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Presentation
at the Continuous Medical Education program of the Department of Internal
Medicine KFMC on May 14, 2013 12.30-1.30pm by Dr Omar Hasan Kasule MB ChB
(MUK), MPH (Harvard), DrPH (Harvard) Chairman of the KFMC Ethics Committee and
Chairman of the KFMC Institutional Review Board (IRB)
RESEARCH vs CARE: tension and conflict of roles
·
Dilemma of research vs
care manifests at the national level (budgetary allocations, legislative
framework), institutional level (Incentives for clinicians to engage in
research[1], protected time for
research, space, equipment), and the individual level (ethical dilemmas as
physician scientists prioritize between research and care and may be cut
corners)
·
Violating the doctor’s
duty to treat in pursuit of science vs. Poor medical care for lack of research
·
Conflict between the
role of the doctor (best interests of the patient) and the role of the
researcher (produce knowledge that may not immediately benefit the patient)[2]
·
Examples of conflict: nurses
experiencing role conflict as clinicians and researcher-interviewers in a
stroke study[3],
Physician scientists too busy in research and not on the wards[4]
RESEARCH vs CARE: manifestations
·
Informed consent
lacking in inappropriate: no full disclosure in eagerness to recruit patients,
no time to explain and check understanding of the consent material. No
disclosure eg in depression research[5]
·
Unnecessary research: experimenting
on a drug already proved beneficial resulting in withholding effective treatment in the
control group
·
Double standards in
research ethics and medical care re:HIV in Africa[6] and relativising standards
of care for research subjects to the standards of the country[7]
·
Other ethical issues:
Research in the critical care unit[8], Referring patients with
negative symptoms to outcome research[9], Discovery of health risks
in the normal group[10]
·
Gate keepers preventing from / not informing
about research[11]
·
Research on patients under DNR orders[12]
THE PHYSICIAN INVESTIGATOR / PHYSICIAN SCIENTIST
·
Physician scientist
bridges the gap between the bench and the bedside[13] but we are experiencing a
shortage / lack of physician scientists[14] [15]
·
Physician scientist
training programs such as the MD/PhD[16] [17] [18] [19] not available everywhere
·
If research funding is
limited then young physicians are forced to provide more service to generate
income instead of research[20]
·
Biggest hindrance to
research is lack of time[21]
·
Private physicians are
getting interested in research because of benefits[22] with drug companies
moving their research from medical centers to private physician offices[23]. Ethical controls are
looser at private offices
CASE #1: INFORMED CONSENT
·
An investigator wants to determine the levels of
biochemical mediators in patients with chronic illnesses.
·
He goes to the outpatient clinic and asks his
colleagues if he could have the leftover blood from blood samples obtained from
patients.
·
Since this would not require any additional
needle sticks, the investigator concludes that informed consent is not needed
from the patients.
·
His colleagues agree and add that asking
patients if they could use the spare blood would make the patients suspicious
as to whether they needed to have any laboratory tests performed on them.
CASE #2: MINIMIZING RISKS IN A
RESEARCH STUDY:
·
An investigator plans to assess the safety and
efficacy of a drug to treat Hepatitis C. This drug is known to have bone marrow
and renal toxicities.
·
Part of the study procedures involves testing
for the presence of Hepatitis C and performing a post-intervention liver
biopsy.
·
What could a research ethics committee require
of the investigator to minimize the risks in this study?
CASE #3: SUBJECT RECRUITMENT FOR A FEE:
·
A pharmaceutical company
plans a post marketing survey of its general analgesic and approaches a general
practitioner to recruit patients for SAR500 per patient recruited and fully
followed up.
·
The GP does not ask for
inclusion and exclusion criteria and recruits as many patients as possible.
·
The GP does not disclose
full details of the study
CASE #4: ADMISSION FOR RESEARCH AND NOT TREATMENT:
·
A consultant undertaking
research on sleep disorders approached residents in various outpatient clinics
(medical and surgical) and gave them inclusion and exclusion criteria for his
study
·
He asked that those who
fulfilled the criteria should be referred to him and told that they need
further treatment
·
He recruited them into
the study without full disclosure of the objectives because that would affect
study validity
CASE #5: DELAYED DISCHARGE FOR RESEARCH:
·
A consultant ordered
residents that patients on his study who complete the study intervention should
be kept on the ward for another three months for follow up because their return
was not guaranteed
CASE #6: MORE CARE FOR RESEARCH SUBJECTS:
·
A consultant researcher
started the ward round by seeing patients on the trial and telling the
assistant consultants and residents to finish seeing the rest of the patients.
CASE #7: DISINTEREST IN THE PATIENT
·
An oncologic surgeon
would start the surgery and remove the tumor. He would rush to the laboratory
to examine the frozen specimen with the pathologists and leave the residents to
close the abdomen
HISTORICAL BACKGROUND:
earliest human experiments
·
Edward Jenner (1749-1823) first tested smallpox
vaccines on his son and on neighborhood children.
·
Johann
Jorg (1779-1856) swallowed 17 drugs in various doses to record their
properties.
·
James
Lind’s experiment on treating scurvy among sailors A Treatise of the Scurvey 1753
TENSION BETWEEN SCIENCE AND PATIENT SAFETY IN ANCIENT TIMES
·
Moses Maimonides (1135 – 1204) instructed
colleagues always to treat patients as ends in themselves, not merely as means
for learning new truths.
·
Claude Bernard (1865) wrote “[The first
principle of medical morality] “consists in never performing on man an
experiment which might be harmful to him to any extent, even though the result
might be highly advantageous to science.”
·
Louis Pasteur (1822-1895), "agonized over
treating humans, even though he was confident of the results obtained through
animal trials. He finally did so only when he was convinced the death of the
child, the first test subject, "appeared inevitable."
EXAMPLES OF UNETHICAL RESEARCH 1
·
1896:
Dr. Arthur Wentworth performed spinal taps on 29 children at Children's
Hospital, Boston, to determine if the procedure was harmful. Dr. John Roberts
of Philadelphia, noting the non-therapeutic indication, labeled Wentworth's
procedures "human vivisection."
·
1897:
Italian bacteriologist Sanarelli injected five subjects with bacillus searching
for a causative agent for yellow fever without their informed consent.
EXAMPLES OF UNETHICAL RESEARCH 2: NAZI WWII EXPERIMENTS
·
High Altitude Experiments: Prisoners exposed to
low oxygen to test how long pilots ejected from fighter aircraft can survive in
air
·
Hypothermia Experiments: Prisoners submerged in
cold water to find out how long pilots can survive if parachuted into cold sea
water
·
Malaria Experiments: Prisoners infected with
malarial mosquitoes and treated with drugs to discover the effective
anti-malarials
·
Typhus experiments: Injection of typhus in
subjects who had got the antityphus vaccine
EXAMPLES OF UNETHICAL RESEARCH 3: JAPANESE WWII EXPERIMENTS
·
Live
dissections of prisoners deliberately infected to study the effects of
infection
·
Exposure
to freezing temperatures to see the body response
·
Grenade
tests on human targets
·
Deprivation
of food and water to study effects and survival
·
Temperature
experiments to see the relationship between temperature, burns, and survival
·
Prisoners
placed into centrifuges and spun until death
EXAMPLES OF UNETHICAL RESEARCH 4: US violations published in journals (Dr Henry Beecher 1966)
·
Deliberately
infecting institutionalized children (intramuscular injection or oral
administration) with a mild form of the hepatitis virus
·
Injecting
live cancer cells into debilitated patients without their knowledge of the true
nature of the injected cells
·
Withholding
antibiotics from patients with rheumatic fever
EXAMPLES OF UNETHICAL RESEARCH 5:Tuskegee Syphilis Study (1932-1972):
· 400 men with syphilis were enrolled into the study without truly informed consent over a 40 year period
· Deception: not told that alternative treatment was available were denied penicillin after 1940s when its effectiveness was known.
· The study continued to follow these men until 1972 when the first public accounts of the study appeared in the national press.
· The study resulted in 28 deaths, 100 cases of disability, and 19 cases of congenital syphilis
· Ethical violations: informed consent, deception, withhold treatment and info
EXAMPLES OF UNETHICAL RESEARCH 6: Japan
· In 1951, Japanese investigators undertook a study assessing carbohydrate metabolism in which small pieces of brain tissues were surgically obtained from 70 schizophrenic patients in a psychiatric hospital.
· At least three subjects died after the lobotomy, and medical records testified that two of them probably died of excision.
· No subjects or their families were asked to give informed consent for the operations.
· Nobody criticized this experiment until 1971, when a resident of Tokyo University Hospital reported the investigators to the Japanese Society for Psychiatry and Neurology.
EXAMPLES OF UNETHICAL RESEARCH 7: China
· In the 1980s, a clinical trial was performed in several cities in China examining the relationship between folate and neural tube defect (NTD).
· The initial trial proposed to enroll 65,000 pregnant women in six rural counties outside of Beijing. The original design raised questions regarding informed consent.
· Also, at the time of the trial, British investigators had established that folate was protective against NTDs. Subsequently, the clinical trial was modified to a community intervention program.
EXAMPLES OF UNETHICAL RESEARCH 8: India
· Between November 1999 and April 2000, 25 patients with oral cancers at the Regional Cancer Centre, Thiruvananthapuram (a government institution) had their tumors injected with an experimental chemical in order to evaluate its anti-tumor properties. The patients were not told that the use of these agents were experimental.
· Also, the trial had not been approved
· Patients were denied the established treatment for their condition,
EXAMPLES OF UNETHICAL RESEARCH 9: Africa and Thailand
· AZT placebo trials: In the early 1990s in trials done in the United States and France researchers established that treating HIV-positive women with AZT decreased HIV transmission from mother to child during birth by two thirds.
· The ACTG 076 regimen became the standard of care for HIV-infected women and their newborns in the US and other more developed nations.
· Research in Africa and Thailand tested a shorter, less intense and therefore less expensive AZT regimen using a placebo group (denied a known effective treatment). It was reasoned that the placebo group would not have afforded the treatment anyway
EXAMPLES OF UNETHICAL RESEARCH 10: Latin America
· Surfaxin study: Surfaxin was a proven effective treatment for the infant respiratory depression syndrome in the US
· A trial of surfaxin vs placebo could not ethically be carried out in the US because the placebo would be denied an effective treatment
· The company proposed conducting this study in Latin America where infants with lung illnesses do not usually have access to effective treatment
NURENBERG CODE
1.
The voluntary consent of the human subject is
absolutely essential”:
2.
The
Research objective should be aimed for the good of the society.
3.
Research
should be based on prior animal work.
4.
The
risks should be justified by the anticipated benefits.
5.
Only
qualified scientists must conduct research.
6.
Physical
and mental suffering must be avoided.
7.
Research
in which death or disabling injury is expected should not be conducted.
8.
Facilities
and resources to conduct well-designed research should be available.
9.
Subjects
must be free to stop at anytime.
10.
The
investigator should stop the study if he/she believes that continuation of the
study will result in serious injury, disability or death of the research
subject.
HELSINKI DECLARATION 1964: EXPANSION OF THE NURENBERG CODE
· Research conducted in the context of medical care
· Human subjects who lacked decision-making capacity
· Research involving vulnerable individuals
· Independent review by research ethics committees
THE BELMONT REPORT (1979): PRINCIPLE OF RESPECT FOR PERSONS
· Individuals be treated as autonomous human beings and be allowed to choose for themselves.
· Extra protection for individuals with impaired ability to decide for themselves.
· Elements of respect for persons include: obtaining informed consent from individuals who are capable of choosing what shall and shall not happen to them.
· Elements of informed consent should include: disclosure of information, comprehension,voluntariness (be free from coercive influences and undue inducement
· For individuals who lack decision-making capacity, extra safeguards are in place to provide them with additional protection.
THE BELMONT REPORT (1979): Principle of Beneficence
· While the term “beneficence” is usually understood to cover acts of kindness or charity, in the realm of research ethics, beneficence is understood as an obligation to:
· Do no harm (non-maleficence)
· Minimization of harms
· Maximization of benefits
· Beneficence requires that there be an analysis of the risks and benefits to the subjects, making sure that there is a favorable risk-benefit ratio.
THE BELMONT REPORT (1979): Principle of Justice
· The principle of justice in the sense of “fairness in distribution” requires:
· research is designed so that its burdens and benefits are shared equitably among groups of populations.
· fairness in the selection of research subjects, e.g., one should not select subjects based on their easy availability or their compromised position (e.g., individuals in a mental institutions).
EIGHT REQUIREMENTS FOR CLINICAL RESEARCH
1.
Independent Review of Protocols:
2.
Community Partnership:
3.
Social Value:
4.
Scientific Validity:
5.
Fair Subject Selection:
6.
Favorable risk/benefit ratio:
7.
Informed consent:
8.
Respect for enrolled subjects:
GCP
GUIDELINES ON INVESTIGATOR ON MEDICAL CARE OF TRIAL SUBJECTS
·
A qualified physician (or dentist,
when appropriate), who is an investigator or a sub-investigator for the trial,
should be responsible for all trial-related medical (or dental) decisions.
·
During and following a subject’s
participation in a trial, the investigator/institution should ensure that
adequate medical care is provided to a subject for any adverse events,
including clinically significant laboratory values, related to the trial. The
investigator/institution should inform a subject when medical care is needed
for intercurrent illness(es) of which the investigator becomes aware.
·
It is recommended that the
investigator inform the subject’s primary physician about the subject’s
participation in the trial if the subject has a primary physician and if the
subject agrees to the primary physician being informed.
·
Although a subject is not obliged to
give his/her reason(s) for withdrawing prematurely from a trial, the
investigator should make a reasonable effort to ascertain the reason(s), while
fully respecting the subject’s rights.
CAPABILITY TO DO THE
STUDY
·
Does the investigator have adequate
time to devote to study oversight and the work that he/she must perform?
·
Does the investigator’s “style of
practice” fit the study procedures?
·
Are there anticipated personal,
financial, or professional obligations for the investigator or staff that might
interfere with meeting the study commitments?
·
Are adequate personnel available to
complete and process the required records?
·
Do the investigator and
administration agree with the terms of the contract set forth by the sponsor?
·
Is the proposed study budget
adequate?
·
How will each aspect of the protocol
procedures be executed?
·
Is the timing of the procedures
(study windows) reasonable?
·
Do the investigator and study staff
members understand the requirements for data collection and reporting?
·
Will the subjects' data be readily
accessible to sponsor and regulatory representatives for review?
·
Can study charts and study-specific
records be maintained for at least two years after the study has been completed
or the investigational product has been approved for marketing?
·
Are facilities and equipment
adequate to perform the study?
·
Can subjects be recruited and
complete the study during the timeframe desired by the sponsor
MEDICAL CARE OF
TRIAL SUBJECTS
·
ICH E6 Section 4.3 describes the
investigator's responsibilities with respect to medical care of subjects.
·
According to the guidance,
investigators should make certain that adequate medical care is provided to the
subjects for adverse events (AEs), and abnormal laboratory values that are
related to the trial.
·
If the investigator becomes aware
that medical care is needed, the investigator should inform the subject.
·
A qualified physician (or dentist,
when appropriate) should be responsible as either an investigator or
sub-investigator for all trial related medical (or dental) decisions.
·
According to ICH E6 Section 4.3.3,
if the subject agrees, the investigator should inform the subject's primary
physician about the subject's participation in the trial.
FDA 1527
INVESTIGATOR STATEMENT
·
Personally
conduct or supervise the study in accordance with the protocol and with GCP
guidelines.
·
Protect
the health and welfare of research subjects in accordance with 21
CFR 50
(Protection of Human Subjects) by informing subjects that the product is
investigational, ensuring that study procedures are explained adequately and
performed appropriately, and by promptly identifying and reporting safety
information, among other responsibilities
·
Report
to the sponsor adverse events (AEs) that occur
·
Ensure
that all personnel assisting in the conduct of the trial understand their
obligations and commitments
·
Maintain
adequate and accurate records and to make these records available for
inspection
·
Ensure
that an IRB that complies with the requirements in 21
CFR 56
(Institutional Review Board) provides initial and ongoing review and approval
of the investigation
INVESTIGATOR FINANCIAL
DISCLOSURE
·
Compensation made to the
investigator in which the value of compensation could be affected by study
outcome
·
A proprietary interest in the tested
product, including, but not limited to, a patent, trademark, copyright or licensing
agreement
·
Any equity interest in the sponsor
of a covered study (that is, any ownership interest, stock options, or other
financial interest whose value cannot be readily determined through reference
to public prices)
·
Any equity interest in a publicly
held company that exceeds $50,000 in value
REFERENCES