VOLUME 9 NUMBER 6
N O V E M B E R –D E C E M B E R 2008
In the News
Applying the federal wide assurance policy to clinical
and social/behavioral research: New questions prompt
changes
Terry Hartnett and John H. Mather, MD, CIP
Education and training preferences
of clinical research managers
Carolynn Thomas Jones, MSPH, RN; Lynda Harrison, MSN, PhD;
Sheree Carter, RN, MSN; and Penelope M. Jester, BSN, MPH, CCRC
ISSUES IN HUMAN SUBJECTS RESEARCH
Participation by women in clinical research
Sue Coons, MA
Regulatory Update
In This Issue
VOLUME 9 NUMBER 6
In the News . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Applying the Federalwide Assurance policy to clinical
and social/behavioral research: New questions prompt changes . . . . . 196
Terry Hartnett and John H. Mather, MD, CIP
When a research institution applies for and accepts federal funding from the Department of Health and Human Services (HHS) to conduct
research studies, it also accepts the inherent responsibility to protect human subjects enrolled in these studies. A written document designated
as a Federalwide Assurance is an agreement signed by institutional officials that demonstrates commitment to the principles of human subjects protection in Federal Regulations 45 CFR 46. This article discusses questions about whether this formal written commitment also should
apply to research that is not funded by HHS but by another federal agency, the appropriate mechanism for protecting all human subjects
enrolled in trials, and whether federal regulations require that institutions formally commit to assure protections for all research participants
regardless of the source of funding. (1.5 nursing contact hours)
Education and training preferences
of clinical research managers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
Carolynn Thomas Jones, MSPH, RN; Lynda Harrison, MSN, PhD;
Sheree Carter, RN, MSN; and Penelope M. Jester, BSN, MPH, CCRC
There is widespread recognition that training and education of clinical research managers are insufficient. This article reviews literature related
to clinical research manager training and education and presents results of a survey to assess perceived education needs and preferences
among clinical research coordinators from a variety of U.S. sites. The survey findings suggest that respondents had a variety of different job
titles and educational backgrounds, consistent with literature reports that there is a lack of clarity about the coordinator role. There also were
wide differences in the types of clinical research training that respondents received. (1.5 nursing contact hours)
Continuing Education .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
ISSUES IN HUMAN SUBJECTS RESEARCH
Participation by women in clinical research . . . . . . . . . . . . . . . . . . . . . 215
Sue Coons, MA
The road for women to participate in clinical research has changed significantly in the last 30 years. Although the number of women participating in clinical studies funded by the National Institutes of Health is about equal to or slightly more than the number of men participating,
excluding those participating in sex-specific studies, this has not always been the case. Still, women’s health advocates say more needs to be
done. Research is needed to better understand the importance of sex-based differences. This article examines women’s health research in the
last 30 years and then provides feedback from women’s health advocates.
Regulatory Update. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Research Practitioner / VOLUME 9 NUMBER 6
Research Practitioner
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Research Practitioner / VOLUME 9 NUMBER 6
Authors
Terry Hartnett
Medical Writer
Pittsburgh, Pennsylvania
John H. Mather, MD, CIP
President
UNI-CORN LLC
Washington, DC
Carolynn Thomas Jones, MSPH, RN,
Clinical Research Consultant, School
of Nursing, University of Alabama
at Birmingham
Lynda Harrison, MSN, PhD
Professor and Co-Deputy Director World
Health Organization Collaborating Center
on International Nursing, School of Nursing,
University of Alabama at Birmingham
Sheree Carter, RN, MSN
Program Director II, Arthritis Clinical
Intervention Program, Department
of Medicine, University of Alabama
at Birmingham
Penelope M. Jester, BSN, MPH, CCRC
Program Director II, NIAID Collaborative
Antiviral Study Group, Department
of Pediatric Virology, University of Alabama
at Birmingham
Sue Coons
Medical Writer
Columbus, Ohio
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Editorial Board
Kay Ball, RN, BSN, MSA, CNOR, FAAN
Nurse Consultant/Educator
K & D Medical Inc.
Lewis Center, Ohio
Paul Bleicher, MD, PhD
Chairman
Phase Forward Inc.
Boston, Massachusetts
Erin Brower, MS, CIP
Director of Operations
New England IRB
Wellesley, Massachusetts
Anna J. DeMarinis, MA, CQA(ASQ), MT(ASCP)SBB
Principal
The DeMarinis Group
North Attleborough, Massachusetts
Lee Ferrell, CCRA, CCRP
Director, Site Start Up
Clinical Operations
Quintiles, Inc.
Research Triangle Park, North Carolina
David Ginsberg, DO
Vice President, Clinical and Medical Affairs
KV Pharmaceutical Co.
St. Louis, MO
Dónal P. O’Mathúna, BS (Pharm), MA, PhD
Senior Lecturer in Ethics, Decision-Making, and Evidence
School of Nursing
Academic Member, Biomedical Diagnostics Institute
Dublin City University
Dublin, Ireland
Mark Parascandola, PhD, MPH
Staff Writer
Washington, DC
Sandra M. Sanford, RN, MSN, CCRC, CIP
Director, Research Subject Protections
George Mason University
Fairfax, Virginia
Judith M. Scheer, SM, RN, CCRC
Chair, Partners Human Research Committee
Massachusetts General Hospital and Brigham & Women’s Hospital
Boston, Massachusetts
Barbara S. Turner, RN, DNSc, FAAN
Professor and Senior Nurse Scientist
Duke University School of Nursing
and General Clinical Research Center
Durham, North Carolina
Janet F. Zimmerman, MS, RN
Senior Director, Training Services
PharmaNet
Princeton, New Jersey
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covered by this CNE program. Ms. Ball is on the speaker’s bureau for AORN. Ms. Carter, Ms. Coons, Ms. Coplin, Dr. Harrison,
Ms. Hartnett, Ms. Jester, Ms. Jones, Dr. Mather, Ms. Sanford, and Mr. Zisson have stated they have no relationships with companies related
to the field of study covered by this continuing education program.
Research Practitioner / VOLUME 9 NUMBER 6
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In the News
Alternative medicine trial suspends recruitment
Investigators in a high-profile randomized clinical trial
designed to test an alternative therapy for heart disease have suspended recruitment of new subjects. The
study evaluates a procedure called chelation as a
potential treatment for atherosclerosis. The most
ambitious government-sponsored alternative therapy
trial to date, the study has been watched closely by
both proponents and critics of alternative and complementary medicine. While the suspension was voluntary, it occurred after the federal Office of Human
Research Protections received complaints from external investigators about the conduct and ethics of the
study.
Chelation involves intravenous injection of ethylenediamine tetraacetic acid (EDTA), a synthetic amino
acid. Chelation has been used since the 1940s to treat
heavy metal poisoning from compounds such as lead,
mercury, and copper. EDTA binds to these metals and
creates a new compound that can be excreted in
urine, thereby allowing the metals to be removed
from the body. EDTA also binds to calcium, which is
one of the components in the deposits that build up
inside the arteries in atherosclerosis. In the 1950s, scientists speculated that EDTA might remove the calcium and promote the breakup of deposits in the arteries. More recently, scientists have proposed other theories to describe the mechanism by which chelation
might treat or prevent heart disease. However, none
of these theories have been rigorously tested in scientific studies. FDA has approved chelation for use in
treating heavy metal poisoning, but not for any other
application.
Nevertheless, some practitioners have been offering
chelation treatments for heart disease. A single chelation treatment session lasts from two to four hours,
and patients receive up to 30 treatments in the first
month. Patients then typically continue preventive
treatments once a month on an ongoing basis. A single
session may cost between $100 and $150. Because
chelation is not a proven treatment, patients normally
pay for the treatment themselves, as insurance compa-
nies and Medicare do not cover it. Chelation therapy
also is not without risk and carries some potentially
serious adverse effects, including bone marrow depression, allergic reactions, and kidney failure.
Currently available evidence is insufficient to determine whether chelation is effective or safe for treating
heart disease. Advocates of chelation point to evidence from case series and testimonials from individual patients to support their claims that chelation benefits patients. However, even if some patients have
improved after treatment, such improvement may be
due to a placebo effect or to other health changes
patients have made. A few controlled clinical trials
were conducted to test chelation during the 1990s,
and all yielded negative results. Yet, it is possible that
these studies were too small to detect a modest effect.
In August 2002, the National Center for
Complementary and Alternative Medicine (NCCAM)
and the National Heart, Lung, and Blood Institute
(NHLBI) announced that they were launching the
Trial to Assess Chelation Therapy (TACT). The 5-year,
$30-million study would be led by Gervasio A. Lamas,
director of cardiovascular research and academic
affairs at Mount Sinai Medical Center–Miami Heart
Institute in Miami Beach, Florida. Lamas has since
moved to the University of Miami Miller School of
Medicine and continues to direct the study. The
announcement cited a “public health imperative” to
study chelation therapy because patients already were
using the therapy despite the lack of evidence of its
effectiveness. Indeed, the press release stated that
more than 800,000 patient visits had been made for
chelation therapy in the United States in 1997,
although this figure includes multiple visits by the
same patients and use of chelation therapy for conditions other than heart disease.
The TACT study aims to enroll more than 2,000 subjects, aged 50 years and older who had a prior heart
attack, at 120 clinics and doctors’ offices across the
United States and Canada. Participants in the study
receive the treatment free of charge and can continue
with any other treatments they are receiving for heart
disease. Subjects are randomized to one of four groups,
including chelation with or without high-dose
vitamin supplements or a chelation placebo with or
without high-dose vitamin supplements. Because
Research Practitioner / VOLUME 9 NUMBER 6
193
chelation practitioners often use high doses of vitamin
supplements as an adjunct to the treatment, the study
is designed to test both the chelation procedure and
the vitamins. Subjects receive a total of 40 infusions,
including one infusion per week for 30 weeks followed
by an additional 10 infusions at longer intervals.
Investigators will track a number of outcomes in the
subjects, including heart attack, stroke, hospitalization
for angina, coronary revascularization, and death. The
study also will assess quality of life and cost effectiveness, and subjects will be followed for up to five years.
So far approximately 1,500 subjects have been
enrolled in the study.
In the meantime, several prominent medical organizations, including the American Heart Association
(AHA), American Medical Association, and American
College of Cardiology, have come out against the
treatment, insisting that there is insufficient evidence
to support its effectiveness and that it may be dangerous. For example, the AHA’s official policy statement
on the issue warns that the organization “finds no scientific evidence to demonstrate any benefit of this
form of therapy. Furthermore, employment of this
form of unproven treatment may deprive patients of
the well-established benefits attendant to the many
other valuable methods of treating these diseases.”
Some of the criticisms also call into question the scientific justification for conducting the study. For
example, the AHA has proposed two conditions that
would need to be met to establish that chelation is safe
and effective. First, they require a demonstration that
EDTA actually can safely remove calcium from arterial
plaque, supporting the hypothesis on which the treatment is based. This would be tested in a small laboratory-based study. Only after this first step would
researchers move on to the second step, a controlled
clinical trial in a large population. The AHA proposal
seems to suggest that TACT investigators skipped a
crucial step by embarking on a large human study
without adequate demonstration of safety and efficacy in the laboratory. They also urge that any such clinical trial must follow a rigorous design and include
adequate oversight from external investigators and
community members.
External investigators also have directly attacked the
study. The most vehement critic has been Kimball C.
Atwood, a practicing anesthesiologist who has made a
194
Research Practitioner / VOLUME 9 NUMBER 6
second career as a critic of alternative medicine. He is
co-editor of a Web site called Naturowatch, described
as a “skeptical guide” to naturopathy, and has advocated against the medical licensure of naturopaths.
Last May, the Medscape Journal of Medicine published a
paper led by Atwood titled “Why the NIH Trial to
Assess Chelation Therapy (TACT) Should Be
Abandoned.” Atwood’s coauthors included Elizabeth
Woeckner, president of Citizens for Responsible Care
and Research Incorporated, a non-profit organization
that advocates for the protection of human research
subjects. The authors, drawing on Freedom of
Information Act requests and court documents along
with other sources, urged that the trial is “unethical,
dangerous, pointless, and wasteful.”
In addition to challenging the scientific basis of the
trial, the authors charged that some of the study investigators are not qualified to serve in that role because of
claims of scientific misconduct, medical board citations, or other questionable activities. They also drew
connections between practitioners of chelation therapy
and previously debunked quack remedies, most notably
Laetrile. And they claimed that the risks involved in the
study have not been adequately communicated to subjects and the public. In particular, they claimed that the
consent form is misleading because it does not
acknowledge prevailing medical opinion that chelation
is ineffective and the lack of a body of basic or clinical
evidence supporting its effectiveness. Indeed, the study
consent form contains several pages of detail on the
study procedures, but relatively little information on
the background rationale for the study or the potential
risks of chelation therapy.
Although the study sponsors did not issue a formal
statement about the suspension, on September 3, the
American College for Advancement in Medicine
(ACAM), an organization representing practitioners of
chelation and other alternative and complementary
therapies, issued a statement. ACAM announced its
support for the decision to suspend patient accrual
pending investigation. ACAM president Jeanne Drisco
stated that “We believe that the Office of Human
Research Protection will find that the allegations are of
a political nature” and called for “a swift end to the
moratorium and resumption of the trial.”
Few details have been released so far about the nature
of the investigation that is underway. The fact that
patients already enrolled are continuing to undergo
treatments suggests that the study leaders and sponsors do not see immediate danger to subjects.
However, the investigation is a reminder of the controversial nature of the study and of clinical tests of
alternative medicine in general. Even if the study
resumes recruitment, it will likely continue to be
watched closely.
News reporting and drug industry sponsorship
Medical journals, scientific conferences, and professional organizations have devoted increasing attention in recent years to industry sponsorship of clinical
trials. Essentially all major medical journals now have
some form of disclosure policy. However, when study
findings are reported in the news media, is information about funding disclosed on a regular basis? A new
study in the October 1 issue of the Journal of the
American Medical Association reports that the news
media often fail to include such information.
Over a period of four years, Michael Hochman at
Harvard Medical School and colleagues reviewed articles from U.S. newspapers and news Web sites reporting on pharmaceutical company-funded medication
studies. They limited their review to news reports of
studies that originally had been published in the five
leading medical journals based on impact factor,
including the New England Journal of Medicine, JAMA,
Lancet, Annals of Internal Medicine, and Archives of
Internal Medicine. All of these journals have written disclosure policies that would require industry funding to
be disclosed in the published paper.
funding sources for industry-sponsored studies. Most
(77%) also insisted that their publications referred to
drugs by their generic names. However, only 3% of
newspapers had a written policy requiring disclosure
of industry funding and only 2% had a policy requiring use of generic names when available.
These results suggest that news media currently do not
adequately communicate information about industry
funding of drug studies being reported to readers. This
observation warrants concern, because the practice of
disclosing funding information and other information
about potential conflicts of interest is based on the
expectation that readers should have this information
available when reading about research findings. While
the presence of industry funding does not necessarily
weaken the study, this information is disclosed to
readers so that they can make their own assessment of
the validity of the study authors’ conclusions.
Additionally, the failure to regularly report funding
information may, over the long term, mislead readers
to believe that few therapeutic studies are funded by
pharmaceutical companies, which could actually
make them excessively suspicious of studies where
industry support is disclosed. Improving public understanding of the nature of the medical research enterprise will be of benefit to all, including researchers,
sponsors, and the public.
Mark Parascandola, PhD, MPH
Staff Writer
Of 306 news articles the investigators identified, they
found that fewer than half (42%) reported that the
research had been supported by a pharmaceutical
company. The researchers also looked at whether news
articles referred to drugs under their generic or brand
names. They found that of those articles reporting on
drugs available in both forms, most (67%) identified
the drug by brand name rather than the generic name.
The researchers also surveyed editors at 100 newspapers with the greatest circulation to assess their policies and practices related to reporting of pharmaceutical industry-funded studies. In conflict with the analysis of actual news reports, most editors (88%) maintained that their articles usually or always disclosed
Research Practitioner / VOLUME 9 NUMBER 6
195
Applying the Federalwide Assurance policy
to clinical and social/behavioral research:
New questions prompt changes
Terry Hartnett and John H. Mather, MD, CIP
When a research institution applies for and accepts federal funding from the Department of Health and Human
Services (HHS) to conduct research studies, it also accepts the inherent responsibility to protect human subjects
enrolled in these studies. A written document designated as a Federalwide Assurance (FWA) is an agreement
signed by institutional officials that demonstrates commitment to the principles of human subjects protection in
federal regulations 45 CFR 46. Questions have recently arisen about whether this formal written commitment
also should apply to research that is not funded by HHS but by another federal agency. Within the past year,
the Department of Defense has implemented an addendum to the FWA for all research sponsored by a
Department of Defense branch/component. What is the appropriate mechanism for protecting all human subjects enrolled in trials? Do federal regulations require that institutions formally commit to assure protections for
all research participants regardless of the source of funding?
meant that any alleged violation of the
regulations could result in temporary or
longer suspension of that institution’s
assurance and, therefore, possibly its
entire research program.
In the past decade, the number of institutions that have “checked the box (electing
to apply HHS regulations to all research) in
the FWA filing has decreased significantly.
Key words: checklist, Common Rule, Federalwide Assurance, human subjects protection, subparts B,
This is a legal option. For many instituC compliance
tions, the choice is based on interpretation
of the regulations. For example, applying
A core ethical and legal principle of any research study
the assurance to subpart B of the regulations presents
involving the direct participation of human subjects
a possible requirement to do a pregnancy screening for
must be the protection of the subjects from any harm
all women involved in non-biomedical research. This
or undue risk. Human subjects protection regulations
is based on the requirement that pregnant women
in the United States are based in large part on the
cannot be enrolled in research unless there is direct
Belmont Report, published in 1979. The federal regulabenefit to the woman or the fetus. Therefore, strict
tions grew out of abuses such as medical experiments
interpretation would require screening.
conducted by the Nazis on non-German nationals,
The majority of institutions that currently hold an
including Jews and “asocial” persons during World
FWA no longer choose to apply it to all studies. A sepWar II, and the “United States Public Health Service
arate dilemma has arisen within the Department of
Syphilis Study” conducted in Alabama beginning in
Defense (DoD). Recently, DoD implemented a new
1932 and continuing until 1972.
requirement that an addendum to the FWA be signed
The Federalwide Assurance (FWA) process is the
by an institution that chooses to accept DoD funding.
enforcement mechanism created by the Department
The addendum is a tool used to ensure that the instiof Health and Human Services (HHS) to assure comtution understands that accepting DoD funding
pliance with the regulations governing HHS-funded
requires a commitment to adhere to key additional
research (45 CFR 46). The former Office for Protection
human subjects protection requirements established
from Research Risks (OPRR) and now the Office of
by the individual DoD components. The Department
Human Research Protections (OHRP) requires this
of the Navy (DON), for example, has used the addenwritten commitment for any research that is funded
dum since March 2006. The DON addendum highby HHS. For many years, most research institutions
lights key additional requirements. All of the top-level
voluntarily agreed to apply this commitment to all
requirements from the 11 DoD components are being
human subjects research regardless of the funding
harmonized into a common addendum that will be
source. This gave the government (OPRR/OHRP)
completed by the end of 2008.
authority over all research at that institution and
196
Research Practitioner / VOLUME 9 NUMBER 6
Hartnett and Mather / Applying the Federalwide Assurance policy to clinical and social/behavioral research
History of the assurance process
The federal government created its initial assurance
program in 1991.1 At that time there were two types of
assurances—the Single Project Assurance (SPA) and the
Multiple Project Assurance (MPA). The MPA was the
most common and was applied “during fixed and
renewable periods to a broad spectrum of unrelated
research activities.” The SPA was for a specific HHS
research-funded activity at a performance site where
an MPA or other assurance amendment did not apply.
The Inter-Institutional Amendment applied in the situation in which one site for the research did not have
an Institutional Review Board (IRB) to oversee the
study. The Cooperative Project Assurance Amendment
applied to multi-protocol, multi-site research. SPA and
MPA filings were signed by a single signatory institution or jointly by two or more institutions and in the
majority of sites elected to comply with all subparts of
45 CFR 46 and the Common Rule.
Ivor Pritchard, the current acting director of OHRP,
explains that the MPA and SPA system became an
overwhelming burden for both the institutions and
the government, with more than 500 MPAs and
numerous SPAs. The goal of the FWA—first created in
2000 and modified in 2002—was to allow institutions
to use one assurance for all federally funded research.
The assurance serves three general purposes:
1. It gives OPRR/OHRP information about the institution (the makeup of the IRB, background and
number of members, and contact information for
signatory officials).
2. Most importantly, says Pritchard, it commits the
institution to having and following policies and
procedures to protect human subjects who enroll
in research. It requires the IRB and others, including the investigator, to report any breach of these
internal policies.
3. It serves as the instrument through which the
government exercises its oversight and enforcement mechanism.
OHRP currently has 7,790 active domestic (U.S.) FWAs.
Section 4 of the assurance is titled “Applicability” and
includes the optional “checkbox.” It states:
This Institution elects to apply the following to
all of its human subjects research regardless of
the source of support, except for research that is
covered by a separate assurance:
[ ] The Common Rule (department and agencies
of the federal government that have adopted the
Common Rule and its applicability to the Code
of Federal Regulations).
[ ] The Common Rule and subparts B, C, and D
of the HHS regulations at 45 CFR part 46.
Of the active domestic FWAs, 2,567 currently check
neither of these options; 2,439 check the first option
only; 2,784 check both boxes.
Pritchard says the checkbox is an outgrowth of the
prior assurance. When the regulations initially were
established, he says, they applied only to Department
of Health Education and Welfare (the former name of
HHS) supported activities, grants, and contracts. In
1970, the National Commission for the Protection of
Human Subjects of Biomedical and Behavioral
Research published a report on various aspects of
human subjects protection that included the recommendation that all research be covered under the
assurance process regardless of the source of funding.
“There was a great deal of pushback from the field
regarding the burden this posed, and HHS backed off
in 1981,” says Pritchard. “Since then, there has been
an ongoing debate back and forth about whether the
assurance should apply to all research or only HHSfunded research.” Institutions protect human subjects
in their research because it is the “ethical thing to do,”
not because of any federal requirement or because of
the source of funding, says Pritchard. “For this reason,
we decided to give institutions the choice,” he adds.
Why are institutions changing their option?
Throughout the 1990s, the percentage of institutions
checking one or both boxes was at 75% or higher. The
rate of compliance with regulations was likewise high.
Throughout the decade, OPRR suspended an assurance only four times. A number of prestigious academic medical centers with large research programs
were either shut down temporarily or severely reprimanded for suspected breaches of oversight during a
period of heightened enforcement. OPRR’s actions
jeopardized millions of dollars in federal research
grants to these academic institutions. The mainstream
Research Practitioner / VOLUME 9 NUMBER 6
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Applying the Federalwide Assurance policy to clinical and social/behavioral research / Hartnett and Mather
media covered these shutdowns and the institutions
involved suffered a loss of public respect.
The increasing oversight climate of OPRR/OHRP may
have been the initial impetus behind the institutional
shift in the view of checking the box for all research.
Why invite OHRP scrutiny and perhaps media attention when it is not a requirement? Why spend hours
talking to HHS officials when the problems can be
handled internally? Yet, many institutions have chosen to mark the box pertaining to the Common Rule.
Sentiments about too much government oversight are
far outweighed by another over-arching one:
Institutional policies and procedures to protect
research subjects should be the same regardless, and
many institutions that have revisited the question on
the FWA form in the past five to 10 years say that
nothing has changed in their daily practice. There
should be no double standard.
There are no right or wrong choices when applying
the FWA. Institutions that opt not to check the box
must be vigilant about their institutional policies and
procedures to protect human subjects and may want
to consider additional internal reporting requirements. Regardless, institutional officials should be
mindful of the implications of both applying and not
applying the assurance to all federally funded studies.
Some research professionals who are responsible for
human subjects protection at their institutions say that
checking the box may no longer be the best option for
their institution for several important reasons:
1. Subpart B requirements. Subpart B—Additional
Protections Pertaining to Research, Development, and Related Activities Involving Fetuses,
Pregnant Women, and Human in vitro
Fertilization outlines regulations regarding pregnant women as subjects (45 CFR 46.207). The
regulations state, “No pregnant woman may be
involved as a subject in an activity by this subpart, unless: (1) the purpose of the activity is to
meet the health needs of the mother, and the
fetus will be placed at risk only to the minimum
extent necessary to meet such needs, or (2) the
risk to the fetus is minimal.” If the institution
checks the second box stating its intention to
apply the regulations to subpart B, it can then be
found in non-compliance if it enrolls a pregnant
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Research Practitioner / VOLUME 9 NUMBER 6
woman unknowingly in any research study that
does not offer direct benefit. Most social and
behavioral studies do not meet this criteria.
Therefore, strict interpretation of this section of
the regulations would mandate a screening for
pregnancy for most social and behavioral
research. Some institutions say this juxtaposition
has led them to uncheck the second box because
it would make most social/behavioral studies
much more burdensome, if not impossible, to do.
Checking the first box and applying this requirement for pregnancy testing to the Common Rule
would refer only to studies funded by agencies
like the DoD and Department of Veterans Affairs
(DVA) that apply the Common Rule, in addition
to HHS-funded studies.
OHRP’s director of the Office of Policy and
Assurances, Irene Stith-Coleman, explains the
agency’s position: “OHRP has taken the general
stance that when an IRB reviews research that will
involve women of childbearing potential, the IRB
does not routinely need to review the research in
accordance with the requirements of subpart B,
unless it is known that pregnant women will definitely be included as subjects. Furthermore, it is
OHRP’s position that the HHS regulations at subpart B do not require routine screening of female
subjects for pregnancy prior to enrolling them in
social and behavioral research. However, if during
the conduct of the study, an investigator learns
that a research subject is pregnant and the
research was not reviewed and approved by the
IRB in accordance with the provisions of subpart
B, the investigator should promptly notify the IRB
of this, and in general, all research interactions
and interventions with, and obtaining identifiable private information about, the pregnant
woman-subject must cease until the requirements
of subpart B have been satisfied, except in circumstances in which it is in the best interest of
the subject to remain in the research study.”
2. Subpart C requirements. Subpart C—Additional
Protections Pertaining to Biomedical and
Behavioral Research Involving Prisoners as
Subjects outlines specific criteria for enrolling
prisoners in biomedical or social/behavioral
research (45 CFR 46.306 (2)) Some research
Hartnett and Mather / Applying the Federalwide Assurance policy to clinical and social/behavioral research
professionals worry that the prisoner regulations
were written before changes in the penal system,
such as halfway houses and electronic monitors,
and before the advent of HIV/AIDS. There are
many unanswered questions, for example, about
appropriate steps to take when a prisoner in an
HIV/AIDS study who has been under electronic
surveillance is arrested for driving under the
influence and is temporarily incarcerated. The
regulations do not address whether the prisoner
must be dropped from the study at this point
because oversight has changed. Because the regulations are subject to wide interpretation at this
time, it may be judicious not to check the second
box and thus opens the institution to scrutiny on
subpart C compliance.
3. Sites “engaged in research.” Subpart A applies
regulations to any sites deemed to be “engaged in
research.” According to OHRP guidance, there are
two criteria that meet this definition.2 First, the
institution must “obtain data about living individuals for research purposes through intervention or interaction with them” or “obtain individually identifiable private information for
research purposes.” OHRP further adds that, “An
institution is considered to be engaged in human
subjects research whenever it receives a direct
HHS award to support such research, even if all of
the human subjects activities will be performed
by agents or employees of another institution.
When the direct awardee institution subcontracts
all human subjects activities to another institution, the direct institution would still be considered engaged in research. The awardee institution
bears the ultimate responsibility for protecting
subjects involved in the research conducted
under the award. Seeking or obtaining informed
consent from a research participant is considered
engagement in research.”
Strict interpretation of this definition and
OHRP’s guidance would suggest that social and
behavioral studies cannot be conducted in
schools unless the school has an IRB to conduct
continuing review and oversight. This could
potentially limit the institution’s ability to do
school-based research.
4. Accreditation requirements. Since the
advent of accreditation for human subjects protection programs five years ago, the Association
for the Accreditation of Human Research
Protection Programs (AAHRPP) has accredited a
significant majority of medical schools, researchintensive universities, and DVA facilities in the
United States. According to AAHRPP’s Executive
Director Marjorie Speers, there are 138 accredited
programs to date, representing more than 620
parent organizations and hundreds more in the
pipeline. Development and implementation of
policies and procedures to assure human subjects
protection for all research subjects regardless of
funding source is a requirement for accreditation.
The human research protection program must
have equivalent protection program/policies.
Accreditation standards also require that an evaluation regarding human research protections be
made for all exempt studies. Institutions are more
comfortable with a decision to uncheck the box,
says Speers, because of accreditation. “Protecting
human subjects is an ethical obligation regardless
of the funding source,” says Speers. “The FWA is
simply a relationship between the institution and
OHRP. It is a pledge to follow the federal regulations but it is not a guarantee of ethical behavior,” she adds.
Some institutions have added their own requirements such as reporting any unanticipated problems in a study in a summary form to the university or hospital president. If an institution is
performing due diligence and is cognizant of the
need for ongoing oversight, there should be little
if any difference in institutional behavior regardless of whether officials decide to check or
uncheck the box(es) on the FWA application.
However, if institutional oversight/policies and
procedures are lacking or insufficient, OHRP may
write a finding of non-compliance across all programs. One human research protection professional puts it this way: “If you have mud on your
face, you look bad to the government and to the
public regardless of whether you have checked
the FWA box.” The bottom line is that institutions must manage their own risk.
Research Practitioner / VOLUME 9 NUMBER 6
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Applying the Federalwide Assurance policy to clinical and social/behavioral research / Hartnett and Mather
5. Ethical behavior. Research institutions now
have more knowledge and capacity in research
compliance than in the past. They know what
the regulations require and what ethical behavior
demands. The ethical obligation to protect subjects should be inherent in the institution’s culture and not tied only to the symbolic marking of
a check off box on a federal form. Some institutional officials say that they prefer to spend more
time thinking and acting on human subjects protections than on the FWA document.
Defense Department addendum(s)
The DoD is like all other federal agencies in that it follows the same basic requirements for human subjects
protection listed in the Common Rule. In some
instances, separate components have initiated their
own additional requirements. According to Patty
Decot, assistant director for Regulatory Affairs and
International Biosystems Programs, Office of the
Deputy Undersecretary of Defense (Science and
Technology), the addendum itself is not a requirement
but rather a “tool to communicate with grantees about
these additional requirements.” Decot says DoD needed a way to inform grantees about the individual
requirements to prevent delays in the study due to a
need to conform to the requirements (e.g., rewriting
the protocol).
The DoD used the DVA addendum as a model for its
addendum. It might be noted here that the DVA
adopted the FWA as promulgated by OHRP in 2001
and expects the box to be checked. The research at the
DVA, generally considered an intra-mural program as
no external grants are made to investigators outside of
DVA, only relates to subpart A (the Common Rule)
and does not extend to subparts B, C, and D.
The DON requires any institution that receives its
funding to agree to the DON addendum. Currently
120 research institutions have signed the DON addendum.
There are additional requirements in these areas:
• Initial and continuing research ethics training for
all personnel who conduct, review, approve,
oversee, support, or manage human subjects
research
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Research Practitioner / VOLUME 9 NUMBER 6
• Written documentation by a designated official
(other than the investigator) whether research
meets criteria for exemption
• New research protocols and substantive amendments to approved research must undergo scientific approval prior to ethics (IRB) review
• Procedures for addressing conflicting and competing interests
• Provisions for research-related injury
• Additional protections for military research subjects to minimize undue influence
• Additional protections for pregnant women, prisoners, and children
• Additional safeguards for research conducted
with international populations
• Limitations on research where consent by legally
authorized representatives is proposed
• Limitation on exceptions from informed consent
in emergency medicine research
• Additional review for U.S. Navy-wide survey
research
• Requirements for reporting unanticipated problems, adverse events, and research-related injury
• Oversight by the DON human research protection program through headquarters-level review
of research protocols (including relevant IRB
meeting minutes) after local institutional
approval and site visit by the institution’s human
research protection program
• Recordkeeping requirements
• Addressing and reporting allegations of noncompliance with human research protections
• Addressing and reporting allegations of research
misconduct
• Provisions for research with human subjects
using investigational test articles (drugs, devices,
and biologics)
• Prohibition of research with prisoners of war and
detainees
• Classified research
Decot says the new addendum currently being developed will have two sections—one on DoD require-
Hartnett and Mather / Applying the Federalwide Assurance policy to clinical and social/behavioral research
ments (Directive 3216.02) and one covering requirements of the 11 DoD branches/components. The institutional official who signed the original FWA also
must sign the addendum.
Historically, when OHRP or DoD has a report of noncompliance or an adverse event in a trial sponsored by
both HHS and DoD, OHRP will send a letter to the
institutional official requesting information. If the
study in question is not funded by HHS but by DoD
alone, DoD will take over the investigation. If the
problem is found to be systemic and not tied to a singular protocol, DoD may refer the complaint back to
OHRP for further review.
Decot says that DoD follows all subparts and therefore
not checking the FWA box pertaining to the subparts
would mean that the institution does not formally
agree to comply with DoD regulations. She says that
new language will be added to the revised DoD addendum that will allow pregnant women to participate in
more types of research funded by DoD. If a universitybased researcher wants to collect information from a
DoD school or the DoD school system, DoD regulations would not consider the school(s) as “engaged” in
research. The study protocol must be approved by
school officials, but the school itself would not need a
separate assurance, says Decot.
DoD regulations for human subjects protection also
require that a monitor be appointed to observe critical
phases of a research study that is deemed greater than
minimal risk by the reviewing IRB. The regulations
currently refer to this as a “medical monitor,” but the
wording will be changed to “research monitor” with
the new harmonizing addendum to cover social and
behavioral research in all DoD-funded studies. The
role of the monitor is to mitigate any research risk to
the subjects enrolled in the study. In a social and
behavioral study, the risk may be in recruitment or
data handling and this must be monitored as well.
Decot says the DoD has a three-pronged strategy for
communicating with research institutions regarding
regulations governing human subjects protection: (1)
work with the IRB and principal investigator(s), (2) use
the addendum, and (3) create a new standard clause in
the contract for the study that covers the DoD requirements, including specific requirements by components of DoD such as the DON. This new clause is in
the development stages and will be published in the
Federal Register for public comment by the end of year.
Summary and conclusion
Overall, institutions should make an individualized
determination of how best to apply the assurance to
their own research. As a matter of note, if an institution
decides to stop checking the box, it should be aware
that OHRP retains oversight authority for any research
that began when the box was checked. According to
Stith-Coleman, “If a domestic institution voluntarily
chooses to apply subparts B, C, and D of 45 CFR part
46 to all research regardless of support by checking the
second option under section 4(b) of the FWA form,
OHRP expects that the institution will comply with all
requirements of subparts B, C, and D for all nonexempt research involving human subjects in which
the institution is engaged. In such circumstances,
OHRP has the authority to enforce compliance by the
institution with this commitment for all research to
which the FWA applies that is not federally conducted
or supported. If an institution checked the box on its
FWA form voluntarily extending the Common Rule
and subparts B, C, and D to all research regardless of
support and then un-checks the box, OHRP retains
authority to evaluate allegations of noncompliance
related to non-federally supported research that was
conducted at the institution during the time period
when the FWA did apply to such research.”
References
1
2
Office for Protection from Research Risks. Sample language for a Department of Health and Human Services
multiple project assurance for compliance with DHHS
regulations for the protection of human subjects (45
CFR 46) in accordance with the federal policy. Available
at: www.hhs.gov/ohrp/humansubjects/assurance/
mpa.htm#preface. Accessed October 29, 2008.
Department of Health and Human Services. Guidance on
Engagement of Institutions in Human Subjects Research.
Available at: www.hhs.gov/ohrp/humansubjects/guidance/engage08.html. Accessed October 29, 2008.
Research Practitioner / VOLUME 9 NUMBER 6
201
Education and training preferences
of clinical research managers
Carolynn Thomas Jones, MSPH, RN; Lynda Harrison, MSN, PhD; Sheree Carter, RN,
MSN; and Penelope M. Jester, BSN, MPH, CCRC
There is widespread recognition that training and education of clinical research managers (CRMs) are insufficient. This article follows up a previous article focused on issues in CRM education and training,1 and includes a
literature review and results of a survey to assess perceived education needs and preferences among clinical
research coordinators personnel from a variety of U.S. sites. The authors of this paper use the term “Clinical
Research Manager” for consistency throughout the paper, acknowledging that there remains a lack of clarity in
defining the role and differentiating the many titles that are currently in use. The survey findings suggest that
respondents had a variety of job titles and educational backgrounds, consistent with literature reports that there
is a lack of clarity about the coordinator role. There also were wide differences in the types of clinical research
training that respondents received. Respondents preferred training programs that are flexible, accessible, and
affordable, and were highly interested in distance-learning courses. Respondents also identified content that
they would find most valuable to their roles in categories related to ethical and cultural issues, research management, research methods, regulatory processes, and other clinical and professional topics. The purpose of this
article is to present a brief review of literature related to CRM roles and educational preparation, and to present
findings from an online survey to identify education and training preferences of research coordinators in the
United States.
this paper, CRM is used as a term for the
wide range of titles represented by the
coordinators described in the literature
and respondents to the survey.
Additionally, the authors of this paper
define a CRM as the person who assumes
overall responsibility for coordinating the
implementation of a clinical study.
Responsibilities also include management
and sometimes development of study protocols, preparing Institutional Review
Board (IRB) proposals, overseeing participant recruitment and retention, data colKey Words: clinical research coordinator, clinical research education and training, clinical research manager, core
lection and management, and assisting
competencies, education, study coordinator certification, training
with analysis and dissemination of results.
The CRM is responsible for ensuring that
the study conforms to national and interThe contributions of clinical research managers
national guidelines and regulations. In addition to
(CRMs) are critical to the success of clinical research.
ongoing confusion about the various CRM job titles
Ehrenberger and Lillington2 noted that as the number
and roles, the skill sets and specific educational prepaand complexity of clinical trials is increasing, it is
ration for CRMs remain nebulous.
essential to ensure that these trials are completed the
right way (consistent with protocols), at the right
Review of literature
time, by the right specialists, and consistent with
guidelines of the FDA and Department of Health and
Anderson noted that various groups have recomHuman Services3,4 and Good Clinical Practice (GCP)
mended the scope of the role and standards of practice
guidelines of the International Conference on
for study coordinators, including professional clinical
Harmonization.5 Shamoo and Resnik noted increasing
research organizations (CRO), university programs,
levels of scientific, legal, institutional, financial, and
and industry sponsors.7 Although there is no consenethical issues that required principles of leadership
sus about certification requirements for the CRM role,
and moral integrity of clinical research coordinators to
as many as 12,000 clinical research coordinators
fulfill their overarching responsibility to assure the
worldwide have passed the Association of Clinical
quality and integrity of studies.6 Because of the wide
Research Professionals (ACRP) certification exam since
range of management roles that culminated in the
it was initiated in 1992,8 and more than 5,600 have
application of daily ethical decision-making, they utipassed the Society of Clinical Research Associates
lized the term “clinical research manager” as an over(SoCRA) since 1995.9 Those persons taking either the
arching term for study coordinator. For the purpose of
ACRP or SoCRA certification exams were required to
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Research Practitioner / VOLUME 9 NUMBER 6
Jones, Harrison, Carter, Jester / Education and training preferences of clinical research managers
meet parameters set forth by the qualifying organizations including: membership to the organization and
documentation of training, education, and/or specific
numbers of years of experience in the field of coordinating clinical research. Examinees were charged a fee
for the exam with requirements for continuing education and additional fees for renewal of certification
status. Examinees for either organization may come
from a variety of backgrounds ranging from physicians, biology majors, psychology majors, allied
health professionals, nurses, and data entry technicians. While being a registered nurse is not always prerequisite for employment in all CRM positions, many
CRMs in the United States are registered nurses. Mori
et al. noted that there is no certification exam specific
for clinical research nurse specialists, and they proposed that the American Nurses Credentialing Center
develop such an exam as a means to achieve standardized accountability and improve patient care and
clinical research.10
In 2003, a group of educators representing seven institutions in the United States and Australia formed the
Consortium of Academic Programs in Clinical
Research (CoAPCR), with support from the Drug
Information Association (DIA). The mission of the
CoAPCR is to “facilitate the development of highquality educational programs encompassing all areas
of clinical research that are based in academic creditgranting institutions.”11 The Consortium now has
members representing 14 universities and research
organizations in the United States, the United
Kingdom, and the Netherlands. At the 44th DIA
Annual Meeting held in 2008 in Boston, representatives from the Consortium proposed core competencies for all levels of professionals involved with clinical research (including principal investigators, ethicists, pharmacologists, biostatisticians, research
administrators, and research coordinators). The longterm goal is to use these competencies as a basis for
identifying the specific defined knowledge base for
each of the members of the clinical research team
within nine areas to guide development of educational programs and certification requirements for different clinical research professionals. The competency
areas include:
1. Knowing the process of drug development
2. Recognizing research questions
3. Understanding measurement and study design
4. Conducting ethically responsible research
5. Knowing applicable regulatory law
6. Understanding data analysis and data management
7. Knowing clinical operations, good clinical practice, and project management
8. Scientific communication
9. Teamwork, management, and leadership12
The CoAPCR stressed during 2008 DIA presentations
that competencies are outcomes linked to workforce
needs. The nine core competencies are illustrated in
Figure 1 in a wagon-wheel diagram, illustrating the
reliance on each competency for a fully reliable skillset. Lack of aptitude or performance in any of these
areas could derail the site’s clinical research effort,
affecting quality, efficiency, integrity, and ethics. Each
defined role in the research team would reflect measurable knowledge, minimal skills, and attitudes in
each competency area to effectively participate.12 This
approach allows for a multidisciplinary approach to
acquire higher levels of learning and experience, from
novice to expert professional. Using this model, specific job description levels could be based on competency measures and expected outcomes. Effective educational programs adopting this model would therefore set curricula accordingly. A long-range goal of the
CoAPCR is to form accreditations “to codify the
knowledge base of the profession and identify its content at the various academic levels of instruction (e.g.,
baccalaureate, post-baccalaureate, master’s, and doctorate).”13 It seeks membership and active consensus
among those institutions offering courses of study for
study coordinators at the certification, undergraduate,
and graduate levels.
Despite these disparate efforts to clarify the roles and
responsibilities of the CRMs, there is little consensus
about the role or educational requirements within the
United States and globally. For example, in one study
of clinical research nurses in England, only 72%
reported that they had a job description and 50% of
those who had job descriptions reported that the
descriptions did not accurately reflect their duties.14
Raja-Jones noted a similar lack of clear definition
of the CRM role in the United Kingdom, and noted
Research Practitioner / VOLUME 9 NUMBER 6
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Education and training preferences of clinical research managers / Jones, Harrison, Carter, Jester
Figure 1. Core Competencies of Clinical Research Roles (Consortium of Academic Programs in Clinical Research)
Teamwork,
management, and
leadership
Knowing
process
of drug, device
development
Recognizing
research
questions
Scientific
communication
Understanding
measurement
and
study design
Core Competencies
in Clinical
Research Roles
Conducting
ethically
responsible
research
Knowing clinical
operations, GCPs,
and project
management
Understanding
data analysis
and data
management
similarities between the scope of practice of research
nurses and clinical nurse specialists, since the role
encompassed roles of practitioner, researcher, and educator with a high degree of autonomy.15 However,
Raja-Jones noted that clinical research nurses often
feel unprepared for their roles.
The terms “study coordinator” or “research manager”
often are used to refer to a variety of professionals who
contribute to the clinical research enterprise, including research nurses, clinical research managers, project
managers, and clerical data entry personnel. The CRM
role may include a wide range of responsibilities and
require different skills depending on the unique needs
of individual studies.14 Responsibilities may include
assisting with literature review and development of
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Research Practitioner / VOLUME 9 NUMBER 6
Knowing
applicable
regulatory
law
study protocols; obtaining IRB or Ethics Committee
approval for the study; recruitment and retention of
study participants; advocacy education; management
and coordination of the research team; budgetary
responsibilities; maintaining study protocols, standard
operating procedures, and quality control; adhering to
good clinical practice guidelines; and assisting with
data management, analysis, and dissemination of
study results. Nurses who function in the CRM role
also may have additional responsibilities related to
specific nursing care such as gaining cooperation from
nursing staff for the conduct of trials in clinical settings, assessing the health status and responses of
study participants to treatments, collecting laboratory
specimens, administering medications or treatments,
and providing appropriate follow-up and treatment
Jones, Harrison, Carter, Jester / Education and training preferences of clinical research managers
for untoward reactions to interventions.2,10,14,16-19
Raja-Jones noted a similar lack of clear definition of
the CRM role in the United Kingdom, and noted similarities between the scope of practice of research nurses and clinical nurse specialists, since the role encompassed roles of practitioner, researcher, and educator.15
Although many commercial educational materials are
available to help CRMs learn about good clinical practice guidelines and other aspects of the CRM role,
there is a need for more structured and ongoing educational programs to help coordinators apply these
guidelines in actual practice.20 Numerous authors
have identified the need to develop more educational
and training opportunities for CRMs. Roberts et al.
reported results from a survey examining positive and
negative aspects of the CRM role from 49 nurses in
Australia and New Zealand who were members of an
ICU Research Coordinators Interest Group (RCIG).21
Negative aspects of the CRMs’ role cited by participants in the ICU RCIG were the lack of training opportunities, the difficulty in knowing what they should
be doing, and the perception that they were primarily
responsible for the success or failure of the research
projects. Hill and MacArthur surveyed clinical research
nurses in England and found that only 50% of the 72
respondents had received training for their specific
responsibilities.14 Similar findings were reported by
Anderson, who surveyed 55 study coordinators working in gene therapy trials supported by the National
Institutes of Health and other major sponsors.7 Most
had learned their responsibilities on the job; 25%
reported that they were dissatisfied with the orientation they had received for their roles; and 50% indicated that the orientation was, at best, “casual.”7 A
total of 92.7% of these respondents perceived that
continuing education for their roles was necessary.
Spilsbury and colleagues conducted a qualitative focus
group study with nine clinical research nurses in
England and found that these nurses reported a lack of
confidence in their roles, reported conflict between
their roles as researchers and nurses, and noted the
need for training and support to meet the multiple
demands of the clinical nurse researcher role.22 Carter
et al. reviewed available CRM educational programs in
the United States and noted wide diversity across programs in terms of content, length, cost, and requirements.1 These writers concluded that coordinated
consensus regarding the need for and content of formal CRM educational offerings by leadership from
individual clinical research sites, research sponsors,
and academic institutions is needed.1
Methods
Because of the lack of consensus about the CRM role
and educational requirements, in planning for development of a certificate and master’s degree program
for clinical research management and coordination,
we conducted a descriptive survey of clinical research
coordinators in the United States to identify their job
titles, previous training, and preferences for future
education and training. We used a convenience sampling technique of study coordinators, managers, and
study staff working in a variety of settings across the
United States. The study was approved by the IRB of
the University of Alabama at Birmingham (UAB). Two
methods were used to recruit survey participants. We
sent an invitation to participate through e-mail and email listservs. This included CRMs within the
Birmingham, Alabama, area (UAB study personnel,
local private practice, and corporate research sites) and
CRMs throughout the United States. National contacts
came from a variety of sources including: CRO contacts, lists of research contacts who worked at General
Clinical Research Centers (GCRCs), the National
Institutes of Allergy and Infectious Disease (NIAID)
Collaborative Antiviral Study Group multicenter study
sites, the NIAID Bacterial and Mycoses Study Group
multicenter study sites, and members of the
Southeastern chapters of the ACRP. The second
method was to ask all contacts to forward this invitation to other CRMs and clinical research staff to broaden the reach. The invitation letter explained that the
purpose of the study was to identify training and educational preferences of CRMs, and invited recipients to
log onto an Internet site to complete an online survey.
Completion of the survey took 20-30 minutes, and a
total of 167 responses were received between March
and May 2007. Because of the nature of the sampling
technique used, it is not possible to determine how
many coordinators received the invitation to participate in the study. We recognize that this sample may
not be representative of all CRMs in the United States.
A primary purpose of our needs assessment was to
Research Practitioner / VOLUME 9 NUMBER 6
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Education and training preferences of clinical research managers / Jones, Harrison, Carter, Jester
identify needs for an educational program in a school
of nursing; therefore, we sent our survey invitation to
many groups that included primarily nursing study
coordinators or CRMs. Because of our interest in offering certificate courses to persons from other disciplines, we included non-nurse study staff and also sent
our survey to members of the Southeastern chapter of
the ACRP and CRO contacts, which includes members
of other disciplines as well.
Findings
Job Titles and Educational Preparation. Seventy-nine
percent of the study coordinators surveyed indicated
that they were licensed health care professionals.
Among those, 90% were nurses. The highest educational levels represented in the survey were bachelor’s
(47%) and master’s (27%) degrees. Only 7% of respondents had fewer than one year of clinical research experience, and the remaining respondents averaged nine
years of clinical research experience. Most (90%)
respondents were currently working in clinical research
roles. Participants reported a wide variety of job titles.
Table 1 illustrates the numbers of participants reporting different job titles; participants reported 72 different titles, illustrating the current level of ambiguity and
lack of clarity in the different roles in clinical research
coordination nationally.
Previous Clinical Research Training. Only 35% of
respondents indicated that they had clinical research
certification by the ACRP or SoCRA. All respondents
indicated that their primary method of job training
was “on-the-job training” by the principal investigator
or other study coordinators. The secondary methods
of training included: professional meetings/conferences (67%), institutional workshops/seminars (56%),
self-study with books or journals (58%), pharmaceutical company presentations/seminars (34%), Internet
self-study (32%), and audiovisual conferencing (27%).
Two respondents indicated that they received formal
training through a non-credit college course. A single
respondent indicated having a post-master’s certificate
in clinical research from a U.S. university.
Interest in Continued Education. A majority of
respondents (86%) indicated that they were motivated
to continue their education in clinical research at this
time. A third of respondents (34%) indicated that
206
Research Practitioner / VOLUME 9 NUMBER 6
continued education would include doctoral studies.
Types of clinical research education programs desired
by respondents are ranked in Table 2, with an average
to high level of interest across programs. The survey
tool listed a wide range of course topics based on available curriculum from ongoing clinical research coordinator programs. Respondents were asked to rate their
level of interest in each topic on a 5-point scale (1= no
interest, 5 = great interest). Specific topics of interest
cited by respondents fell into five major categories:
1. Research management
2. Research methods
3. Regulatory affairs
4. Ethical and cultural issues
5. Clinical/professional topics
These topics and are listed in Table 3 in order of mean
preference scores. Most topics received a score greater
than 3.0, illustrating general interest in most of the
listed topics. The majority of individuals preferred
receiving academic credit for courses taken. There was
great interest in master’s programs—72% in non-nursing and 62% in nursing graduate programs. There was
also a strong interest in a post-bachelor’s academic certificate in clinical research (64%). Participants also
rated their interest in different teaching strategies for
educational program delivery. (See Table 4.) Most
respondents expressed a strong interest in distancelearning modalities (94%), compared to traditional
classroom settings (64%). Experiential learning opportunities, use of portfolios, and working with clinical
research mentors were other curriculum modalities
highlighted by respondents positively.
Motivators and Barriers to Continued Education.
Motivators for continuing their education included:
personal growth (93%), improving professionalism of
clinical research coordinator discipline (94%),
improved chance for future advancement (73%),
improved chance for salary increases (84%), and
chance for future work in the pharmaceutical industry
(50%). The primary barrier to continued education for
respondents was related to time (85%). Another significant barrier was lack of available programs (75%).
Other barriers included: cost (68%), personal obligations (60%), available program curricula not relevant
(33%), lack of mentors (31%), distance (34%), and lack
Jones, Harrison, Carter, Jester / Education and training preferences of clinical research managers
Table 1. Job Titles Reported by Respondents (n = 167)
Research Nurse Coordinator
32
Clinical Trials Project Manager
1
Clinical Research Coordinator
15
Clinical Trials Manager
1
Research Nurse Manager
8
Data Manager
1
Study Coordinator
5
Director, Regulatory Compliance & Support
1
Certified Clinical Research Coordinator
4
Financial Assistant
1
Research Coordinator
4
Financial Associate
1
Senior Clinical Research Coordinator
4
Independent Consultant
1
Certified Pediatric Nurse Practitioner
3
Investigational Study Pharmacist
1
Clinical Research Associate
3
Manager, Clinical Trials Quality Assurance
1
Clinical Research Nurse
3
Nurse Administrator, Pediatrics
1
Clinical Research Nurse Coordinator
3
Nurse Manager
1
Certified Regional Nurse Practitioner
3
Nurse Manager, Research Coordinator
1
Director of Clinical Research
3
Nurse Practitioner/Research Coordinator
1
Program Coordinator II
3
Nurse Research Coordinator
1
Research Assistant
3
Office Associate I
1
Research Nurse Specialist
3
Oncology Clinical Manager of Research
1
RN Clinical Research Coordinator
3
Pediatric Surgery Clinician
1
Clinical Trials Administrator
2
Program Coordinator and Study Coordinator
1
Nurse Clinician
2
Program Coordinator for Research
1
Nurse Research Manager
2
Program Director II
1
Program Coordinator
2
Program Manager II
1
Program Manager
2
Project Coordinator/Regulatory
1
Project Coordinator
2
Project Manager
1
Project Manager/Study Coordinator
2
Quality Manager
1
Research Manager
2
Registered Nurse III
1
Research Nurse Clinician
2
Regulatory Affairs Coordinator
1
Research Specialist
2
Regulatory Manager
1
Administrator
1
Renal Transplant Coordinator
1
Associate Professor
1
Research and Multidisciplinary Care Coordinator
1
Bariatric Nurse Coordinator
1
Research Assistant II
1
Clinical Director
1
Research Data Coordinator
1
Clinical Manager
1
Research Nurse
1
Clinical Project Manager
1
Research Study Coordinator
1
Clinical Research Coordinator/Manager
1
Senior Study Coordinator
1
Clinical Research Nurse/Perinatal Coordinator
1
Spina Bifida Coordinator
1
Clinical Trial Budget Analyst
1
Senior Director, Training Services
1
Research Practitioner / VOLUME 9 NUMBER 6
207
Education and training preferences of clinical research managers / Jones, Harrison, Carter, Jester
Table 2. Respondents’ Interest in Participating
in Different Types of Educational Programs
Table 3. Respondents’ Interest in Clinical Research
Topics
Rating Average
Individual College Course (for academic credit)
3.98
Clinical research site management
4.24
Academic degree (MS in clinical research management)
3.53
Clinical research protocol management
4.20
Academic degree (MSN in clinical research management)
3.25
Current topics in clinical research management
4.14
Academic specialty certificate (post-baccalaureate)
3.09
Operational leadership in clinical research
4.07
Academic degree (AD/diploma to MSN in clinical research
management)
Clinical research data management
3.93
2.74
Quality assurance
3.90
Individual college course (not for academic credit)
2.57
Monitoring clinical research
3.89
Academic specialty certificate (undergraduate)
2.18
Grants and contract administration
3.49
Program planning
3.27
(1 = No Interest, 5 = Great Interest)
of professional support (26%). Lack of a bachelor’s
degree was listed as a barrier for 22% of respondents.
The survey did not inquire about specific job-related
barriers or lack of support by principal investigators.
Discussion
With the increasing cost and complexity of conducting clinical trials, a professional, well-educated, and
skilled work force is critical. In clinical research, it is
often the case that the CRM is the fulcrum for successfully completing clinical trials. Providing all the
appropriate learning and professional tools to a CRM
is the fundamental mechanism to assure that studies
are efficiently and appropriately conducted. Findings
from the published literature are supported by these
survey results.
The authors acknowledge that a convenience sample
is a limitation of the survey. The study did not build in
a way of tracking the total number of solicitations sent
out, since many solicitations were by listserv and referral to achieve a wider reach; therefore, a response rate
could not be calculated. Moreover, respondents may
have been self-selected. Those less interested in educational pursuits might have had less motivation to
complete the survey. Additionally, the survey did not
exclude non-nurse participation; however, the authors
acknowledge that results may be biased to nurse
respondents since many CRMs in GCRCs and NIHfunded studies who work in academic research centers
are nurses. If the study had a funding source, it would
208
I. Topics Related to Management of Clinical Research
Research Practitioner / VOLUME 9 NUMBER 6
II. Topics Related to Research Methods
Protocol and case report form development
3.90
Research methodology
3.86
Virtual clinical trial practicum
3.70
Literature review of clinical studies
3.56
Simulation, mock patients, and case studies in clinical research
3.54
Behavioral medicine: communication, prevention, coherence
3.37
Epidemiology
3.36
Biostatistics
3.15
III. Topics Related to Regulatory Affairs
Issues in regulatory affairs
3.86
Clinical research industry
3.80
New product development
3.65
IV. Topics Related to Ethical and Cultural Issues
Bioethical decision-making
3.86
Seminars in cultural competency
3.23
Issues in international studies
3.05
V. Clinical and Professional Core Topics
Pathophysiology
3.54
Pharmacology
3.41
Scientific writing
3.37
(1 = No Interest, 5 = Great Interest)
have been strengthened by marketing the survey
through an advertisement in clinical research publications or the purchase of mail contacts.
Jones, Harrison, Carter, Jester / Education and training preferences of clinical research managers
Table 4. Respondents’ Preferences
for Teaching Strategies
Rating Average
Distance education (online, e-mail, etc.)
4.45
Experiential learning opportunities
3.91
Development of portfolios to document experiences and achievements
3.77
Virtual clinical trial practicum
3.7
Simulation, mock patients and case studies in clinical research
3.54
Opportunities to interact with international coordinators (via e-mail)
3.46
Traditional classroom setting
3.04
(1 = No Interest, 5 = Great Interest)
Clarifying CRM job titles and competencies is necessary to develop the content of training programs;
defining and identifying types of preparation for CRM
roles is also essential. Seventy-two different job titles
were identified by the 167 respondents. The published
literature supports this lack of clarity in clinical
research roles.14,15 Shamoo and Resnik’s emphasis on
the broad ethical brushstrokes of CRM responsibilities
further supports a need to develop higher levels of
education and training.6 The broad diversity of job
titles and educational experiences reported by survey
respondents characterizes a lack of universally defined
roles and educational pathways. Without defined outcome parameters associated with competency-based
roles, workforce needs may go unmet and ultimately
clinical research is at risk for quality and integrity
breaches. The development of core competencies and
educational programs can work in tandem to help
bridge the gaps in clarity.
Respondents expressed strong interest in pursuing and
participating in clinical research educational programs. Of the types of training preferred, academically based programs focused on individual credit hours
ranked highest. It should be noted that although 67%
of the respondents preferred a post-baccalaureate certificate, only one of the 167 respondents reported participating in a post-master’s certificate program and
two respondents received training through a noncredit college course. However, with 84% of the
respondents expressing motivation to seek continuing
educational experiences in clinical research, clearly
this is an unmet need. As reported in 2007, three
baccalaureate degree programs in clinical research, six
master’s in nursing (MSN) in clinical research, and
seven non-nursing master’s degrees in clinical research
existed at academic institutions in the United States.1
Since that publication, new programs have evolved or
are evolving, an increasing trend to meet this need.
However, cost of tuition and inadequate distancelearning options remain obstacles.
The respondents expressed strong interest in academic-based education, whether for degree or certificate.
Ninety-four percent of the respondents preferred Webbased distance learning. The development of asynchronous and synchronous distance-learning programs would address barriers noted by the respondents. Furthermore, the cost of tuition can be generally less than traditional classroom courses. Flexibility of
time expenditure is inherent in distance-learning
courses and access to mentors readily available, especially with electronic communication methods. With
current developed and evolving technology, webbased distance education and training programs are
powerful modes of training.
Although the education topics of interest were diverse,
five overlapping curriculum topics were identified (See
Figure 2.):
1.Rresearch management
2. Research methods
3. Regulatory affairs
4. Ethical and cultural issues
5. Clinical/professional topics
Of the 30 clinical research topics identified by the
respondents, nearly 30% of the topics were related to
research management. This is in keeping with the
nine competencies identified by CoAPCR, as essential
to effective management of clinical research.13 (See
Figure 1.) The roles and responsibilities of a clinical
research coordinator are diverse and expansive. To
address the respondents’ stated needs, a curriculum
should be designed to include multiple categories that
build upon the nine core competencies that are
included among the five overlapping topical streams.
The need and desire for education and training of clinical research coordinators is not only desired by CRMs
as reflected in this survey, but also recognized by
research sponsors and regulatory bodies. In a draft
Research Practitioner / VOLUME 9 NUMBER 6
209
Education and training preferences of clinical research managers / Jones, Harrison, Carter, Jester
Figure 2. Five Overlapping Curriculum Topics for CRM Educational Program Content
I.
Research
Management
V.
Clinical and
Professional
Topics
II.
Research
Methods
IV.
Ethical and
Cultural Issues
guidance for industry, dated May 2007 and titled
Protecting the Rights, Safety, and Welfare of Study
Subjects—Supervisory Responsibilities of Investigators,
training and education of research staff is highlighted
as an investigator responsibility needing further definition and guidance.23 Key in this guidance is a
description of the principal investigator’s responsibility to assure that research staff members are adequately trained in the knowledge of protocol requirements
and that staff are aware of regulatory requirements
and acceptable standards for the conduct of clinical
trials, are competent in tasks that are delegated to
them, and are given additional training as needed.
Proper documentation of roles and definition of outcomes, competencies, and training would be possible
requirements for adherence to this guidance. FDA
guidance such as this leads to the evolution of GCP
standards and definitions that are further required by
research sponsors in site selection, grant awards, and
monitoring. Clinical research sites may be further
210
Research Practitioner / VOLUME 9 NUMBER 6
III.
Regulatory
Affairs
burdened with fulfilling higher level site management
and documentation of demonstrated training and
operational outcomes. How can adherence to guidance be assured when the roles, competencies, and
educational requirements remain cloudy?
Recommendations
Based on the results of this survey, the evolving developments in CRM education and training, and the role
definition set forth in the literature and by CoAPCR,
the authors of this paper recommend the following:
• CRM education programs should be offered and
supported by academic institutions, and those
institutions should become active members of
CoAPCR.
• CRM education programs should allow for specialty certification that can expand to accommodate full graduate degree requirements for interested participants.
Jones, Harrison, Carter, Jester / Education and training preferences of clinical research managers
• Curriculum content should include all aspects of
developing, managing, evaluating, and reporting
clinical research in adherence with GCPs, and be
categorized to include the five overlapping course
topics identified in this paper and the nine core
competencies described by CoAPCR.
• Courses should be developed and offered as parttime, asynchronous, Web-based distance-education programs with opportunities for mentoring
and individualized preceptorships.
• Roles and competencies for clinical research personnel should be defined, standardized, and
accepted.
10
11
12
13
14
15
CRM education and training is critical to the future of
clinical research. There is clearly a need for key academic centers to work together to pursue developing
models of education that contribute to defining,
expanding, teaching, and evaluating courses based on
core competencies in clinical research. Gaps in CRM
roles and education will narrow as these developments
continue.
16
17
18
19
References
1
2
3
4
5
6
7
8
9
Carter SC, Jones CT, Jester PM. Issues in clinical research
manager education and training. Research Practitioner.
2007;8:48-60.
Ehrenberger HE, Lillington L. Development of a measure to delineate the clinical trials nursing role. Oncol
Nurs Forum. 2004;31:E64-8.
U.S. Department of Health and Human Services. U.S.
Food and Drug Administration. FDA Regulations
Relating to Good Clinical Practice and Clinical Trials.
Available at: www.fda.gov/oc/gcp/regulations.html.
Accessed October 27, 2008.
U.S. Department of Health and Human Services. Code
of Federal Regulations. Title 45, Part 46. Protection of
Human Subjects. Available at: www.dhhs.gov/ohrp/
humansubjects/guidance/45cfr46.htm. Accessed
October 27, 2008.
International Conference on Harmonisation of
Technical Requirements for Registration of
Pharmaceuticals for Human Use. Available at:
www.ich.org. Accessed October 27, 2008.
Shamoo AE, Resnik DB. Ethical issues for clinical
research managers. DIA J. 2006;40:371-383.
Anderson G. Ethical preparedness and performance of
gene therapy study co-ordinators. Nurs Ethics. 2008;
15:208-21.
Association of Clinical Research Professionals. Available
at: www.acrpnet.org. Accessed August 29, 2008
Society of Clinical Research Associates. Available at:
www.socra.org. Accessed October 27, 2008.
20
21
22
23
Mori C, Mullen N, Hill EE. Describing the role of the
clinical research nurse. Research Practitioner. 2007;8:220228.
The Consortium of Academic Programs in Clinical
Research. Available at: www.coapcr.org/index.php?
option=com_content&task=blogcategory&id=6&
Itemid=2. Accessed August 10, 2008.
Sonstein SA. Core competencies for entry-level positions
in clinical research. In: 44th Annual Meeting of the
Drug Information Association. Boston; 2008.
The Consortium of Academic Programs in Clinical
Research. Mission. Available at: www.coapcr.org/
index.php?option=com_frontpage&Itemid=1. Accessed
August 10, 2008.
Hill G, MacArthur J. Professional issues associated with
the role of the research nurse. Nurs Standard. 2006;
20:41-47.
Raja-Jones H. Role boundaries—Research nurse or clinical nurse specialist? A literature review. J Clin Nurs.
2002;11:415-420.
Cronin V, Cheesman J, McCoshen M, et al. Clinical trials research, a collaborative approach: Nursing, research,
and clinical practice. CANNT J. 2006;16:33.
DeMarinis AJ. Supervisory responsibilities of investigators. Research Practitioner. 2008;8:137-47.
Pelke S, Easa D. The role of the clinical research coordinator in multicenter clinical trials. JOGNN: J Obstet
Gynecol Neonatal Nurs. 1997;26:279-285.
Yin CX. Improving the quality of clinical research:
Recognizing issues in training. Research Practitioner.
2008;9:20-23.
Trocky NM. The journey to becoming a research nurse.
Clin J Oncol Nurs. 2001;5:1-3.
Roberts BL, Rickard CM, Foote J, McGrail MR. The best
and worst aspects of the ICU research coordinator role.
Nurs Critical Care. 2006;11:128-135.
Spilsbury K, Petherick E, Cullum N, et al. The role and
potential contribution of clinical research nurses to clinical trials. J Clin Nurs. 2008;17:549-557.
U.S. Department of Health and Human Services. Food
and Drug Administration. Guidance for Industry.
Protecting the Rights, Safety, and Welfare of Study
Subjects—Supervisory Responsibilities of Investigators.
Available at: www.fda.gov/CBER/gdlns/studysub.pdf.
Accessed September 25, 2008.
Research Practitioner / VOLUME 9 NUMBER 6
211
Continuing Education
Exam for Continuing Education
Research Practitioner 9.6
Instructions
Continuing Nursing Education
1. Read the articles: Applying the Federalwide
Assurance policy to clinical and social/behavioral
research: New questions prompt changes and
Education and training preferences of clinical
research managers.
2. Take the CNE test on-line at www.ahcpub.com/
testweb/ or use the enclosed Scantron sheet, completed according to directions. All sections of the
test must be completed to receive a Credit Letter.
3. Complete the Independent Study Evaluation.
4. Mail the completed answer sheet and evaluation
by November 30, 2009 to:
AHC Media LLC
Attn. Continuing Education Department
PO Box 740058
Atlanta, GA 30374-0058
Faxes cannot be accepted.
AHC Media LLC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on
Accreditation.
Provider approved by the California Board of Registered Nursing, Provider
# 14749, for 3 Contact Hours.
This activity is approved for 3 nursing contact hours using a 60-minute
contact hour.
Take the Continuing Nursing Education Test On-line
Subscribers who order their journal with CNE contact
hours can take the test on-line.
1. To access the test site, please log on to:
http://www.ahcpub.com/testweb/. You will be
3 CNE hours
Applying the Federalwide
Assurance policy to clinical and
social/behavioral research:
New questions prompt changes
1.5 nursing contact hours
1. A Federalwide Assurance (FWA) is required for all
non-exempt research funded by the Department
of Health and Human Services (HHS), including
the National Institutes of Health.
A. True
B. False
2. Institutions that have an FWA must agree to follow
human subjects protection regulations for all
research supported by federal funding.
A. True
B. False
3. The FWA serves which of the following purposes?
A. To give OHRP contact information on institutional officials and IRB members
B. To commit the institution to having and following procedures to protect human subjects
in research studies
C. To require the IRB to report any breach of
policy
D. To allow the federal government (OHRP) to
exercise oversight and enforcement of HSP regulations
E. All of the above
asked to register. Your subscriber number is on the
address label of the Scantron sheet. Please contact
Customer Service at 800-765-9647 if you do not know
your subscriber number.
2. Fill in the answers and submit.
3. Once you have passed, you will receive confirmation.
The Credit Letter will be mailed to you within 6 weeks.
212
Research Practitioner / VOLUME 9 NUMBER 6
4. Institutions with a FWA can choose to agree to:
A. follow the Common Rule requirements for
human subjects protection.
B. follow the Common Rule and subparts A, B, C
and D.
C. follow human subjects protection regulations
for HHS funding only.
D. All of the above
5. Research institutions seeking AAHRPP accreditation must have uniform policy and procedures for
all research regardless of the funding source.
A. True
B. False
6. Subpart B states that no pregnant woman may be
enrolled as a research subject unless:
A. the research is intended to meet the health
needs of the woman.
B. the fetus is at risk only to the minimal extent
necessary to meet the health needs of the
mother.
C. the risk to the fetus is minimal overall.
D. All of the above
7. HHS regulations require routine pregnancy screening for all women enrolled in social/behavioral
research.
A. True
B. False
8. If an investigator of a social/behavioral research
study learns that a woman in the study is pregnant
and the research was not previously approved by
the IRB for compliance with subpart B, the investigator should:
A. contact the IRB immediately.
B. cease all research activity with the pregnant
woman immediately unless it is in the best
interest of the pregnant woman to remain in
the study.
C. Both A and B
9. DoD regulations for human subjects protection are
separate from HHS and the Common Rule and
must be followed for all DoD-sponsored research.
A. True
B. False
10. DoD regulations require a monitor to observe critical phases of social behavioral as well as clinical
studies.
A. True
B. False
Education and training
preferences of clinical research
managers
1.5 nursing contact hours
11. Proposed core competencies for clinical research
roles defined by CoAPCR include all the following,
except:
A. knowing clinical operations, good clinical practice, and project management.
B. knowing applicable regulatory law.
C. conducting ethically responsible research.
D. conducting statistical matrixes according to the
corresponding clinical phase of the trial.
12. Performing the duties of clinical research manager
(CRM) is limited to the following profession(s):
A.
B.
C.
D.
LPN or LVN
RN
any medical professional can be a CRM
There is no defined role limitation.
13. Lack of training opportunities, the difficulty in
knowing what they should be doing, and the perception that they were primarily responsible for
the success or failure of the research projects:
A. is unique to CRMs in the United Kingdom.
B. is unique to CRMs in the United States.
C. is reported by CRMs in Australia and New
Zealand.
D. is universal to all CRMs.
14. A wide diversity exists in U.S. education programs
for the CRM in the area(s) of:
A.
B.
C.
D.
E.
content.
cost.
requirements.
length.
All the above
15. The primary method of education reported in the
literature for the CRM is by:
A. on-the-job training.
B. local Institutional Review Board training
programs.
C. regional Community College Certificate
training programs.
D. on-line certification programs.
Research Practitioner / VOLUME 9 NUMBER 6
213
16. Regulatory affairs was not a high interest topic
chosen by the survey participants, as many reported receiving quarterly training updates via their
own governing IRBs.
A. True
B. False
17. Traditional classroom settings remain the most
preferred methodology for education in clinical
trials management by the survey respondents.
A. True
B. False
18. There is no clear basis for mandating consistency
in coordinator training programs as FDA-approved
clinical trials are not complex by design to warrant
advanced training.
A. True
B. False
19. The broad diversity of job titles and educational
expertise reported by study participants:
A. characterize a lack of universally defined roles
and education pathways.
B. is a symptom of a greater issue concerning the
inadequate compensation for conducting clinical trials.
C. was just limited to coordinators in the
Midwestern part of the United States.
D. sparked the CoAPCR to set forth the nine core
competencies in clinical research.
20. A current draft guidance for industry, Protecting the
Rights, Safety, and Welfare of Study Subjects—
Supervisory Responsibilities of Investigators, states
that study coordinators should seek out resources
such academic medical centers or one of the two
certification organizations to receive adequate
training prior to pursuing a career in clinical trails
management.
A. True
B. False
214
Research Practitioner / VOLUME 9 NUMBER 6
ISSUES IN HUMAN SUBJECTS RESEARCH
Participation by women in clinical research
Sue Coons, MA
The road for women to participate in clinical research has changed significantly in the last 30 years. In 1977,
FDA recommended that women of child-bearing potential be excluded from participating in early phase clinical
trials. In 1993, however, women won the right by law to be included in Phase 3 research. Now the number of
women participating in clinical studies funded by the National Institutes of Health is about equal or slightly
more than the number of men, excluding those participating in sex-specific studies. Still, women’s health
advocates say more needs to be done. Research is needed to better understand the importance of sex-based
differences. In addition, 25% of women in a recent study said they did not know opportunities existed for
healthy women to take part in medical research. This article examines women’s health research in the last 30
years and then provides feedback from women’s health advocates.
Key words: clinical research, female subjects, women’s health
From exclusion to inclusion by law
A controversial 1997 FDA policy recommended
excluding any “premenopausal female capable of
becoming pregnant” until reproductive toxicity studies were conducted and some evidence of effectiveness
had become available. The recommended exclusion
explicitly did not apply to women with life-threatening diseases.1 Women’s health advocacy groups
charged that the guideline raised ethical and legal
questions, such as deciding for women that protecting
the fetus outweighed other possible interests. The
groups also argued that the policy had a chilling effect
on access to later clinical trials, despite its focus on
early phase trials. “Effectively, [the policy] gave the
drug companies an excuse [not to include women],”
says Sherry Marts, vice president of scientific affairs for
the Society for Women’s Health Research in
Washington, DC. “It was pretty rare for a new drug
study to have women in it.”
The report of the Public Health Service Task Force on
Women’s Health in 1985 supported the advocates’
claims, concluding that more attention needed to be
given to women’s health issues.2 Following this report,
the National Institutes of Health (NIH) established a
policy in 1986 for the inclusion of women in clinical
research. This policy was first published in the NIH
Guide to Grants and Contracts in 1987.3 In a later 1987
© 2008 CenterWatch
version of the NIH guide, a policy encouraging the inclusion of minorities in clinical studies was first published as well. In
1990, NIH established the Office of
Research on Women’s Health (ORWH) to
serve as a focal point for women’s health
research funded by NIH.
Congress then made inclusion of women
and minorities in clinical research into
public law, through a section in the NIH
Revitalization Act of 1993, titled Women and Minorities
as Subjects in Clinical Research. The Revitalization Act
essentially reinforced existing NIH policies, but with
four major differences:3
• NIH ensures that women and minorities are
included in all human subjects research;
• Inclusion of women and minorities in Phase 3
clinical trials are in numbers adequate to allow
for valid analyses of differences in intervention
effect;
• Cost is not allowed as an acceptable reason for
excluding these groups;
• NIH initiates programs and support for outreach
efforts to recruit and retain women and minorities and their subpopulations as volunteers in
clinical studies.
In 1994, NIH revised its inclusion policy to meet this
mandate. In 2001, NIH updated the NIH Policy and
Guidelines on the Inclusion of Women and Minorities as
Subjects in Clinical Research. The guidelines incorporate
the definition of clinical research as reported in the
1997 Report of the NIH Director’s Panel on Clinical
Research and the Office of Management and Budget
Statistical Policy Directive No. 15, Race and Ethnic
Standards for Federal Statistics and Administrative
Research Practitioner / VOLUME 9 NUMBER 6
215
Participation by women in clinical research / Coons
Reporting. They also provide additional guidance on
reporting analyses of sex/gender and racial/ethnic differences in intervention effects for NIH-defined Phase
3 clinical trials.3
Getting the word out
After its inception, the ORWH had three interrelated
obstacles to overcome, according to ORWH director
Vivian W. Pinn. First, critics charged that the office
was a waste of money and expertise, that the biomedical concerns of women would be revealed through
ongoing research. To counter this, ORWH began supporting and supervising scientific, research-oriented,
evidence-based initiatives and investigations that
operate within the same context as legitimate research
in any other area of medical science. Second, critics
charged that focusing on women’s health might create
undue competition with those health and medical
concerns commonly identified with boys and men.
However, much of women’s research has brought
insight into both women’s and men’s health, she says.
Third was the concern that the office would promote
a “men vs. women” atmosphere in research. In
response, ORWH began multiple collaborations, both
within the NIH community and branching out into
outside groups and international research institutions.4
ORWH not only wanted more women to get into clinical research, but also wanted them to see the studies
through, Pinn says. Many of the women simply didn’t
know that research opportunities existed. “One of the
past contributing factors to the lack of women being
in clinical studies was either they were not included in
the design of the study or they were not made aware
of research studies in which they could participate,”
she says. Treatment studies had more success at
recruiting women. “In treatment studies, people know
they may have an option of having access to studies
that may be providing some cure for a disease or testing some new drug or medication for a disease.”
Prevention trials with healthy volunteers, on the other
hand, “may not seem as pressing.”
A perpetual question is how women find out about
the possibilities of participating in medical research,
Marts says. “It is sort of a truism in the not-for-profit
world that people don’t volunteer if they are not
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Research Practitioner / VOLUME 9 NUMBER 6
asked. So if women aren’t being asked to volunteer for
studies or to consider being in a study, then it is going
to perpetuate this issue of not having enough women
in medical studies and the sense that a lot of clinical
investigators seem to have—whether it is based in reality is hard to tell—that it is hard to recruit women.” In
response to the issue of asking woman to participate in
clinical trials, the society launched a public education
campaign, “Some Things Only a Woman Can Do,” in
1993. The society planned this as a print campaign
primarily. The Web site, www.womancando.org/,
which was almost an afterthought to the campaign,
became a hub of activity. It has had the most legs of
the whole campaign, Marts says, and will soon be
updated, although the information on it is still “100%
valid and useful.”
The study that couldn’t succeed
The doubters who say it is hard for clinical researchers
to recruit women had lots to say when the study
design of the Women’s Health Initiative (WHI) was
announced. “When we were designing that study in
the early ’90s, I remember very clearly that we were
told that we would never get older women to participate,” Pinn says.
The WHI, a multi-million dollar, long-term prevention trial and observational study, was one of the
largest of its kind. Sponsored by NIH and the National
Heart, Lung, and Blood Institute (NHLBI), it involved
161,808 postmenopausal women, ages 50-79. “[In this
trial], a lot of lessons were learned about how to reach
out to women, especially older women,” Pinn says. At
the clinic level, several factors may have contributed
to successful recruitment.5 First, the clinic was made as
accessible as possible to the women. This could
involve staffing a satellite clinic part- or full-time and
providing parking and/or reimbursement for transportation costs. Investigators made clinic hours convenient for women, and the clinic was managed by
competent and friendly staff members. Second, clinic
recruitment goals were monitored weekly, including
close review of reports distributed from the Clinical
Coordinating Center and yields from mailings and
other recruitment activities. Third, the use of mass
mailings was found to be critical to reach the large
numbers of women needed for WHI. Although most
Coons / Participation by women in clinical research
clinics tried other strategies, in the long run, all clinics
relied on mass mailings as their primary recruitment
method. “One of the greatest accomplishments of the
Women’s Health Initiative was demonstrating that we
could get older women who were healthy to come
into a clinical study and to remain as participants in
that study over years,” Pinn says. When she speaks at
events, she often sees women who will stand up and
say they are proud of being in the WHI, even if they
know the results won’t benefit them as much as the
next generation.
A snapshot of women in clinical research today
Since 1977, women overall have made tremendous
inroads in becoming a vital component of clinical
research. Looking at the men and women who participate in NIH-funded studies, women make up 63.9%
of all participants, men 31.2%, with 1.3% unknown.
“It is self-identification,” Pinn explains. “We try to get
the full data, but sometimes it is not delineated.”
ORWH has heard criticism that with these percentages, men’s health issues may lack attention now.
These figures encompass all NIH-funded research studies, however, including those that are sex-specific,
such as those investigating menopause, ovarian cancer, and fibroids. “As we have paid more attention to
women’s health research since the early ’90s, we have
tremendously increased the number of studies relating
to menopause,” Pinn says. “Now we are focusing also
on menstruation, both the beginning and the sensation of menstruation and puberty. We are also looking
at the role of the menstrual period and premature
ovarian failure. These are all conditions that were not
studied as much in the past.” Other areas that needed
attention, such as biomarkers for ovarian cancer, are
getting it as well.
If you then take the numbers of clinical studies and
eliminate those that are sex-specific, there is a pretty
good balance between men and women, Pinn says.
“It’s about equal.” For the last year of data, the percentages were 52% female vs. 46% male. In the past it
has varied anywhere between that and 49% to 51%.
“We feel we have made great progress.” In Phase 3
clinical trials, there are a few more men than women,
while in overall research—all phases—there are more
women than men. “The bottom line is that if you look
at the numbers of women in clinical studies, it is kind
of difficult to say that women are not participating,
because there were nine-and-one-half million women
enrolled in NIH clinical studies in 2006. A little more
than five million men were enrolled. But looking overall at individual studies, there may be some investigators and some areas where it may be more difficult to
have women come in than men. At least for NIHfunded studies, we can feel fairly certain that women
are adequately represented.”
The challenges that remain
Women are participating in clinical research in greater
numbers, but a survey published by the Society for
Women’s Health Research in 2008 found that 25% of
women still didn’t know that research opportunities
exist for healthy volunteers.6 The survey was taken of
2,028 U.S. adults 18 years and older. Slightly more
than 9% of the women in the survey had participated
in a medical research study.7
Some physicians are reporting continued challenges
to recruiting women in their studies, as well. Peter J.
Schmidt, a clinician and investigator at the National
Institute of Mental Health, has seen declining numbers of women volunteering for certain studies, primarily those investigating postpartum depression and
midlife perimenopausal depression. “When we consider what we have to offer in terms of our program
and our expertise and the studies that are available, I
was surprised about our continuing difficulty in
recruiting people.” He says the challenges may be stigmas related to mental and behavioral health research;
there may be stigmas associated with research in general. “But I also wonder how much is just education
and access to this information. Certainly in many of
the minority groups that we have worked with, people
just don’t know that these studies are out there. Once
we provide them with information, some of our
recruiting efforts seem to improve,” Schmidt says.
Outreach has proven effective, particularly in minority communities. The women have responded more
positively to word-of-mouth communication than
printed material about the trials. “I think having people in the community getting our name and [information about] our trial out overcomes the stigma of us
being in a government facility, the stigma of research,
Research Practitioner / VOLUME 9 NUMBER 6
217
Participation by women in clinical research / Coons
and the stigma of behavioral health,” Schmidt says.
“That seems to have reduced some of those as obstacles and their impact for people, at least finding out
about the studies. The women in my studies tell me
that they often heard about it from a friend, that it
was OK to come up here. Then it was a question of
whether it was something that would be of interest to
them.”
designed to measure these differences as primary
outcomes. “A difficulty is that often differences in
effect are suspected only on completion of the study,”
the editorial says. “Clarifying the reason for such differences through studies into underlying biological
mechanisms would help in the development of appropriate recruitment strategies, and possibly of trial
design and therapy.”8
The society’s study shows that most women are not
getting information about clinical research from their
physicians. In the survey, 93% of the women reported
that their doctor had never talked to them about participating in any type of medical research.7 One of the
problems is that physicians have so many things to
talk about with their patients, Marts says. “There is
only so much time in a clinic visit. They are going to
be selective about what they talk about.” Some physicians also may be concerned that referring patients to
clinical research would add to their administrative burden or cause them to lose patients to other physicians.
“There is probably a role for medical societies, both
national and local, in educating their members about
why it is valuable to refer their patients, when it is useful, and what it means for their practice.”
Women’s health advocates also have suggested that
women are underrepresented in certain cardiovascular
trials. Elderly persons and women had been underrepresented in randomized controlled trials (RCTs) of
acute coronary syndromes prior to 1990, according to
a study published in the Journal of the American Medical
Association in 2001. The investigators searched for
English-language articles from January 1966 to March
2000 regarding myocardial infarction, unstable angina, or acute coronary syndromes and found that
attempts at making cardiovascular RCTs more inclusive appear to have had limited success. “Thus,
women and elderly persons remain underrepresented
in published trial literature relative to their disease
prevalence. Because safety and efficacy can vary as a
function of sex and age, these enrollment biases
undermine efforts to provide evidence-based care to
all cardiac patients.”9
As shown by the success of the society’s information
Web site, the Internet is gaining ground for women as
the place to go for information about clinical research.
“I have found that with the Internet and the fact that
getting into clinical research studies no longer requires
a doctor’s referral, I’m getting calls from people who
know about clinical trials because of clinicaltrials.gov,
the National Libraries of Medicine Web site that lists
NIH studies as well as studies by industry,” Pinn says.
“Women are catching on, older as well as younger.
Family members are catching on to using clinicaltrials.gov, too. In our office, we always give that
address to publicize it.”
Women’s health advocates say that clinical research
still needs more investigation into whether gender, a
person’s identification and behavior, has an impact on
how the person responds to a medication. “We will
never know if we don’t ask the question,” Marts says.
According to an editorial published in 2001 in the
Lancet, NIH guidelines were revised in 2000 to state
that if an intervention was expected to produce differences of clinical or public health importance among
subgroups (such as men or women), the study must be
218
Research Practitioner / VOLUME 9 NUMBER 6
There are some differences between the sexes in ages
of onset of heart disease and some other factors, Pinn
says. “But I do know there has been tremendous
progress. NHLBI has one of the best and one of the
earliest administered policies requiring inclusion of
women in clinical studies. At least in NHLBI-funded
studies, there has been a great effort over the past 10
years or so to rectify the lack of precious studies on
women in heart disease. The bottom line is if we are
getting more information on women in heart disease.
“We know our job is not done,” Pinn concludes. “We
are still seeking answers and I certainly can’t claim we
have answered them all. We have come a long way in
the last 16 years, but we know we have more to do.”
References
1
2
U.S. Food and Drug Administration. Executive
Summary—Gender Studies in Product Development.
Available at: www.fda.gov/womens/gender/Exec4.htm.
Accessed October 8, 2008.
Women’s health. Report of the Public Health Service
Coons / Participation by women in clinical research
3
4
5
6
7
8
9
Task Force on Women’s Health Issues. Public Health
Rep. 1985;100:73-106. Available at: www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1424718. Accessed
October 8, 2008.
Office of Research on Women’s Health. Inclusion of
Women in Clinical Research. Available at:
http://orwh.od.nih.gov/inclusion/inclintro.html.
Accessed October 8, 2008.
Pinn VW. The view from the National Institutes of
Health: A decade with the Office of Research on
Women’s Health, Gender Medicine. 2004;1:5.
Hays J, Hunt JR, Hubbell FA, et al. The Women’s Health
Initiative recruitment methods and results. Ann
Epidemiol. 2003;13:S18–S77.
Society for Women’s Health Research. Doctors don’t talk
to their patients about participating in research.
Available at: www.womenshealthresearch.org/site/
News2?page=NewsArticle&id=7587. Accessed September
15, 2008.
Society for Women’s Health Research. Survey of U.S.
Adults on Clinical Trials Research Participation.
Available at: www.womenshealthresearch.org/
site/DocServer/WomensHealthWeekSurveyResults.pdf?d
ocID=2041. Accessed September 15, 2008.
Recruitment of women to clinical trials. Lancet
2001;358:853.
Lee PY, Alexander KP, Hammill BG, et al. Representation
of elderly persons and women in published randomized
trials of acute coronary syndromes. JAMA. 2001;
286:708-13.
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Research Practitioner / VOLUME 9 NUMBER 6
219
Regulatory Update
FDA announces investigator’s debarment
In the September 2, 2008, Federal Register, FDA issued
an order under the Food, Drug, and Cosmetic Act (the
Act) permanently debarring Maria Anne Kirkman
Campbell from providing services in any capacity to a
person who has an approved or pending drug product
application. FDA based this order on a finding that
Campbell was convicted of a felony under federal law
for conduct relating to the development or approval,
including the process for development or approval, of
a drug product, and conduct otherwise relating to the
regulation of a drug product under the Act. The Act
requires debarment of an individual if FDA finds that
the individual has been convicted of a felony under
federal law.
On March 25, 2004, the U.S. District Court for the
Northern District of Alabama accepted Campbell’s
plea of guilty and convicted her of one count of mail
fraud, a felony. Specifically, Campbell admitted to submitting a fraudulent case report form (CRF), reflecting
enrollment of a nonexistent person, while serving as a
clinical investigator in a clinical study designed to test
the safety and effectiveness of an antibacterial drug
product, Ketek (telithromycin), for the treatment of
respiratory tract infections. The clinical study was to
be submitted to FDA in support of approval of Ketek.
As a result of the debarment, any person with an
approved or pending drug product application who
knowingly uses the services of Campbell in any capacity, during her period of debarment, will be subject to
civil money penalties. If Campbell, during her period
of debarment, provides services in any capacity to a
person with an approved or pending drug product
application, she will be subject to civil money penalties. In addition, FDA will not accept or review any
abbreviated new drug application submitted by or
with the assistance of Campbell during her period of
debarment.
The FDA inspection that uncovered these violations of
FDA regulations occurred between October 15-24,
2002. Prior to the debarment, FDA issued a Notice of
Initiation of Disqualification Proceedings and
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Research Practitioner / VOLUME 9 NUMBER 6
Opportunity to Explain (NIDPOE) letter to Campbell
on May 18, 2006. The subject protocol was titled
“Randomized, Open-Label, Multicenter Trial of the
Safety and Effectiveness of Oral Telithromycin (Ketek®)
and Amoxicillin/Clavulanic Acid (Augmentin©) in
Outpatients with Respiratory Tract Infections in Usual
Care Settings,” sponsored by Aventis Pharmaceuticals,
Inc.
According to the NIDPOE letter, FDA’s inspection
raised numerous concerns with this study including
potential fabrication of study subjects, fabrication of
study data, and enrollment of ineligible subjects. The
FDA Field Investigator referred the matter to FDA’s
Office of Criminal Investigations (OCI) for further
investigation. Between November 7, 2001, and March
2002, Campbell completed CRFs for 407 subjects purportedly enrolled in the aforementioned study. The
CRFs were submitted to the sponsor and reflected the
enrollment of the subjects and their participation in
the study. In the course of its investigation, OCI gathered evidence that more than 200 subjects purportedly enrolled in this study had not, in fact, participated,
and that one subject did not exist.
OCI’s investigation determined that Campbell falsified CRFs that were submitted to the sponsor and falsified documentation to support the existence of a fictitious subject. A federal grand jury returned a 21count criminal indictment on August 29, 2003. On
October 23, 2003, Campbell pled guilty to a single
count of the indictment to resolve all the charges,
admitting she used the mail in furtherance of a
scheme to defraud by submitting a CRF to the sponsor’s contract research organization (CRO) for a subject who did not exist. She was sentenced on March
24, 2004, to 57 months in prison, fined $557,251.22,
given three years supervised release after her prison
term is served, and ordered to make restitution to
Aventis Pharmaceuticals in the amount of
$925,774.61.
Interested persons should also read the related FDA
warning letter to Sanofi Aventis, the sponsor of the
clinical trial (www.fda.gov/cder/warn/2007/07-HFD45-1002.pdf), for more details about the aforementioned FDA inspection, including another problem
site and the efforts of the CRO to document these
violations.
FDA needs medical device advisory panel
members
In the October 15, 2008, Federal Register, FDA solicited
nominations for voting members to serve on various
device-specific panels of the Medical Devices Advisory
Committee in FDA’s Center for Devices and
Radiological Health. Nominations will be accepted for
current vacancies and those that will or may occur
through August 31, 2009. Because scheduled vacancies
occur on various dates throughout each year, no cutoff date is established for the receipt of nominations.
However, when possible, nominations should be
received at least six months before the date of scheduled vacancies for each year, as indicated in the notice.
All nominations for membership should be sent electronically to CV@OC.FDA.GOV, or by mail to Advisory
Committee Oversight & Management Staff (HF-4),
FDA, 5600 Fishers Lane, Room 15A-12, Rockville, MD
20857. Information about becoming a member on an
FDA advisory committee can be obtained at FDA’s Web
site at www.fda.gov/oc/advisory/default.htm.
The specific panels needing voting members included:
• Dental Products
• Ear, Nose, and Throat Devices
• Gastroenterology and Urology Devices
• General and Plastic Surgery Devices
• Hematology and Pathology Devices
• Immunology Devices
• Microbiology Devices
• Molecular and Clinical Genetics Devices
• Neurological Devices
• Obstetrics and Gynecology Devices
• Ophthalmic Devices
exemption of certain devices from portions of the Act,
(7) advise on the necessity to ban a device, and (8)
respond to requests from FDA to review and make recommendations on specific issues or problems concerning the safety and effectiveness of devices. Each panel
also may make appropriate recommendations to the
Commissioner on issues relating to the design of clinical studies regarding the safety and effectiveness of
marketed and investigational devices.
Persons nominated for membership on the panels
should have adequately diversified experience appropriate to the work of the panel in such fields as clinical and administrative medicine, engineering, biological and physical sciences, statistics, and other related
professions. The specialized training and experience
necessary to qualify the nominee as an expert suitable
for appointment may include experience in medical
practice, teaching, and/or research relevant to the field
of activity of the panel. The current needs for each
panel are listed in detail in the notice. The term of
office is up to four years, depending on the appointment date.
Anyone may nominate one or more qualified persons
for membership on one or more of the advisory panels. Self-nominations are also accepted. Nominations
will include a complete curriculum vita of each nominee, current business address, and telephone number.
Nominations will specify the advisory panel(s) for
which the nominee is recommended. Nominations
will include confirmation that the nominee is aware of
the nomination, is willing to serve as a member if
selected, and appears to have no conflict of interest
that would preclude membership. Potential candidates will be required to provide detailed information
concerning financial holdings, employment, and
research grants and/or contracts to permit evaluation
of possible sources of conflict of interest.
• Orthopaedic and Rehabilitation Devices
• Radiological Devices
The panels (1) advise the FDA Commissioner regarding
classification or reclassification of devices into one of
three regulatory categories, (2) advise on possible risks
to health associated with the use of devices, (3) advise
on formulation of product development protocols, (4)
review premarket approval (PMA) for medical devices,
(5) review guidance documents, (6) recommend
FDA final guidance on immune globulin
for primary humoral immunodeficiency
In the July 17, 2008, Federal Register, FDA announced
the availability of a final guidance document titled
Guidance for Industry: Safety, Efficacy, and
Pharmacokinetic Studies to Support Marketing of Immune
Globulin Intravenous (Human) as Replacement Therapy
Research Practitioner / VOLUME 9 NUMBER 6
221
for Primary Humoral Immunodeficiency, dated June
2008. The guidance document provides investigational new drug application (IND) and biologics license
application (BLA) sponsors with FDA’s recommendations for the design of clinical trials to assess the safety, efficacy, and pharmacokinetics of human immune
globulin intravenous (IGIV) products as replacement
therapy in primary humoral immunodeficiency. This
guidance is intended to assist sponsors in the preparation of the clinical/biostatistical and human pharmacokinetic sections of a BLA. It does not address other
sections of a BLA, such as chemistry, manufacturing
and controls, and preclinical toxicology for an IGIV
product for this indication. The guidance is the final
version of a draft guidance of the same title dated
November 2005.
Changes from the draft version include recommendations for compliance with the Pediatric Research
Equity Act of 2007, refinements to the criteria for diagnosing serious infections, refinements to the recommended safety analyses of adverse experiences temporally related to infusions, and additional guidance on
the methodology of pharmacokinetic studies.
FDA accepts written or electronic comments on final
guidance documents at any time. The comments will
be considered for future guidance revisions. Submit
written comments on the guidance to the Division of
Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Room 1061,
Rockville, MD 20852. Submit electronic comments to
www.regulations.gov. Submit a single copy of electronic comments or two paper copies of any mailed
comments, except that individuals may submit one
paper copy. Comments are to be identified with
Docket Number FDA-2005-D-0208 (formerly Docket
No. 2005D-0438).
OHRP final guidance on who is “engaged”
in human subjects research
In the October 23, 2008, Federal Register, the
Department of Health and Human Services’ (HHS)
Office for Human Research Protections (OHRP)
announced the availability of a guidance document
titled OHRP Guidance on Engagement of Institutions in
Human Subjects Research. HHS, through OHRP, regulates research involving human subjects conducted or
222
Research Practitioner / VOLUME 9 NUMBER 6
supported by HHS in regulations found at 45 CFR Part
46. The HHS human subjects protection regulations
stipulate requirements for the conduct of HHS-conducted or -supported research, including requirements
for review and approval by an institutional review
board (IRB) before research involving human subjects
may begin, criteria for IRB approval of research, and
requirements for informed consent or the waiver of
informed consent.
This guidance document makes final the draft guidance of the same title published on December 8, 2006.
OHRP received 24 comments on that draft and those
comments were considered in making this final version. This final document replaces two existing OHRP
guidance documents on the engagement of institutions in human subjects research: a January 26, 1999
document on Engagement of Institutions in Research and
a December 23, 1999, document on Engagement of
Pharmaceutical Companies in HHS Supported Research.
While this is a final document, comments on OHRP
guidance documents are accepted at any time. Submit
written comments to Engagement Guidance
Comments, OHRP, 1101 Wootton Parkway, Suite 200,
Rockville, MD 20852. Comments may be sent via
e-mail to ohrp@hhs.gov or via facsimile to (240) 4536909.
This guidance is only applicable to HHS-conducted or
-supported research projects that have been determined to involve human subjects and that are not
exempt from HHS regulations. Once an activity is
determined to involve non-exempt human subjects
research, this guidance can be used to determine
whether an institution involved in some aspect of the
research would be considered “engaged” in human
subjects research, and would thus need to (1) hold or
obtain an applicable OHRP-approved Federalwide
Assurance (FWA), and (2) certify to the HHS agency
conducting or supporting the research that the
research has been reviewed and approved by an IRB
designated in the assurance and will be subject to continuing review by an IRB.
The guidance document describes (1) scenarios that, in
general, would result in an institution being considered engaged in a human subjects research project; (2)
scenarios that would result in an institution being considered not engaged in a human subjects research project; and (3) IRB review considerations for cooperative
research in which multiple institutions are engaged in
the same non-exempt human subjects research project.
The guidance document is intended primarily for IRBs,
research administrators and other relevant institutional officials, investigators, and funding agencies that
may be responsible for the conduct, review, and oversight of human subjects research that is conducted or
supported by HHS.
and agrees that in some circumstances, institutions that receive an award for non-exempt
human subjects research, but that do not carry
out any of the activities involving human subjects, should not be considered engaged in the
human subjects research. OHRP will continue to
consider this issue in consultation with the HHS
funding agencies.
Most of the comments received on the draft guidance
document expressed general support for OHRP’s draft.
Some comments suggested clarifying changes and
others recommended more substantive changes to the
scenarios described in the draft guidance. All of the
comments received were considered as the guidance
was made final. A discussion of the main comments
follows.
• Institutions Not Engaged in Human Subjects
Research
• Institutions Engaged in Human Subjects Research
OHRP’s draft guidance proposed that institutions
that receive an award through a grant, contract,
or cooperative agreement directly from HHS for
non-exempt human subjects research (awardee
institutions) would generally be considered
engaged in human subjects research, even if all
activities involving human subjects are carried
out by agents of another institution. A few comments urged OHRP to reconsider its view that
such awardee institutions should generally be
considered engaged in human subjects research
when all activities involving human subjects are
carried out by agents of another institution. The
comments noted that considering such awardee
institutions to be engaged in human subjects
research often results in duplicative review by
IRBs and administrative burden for awardee institutions that choose to modify their FWAs to rely
on another institution’s IRB to satisfy applicable
regulatory requirements. These comments questioned whether human subjects were offered
greater protections by considering such awardee
institutions to be engaged in human subjects
research.
OHRP believes that institutions that receive an
award directly from HHS for non-exempt human
subjects research should generally be considered
engaged in human subjects research. However,
OHRP understands these comments’ concerns
Release of identifiable private information or biological specimens. In the December 8, 2006, Federal
Register, OHRP noted it was particularly interested in the public’s comments on the proposal that
institutions whose employees or agents release to
investigators at another institution identifiable
private information or identifiable biological
specimens pertaining to the subjects of the
research, not be considered engaged in human
subjects research. The public comments supported this proposed scenario. OHRP retained this
scenario in the final guidance document, with
only minor clarifying changes (scenario B6).
Administration of clinical trial-related medical services. In the same Federal Register notice, OHRP also
noted it was particularly interested in the public’s
comments on the proposal that institutions
(including private practices) not selected as
research sites whose employees or agents administer clinical trial-related medical services, not be
considered engaged in human subjects research
provided that specified conditions were met. One
of the proposed conditions was that the institution’s employees or agents do not administer the
primary study interventions being tested under
the protocol. The public comments on this proposed scenario were generally supportive, but
several comments sought clarifications on some
of the proposed conditions. In addition, a few of
the comments recommended that OHRP expand
the scenario to permit the employees or agents of
an institution not selected as a research site to
administer the study intervention being tested or
evaluated under the protocol, and still not consider such an institution to be engaged in human
subjects research.
Research Practitioner / VOLUME 9 NUMBER 6
223
In the final guidance, OHRP retained the proposed scenario, with minor changes in response
to the public comments (scenario B2). However,
OHRP also has included another scenario in the
final guidance that would allow employees or
agents of an institution not initially selected as a
research site to administer the study interventions being tested or evaluated under the protocol, provided that this occurs on a one-time or
short-term basis, and specified conditions are
met (scenario B3). OHRP believes this is responsive to the concern raised in a public comment
that research subjects are sometimes unexpectedly hospitalized or otherwise unexpectedly unable
to receive a study intervention being tested or
evaluated in a protocol from an institution that
previously had been designated as a research site.
FDA workshop on breast cancer thermal
ablation treatment
In the July 21, 2008, Federal Register, FDA announced a
September 15, 2008, public workshop to discuss the
issues associated with the development and implementation of feasibility trials for local treatment of
breast cancer by thermal ablation (i.e., cryoablation,
focused ultrasound, interstitial laser, microwave,
radiofrequency ablation). FDA invited stakeholders to
attend this public workshop to discuss how standardized protocols for evaluation of tissue biopsy pathology, selection of tumors amenable to ablation, image
guidance for ablation, post-ablation imaging and
assessment, and tissue pathology of ablated specimens
can be developed and used in breast cancer thermal
ablation clinical trials. The public workshop served as a
forum for discussing where within the multispecialty
care path involving operative therapy, chemotherapy,
and radiation therapy, thermal ablation may play a
role. The transcript of the workshop is at www.
blsmeetings.net/2008ThermalAblationWorkshop/
Transcripts.pdf.
FDA draft guidance on antibacterial drugs
for chronic bronchitis in COPD
In the August 22, 2008, Federal Register, FDA
announced the availability of a draft guidance
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Research Practitioner / VOLUME 9 NUMBER 6
document titled Acute Bacterial Exacerbations of Chronic
Bronchitis in Patients with Chronic Obstructive Pulmonary
Disease: Developing Antimicrobial Drugs for Treatment.
The purpose of this draft guidance is to assist clinical
trial sponsors and investigators in the development of
antimicrobial drugs for the treatment of acute bacterial exacerbations of chronic bronchitis in patients with
chronic obstructive pulmonary disease (ABECBCOPD). FDA’s thinking in this area has evolved in
recent years, and when made final, this guidance will
inform sponsors of the changes in FDA’s recommendations. Specifically, this draft guidance recommends
that ABECB-COPD clinical trials be designed as superiority rather than non-inferiority trials, and discusses
some possible study designs that might be employed in
an ABECB-COPD trial designed to show superiority.
This draft guidance discusses patient-reported outcome
instruments for assessing clinical response, and the use
of time to resolution of symptoms as a possible
approach to assessing the primary endpoint in clinical
studies.
Although FDA accepts comments on any guidance at
any time, comments on this draft should be received
at FDA by November 20, 2008. Follow the instructions
above on submitting comments. Comments are to be
identified with Docket Number FDA-2008-D-0419.
FDA draft guidance on clinical trials
for incontinence devices
In the September 19, 2008, Federal Register, FDA
announced the availability of a draft guidance document titled Clinical Investigations of Devices Indicated for
the Treatment of Urinary Incontinence. This draft guidance document describes FDA’s proposed recommendations for clinical trials of medical devices indicated
for the treatment of urinary incontinence.
Urinary incontinence is defined as the involuntary
loss of urine. This draft guidance is intended to assist
device manufacturers who plan to conduct clinical trials of devices intended to treat urinary incontinence
in support of PMA applications or premarket 510(k)
notification submissions. The draft guidance describes
FDA’s proposed recommendations for human clinical
trials that involve the use of any type of urinary incontinence device, including, but not limited to, urological clamp for males; non-implanted, peripheral and
other electrical continence devices; protective garment for incontinence; surgical mesh; electrosurgical
cutting and coagulation device and accessories; perineometer; gynecologic laparoscope and accessories;
and vaginal pessary.
Although FDA accepts comments on any guidance at
any time, comments on this draft should be received
at FDA by December 18, 2008. Follow the instructions
above on submitting comments. Comments are to be
identified with Docket Number FDA-2008-D-0457.
FDA cites orthopedic surgeon for IDE and
informed consent violations
Bruce Ziran, director of Orthopaedic Trauma at the St.
Elizabeth Health Center in Youngstown, OH, received
an August 27, 2008, warning letter from FDA. The
warning letter resulted from an FDA inspection conducted from April 23 to May 2, 2008. The deviations
from FDA regulations excerpted from the letter were
the following:
• You allowed subjects to participate in an investigation without FDA approval.
A physician that conducts an investigation,
which is defined as a clinical investigation or
research involving one or more subjects to determine the safety or effectiveness of a medical
device, with a device for an indication that has
not been FDA-approved or cleared shall not allow
subjects to participate in the investigation. The
FDA-approved indication for the [redacted device
name] states, [redacted]. Thus the approved indication is for use of the device alone. Your protocol indicates that you were conducting an investigation to determine the safety and effectiveness
of the device in combination with either an
[redacted] or [redacted]. This clinical investigation of the safety and effectiveness of a new indication for the device requires an FDA-approved
investigational device exemption (IDE). You
allowed subjects to participate in the investigation without FDA approval.
In your response you state upon recognizing the
problem you took immediate action to suspend
the study and sent a letter to the subjects
involved informing them of the issue and
provided them with an opportunity to contact
you. In addition, your corrective action includes
a statement that you will seek out education
material/course regarding IDE/humanitarian use
device (HUD) issues before being part of an investigation that uses such devices. This response is
incomplete in that you did not provide documentation of notification of all of the subjects.
Please provide a copy of the letter sent to the subjects, the IRB approval of the letter, and documentation that all subjects were notified.
• Failure to maintain accurate, complete, and current records relating to documents evidencing
informed consent and failure to maintain case
histories that document that informed consent
was obtained prior to the subjects’ participation
in the study.
A participating investigator shall maintain accurate, complete, and current records relating to
documents evidencing informed consent and the
case histories shall include documentation that
informed consent was obtained prior to the subjects’ participation in the study. You failed to
maintain case histories that document that
informed consent was obtained from subjects
prior to their participation in the study. Study
consent forms for [redacted] subjects enrolled in
the study were dated after the study procedure
was performed.
In your response you state your clinics were
housed off the main campus temporarily and this
required weekly transport of patients’ charts
some of which were misplaced or lost. You tried
to find the lost consent documents and if they
could not be found, re-obtained consent from
the subjects; however, the re-obtained consent
forms do not indicate that consent was obtained
prior the subjects’ participation in the study. As a
result of possible loss, you instituted periodic
checkpoints of source documents to ensure
appropriate maintenance of the records; however, you acknowledged your periodic checks were
insufficient. Your corrective action states you will
recommend that the IRB institute a policy to
avoid any investigational studies when patient
records are subject to a risk of loss or misplacement. Your response is inadequate in that you as
Research Practitioner / VOLUME 9 NUMBER 6
225
the principal investigator are responsible for
maintaining accurate, complete, and current
records relating to documents evidencing
informed consent.
Your corrective action further states that you will
recommend that your office provide documentation that an informed consent discussion
occurred and include the time and date of consent. This response is inadequate in that you did
not provide the procedure and documentation of
training of all applicable personnel for this policy. Please provide copies of policies, procedures,
and trainings with expected completion dates
that are being developed and implemented to
ensure subjects’ case histories contain documents
evidencing informed consent. In addition, your
corrective action lacks any policies and procedures to ensure all subjects have obtained
informed consent prior to any study-related procedures. Please provide copies of policies, procedures, and trainings with expected completion
dates that are being developed and implemented
to ensure informed consent is obtained with the
most current IRB approved consent document
prior to any study-related procedures being performed.
• Failure to ensure all required elements of
informed consent were documented and provided to study subjects.
Although the IRB reviews and approves the
informed consent document, it is ultimately the
responsibility of the investigator to ensure the
informed consent process meets the regulatory requirements (emphasis added). Your consent documentation does not include all the essential elements
listed in 21 CFR 50.25. The written consent document must include the elements of informed
consent required by 21 CFR 50.25. Research subjects voluntarily agree to participate in a clinical
investigation. In order to make an informed decision to participate, they must be given all applicable information. Examples of the failure to
include essential elements in consent documents
include:
- The informed consent document does not
identify that the implantation of [redacted]
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Research Practitioner / VOLUME 9 NUMBER 6
combined with [redacted] or [redacted] is an
experimental procedure.
- The investigational plan identifies risks to
include [redacted] reaction. However, the consent document lacks identification of any of
these risks with this investigational device.
In your response you state you discussed such
issues verbally with patients and that you will
make your best efforts to provide documentation
of such discussions with the subjects and ensure
it is present in written consents in future studies.
This response is incomplete in that you did not
provide documentation that you informed your
subjects that this was an experimental procedure
with additional risks that are identified in the
investigational plan. Please provide documentation that subjects have been informed, and provide copies of policies, procedures, and trainings
with expected completion dates that are being
developed and implemented to ensure informed
consent documents contain all the essential elements in accordance with 21 CFR 50.25.
In your response you state you believed that
since the study was vetted by the sponsor as well
as every participating IRB, you would have been
informed of the need for an IDE and there would
not be any regulatory concerns. The IDE regulations describe sponsor responsibilities as well as
those of investigators. IRB responsibilities are
found in 21 CFR Part 56. These three sets of
responsibilities overlap to ensure appropriate
conduct of clinical studies and the protection of
the rights and welfare of participating subjects.
You are held responsible for knowing and following the regulations pertinent to your activities as
a clinical investigator in FDA-regulated studies.
FDA pilot project on electronic study data
submissions
In the August 19, 2008, Federal Register, FDA’s Center
for Drug Evaluation and Research (CDER) sought
sponsors interested in participating in a pilot project
to test the submission and processing of clinical study
data provided electronically in a standardized format.
This pilot will test the data extract, validation, and
load procedures developed to populate “Janus,” the
study data repository component of a common, standards-based infrastructure that is being developed
jointly by FDA and the National Cancer Institute
(NCI) to support the exchange of clinical research
data. The pilot also will test a new XML (extensible
markup language)-based submission format for standardized clinical study data. FDA anticipates that a
successful pilot will enable CDER to routinely receive,
process, and store all standardized clinical study data
in a data warehouse environment that will enhance
the center’s capability to manage and review standardized study data.
Janus is designed to enhance FDA’s capability to manage and review standardized study data. The Janus initiative is part of a larger effort to implement a common, standards-based electronic infrastructure that
supports the submission, validation, data warehousing, access, and analysis of structured scientific data to
support regulatory review. CDER has been accepting
voluntary electronic submissions of standardized clinical study data since July 2004. Applicants wishing to
provide clinical study data in standardized format are
advised to follow the Study Data Tabulation Model
(SDTM) defined by the Clinical Data Interchange
Standards Consortium (CDISC). CDISC is an open,
multidisciplinary, nonprofit organization that has
established worldwide industry standards to support
the electronic acquisition, exchange, submission, and
archiving of clinical trial data and metadata for medical and biopharmaceutical product development
(www.cdisc.org).
FDA is planning to amend the regulations governing
the format in which clinical study data and bioequivalence data are required to be submitted for NDAs,
BLAs, and abbreviated new drug applications (ANDAs)
to require that clinical data submitted for NDAs, BLAs,
and ANDAs, and their supplements and amendments
(1) be provided in electronic format and (2) use a standardized data structure, terminology, and code sets as
referenced in FDA guidance to enable efficient and
comprehensive data review.
The goals of the new Phase 3 pilot are as follows:
• Transition the Phase 2 pilot to operational
production;
• Test the electronic processing of standardized
clinical study data, including the successful validation and loading of data into the Janus study
repository and subsequent access to that data by
reviewers using a combination of analytical and
visualization tools;
• Test a new XML-based submission format for
CDISC content (CDISC-HL7 messages, see below)
currently under development;
• Extend the Janus logical data model and serviceoriented architecture to support submission of
CDISC-HL7 messages;
• Integrate with NCI’s Enterprise Vocabulary
Service (EVS);
• Test the integration and analysis of clinical study
data stored in Janus with pharmacogenomic data
currently being received through the Voluntary
Genomic Data Submissions (VGDS) program.
CDER’s experience during Phase 2 showed that SDTM
files routinely fail the Janus validation procedures and
cannot be loaded into Janus automatically. Pilot participants would work closely with Janus technical staff
to review the validation errors, correct them, and
resubmit the files. The ability to successfully load data
into the Janus repository is an important pilot milestone. Experience gained as a result of working with
participating sponsors during this pilot will help FDA
improve the validation criteria, which subsequently
will help improve the quality of future study data submissions. Pilot participants will also gain valuable
experience in creating and submitting quality standardized data submissions. Of particular interest are
pilot participants who are also able to provide pharmacogenomic data (i.e., VGDS) with the CDISC data.
This will enable FDA to test the integration of clinical
data stored in Janus with pharmacogenomic data.
Although a VGDS is not required to participate in this
pilot, it is a desirable component of the pilot and is
encouraged whenever possible.
FDA requested written or electronic requests to participate in the pilot project by November 17, 2008, but
general comments on the Janus operational pilot project are welcome at any time. Follow the instructions
above on submitting comments. Comments are to be
identified with Docket No. FDA-2008-N-0428.
Research Practitioner / VOLUME 9 NUMBER 6
227
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