowered
hibit health plans from using genetic information under state law to consent to certain healthcare
for underwriting purposes. services (e.g., prenatal care or substance abuse)
without a parent’s or guardian’s permission is also
Efforts at the national level to better protect empowered to exercise control of resulting health
social security numbers have been equally inef- information.63 If the minor is involved in research
fective, though a number of local initiatives have using such information, these laws will determine
succeeded.60 who has the legal authority to sign research docu-
ments including authorization forms.64
State Privacy and Mandatory
Disclosure Laws Electronic Records and Signatures
Researchers must also be aware of any applicable In addition to the challenges of complying with
state law requirements. HIPAA, the Common Rule, and a patchwork
of sometimes inconsistent state privacy laws,
researchers and research institutions have obliga-
tions under HIPAA and other federal and state
laws to adopt policies, procedures, and systems to
secure electronic health and research information.
This act may apply to some research transactions. Business Associates of covered entities must notify
The applicability will depend on whether the state the covered entity when a breach occurs on their
has adopted the Uniform Electronic Transactions watch. Sub-contractors of business associates must
Act and elected to preempt certain eSIGN notify the business associate who, in turn, noti-
provisions. fies the covered entity. The covered entity has the
responsibility of notifying the individuals affected
2. Uniform Electronic Transactions by the breach.
Act (UETA)
UETA was developed by the National Conference
Information Security and
of Commissioners on Uniform State Laws in 1999 Human Research
and was recommended to the states for adoption. Information security is an essential component of
All but a few states have adopted UETA and the an effective system to protect the confidentiality of
remaining ones have enacted laws recognizing research data.
electronic signatures. UETA recognizes electronic
records and signatures (defined consistently with HIPAA Security Rule
eSIGN) as valid and binding to the same degree While the Privacy Rule directly affects the conduct
as their paper equivalents, so long as both parties of clinical research by controlling how research-
agree to the electronic transaction. The legislation ers gain access to much of the information needed
establishes security, authentication, authoriza- to perform clinical studies, the Security Rule100
tion, and non-repudiation standards for creation, covers electronic protected health information
use and storage of electronic records and signa- (ePHI) that a covered entity or business associate
tures. While this law does not specifically apply to creates, receives, maintains, or transmits. HITECH
research, it may be applicable to data maintained included provisions to make business associ-
electronically and the use of electronic signatures. ates responsible for compliance with the HIPAA
Security Rule and the Interim Breach Notification
Breach Notification Rules Rule. With the enactment of the Omnibus (Final)
The Breach Notification Rule, finalized with the Rule in 2013, business associates and their sub-
passage of the Omnibus Rule in 2013, requires contractors became directly liable for compliance
that a covered entity notify the individual and with all the requirements of the Security Rule,
the Secretary of the Department of Health and many of the requirements of the Privacy Rule, the
Human Services (DHHS) of any breach of “unse- requirements of the Breach Notification Rule, and
cured” (defined as making the protected health subject to the Enforcement Rule.
information unusable, unreadable, and indeci-
pherable) protected health information that has
The records generated by clinical research must While development of the research record is
serve several purposes, so it is understandable that essential from a regulatory and GCP perspective,
their management is governed by a wide variety ensuring that the subject/participant is aware of
of external organizations with specific stan- the record and its content is very important and a
dards and/or rules and regulations. The research right of the participant. That right is included in
study record includes documentation prepared the Subject’s Bill of Rights and includes the follow-
by the principle investigator and contains study ing elements:
notes, informed consent forms, Health Insurance
• HIPAA authorization
Portability and Accountability Act (“HIPAA”)
authorization forms, offsite lab results as well as • Definition of the patient safety considerations
other outside records. A legal medical record must for including and excluding information
also be maintained for each patient as per federal in the chart
regulatory and state licensing requirements and • Documentation expected to be found in the
should contain clinical data (both inpatient and medical record
outpatient), as well as consent forms and the spe-
cific entity admission terms and conditions. • Records excluded from the medical record and
found only in the research record
There is always the question of who decides what The essential elements of a research study record
needs to be included in the medical record. For include, at a minimum, the following documents:
most research institutions, the possible decision
• Comprehensive Agreement between the
makers may include, but may not be limited to:
Sponsor and Investigator that clearly outlines
the roles and responsibilities of both the sponsor
1. IRB and investigator during the life of the research
The IRB bases its ability to determine the content study; this should include such elements as
of the research medical record on the Criteria for formal reporting requirements, publication
IRB Approval for Research in the CFRs, “When agreements etc.
appropriate, there are adequate provisions to pro- • Investigator Brochure developed and provided
tect the privacy of subjects and to maintaining the to the investigator by the sponsor prior to the
confidentiality of the data” 45 CFR 46.111(a) (7) initiation of the study. The brochure should be
the most recent version (all obsolete versions
2. Health System Governing Body should be removed) and should include relevant
For health system organizations that have been, and current scientific information about each
or want to be accredited by the Joint Commission of the investigational drugs or devices that have
(JCAHO), there are accreditation standards that been provided to the investigator.
specify the content of the medical record. • Signed Protocol and Amendments, if any, and a
sample Case Report Form (CRF).
What records are typically needed?
• Information given to the Trial Subject to pro-
Every human subject protocol needs a research vide the potential subject with sufficient data to
record, medical record, and billing record to the make an informed decision regarding his/her
grant or payer that documents each encounter participation in the study should be included
and/or visit. FDA regulations require investiga- in the record. The main categories of informa-
tors to maintain “case histories.”3 An investigator tion include:
is required to prepare and maintain adequate and
accurate case histories that record all observations 1. Informed Consent—The informed consent
and other data pertinent to the investigation on form documents that consent was obtained
each individual administered the investigational in accordance with regulations, GCP and
drug or employed as a control in the investigation. the specific protocol. The informed consent
Case histories include the case report forms and form should be dated prior to the initial
supporting data including, for example, signed participation date for each participant
in a clinical trial. Non-English speaking
A mechanism must be developed for early ter- 3. Large or multi-center trials and trials in which
mination if unusual circumstances dictate that a the protocol requires blinding of the investiga-
cooperative study should not be continued. Such tors, should have a data and safety monitoring
action might be contemplated if the accumulated unit. The unit should consist of clinical experts
data answer the original question sooner than in the disease under investigation, biostatis-
anticipated, if it is apparent that the study will not
ticians, and scientists from other pertinent
or cannot achieve its stated aims, or if scientific
advances since initiation render continuation disciplines. Physicians engaged in the care of
superfluous. This is obviously a difficult decision study patients or directly responsible for evalu-
that must be based on careful analysis of prog- ating clinical status are excluded.
ress and future expectation. If the National Heart
Institute must initiate such action, it must do so That NIH standard is closely echoed in the 1998
only with the advice and on the recommendation NIH Policy for Data and Safety Monitoring. It is
of consultants. also reflected in the definitions we see today in the
FDA guidance of 2006:
The Greenberg Report and the Coronary Drug
Project contributed significantly to the way in A clinical trial DMC is a group of individuals with
which clinical research is practiced today. In pertinent expertise that reviews on a regular basis
addition to establishing the concept of formal accumulating data from one or more ongoing
Committee for Medical Products for Human NIH Guide for Grants and Contracts. (8:8) 5 June
Use (CHMP). Guideline on Data Monitoring 1979 pg. 29.
Committees. London: EMEA, July 2005.
Greenberg, B. et al. Organization, Review and
Further Guidance on a Data and Safety Administration of Cooperative Studies (Greenberg
Monitoring for Phase I and Phase II Trials. NIH Report): A Report from the Heart Special Project
Guide. 5 Jun. 2000. 23 Jan. 2008 Committee to the National Advisory Heart
Council, May 1967.
http://grants.nih. gov/grants/guide/notice-files/
NOT-OD-00-038.html. Meinert, Curtis L. Clinical Trials: Design,
Conduct and Analysis. Second Edition. 2012.
NIH Policy for Data and Safety Monitoring.
NIH Guide. June 10, 1998. January 23, 2008.
http://grants. nih.gov/grants/guide/notice-files/
not98-084.html.
http://deainfo.nci.nih. gov/grantspolicies/
datasafety.htm.
4. Protocol as Part of Clinical Trial Agreement. 6. Interpreting the Clinical Trial Agreement.
The protocol is usually always incorporated into The following are basic points that apply to inter-
the contract through an exhibit. Protocol activi- preting a clinical trial agreement:
ties often are defined as the “Services” in a clinical
• The clinical trial agreement is interpreted as
trial agreement; in other words, the protocol
a whole – the main body of the contract, the
activities are what the institution is committing
incorporated protocol, the budget exhibit are
itself to do. Since the “Services” under a clinical
one, singular contract.
trial agreement are rarely distinguished as “for
research purposes only” services and “clinical • The plain language of the contract will be con-
care” services, any activity required by the proto- sidered to mean what it says. This is particularly
col can become a “Service” under the contract. so when two highly sophisticated parties (uni-
versities and drug/device companies) negotiate
It is important to keep in mind that the protocol is contracts.
not merely a scientific document. Because the pro-
tocol in toto is usually incorporated by reference • If the parties disagree on the meaning of the
into the clinical trial agreement, the protocol is a terms, then ancillary evidence can be used to
contractual document as well. How the investiga- show that the words did not mean what was
tor performs under the protocol and what services written – based on actions of the parties or
are required by the protocol (whether they be “for based on evidence/material from the time of
research purposes only” or are “standard of care”), executing the contract that shows what the real
they are still contractual services and carry all intent of the parties are. It is rarely sufficient
obligations of a valid contract. for one party to take plain language interpreta-
tions and assert they mean something different
5. Sponsorship Budget/Compensation Exhibit. without evidence that the other party also
The sponsorship budget is usually set out as an understood the terms to be different.
exhibit in the clinical trial agreement. It is criti- • If terms are ambiguous, then the general rules
cal to understand that the budget/compensation of contract interpretation instruct courts to
exhibit is part of the contract. The sponsorship interpret the language against the drafter of the
budget is every bit a part of most contracts as is agreement and in favor of the party that took
the main body of the contract. Keeping the spon- the words to mean something different than
sorship budget and the main body of the contract what the drafter wrote. This is usually used
harmonized – recognizing that the protocol are when the parties disagree on the meaning of
the services – is vital to successfully negotiating the term and the terms are ambiguous. Clear,
a clinical trial agreement with as few ambiguities plain words rarely can utilize this canon of
as possible. It is also important for keeping mind interpretation.
how the clinical trial agreement is incorporated.
• If the terms in the main body of the contract
are not in sync with the budget exhibit (or if the
terms within the exhibit contradict themselves),
If the language indicates that certain services are When the language of the informed consent con-
free, then those services cannot be billed. For tradicts itself as written above, then surrounding
instance, the informed consent document may language should be used to interpret the contra-
indicate that the “CT scans conducted during dictory language. In the example above, there are
screening will be at no cost.” This only requires merely two sentences written out. If the language
the CT scans that are done at the start of the occurs in the context of a longer paragraph in
enrollment process during screening to be pro- which the language has multiple permutations
vided without charge to the patient. However, if of “there are no costs to you,” followed by a brief
the language states that “all imaging services that line discussing standard of care as billable, then
are part of this research study” will be provided the language would likely be construed in favor of
free, then no imaging services (whether X-Rays, the patient. If the opposite is true, then the weight
CTs or MRIs) can be billed to the patient if the may be on the side of billing for the standard of
imaging service is required by the protocol. care services.
Statements in the protocol that usually affect bill- Routine costs in clinical trials include:
ing are those statements that indicate something • Items or services that are typically provided
is being required by the protocol only for research absent a clinical trial (e.g., conventional care);
purposes or for data collection purposes. In con-
ducting a Medicare Coverage Analysis, these • Items or services required solely for the provi-
statement must be taken at face value until the sion of the investigational item or service (e.g.,
investigator indicates otherwise. administration of a noncovered chemotherapeu-
tic agent), the clinically appropriate monitoring
of the effects of the item or service, or the pre-
vention of complications; and
Appendix
• Items or services needed for reasonable and
The following is a re-print of the July 2007 necessary care arising from the provision of an
Medicare Clinical Trial Policy (National Coverage investigational item or service—in particular,
Determination 310.1) for the diagnosis or treatment of complications.
Indications and Limitations of This policy does not withdraw Medicare cover-
Coverage age for items and services that may be covered
according to local medical review policies
Effective for items and services furnished on or (LMRPs) or the regulations on category B inves-
after July 9, 2007, Medicare covers the routine tigational device exemptions (IDE) found in 42
costs of qualifying clinical trials, as such costs are CFR 405.201-405.215, 411.15, and 411.406. For
defined below, as well as reasonable and neces- information about LMRPs, refer to www.lmrp.
sary items and services used to diagnose and treat net, a searchable database of Medicare contractors’
complications arising from participation in all local policies.
clinical trials. All other Medicare rules apply.
For noncovered items and services, including
Routine costs of a clinical trial include all items items and services for which Medicare payment
and services that are otherwise generally available is statutorily prohibited, Medicare only covers
to Medicare beneficiaries (i.e., there exists a benefit the treatment of complications arising from the
category, it is not statutorily excluded, and there delivery of the noncovered item or service and
is not a national non-coverage decision) that are unrelated reasonable and necessary care. However,
provided in either the experimental or the control if the item or service is not covered by virtue of a
arms of a clinical trial except: national noncoverage policy in Pub. 100-03, NCD
• The investigational item or service, itself unless Manual and is the focus of a qualifying clini-
otherwise covered outside of the clinical trial; cal trial, the routine costs of the clinical trial (as
defined above) will be covered by Medicare but the
• Items and services provided solely to satisfy data
noncovered item or service, itself, will not.
collection and analysis needs and that are not
used in the direct clinical management of the
patient (e.g., monthly CT scans for a condition
usually requiring only a single scan); and
Effective September 19, 2000, clinical trials that Should CMS find that a trial’s principal investiga-
are deemed to be automatically qualified are: tor misrepresented that the trial met the necessary
qualifying criteria in order to gain Medicare
1. Trials funded by NIH, CDC, AHRQ, CMS, coverage of routine costs, Medicare coverage of
DOD, and VA; the routine costs would be denied under §1862(a)
(1)(E) of the Act. In the case of such a denial, the
2. Trials supported by centers or cooperative Medicare beneficiaries enrolled in the trial would
groups that are funded by the NIH, CDC, not be held liable (i.e., would be held harmless
AHRQ, CMS, DOD and VA; from collection) for the costs consistent with the
provisions of §§1879, 1842(l), or 1834(j)(4) of the
3. Trials conducted under an investigational Act, as applicable. Where appropriate, the billing
new drug application (IND) reviewed by providers would be held liable for the costs and
the FDA; and fraud investigations of the billing providers and
the trial’s principal investigator may be pursued.
4. Drug trials that are exempt from having an
IND under 21 CFR 312.2(b)(1) will be deemed Medicare regulations require Medicare+Choice
automatically qualified until the qualifying (M+C) organizations to follow CMS’s national
criteria are developed and the certification coverage decisions. This NCD raises special issues
process is in place. At that time the princi- that require some modification of most M+C
pal investigators of these trials must certify organizations’ rules governing provision of items
that the trials meet the qualifying criteria in and services in and out of network. The items and
order to maintain Medicare coverage of rou- services covered under this NCD are inextricably
tine costs. This certification process will only linked to the clinical trials with which they are
affect the future status of the trial and will associated and cannot be covered outside of the
not be used to retroactively change the earlier context of those clinical trials. M+C organizations
deemed status. therefore must cover these services regardless of
whether they are available through in-network
The CMS, through the national coverage determi-
providers. M+C organizations may have reporting
nation (NCD) process, through an individualized
requirements when enrollees participate in clinical
assessment of benefits, risks, and research poten-
trials, in order to track and coordinate their mem-
tial, may determine that certain items and services
bers’ care, but cannot require prior authorization
for which there is some evidence of significant
or approval.
medical benefit, but for which there is insufficient
evidence to support a “reasonable and necessary”
7. Defense and prosecution of criminal and 21. Public relations, with very limited exceptions;
civil proceedings, claims, appeals and patent
22. Selling and marketing, with limited
infringement, except when the federal govern-
exceptions;
ment has specifically authorized the condition
causing the action; 23. Student activity costs, with limited exceptions;
8. Direct costs; 24. Travel costs.
9. Donations or contributions made by the
institution; Subrecipient Monitoring
In the case of an award being made to an institu-
10. Entertainment; tion or, quite rarely, an individual (what is referred
to as an “‘awardee”), that institution is fully
11. Fines and penalties;
responsible for meeting all obligations set out in
12. Fund raising; the proposal and award. Remember, the proposal
2. Subrecipient should provide its audit cer- 7. Payments should further be tied to the timely
tifications on an annual basis during the progress of the project and submission of
project period. reports to awardee in accordance with the pro-
posal and award. (Failure of the subrecipient to
• Oversight of the IRB(s)’ activities to ensure they In addition to these general requirements, there
are functioning as intended are a series of very specific requirements for IRB
• Ensure equitable and enforceable consequences composition, including:
for non-compliance with policies and proce- • The IRB membership cannot be all members of
dures and IRB actions. one profession
• Gender cannot be a factor in selecting mem-
The activities of a local IRB should be considered
bers, which would indicate that an IRB with all
a part of an active institutional compliance pro-
male or all female members would probably be
gram where complying with federal regulations
challenged
is of extreme importance. While an institution
may have only one or multiple IRBs, each must • At least one member must be active primarily in
satisfy certain requirements and carryout set of scientific areas
common functions. The discussion of the IRB will
• At least one member must be active primarily in
be divided into the following sections:
non-scientific areas
• IRB membership and responsibilities • At least one member must have no affiliation
• Types of reviews with the institution or be a part of the imme-
diate family of someone affiliated with the
• Human subject informed consent
institution
• Adverse events and protocol deviations.
• A majority of the members must be present
Each section will present the requirements. A dis- to take action on all matters except expedited
cussion of the risk of non-compliance and some reviews and at least one of the members present
of the controls that might be used to mitigate the must have primary activities in a non-scien-
risks of non-compliance will complete the chapter. tific area.
IRB Membership and Responsibilities. Each The IRB is responsible for following documented
IRB must have at least five (5) members with the procedures for:
appropriate diversity of backgrounds to ensure • Conducting initial and continuing reviews
complete and adequate review of research activi- of research
ties normally conducted by the institution. This
• Reporting findings and actions to both the
diversity includes experience, expertise, race,
investigator and the institution
gender, and cultural backgrounds. In addition,
members should possess the professional com- • Determining which projects need review more
petence necessary to review specific research often than annually
activities from the viewpoint of institutional
commitments and regulations, applicable laws,
and applicable standards of professional conduct
Once again, there are a wide variety of mitigation Informed consent is the foundation of all research
strategies that will work to reduce non-compliance involving human subjects. Requirements of
in this area. Those that are most common and informed consent will be covered under the fol-
usually have an impact upon multiple risks when lowing headings:
applied include: • General requirements
• Provide multiple avenues for informing poten- • Essential elements
tial investigators of the requirements for
• Additional elements
proposal acceptance including:
• Alterations and waivers
–– Newsletters
• Vulnerable categories of subjects
–– Focus groups
• Documentation of informed consent.
–– Websites
The general requirements for legally effective
–– Training sessions informed consent establish the conditions which
must be present for a subject to even be presented
• Provide checklists of required information for a
with the required consent forms and information
proposal to be considered
sheets. If these conditions do not exist, there is no
legally effective informed consent, even though
1. The informed consent is obtained under cir- 4. A disclosure of appropriate alternative pro-
cumstances that provide the subject or the cedures or treatments, if any, that may be
subject’s legal representative with sufficient advantageous to the subject
opportunity to consider freely and without
coercion or undue influence whether or not to 5. A statement describing the extent, if any, by
participate in the research project. which confidentiality of records identifying
the subject will be maintained
2. The informed consent is in the language
understandable by the subject or the subject’s 6. For research that involves more than a mini-
legal representative. mal risk, an explanation as to:
a. whether any compensation and any medi-
3. The informed consent does not include any cal treatment are available if injury occurs
language (written or oral) that waives or
appears to waive the subject’s legal rights. b. what those elements consist of
c. where further information may
4. The informed consent does not include any be obtained
language (written or oral) that releases or
appears to release the investigator, the sponsor, 7. An explanation of whom to contact for
the institution or its agents from liability for answers to pertinent questions about the
negligence. research and research subjects’ rights, and
whom to contact in the event of a research-
For an informed consent to be considered legally related injury to the subject
effective, it must contain at least the following
essential elements (unless applicable exceptions 8. A statement that:
apply; see Alterations and Exemptions below). The
a. participation is voluntary
essential elements are:
b. refusal to participate will involve no pen-
1. A statement about the project that indicates: alty or loss of benefits to which the subject
a. it is a research project is otherwise entitled
b. an explanation of the purpose of c. The subject may discontinue participa-
the research tion at any time without penalty or loss
of benefits to which the subject is other-
c. expected duration of the subject’s wise entitled.
participation
d. description of the procedures to Additional elements that may be provided to each
be followed subject are:
e. identification of any procedures that are • A statement that the particular treatment or
experimental procedure may involve risks to the subject that
are not currently foreseeable
–– patient education materials unless imme- The Policy Statement should indicate that the
diately required for the protection of IRB is the authoritative body for authorizing and
study subjects overseeing research studies. In addition, it will
usually specify:
• Obtaining yearly updated, documented, signed,
and dated conflict of interest statements on all • The exact authority or charter of the IRB,
human subject investigators involved in the including whether or not it will act as the
study and maintaining them in the study files Privacy Board
• Promptly reporting (in accordance with the • What proposals for research are covered by
P&P) any serious adverse events, unanticipated this authority
problems, or significant new findings that arise • The criteria for acceptance of proposals as
throughout the course of the study research studies
• Complying with all IRB requests to report on • The pre-conditions for performing research,
the status of the study including annual reviews such as training and certifications.
–– Informed consent forms One of the most effective ways to ensure that all
–– Scientific information forms needed to approve and conduct research
are properly constructed and contain the required
–– Financial information information is to develop a set of standard forms
and templates to be used by all PIs. This tactic
–– Reports. reduces the time required of the IRB to review
and approve both individual document content
Practice aids or guidelines should be prepared for and the proposal to conduct research. For the PI,
any activity that has special and unique require- it provides a simple solution to what is required.
ments. This will enable consistency of treatment A list of possible standard forms and tem-
across many researchers and make review by the plates follows:
IRB and other oversight organizations easier.
Usually these aids or guidelines fall into two cat- • Application for Approval to Use Humans as
egories: study procedures and study populations. Experimental Subjects (exempt)
A sample list of each follows: • Application for Approval to Use Humans as
Subjects (standard)
• Taking action(s) necessary to ensure the The Federal government (Civil False Claims—
integrity of research, to protect the rights and 31USC §§ 3729-33) holds a person or entity liable
interests of research subjects and the public, to for knowingly submitting a false claim for pay-
ensure the observance of legal and contractual ment or using a false record or statement to obtain
requirements payment or causing a third party to do the same,
• Providing appropriate safeguards of the subject and can result in monetary penalties of $5,000–
of allegations and the informants. $11,000 (discretionarily adjustable) per false claim
plus three times the damages sustained by the
In addition, sponsoring organizations would also government. In addition, a person or entity that
expect prompt notification should the institution knowingly and willfully makes or causes to be
become aware during an inquiry or investi- made a false statement or representation on any
gation that: claim with the intent to fraudulently secure over-
payment can be subject to 5 years imprisonment
• Public health or safety was at risk and/or a $25,000 fine (Criminal False Claim 42
• The sponsor’s resources, reputation or other USC § 1320a-7a(a)). Suspension and disqualifica-
interests needed protecting tion from participation in government-sponsored
programs such as Medicare or Medicaid is also a
• There is reasonable indication of possible viola-
possible adverse outcome.
tions of civil or criminal laws
• Research activities should be suspended The liability and risks associated with clinical trial
billing were highlighted with the first false claims
• External action may be necessary to protect
settlement related to billing for routine services
the interests of a subject of the investigation or
provided during clinical trials announced in
someone else potentially affected
December of 2005. The one million dollar settle-
• The scientific community or the public should ment acknowledged overbilling Medicare for
be informed. services already paid by another entity and under
billing Medicare for services assuming that there
Research Finance was an alternative primary payor. In addition, “the
Billing U.S. attorney also (said) that some or all of the
physician and hospital inpatient and outpatient
The Office of Inspector General (OIG) has exer-
services charged to Medicare and Medicaid were
cised enforcement of research billing compliance,
not reimbursable because they were not consid-
giving researchers a new incentive to look closely
ered routine care associated with clinical trials.”
at cost calculations for clinical research, time and
This case of false claims submissions is a key area
effort reporting for grants, budget negotiations
of financial risk in clinical research and suggests
and third-party billing practices. In addition,
that clinical trial sites should become increasingly
there is arguably some obligation to manage the
more familiar with billing statutes, regulations
business aspects of research activity to the extent
and guidelines. (See also, Chapter X Clinical
that organizations establish financial reporting
Research Billing Compliance.)
Institutions should develop pricing standards to Billing Compliance. On June 7, 2000, the
support standardization in budget development as President of the United States issued an execu-
well as a minimum level of payment expectation. tive memorandum directing the Secretary of
Budget negotiations with a sponsor are then based Health and Human Services to explicitly autho-
on verifiable and consistent costing principles with rize [Medicare] payment for routine patient care
logic that provides added leverage to the fund- costs... and costs due to medical complications
ing requests. This type of process and strategy associated with participation in clinical trials.
facilitates responsible and fiscally sound research The Health Care Financing Administration (now
decisions. the Centers for Medicare & Medicaid Services,
or CMS) responded to the executive order with
Mischarging. The overriding statute govern- the clinical trial policy NCD issued on September
ing Medicare billing for patient care items and 19, 2000. The NCD for routine costs in clinical
services performed in the context of clinical trials was implemented through the CMS NCD
research is the Social Security Act. Title XVIII of process and determined the circumstances under
c. generate clinical information that will improve Study sites must have sound financial tracking and
the evidence base on which providers base reporting mechanisms to validate fiscal steward-
their recommendations to Medicare beneficia- ship. It is prudent business practice to track earned
ries regarding the item or service. revenue and reconcile sponsor payments. In addi-
tion, OMB Circular A-100 published by the Office
Upon completion of these reviews, all docu- A “project steward” familiar with the clini-
ments related to the research study should be in cal aspects of the protocol should provide a risk
harmony with one another. For example, subject assessment of the study to the contracts attorney
compensation for study related injury and sub- who will negotiate the legal terms of the clinical
ject responsibility for costs associated with the trial agreement. A modification of this process
research project should be uniformly addressed should be applied to scholarly research activ-
in the consent document and the clinical trial ity being conducted as a requirement of medical
agreement. Subject compensation or stipends education, data collection studies, and nursing
acknowledged in the consent document should and alternative health research projects. All insti-
be included in a cost analysis and covered by the tutional employees conducting research within
study budget. Study budget exhibits should be their scope of employment are held accountable
consistent with billing regulations, reflect sponsor to the institutional Code of Conduct, HIPAA and
2. News stories and US Senate actions spearheaded by Sen. 4. E.J. Emanuel, D. Wendler and C. Grady, “What makes
Charles Grassley are summarized in Grassley’s May 29, clinical research ethical?” JAMA, 283 (2000): 2701-2711.
2012 letter to the NIH located at http://www.grassley.
senate.gov/about/upload/2012-05-29-CEG-to-NIH-Dr- 5. R.J. Amdur and E.A. Bankert, “The Institutional Review
Nemeroff-grant.pdf Board: Definition and Federal Oversight,” In Institutional
Review Board: Management and Function, 2nd ed., Ed.
3. SSA § 1128G(a)(1), which can be found at: http://www.ssa. E.A. Bankert and R.J. Amdur, (New York: Jones & Bartlett,
gov/OP_Home/ssact/title11/1128G.htm 2006), Chapter 1-6.
4. Federal Register / Vol. 76, No. 165 / Thursday, August 25, 6. OHRP Guidance: http://hhs.gov/ohrp/policy/index.html.
2011 / Rules and Regulations, pp. 53256-53293, found at
http://grants.nih.gov/grants/policy/coi/fcoi_final_rule.pdf 7. See specific guidance found in “Information Sheet
Guidances: Guidance for Institutional Review Boards,
5. http://www.imapny.org/conflicts_of_interest/ Clinical Investigators, and Sponsors”: http://www.fda.gov/
search_policies oc/ohrt/irbs/default.htm.
6. NSF does not currently follow the PHS Final Rule for 8. J. Moreno, A.L. Caplan, P.R. Wolpe, et al. “Updating pro-
extramurally-funded investigators. The NSF rules can be tections for human subjects involved in research,” JAMA,
found in the Grants Policy Manual NSF 05-131 July 2005 280 (1998): 1951-1958.
Chapter V-Grantee Standards, located at http://www.nsf.
gov/pubs/manuals/gpm05_131/gpm5.jsp#510. 9. J.P. Kahn and A.C. Mastroianni, “Moving from compli-
ance to conscience: why we can and should improve on
7. In many states, the receipt of state funding for research, or the ethics of clinical research,” Arch. Intern. Med., 161
the conduct of research in a state-funded Institution is sub- (2001): 925-928.
ject to that state’s COI rules.
10. Ibid.
8. An FCOI must either be eliminated or managed.
Elimination is achieved by prohibiting certain conflicted
activities (such as complete divestiture, or disallowing the CHAPTER 7
research) or reducing the amount of the financial interest
to a level below the threshold. An FCOI requires a written 1. A comprehensive list of the laws that FDA enforces is
management plan. available online at http://www.fda.gov/ScienceResearch/
SpecialTopics/RunningClinicalTrials/ucm155713.htm.
9. See 21 C.F.R. §§ 312.3, 812.3(n) 20. A discussion of bioavailability studies and their regulation
is beyond the scope of this chapter.
10. See 21 C.F.R. §§ 312.3, 812.3(i)
21. FDA electronic forms are available online at http://www.
11. See, e.g., 21 C.F.R. §§ 50.3(f), 312.3(b), 812.3(o). fda.gov/opacom/morechoices/fdaforms/.
12. See, e.g., Guidance for Industry: Investigator 22. See “Guidance for Industry, Investigators and
Responsibilities—Protecting the Rights, Safety, Reviewers: Exploratory IND Studies,” available
and Welfare of Study Subjects, available online online at http://www.fda.gov/downloads/Drugs/
at http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/
GuidanceComplianceRegulatoryInformation/Guidances/ UCM078933.pdf
UCM187772.pdf; Guidance for Industry: Oversight
of Clinical Investigations—A Risk-Based Approach to 23. FDA has published industry guidance on respond-
Monitoring, available online at http://www.fda.gov/down- ing to clinical holds, available online at http://www.fda.
loads/Drugs/GuidanceComplianceRegulatoryInformation/ gov/ohrms/dockets/98fr/98282gd.pdf ; see also related
Guidances/UCM187772.pdf. Additional guidance is found FDA guidances, available online at http://www.fda.gov/
at http://www.fda.gov/oc/gcp/default.htm, and the CDER, ScienceResearch/SpecialTopics/RunningClinicalTrials/
CDRH, and CBER web pages. GuidancesInformationSheetsandNotices/; and Office
of Medical Policy, Clinical Hold /Refusal-to-File
13. See 21 C.F.R. §§ 312.50, 812.40. Committee, at http://www.fda.gov/downloads/AboutFDA/
CentersOffices/Guidances/ucm081991.pdf.
Endnotes 165
24. See http://www.fda.gov/oc/ohrt/irbs/drugsbiologics. 36. Specific requirements for a treatment IDE application
html#emergency. are available at: http://www.fda.gov/medicaldevices/
deviceregulationandguidance/howtomarketyourdevice/
25. Instructions for completing a single patient IND for investigationaldeviceexemptionide/ucm046706.htm.
emergency (or compassionate use) are available online at
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ 37. See http://www.fda.gov/MedicalDevices/
HowDrugsareDevelopedandApproved/ DeviceRegulationandGuidance/HowtoMarketYourDevice/
ApprovalApplications/ InvestigationalDeviceExemptionIDE/ucm051345.htm
InvestigationalNewDrugINDApplication/ for a description of the requirements for a continued
ucm343022.htm. Contact information for submis- access IDE application; see also http://www.fda.gov/
sion of an emergency use IND is available at http:// BiologicsBloodVaccines/DevelopmentApprovalProcess/
www.fda.gov/Drugs/DevelopmentApprovalProcess/ InvestigationalNewDrugINDorDevice
HowDrugsareDevelopedandApproved/ ExemptionIDEProcess/default.htm.
ApprovalApplications/
InvestigationalNewDrugINDApplication/ucm107434.htm. 38. 21 C.F.R. §§ 312.6, 812.5
26. Requests for such authorization may be made at 39. 21 C.F.R. §§ 312.7, 812.7
any time by contacting FDA as provided at: http://
www.fda.gov/Drugs/DevelopmentApprovalProcess/ 40. See http://www.fda.gov/downloads/medicaldevices/
HowDrugsareDevelopedandApproved/ deviceregulationandguidance/guidancedocuments/
ApprovalApplications/ ucm073585.pdf.
InvestigationalNewDrugINDApplication/ucm107434.htm.
41. See http://www.fda.gov/scienceresearch/specialtopics/run-
27. 57 Fed. Reg. 13250 (May 21, 1990). ningclinicaltrials/guidancesinformationsheetsandnotices/
ucm113793.htm.
28. See 21 C.F.R. § 809.10(c)
42. See 21 C.F.R. § 312.10
29. See 21 C.F.R. § 812.3(m)
43. 21 C.F.R. § 812.10
30. Guidance for determining whether a device is SR or NSR is
available online at http://www.fda.gov/downloads/regulato- 44. A list of the types of findings that may be made during an
ryinformation/guidances/ucm126418.pdf. inspection of a clinical investigation is available online at
http://www.fda.gov/downloads/RegulatoryInformation/
31. A separate IDE application is required for studies involving Guidances/UCM126553.pdf.
an exception from the informed consent process under 21
C.F.R. §§ 50.24, 812.20(a)(4)(i). 45. Warning Letters and Notices of Initiation of
Disqualification Proceedings and Opportunity to Explain
32. See http://www.fda.gov/MedicalDevices/ (“NIDPOE”) Letters are posted on FDA’s website: http://
DeviceRegulationandGuidance/GuidanceDocuments/ www.fda.gov/iceci/enforcementactions/warningletters/
ucm070269.htm. default.htm.
33. Additional guidance on early and expanded access to 46. See recent enforcement actions: http://www.fda.gov/ICECI/
investigational devices is available from FDA online at CriminalInvestigations/ucm123086.htm.
http://www.fda.gov/downloads/RegulatoryInformation/
Guidances/UCM127067.pdf. 47. Supporting resources abound. One, published by the
International Conference on Harmonisation and avail-
34. See the IRB Information Sheet available at http://www. able free of charge on FDA’s website, is titled: “Guidance
fda.gov/downloads/RegulatoryInformation/Guidances/ for Industry-E6 Good Clinical Practice: Consolidated
UCM126418.pdf. Guidance.” See http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/
35. Additional requirements apply and are dis- UCM073122.pdf.
cussed at http://www.fda.gov/medicaldevices/
deviceregulationandguidance/howtomarketyourdevice/ 48. 21 U.S.C. §§ 351(a)(2)(B), 351(h), 360(j)(f).
investigationaldeviceexemptionide/default.htm.
Endnotes 167
14. A personal representative may, depending on state law, be a 30. See, e.g., 67 Fed. Reg. 53181, 53234-38 (Aug. 14, 2002).
legal guardian, attorney-in-fact, patient advocate, or next-
of-kin. An unemancipated minor’s personal representative 31. 45 C.F.R. § 164.502(b).
generally is his or her parent or legal guardian. In cases
where the minor may, under state law, consent to health- 32. See http://www.DHHS.gov/ocr/ privacy/hipaa/faq/busi-
care services without an adult’s permission (for example, ness_associates/ 239.html.
for pre-natal care, treatment of STDs, or mental health or
33. 45 C.F.R. § 46.102(f).
substance abuse treatment), the parent or legal guardian
is not considered the minor’s personal representative. 45 34. 45 C.F.R. § 46.111(a)(7); 21 C.F.R. §
C.F.R. §164.502(g). HIPAA also permits covered entities to
withhold PHI from a parent or legal guardian in domestic 35. Nat’l Science Foundation, Frequently Asked Questions
violence cases. Id. and Vignettes: What’s the difference between privacy
and confidentiality?, available at http://www.nsf.gov/bfa/
15. 45 C.F.R. § 164.502(a). An “individual” is the living or dias/policy/hsfaqs.jsp#difference ; see also Robin Levin
decreased individual who is the subject of any given pro- Penslar, Protecting Human Research Subjects: Institutional
tected health information (“PHI”). PHI, in turn, is defined Review Board Guidebook, Ch. 4, Pt. E (1993), available
to include information that (i) is created or received by online at http://grants.nih.gov/grants/guide/notice-files/
a healthcare provider, health plan, employer, or clear- not93-209.html.
inghouse; (ii) relates to an individual’s past, present, or
future condition, provision of healthcare to the individual, 36. 45 C.F.R. § 46.116(a)(5); 21 C.F.R. § 50.25(a)(5).
or related payment; and (iii) identifies the individual or
reasonably could be used to identify the individual. Id. at 37. Robin Levin Penslar, Protecting Human Research Subjects:
§ 160.103. Institutional Review Board Guidebook, Ch. 4, Pt. E (1993),
available online at http://grants.nih.gov/grants/guide/
16. Detailed guidance on drafting research authorizations is notice-files/not93-209.html.
available on the NIH website at: http://privacyruleandre-
search.nih.gov/authorizations.asp. 38. Detailed information on certificates of confidentiality and
the application and approval process are available on the
17. 45 C.F.R. § 164.520. NIH website at http://grants.nih.gov/grants/policy/coc/; see
also Joan E. Sieber, Summary of Human Subjects Protection
18. 45 C.F.R. § 164.524. Issues Related to Large Sample Surveys, at pp. 21-22, U.S.
Dep’t of Justice, Bureau of Justice Stats. (Jun. 2001), avail-
19. 45 C.F.R. § 164.520(a); id. at 164.530(j).
able at http://www.ojp.gov/bjs/pub/pdf/shspirls.pdf.
20. 45 C.F.R. § 164.526.
39. See, e.g., Office for Human Research Protections, Guidance
21. 45 C.F.R. § 164.528. The accounting requirement can be on Research Involving Coded Private Information or
onerous, and requires patient-specific disclosure tracking, Biological Specimens (Aug. 10, 2004), available at http://
unless 50 or more subjects are involved in the study. Id. at www.hhs.gov/ohrp/policy/cdebiol.html ; Office for
164.528(b)(4). Human Research Protections, Request for Public Comment
on OHRP Draft Guidance Document on Engagement of
22. 45 C.F.R. § 164.501. See sub-section C(2) below for a dis- Institutions in Human Subjects Research (Dec. 8, 2006),
cussion of activities that include a research component but available at http://www.hhs.gov/ohrp/archive/requests/
are primarily intended for quality assessment and improve- com120806.html.
ment purposes.
40. For a detailed analysis of the interaction among these
23. 45 C.F.R. §§ 164.510 and 164.512. regulations, see Erin D. Williams, Federal Protection for
Human Subjects: An Analysis of the Common Rule and Its
24. 45 C.F.R. § 164.512(i)(1)(i). Interactions with FDA Regulations and the HIPAA Privacy
Rule, CRS Order Code RL32909 (Jun. 2, 2005), available
25. 45 C.F.R. § 164.512(i)(1)(ii). at http://www.fas.org/sgp/crs/misc/RL32909.pdf; see also
Nat’l Institutes of Health, HIPAA Privacy Rule, available at
26. http://www.hhs.gov/hipaafaq/permitted/research/317.html. http://privacyruleandresearch.nih.gov/default.asp.
27. 45 C.F.R. § 164.512(i)(1)(iii). 41. 45 C.F.R. § 46.116-46.117 (Common Rule); 21 C.F.R. pt.
50, subpt. B (FDA regulations); 45 C.F.R. § 164.502(a)(1)
28. 45 C.F.R. § 164.514(b)(1).
(iv) (HIPAA).
29. 45 C.F.R. § 164.514(e).
48. 45 C.F.R. § 164.512(i)(1)(i)(B). 58. Detailed information on FERPA and PPRA is available on
the U.S. Department of Education website at http://www.
49. 45 C.F.R. § 46.114; see also DHHS Office for Human
ed.gov/policy/gen/guid/fpco/index.html.
Research Protections, FWA Frequently Asked Questions
#12: Who is Covered by a Federalwide Assurance (FWA)?, 59. 5 U.S.C. § 552a; see also Electronic Information Privacy
available at http://www.hhs.gov/ohrp/FWAfaq.html#q12. Ctr., The Privacy Act of 1974 (Aug. 26, 2003), available at
http://epic.org/privacy/1974act/.
50. See, e.g., DHHS Office for Human Research Protections,
Guidance on Research Involving Coded Private Information 60. See, e.g., Electronic Privacy Information Center, Social
or Biological Specimens (Aug. 10, 2004), available at http:// Security Numbers, available at http://epic.org/privacy/ssn/.
www.hhs.gov/ohrp/policy/cdebiol.html, DHHS Office for
Human Research Protections, Guidance of Engagement 61. See, e.g., Barbara D. Bovbjerg, Social Security Numbers: Use
of Institutions in Human Subjects Research (Oct 16, is Widespread and Protections Vary (Gov’t Accountability
2008), available at http://www.hhs.gov/ohrp/policy/ Ofc. Jun. 15, 2004), available at http://www.gao.gov./new.
engage08.html. items/d04768t.pdf ; Electronic Privacy Information Center
Website: http://epic.org/privacy/.
51. 45 C.F.R. § 46.101(b)(4).
62. The National Conference of State Legislatures maintains a
52. 45 C.F.R. § 46.116(a)(1); 21 C.F.R. § 50.25(a)(1). list of state “Age of Majority” laws, available at http://www.
ncsl.org/research/human-services/termination-of-child-
53. Nat’l Cancer Inst. Cancer Diagnosis Program, Legal and
support-age-of-majority.aspx.
Ethical Issues: Informed Consent, available at http://www.
cancerdiagnosis.nci.nih.gov/humanSpecimens/ethi- 63. 45 C.F.R. § 164.502(g)(3).
cal_collection/informed.htm; see also National Action
Plan on Breast Cancer, National Biological Resource Banks 64. 45 C.F.R. § 46.116-46.117.
Working Group, Sunset Report (Jul. 1998); Nat’l Action
Plan on Breast Cancer, Consent Form for Use of Tissue for 65. 21 U.S.C. ch. 9.
Research (May 1997), available at http://www.cancerdiag-
nosis.nci.nih.gov/humanSpecimens/ethical_collection/ 66. 21 C.F.R. pt. 11.
model.pdf; Nat’l Action Plan on Breast Cancer, How is
Tissue Used for Research (May 1997), available at http://
www.cancerdiagnosis.nci.nih.gov/humanSpecimens/ethi-
cal_collection/patient.pdf.
Endnotes 169
67. U.S. Food and Drug Administration, Guidance 90. 21 C.F.R. § 11.100(c).
for Industry: Part 11, Electronic Records; Electronic
Signatures—Scope and Application at p. 5 (Aug. 2003), 91. 21 C.F.R. § 11.100(c)(1).
available at http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/ 92. 21 C.F.R. § 11.200(a)(1).
ucm072322.pdf: “[W]hen persons use computers to gener-
93. 21 C.F.R. § 11.200(b).
ate paper printouts of electronic records, and those paper
records meet all the requirements of the applicable predi- 94. 21 C.F.R. § 11.10.
cate rules and persons rely on the paper records to perform
their regulated activities, FDA would generally not consider 95. Pub. Law 106-229 (Jun. 30, 2000).
persons to be ‘using electronic records in lieu of paper
records’ under §§ 11.2(a) and 11.2(b). In these instances, the 96. See Nat’l Conf. of Commissioners on Uniform St. Laws,
use of computer systems in the generation of paper records Uniform Electronic Transactions Act, available at http://
would not trigger part 11.” www.ncsl.org/research/telecommunications-and-informa-
tion-technology/uniform-electronic-transactions-acts.aspx.
68. 21 C.F.R. § 11.3(6).
97. 15 U.S.C. § 7006(5).
69. 21 C.F.R. § 11.1(b).
98. 15 U.S.C. § 7001 (a).
70. 21 C.F.R. § 11.3(a)(4).
99. 15 U.S.C. § 7001 (c). Additional information about con-
71. 21 C.F.R. § 11.10. sumer consent requirements is available in the Federal
Trade Commission publication, Electronic Signatures in
72. 21 C.F.R. § 11.10(a). Global and National Commerce Act: The Consumer Consent
Provision in Section 101(c)(1)(C)(ii), available at http://www.
73. 21 C.F.R. § 11.10(a).
ftc.gov/os/2001/06/esign7.htm.
74. 21 C.F.R. § 11(b).
100. 45 C.F.R. pt. 164, subpt. C.
75. 21 C.F.R. § 11(b).
101. P.L. 107-347 (Dec. 17, 2002). For a detailed summary of the
76. 21 C.F.R. § 11.10(d). legislation and additional implementation information, see
Nat’l Inst. of Stds. and Technology, Federal Information
77. 21 C.F.R. 11.10(g). Security Management Act (FISMA) Implementation
Project, available at http://csrc.nist.gov/groups/SMA/fisma/
78. 21 C.F.R. 11.10(e) index.html.
80. 21 C.F.R. § 11.10(j). 103. A copy of the notice (No. NOT-OD-08-032) is available at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-
81. 21 C.F.R. § 11.10(j). 08-032.html.
82. 21 C.F.R. 11.10(k). 104. Ass’n of Am. Med. Colleges, Gp. on Info. Resources,
Consequences of Heightened Dept. of Veterans Affairs Info.
83. 21 C.F.R. § 11.30. Security on Academic Med. Ctrs. (Sept. 2007).
84. 21 C.F.R. § 11.50(a)(1)-(2). 105. State breach notification laws, both current and pend-
ing, can be found at the National Conference of State
85. 21 C.F.R. § 11.50(a)(3).
Legislators website, http://www.ncsl.org/research/
86. 21 C.F.R. § 11.70. telecommunications-and-information-technology/security-
breach-notification-laws.aspx; see also Crowell & Moring,
87. 21 C.F.R. § 11.100(a). State Laws Governing Security Breach Notification, available
at http://www.crowell.com/pdf/SecurityBreachTable.pdf.
88. 21 C.F.R. § 11.70.
CHAPTER 11
1. National Coverage Determination 310.1.
9. 42 USC 1395y(m)(2)(C).
Endnotes 171