Transcript 20th Century milestones in clinical research: Looking back

Twentieth Century Milestones
in Clinical Research:
Looking Back and Moving Forward
Michelle Price, M.Ed.
Department of Surgery
UTHSCSA
Grand Rounds – June 19th, 2006
Value of Human Life vs.
Advancement of Knowledge
A human life is nothing
compared to a new fact in
science…the aim of
science is the
advancement of human
knowledge at any
sacrifice to human
life…We do not know of
any higher use we can
put a man to.
Source: Slosson, Edwin in The New York Independent (1895)
Self-experimentation & healthy
volunteers - 1900
Following the self-infection
of two of his colleagues
(resulting in the death of
one),
Walter Reed uses
consent form in study
of yellow fever at Camp
Lazear in Cuba
Yellow Fever Study Informed
Consent & Waiver
The undersigned understands perfectly that in
the case of the development of yellow fever in
him, that he endangers his life to a certain
extent, but it being entirely impossible to him to
avoid the infection during his stay in this island,
he prefers to take the chance of contracting it
intentionally in the belief that he will receive from
the Reed Commission the greatest care and the
most skillful medical service.
Source: Bean WB. Walter Reed and the ordeal of human experimentation; 86.
Dawn of the IRB
1902 – Albert Moll
recommends the
use of advisory
boards to consider
ethical aspects of
planned human
experiments
The Hygienic Laboratory
1904 – Hygienic
Laboratory moves to
Washington, DC
Dr. Joseph J Kinyoun, founder of
the Hygienic Laboratory.
Physicians as Researchers?
1906 – Daniel W. Cathell
advises:
Be careful never to speak of
anything you do for a
patient as an experiment for
every body is more or less
opposed to physicians
‘trying experiments’ upon
themselves or theirs.
Residents as subjects!
1906 – Elie Metchnikoff
(Paris) develops a
calomen ointment for
prophylaxis of syphilis
and convinces a resident
to inoculate himself with
syphilis as the subject of
his doctoral thesis
Rockefeller Institute Hospital
In 1910, Rockefeller
Institute Hospital
opens as the first
dedicated clinical
research facility in
the United States
1913 – George Bernard
Shaw coins the term
‘guinea pigs’ to describe
human research subjects
The folly . . . which sees in
the child nothing more than
the vivisector sees in a
guinea pig: something to
experiment on with a view
to rearranging the world.
World War I (1914-1918)
• US Chemical Warfare Service (1918) Use of chemical warfare agents (mustard
gas) and development of protective gear
• Battle against venereal disease among the
troops
• Hygienic Laboratory and Public Health
Service focused on sanitation around
military bases
National Institute of Health
• 1930 – Ransdell Act
renames the Hygienic
Laboratory the National
Institute of Health (NIH)
• Authorized research
fellowships
• Marked a change in
attitude toward public
funding of medical
research
Senator Joseph E. Ransdell
FDA Authority
• In 1927, the Food and Drug
Administration is created
from the USDA Bureau of
Chemistry
• In 1938, Elixir of
Sulfanilamide kills 107
people
• The Federal Food, Drug and
Cosmetic Act of 1938
requires pharmaceutical
companies to prove drug
safety
World War II (1939-1945)
• 1941 – Office of Scientific Research and
Development establishes Committee on
Medical Research to fund and coordinate
research on military medical problems
• Studies on altitude and
protective gear for pilots
• Oral saline therapy as a firstaid measure on battlefield
• Vaccines and treatments for
tropical diseases
Medical Research under the Nazis
• Racial hygiene studies – twins, genetic,
gynecologic, reproductive, sterilization
• War medicine – effects of poisons,
ammunition, biological & chemical agents,
altitude, extreme temperatures,
sulfonamides for treatment of wound
infection
• Infectious disease & vaccination
Josef Mengele “The Angel of Death”
Nuremburg Code
1946 – Nuremburg
Code requires:
– Voluntary and
informed consent
– Minimizing risks to
subjects
– Results are
valuable to society
The Golden Years at NIH
• NIH grant funding
grew from $4 M in
1947 to > $100 M in
1957
• NIH budget expanded
from $8 M in 1947 to
> $1 B in 1966
President Harry S Truman applied the first trowel of mortar to the NIH Clinical
Center cornerstone (1951).
Kefauver-Harris Amendments
• 1959 – Senate Subcommittee on Anti-trust and
Monopoly investigation of pharmaceutical
studies
• 1961 – Chemie Grunenthal withdraws
thalidomide after it causes approximately 10,000
birth defects
• 1962 – Kefauver-Harris amendments to the
Food, Drug and Cosmetic Act requires that
pharmaceutical companies:
–
–
–
–
Prove drug efficacy
Submit adverse reaction reports to the FDA
Include risk/benefit info in consumer advertising
Use informed consent in clinical trials
Declaration of Helsinki - 1964
• Foundation of human experiments on
scientifically established facts (lab & animal)
• Conduction by scientifically qualified persons
• Restriction of studies to scientific problems
important enough to warrant inherent risks
• Careful assessment of inherent risks in
comparison with foreseeable benefits to the
subjects or others
• Use of special caution in performing clinical
research that has the potential to alter the
subject’s personality by drugs or procedures
Ethics and Clinical Research
1966 – “Ethics and Clinical Research”
(Beecher) details 22 ethically-objectionable
published clinical trials
The most influential single paper ever written about experimentation
involving human subjects (Moreno 2001; Harkness et al 2001)
- Withholding known
treatments
- Conducting toxicity
studies to further
define the toxicology
of a substance
- Injecting toxic levels of
carbon dioxide into the
closed respiratory
system to induce
cardiac arrhythmia
Dr. Henry Knowles Beecher at
Massachusetts General Hospital, 1962
Tuskegee Study
• Jean Heller publishes exposé in 1972
Some of the Tuskegee Study Group clinicians. The third figure to the right is Dr.
Reginald D. James, a black physician involved with public health work in Macon
County, not directly involved in the study. Nurse Rivers is on the left.
Additional Federal Regulations
• 1981 - FDA issues regulations for human
subjects protection
• 1981 – Title 45, Code of Federal Regulations,
Part 46: Protection of Human Subjects
establishes regulations for DHHS-supported
research
• 1991 – DHHS and 15 other governmental
agencies adopt “Common Rule” (45 CFR 46
)governing clinical research
– FDA does not adopt this rule
Inclusion of Women & Minorities
• 1993 – NIH Revitalization Act mandates the
inclusion of women and minorities in federally
funded research
• 1997 – FDA Modernization Act provides
– incentives pediatric studies
– Risk-based regulation of medical devices
– Authorizes public registry of clinical trails
(www.clinicaltrials.gov)
– Expands access to investigational therapies and
diagnostics
Johns Hopkins Research Halted
• In 2001, OHRP suspends all
Federally-funded research at
JHU School of Medicine after
Ellen Roche dies during an
asthma study
• Investigator failed to submit an IND, to
report AE to the IRB, and deviated from
protocol.
• Consent form did not state that inhalation
administration of hexamethonium was
experimental
Clinical Trial Registration
• 2005 – International Committee of Medical
Journal Editors (ICMJE) requires clinical
trial registration for publication
– any research project that prospectively
assigns human subjects to intervention or
concurrent comparison or control groups to
study the cause-and-effect relationship
between a medical intervention and a health
outcome.
Moving Forward
Source: Jill Louise Campbell accessed at http://www.jlcgallery.com/jill_travels.htm
Challenges for the
Clinical Research Enterprise
• Difficulty recruiting and retaining clinical
researchers
• Increasing regulatory burden and
overhead costs
• Fragmented training programs
• Limitations/barriers due to NIH funding
mechanisms, review and programs
structures
Source: Zerhouni, E. A Strong foundation: Building a home for clinical and
translational sciences.
Major Shifts in Priorities at AHCs
• Increases in clinical service demands and
reductions in financial margins limits the
time available for research and mentoring
• Knowledge needed to be an effective
clinical/translational scientist is not easily
acquired
• Young clinical research faculty have
trouble finding a real “home” for their
aspirations
Source: Zerhouni, E. A Strong foundation: Building a home for clinical and
translational sciences.
AAMC Clinical Research Task
Force Recommendations
1. Future physicians should receive
education in the basic principles of
translational and clinical research
(T&CR) in med school and residency
2. T&CR training should be added to
accreditation requirements for med
schools & residency programs
3. T&CR training should include an
advanced degree with a thesis
4. Sufficient support should be given to new
junior faculty to maximize their success
5. T&CR training should be accelerated to
create independent investigators by age
32-34
6. Institutions should facilitate academic
recognition of research contributions
7. NIH should modify K23 & K24 awards to
enhance support
8. Institutions should provide central
oversight, administration and support
for infrastructure
9. Human research protection programs
should be made more efficient
10. A national forum should be established
to: a) facilitate the development of
integrated clinical information systems
and, b) develop DNA and tissue banks
11. AHC should establish collaborations
with community providers to broaden
the diversity and size of the population
base for studies
12. AHC should promote translational and
clinical research as a core mission with
a high priority for institutional funding
Acknowledgement
• I gratefully acknowledge Susan Robinson
and Lu Ann Kirk for their assistance in
preparing this presentation.
References
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Beecher, HK. Special article: Ethics and clinical research. NEJM, 1966, 274: 13541360.
Bean WB. Walter Reed and the ordeal of human experimentation; 86.
Dickler, HB. Clinical research task force II recommendations. Presented at AAMC
Advisory Panel on Research, May 2006 (accessed at
http://www.aamc.org/research/apr/agenda52406.htm
Goldfarb, NM. Milestones in clinical research. J Clin Res Best Pract, 2006, 2: 1-14.
Harden, VA. A short history of the National Institutes of Health (accessed at
http://history.nih.gov/exhibits/history/index.html
Harkness, J, Lederer, SE, Wikler, D. Laying ethical foundations for clinical research.
Bulletin of the World Health Organization, 2001, 79 365-366.
Moreno, JD. Undue Risk: Secret State Experiments on Humans. New York, WH
Freeman, 1999.
Weyers, W. The Abuse of Man: An Illustrated History of Dubious Medical
Experimentation. New York, Ardor Scribendi, Ltd, 2003.
Source: Zerhouni, E. A Strong foundation: Building a home for clinical and
translational sciences. (accessed at www.nih.gov)
Zerhouni, E. NIH at the crossroads: Myths, realities and strategies for the future.
Presented at AAMC Advisory Panel on Research, May 2006 (accessed at
http://www.aamc.org/research/apr/agenda52406.htm