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Recommendations from NHLBI
Workshop Improving Design and Conduct of Clinical Trials
February 8-9, 2001 Bethesda,
MD
The NHLBI Clinical Trials Review Group was
charged with developing suggestions for increasing the effectiveness and
efficiency of the NHLBI Clinical Trials effort. The group included trialists
with a primary interest in heart, lung, and blood diseases representing the
clinical, epidemiological, and biostatistical community as well as staff from
the NHLBI. This report represents the results of a one and a half day
brainstorming session. It has been circulated to all the participants for their
comments, and while it does not represent complete agreement on content, there
are no major areas of disagreement.
The NHLBI has set the pace for the development of
clinical trials in the past. We are now entering a new era in medicine
characterized by:
- An explosion of new diagnostic and therapeutic
technologies fueled by NIH funded basic science, both intramural and
extramural.
- A continued focus with increased intensity on all
elements of the disease spectrum: identification of genetic susceptibility,
primary prevention, treatment of subclinical disease to prevent clinical
manifestations, long-term treatment of chronic disease,and evaluation of
therapies for life threatening acute manifestations.
- A need to understand clinical issues in children
and the elderly.
- A need to link clinical trial findings to delivery
of effective therapy, including to populations currently identified as under
treated.
- An environment in which the financial margin of
clinical care has diminished to the point that institutions receiving grant and
contract money from the NIH can no longer use departmental money and fees
collected from patient care billing to subsidize clinical trials.
- A legal environment in which the details of
contracts compete with the time and effort required to develop scientifically
excellent protocols.
- A changed view of patients from passive recipients
of health care to active consumers of health care and research.
- An increased focus on both the role of local
Institutional Review Boards (IRBs) and the conflict between the importance of
releasing data for research and the protection of patient privacy in federally
funded studies.
In order to meet the challenges and opportunities of
this new environment, the NHLBI should consider a significant revamping of its
approach to its clinical trials effort to include the following strategies:
I. Given the major investment made by the United States in
epidemiological studies, registries, and previous clinical trials, the NHLBI
should develop better ways to use existing and new data to determine the need
for trials and to plan them. Different policies would be needed for ongoing
versus completed studies; clinical trials versus observational studies;
published versus unpublished data; grants versus contracts; individual research
project grants (R01s) versus Cooperative Agreements; and studies that have
published only their major findings versus studies that have published both
major findings and other results. This approach should balance the intellectual
investment that comes from investigator-initiated efforts with the imperative
to use projects supported by public funds for commonly identified national
needs.
- The NHLBI should further refine mechanisms to
facilitate access to existing data sets that it has funded to provide
information to improve understanding of the need for new clinical trials and
for planning them. This mechanism should include a formal agreement regarding
publication policies, which should emphasize confidentiality as
appropriate.
- The NHLBI should work with other government
agencies to develop a mechanism for similar sharing of data sets among agencies
and their grantees.
- The NHLBI should consider the use of registries,
especially with regard to rapidly evolving therapeutic technologies, to
evaluate the need for trials and to enhance understanding of the
generalizability of trial results. Such registries might provide an efficient
structure for adding a randomized component to the registry to evaluate the
appropriateness of practice variations observed in the registry.
- Under some circumstances it may be valuable to add
an intervention component to an ongoing epidemiological study funded by the
NHLBI, in addition to the recognized practice of sometimes adding a significant
epidemiological component to a large clinical trial.
- A more systematic approach should be developed for
making the critical decisions about what to do at the end of clinical trials.
Criteria should be developed for determining when continuation of follow-up for
an extended period should be seriously considered. In such cases a plan should
be enacted far in advance of the trial completion date.
- The NHLBI should support further methodologic work
on the role of observational data analysis in determining the need for trials
or for replacing the need for trials. This methodological work would be quite
inexpensive relative to the cost of full trials and would mostly involve a
pragmatic analysis of issues such as trial costs, estimates of potential
benefits of interventions, and issues such as randomizing after early
termination of a trial for efficacy and estimation of bias in nonrandomized
treatment comparisons.
II. There is no shortage of
excellent ideas for clinical trials that would improve the public health. It is
therefore imperative for the NHLBI to focus on redesigning its systems so that
the greatest efficiency is gained in answering important clinical and public
health questions.
- Formal clinical trials networks should be
considered for some conditions when:
- multiple interventions can be addressed by
trials with similar structure (e.g., patient cohorts, similar protocols, manuals of operations, data collection forms); and
- the time for each study is not prolonged;
and
- the number of patients needed for each study is
small to moderate
or
- when complex technology or complex
behavioral interventions need to be employed.
For example, sickle cell
disease and congenital heart disease are conditions for which consolidated
expertise could reap significant rewards. In the area of primary prevention,
sentinel networks to evaluate biomarkers of atherosclerosis prevention could be
helpful in sorting through the growing number of potential interventions.
Because behavioral interventions, including interventions on lifestyle
behaviors such as diet and exercise need to be evaluated in their complexity
before their use in large, outcome-based trials, networks with behavioral
expertise should be considered.
- These networks provide the possibility
of a major public private partnership in which the infrastructure provided by
the NHLBI could produce a more efficient method of doing clinical trials that
would attract studies funded by industry, thus providing an opportunity for
rapid resolution of the many unanswered questions about diagnostics and
therapeutics.
- Although networks are potentially of great use
in the situations listed above, the NHLBI should carefully evaluate the risks
and benefits of forming networks for conditions requiring large and long
trials. The advantages of networks for such major problems as sudden death,
heart failure, and secondary prevention of heart failure are more debatable,
but a more efficient system for conducting trials in these areas is clearly
needed. The network approach should not detract from the experience and record
of success in the design and conduct of non-network based trials as
appropriate.
- Regardless of whether a formal clinical trial
network is formed in each area, the NHLBI needs to reduce the time from the
concept to trial completion by developing an organized approach to investments
and standards in the following common structural elements:
- Nomenclature -- The development of
common nomenclature for case report forms would allow new trials to be
initiated with considerable shortening of development of case report forms.
Ideally, the NHLBI could play a central role in working towards a common
nomenclature with the FDA, HCFA, the VA, and other professional organizations
to reduce redundant coding by health care providers conducting clinical trials.
- Information technology platform --
Efforts to develop common technology platforms among NHLBI coordinating centers
and investigators would reduce the time to startup and enhance communication
during the conduct of trials. For example, internet-based investigator meetings
and joint, internet-based IRB meetings could markedly reduce time delays.
- Pools of investigators with common training and
operational procedures should be developed for each of the major disease areas
- for certain conditions a formal network may be
preferred
- for other conditions a formal network is not
needed but common procedures could significantly improve the quality and speed
of the clinical trials in each area
- common operational procedures maintained on a
shared information technology platform could enhance the speed of initiation of
trials by reducing the need for training
- certification of investigators and study
coordinators as "NHLBI certified investigators"
- An annual meeting for each of the major disease
areas held by the NHLBI, including trialists, clinicians, patients, and policy
makers could:
- Review research priorities in that area
- Review output of major epidemiological studies
and clinical trials funded by the NHLB
- Review appropriate nomenclature
- Provide training about clinical research for
new investigators and updates for old investigators
- The time for protocol development should be reduced
by:
- having more focused RFPs for contracts and RFAs
for Cooperative Agreements
- having a smaller group finalize the protocol
after the proposed study has been funded
- shortening time to buy in by the clinical
investigators; a more effective information technology platform could allow
this to happen electronically
- The NHLBI should work with OHRP, its networks, and
its investigators to develop more efficient systems for centralized ethical
review and effective audit of the veracity and quality of the conduct of
clinical trials. This system should seek to avoid redundant and ineffective
systems of review of ethics, veracity, and quality. Instead a systematic
approach should be taken so that the public can be assured of high quality
clinical research done with the highest ethical standards.
- The NHLBI should encourage pilot studies in certain
circumstances, either separate from the main study or incorporated in the
startup of the main study. Adequate and appropriate funding mechanisms should
be developed to encourage pilot studies that enhance the efficiency of the main
trials. This approach could hone the practical aspects of a study when existing
data are not sufficient for confidence in its design or feasibility. This
effort should include a reevaluation of feasibility at the conclusion of the
pilot. An approach would be needed so as not to make the conduct of a pilot
study an effort with intellectual or financial risk that is too great from the
perspective of the investigator because of the cost of startup of a new
project. The use of networks for pilots could be one such approach so that a
failed pilot could be rapidly followed by another protocol.
- The NHLBI should conduct a serious evaluation of
the cost of conducting clinical trials at the site level. This is an urgent
need. Almost all sites in NHLBI trials believe that their activities are not
compensated at a level necessary to cover the costs incurred. This leads to
inordinate delays in enrollment and forces sites to conduct less desirable
studies in order to subsidize NHLBI efforts.
- A standard for reimbursement for heart, lung, and
blood trials would create a new ethical standard that would reduce the national
worry about inducement of investigators by payments over and above reasonable
levels. While "overpayment" is not typical of industry-sponsored trials, it
does occur occasionally, and an equal standard could be used for both
government and industry funded trials.
- Large, simple trials remain an important way to
answer critical questions amenable to abbreviated data collection. The NHLBI
should encourage the study of approaches to reducing costs by streamlining the
collection of data in outcome based trials, so that definitive answers can be
obtained at a reasonable cost. Many clinical outcome questions can only be
answered through international collaboration; a better system for working with
international collaboration is needed.
III. The conduct of the best
possible clinical trials in heart, lung, and blood diseases is in the interests
of both the nation and the world. Because of the importance and size of this
mission, the NHLBI should seek methods of optimizing the potential for
collaboration between NHLBI and other organizations. It is in the best interest
of the public to develop a better, more efficient approach to government
interaction and to public private partnerships so that adequate resources are
brought to bear on important clinical trials and so that the trials are
designed and executed in the most effective manner.
- The NHLBI should work with other institutes within
the NIH to develop trials that measure various disease-specific endpoints
(e.g., cardiovascular disease and cancer) at different times in the same
populations. Cancer and rheumatic diseases represent specific areas of
opportunity where long-term therapies have cardiovascular and pulmonary
consequences, and the endpoints relative to one disease occur at a different
time point compared with the other diseases. The intersection of mental health
and heart, lung, and blood diseases represents another important chance for
collaboration among Institutes.
- The NHLBI should also work more closely with the
Department of Veterans Affairs Cooperative Studies Program (CSP) in conducting
joint clinical trials. Heart, lung, and blood diseases represent a significant
portion of the diseases of the veteran population and the CSP has conducted
30-40 percent of its trials in these disease areas over the last 25 years.
- The NHLBI should devote immediate attention to
working directly with HCFA and its investigators to facilitate implementation
of the new HCFA guideline on reimbursement of clinical trials. This effort
should also include ongoing efforts with the Office of the Inspector General,
DHHS. This effort will probably require the creation of an office to maintain
appropriate communication.
- The NHLBI should work to facilitate the co-funding
of clinical trials by the medical products industry, recognizing the increasing
complexity of the legal and conflict of interest environment. This may require
creation of template agreements with the pharmaceutical, biological, and
medical products industries to address their legitimate needs and concerns.
Additionally, further clarification of the principles of public private
partnership is needed. In some cases inexperienced investigators will need
assistance in negotiating with industry to enhance the probability that
government, academia, and industry will meet their goals without breeching the
principles of public-private partnership.
- The NHLBI should work with managed care health
plans to achieve greater participation of plans and their patients in
NHLBI-sponsored clinical trials. Important goals are agreement on coverage of
routine patient care costs by health plans, negotiation on definitions of
routine care costs before initiation of trials with unusually high costs,
inclusion of plan-based physicians in the conduct of trials, and involvement of
health plan representatives in the planning of new trials.
IV. When an investment is made in a
major clinical trial, the potential advantage of adding additional questions
that could not otherwise be answered is self-evident. In order to take maximal
advantage of this opportunity:
- Planning for ancillary studies should occur along
with the plans for the main clinical trial. In many cases the funding may come
later, but unless the substudies are planned in conjunction with the main
trial, the likelihood of their successful completion may be compromised.
- The mechanistic substudy RFA program that was
recently initiated by the NHLBI should continue.
- An equivalent program is urgently needed to fund
methodological research on new statistical methods and the study of the conduct
of clinical trials. The field is suffering from an absence of funding for such
methodological research.
V. In order to maximize the
opportunity to improve its clinical trials program, the NHLBI should consider
further one-day meetings to discuss individual points in these
recommendations. Submitted by Robert Califf, M.D. Chair
E-mail: Calif001@mc.duke.edu
CLINICAL TRIALS WORKSHOP PLANNING
GROUP
Robert Califf, M.D., Workshop Chair Duke
University Medical Center Duke Clinical Research Institute P.O. Box
17969 Durham, NC 27715
Reuben Cherniack, M.D. Department of Medicine
National Jewish Medical and Research Center PPU 3, May Building
1400 Jackson Street Denver, CO 80206 Katherine M. Detre, M.D.,
Dr.P.H. Professor, Department of Epidemiology A531 Crabtree Hall
University of Pittsburgh Pittsburgh, PA 15261 George Williams,
Ph.D. Vice President, Biostatistics and Research Systems Merck
Research Laboratories P.O. Box 4 West Point, PA 19486-0004
Janet Wittes, Ph.D. Statistics Collaborative,
Inc. 1710 Rhode Island Avenue, N.W. Suite 200 Washington, DC
20038
NHLBI Representatives
Lawrence M. Friedman, M.D. Special Assistant to
the Director National Heart, Lung, and Blood Institute National
Institutes of Health Building 31, Room 5A06 31 Center Drive, MSC
2482 Bethesda, MD 20892-2482
Carl Roth, Ph.D., LL.M. Associate Director for
Scientific Program Operation National Heart, Lung, and Blood Institute
National Institutes of Health Building 31, Room 5A03 31 Center Drive
MSC 2482 Bethesda, MD 20892-2482
Peter J. Savage, M.D. Acting Director, Division of
Epidemiology and Clinical Applications National Heart, Lung, and Blood
Institute National Institutes of Health Two Rockledge Center, Room
8100 6701 Rockledge Drive, MSC 7938 Bethesda, MD 20892-7938
CLINICAL
TRIALS WORKSHOP SPEAKERS
Julie Buring, Ph.D. Professor of Ambulatory Care
& Prevention Harvard Medical School & Brigham & Women's
Hospital 900 Commonwealth Avenue (East) Boston, MA 02215
Gregory Burke, M.D., M.S. Associate Professor
Department of Public Health Sciences Bowman Gray School of Medicine 300
South Hawthorne Rd. Winston-Salem, NC 27103
Michaele Christian, M.D. Associate Director
Division of Cancer Treatment and Diagnosis Cancer Therapy Evaluation
Program National Cancer Institute 6130 Executive Blvd., Room 742
Rockville, MD 20852
Jeffrey Cutler, M.D. Director, Clinical
applicarions and Prevention Program Division of Epidemiology & Clinical
Applications National Heart, Lung, and Blood Institute 6701 Rockledge
Drive, Room 8130 Bethesda, MD 20892
Joseph Feczko, M.D. Sr. Vice President Medical
and Regulatory Operations U.S. Pharmaceutical Group Pfizer Inc. 235
E. 42nd St. New York, NY 10017-5755
Robert L. Frye, M.D. Department of Medicine
Mayo Clinic 200 First St. Southwest Rochester, MN 55905
Saul Genuth, M.D. School of Medicine Case
Western Reserve University 10900 Euclid Avenue Cleveland, OH
44106-4951
Peter Greenwald, M.D. Director, Division of Cancer
Prevention National Cancer Institute 31 Center Drive, Room 10A52
Bethesda, MD 20892-2580
Steven Haffner, M.D. Professor Division of
Clinical Epidemiology Department of Medicine University of Texas Health
Science Center at San Antonio 7703 Floyd Curl Dr. San Antonio, TX
78284-7873
Al Hallstrom, Ph.D. Professor of Biostatistics
University of Washington 1107 N.E. 45th Street, Suite 505 Seattle, WA
98195
William G. Henderson, Ph.D. Chief, Cooperative
Studies Program Coordinating Center (151K) Hines VA Hospital 5th
Avenue and Roosevelt Road Hines, IL 60141
James Kiley, Ph.D. Director, DLD, NHLBI 6701
Rockledge Drive RCKL2/Room 10018 Bethesda, MD 20892-7952
Lewis H. Kuller, M.D., Dr.P.H. Department of
Epidemiology Univ. of Pittsburgh, GSPH A526 Crabtree Hall,
Epidemiology 130 DeSoto St. Pittsburgh, PA 15261
Stuart J.
Pocock, Ph.D. Professor of Medical Statistics London School of Hygiene
and Tropical Medicine Department of Medical Statistics Keppel
Street London WC1E 7HT England
Nancy C. Santanello, M.D., M.S. Senior Director,
Epidemiology Merck Research Laboratories PO Box 4, BL 1-7 West
Point, PA 19486
Joseph Selby, M.D. Director, Division of
Research Kaiser-Permanente Medical Center 3505 Braodway Oakland, CA
94611-5714
Russell P. Tracy, Ph.D. Laboratory for Clinical
Biochemistry Research University of Vermont - Aquatec Bldg Rm T-205
55 A South Park Dr. Colchester, VT 05446
Sean Tunis, M.D., MSC. Director, Coverage and
Analysis Health Care Financing Administration Office of Clinical
Standards and Quality Coverage & Analysis Group Mailstop
S3-02-01 7500 Security Boulevard Baltimore, MD 21244-1850
Joel Verter, Ph.D. Biostatistics Center 6110
Executive Blvd., Suite 750 Rockville, MD 20853
Elliott Vichinsky, M.D. Division Head,
Hematology/Oncology Director, Comprehensive Sickle Cell Center
Children's Hospital of Oakland 747 52nd Street Oakland, CA 94609
Robert A. Wise, M.D. Associate Professor of
Medicine Johns Hopkins Asthma and Allergy Clinic 301 Bayview Boulevard
Baltimore, MD 21224
Last Updated June 2011
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