Twentieth Century Milestones in Clinical Research:

Looking Back and Moving Forward

Michelle Price, M.Ed.Department of Surgery

UTHSCSAGrand 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

Walter Reed uses consent form in study of yellow fever at Camp Lazear in Cuba

Following the self-infection of two of his colleagues (resulting in the death of one),

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 first-aid 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 arrhythmiaDr. 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 theClinical 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• Beecher, HK. Special article: Ethics and clinical research. NEJM, 1966, 274: 1354-

1360.• 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