by: lim ju boo
Summary:
Let me briefly summarize my
thoughts before detailing further
First, the researcher needs to have
an aim and objective to embark into the study, especially in a clinical trial
where human subjects are involved. He / she must write out the purpose of the
study based on some existing research, previous findings or a problem, whether
about a disease, an epidemic or a public health problem.
Second, he (includes she) needs to
submit his proposal in writing to a committee for the vetting for the
much-needed research funding that can run into hundreds of thousands of
ringgits or US dollars
Third, he needs to select the
subjects carefully in consultation with a biostatistician on sampling size,
usually randomized with adequate sampling numbers to represent a population.
Fourth, he needs to have
collaborators who specialize in their own fields to help out in their own areas
as a multi-disciplinary team as it is not possible these days to work solely on
his own. For example, a clinician cannot just do the clinical examination only,
as physical examination is subjective and cannot yield any data that are much
needed as evidenced-based. So, the clinician(s) needed scientists also who can
support with their specialized findings and measurements in their analytical
laboratories that can yield the much-needed data for statistical analysis
Firth, the researcher needs to face
the medical ethic committee, often several times who will question the
researcher to ensure the safety of the subjects undergoing a clinical trial
either on a new drug or some nutritional studies
Sixth, the subjects must clearly be
explained about the purpose of such a study, and they must give their written
legal consent to participate in the study
Seventh, what happens if some of
the subjects fell sick during the study? Should they be treated with drugs that
may interfere with the study, especially if the researchers are evaluating a
new drug or a treatment including a food they are taking (drug-nutrient
interaction). If the subject falls sick and is taken off the study, this will
affect the sampling numbers already statically selected out. Should the
subjects be treated non-pharmacologically, such as using naturopathic medicine
by a qualified Naturopathic Doctor that should be drugless. I think in such an
event a pharmacologist also needs to be consulted on drug interactions with
other drugs or nutrients should the subject fall sick but need to be treated
with drugs and retained in the study.
So a nutritionist too needs to be
consulted on food and drug interactions. In short, a multidisciplinary team,
each member in the team leading their own expertise to be consulted.
All subjects in the study too must
comply with strict lifestyle protocols such as not being allowed to take their
own medicines, smoke, eat whatever they like or refuse to cooperate with the
study design and regulations, etc.
The Details:
Clinical trials conducted jointly
among clinicians and medical scientists are among the most vital processes in
advancing medical knowledge and treatment.
Since I was a senior medical
researcher at the Massachusetts Institute of Technology (MIT) in the United
States, and later at the Institute for Medical Research (IMR) in Malaysia
before I retired, let me outline the protocols and pre-requirements we
must adhere to before embarking on a clinical trial:
Pre-Requirements and Protocols for
Conducting a Clinical Trial
1. Define the Research Question and
Objectives
a. The
researcher must identify the hypothesis and specific objectives of the trial.
b. Develop
a detailed plan to determine what the trial seeks to achieve, such as testing a
new drug, treatment, or diagnostic method.
2. Conduct a Comprehensive
Literature Review
a. Examine
existing studies to ensure the trial addresses a novel or unanswered question.
b. Avoid
duplication of previous work unless replication is essential.
3. Develop the Clinical Trial
Protocol
This is the core document that
outlines every aspect of the trial. It must include:
a. Study
design (e.g., randomized control trial, observational study).
b. Inclusion
and exclusion criteria for participants.
c. Methodology,
including interventions, dosages, and timelines.
d. Primary
and secondary endpoints (outcomes being measured).
e. Data
collection and analysis plan.
f. Risk
management and safety monitoring plan.
4. Secure Ethical Approval
The trial must be reviewed and
approved by an Institutional Review Board (IRB) or Ethics
Committee (EC) to ensure it adheres to ethical standards, such as:
a. Protecting
participant rights and safety.
b. Minimizing
risks and ensuring risks are justified by potential benefits.
c. Informed
consent processes are clearly outlined.
5. Obtain Regulatory Approval
Submit the trial proposal to the
relevant health authorities or regulatory agencies:
In the US: Food and Drug
Administration (FDA) for an Investigational New Drug (IND) application.
a. In
Malaysia: Ministry of Health & National Pharmaceutical Regulatory
Agency (NPRA).
b. In
the EU: European Medicines Agency (EMA).
6. Develop Informed Consent Forms
Create clear, comprehensive forms
that explain the trial in lay terms, including:
a. Purpose,
procedures, risks, and benefits of participation.
b. Assurance
of voluntary participation and the right to withdraw at any time.
7. Secure Funding
a. Identify
funding sources such as government grants, private organizations, or
pharmaceutical companies.
b. Budget
for trial costs, including personnel, materials, and facilities.
8. Establish a Research Team
a. Recruit
qualified personnel with expertise in the required fields, including:
b. Principal
investigator (PI) to oversee the trial.
c. Medical
staff, statisticians, data managers, and monitors.
9. Register the Clinical Trial
Register the trial in a publicly
accessible database such as:
Ministry of Health Malaysia
In other countries these may be
required.
ClinicalTrials.gov (US).
EU Clinical Trials Register (Europe).
WHO International Clinical Trials
Registry Platform (ICTRP).
10. Prepare Study Sites
Select and prepare locations where
the trial will take place, ensuring they meet requirements for:
a. Equipment
and facilities.
b. Patient
recruitment and monitoring capabilities.
11. Pilot or Feasibility Study
(Optional)
a. Conduct
a smaller pilot study to test the feasibility of the trial's design, logistics,
and protocols.
12. Secure and Store Data
Management Systems
Ensure a robust system for data
collection, storage, and analysis while maintaining confidentiality and
compliance with data protection regulations (e.g., GDPR, HIPAA).
13. Risk Assessment and Monitoring
Plans
Develop protocols for:
a. Adverse
event reporting.
b. Safety
monitoring by a Data Safety Monitoring Board (DSMB), if required.
14. Participant Recruitment Plan
Design a strategy to recruit and
retain participants, ensuring diversity and representativeness.
15. Final Pre-Trial Review
Conduct a final review of the
protocol, ethical approvals, and logistical readiness.
Key Ethical and Legal Principles
Declaration of Helsinki: Ethical
guidelines for medical research involving human subjects.
Good Clinical Practice (GCP): An
international quality standard for designing, conducting, and reporting trials.
Framework and My Additions
1. Aim and Objective of the Study
The importance of defining the
purpose of the study. To add:
a. Hypothesis
Development: Besides outlining the purpose, the researcher should explicitly
define the null and alternative hypotheses. This ensures clarity in the
statistical analysis later.
b. Alignment
with Global Health Priorities: If the study addresses a pressing public health
issue, it might increase the likelihood of securing funding and ethical
approval.
2. Proposal Submission and Funding
a. Detailed
Budget Breakdown: The researcher must provide a granular budget detailing all
anticipated costs, including personnel, laboratory analyses, participant
compensation, and contingency funds.
b. Pilot
Data: Including preliminary data from smaller studies or feasibility
assessments strengthens the funding proposal.
3. Subject Selection and Sampling
My personal demands when I was the
leader of the medical and scientific team emphasis on statistical rigor
and collaboration with a biostatistician is crucial. To enhance these, we did
these:
a. Stratification:
In addition to randomization, stratified sampling can ensure that subgroups
(e.g., age, gender, comorbidities) are adequately represented.
b. Inclusion
and Exclusion Criteria: Clear criteria must be established to ensure the
selected participants are homogeneous enough for meaningful results but diverse
enough to reflect real-world populations.
c. Recruitment
Challenges: Strategies like community engagement or collaboration with primary
healthcare providers can improve recruitment and retention.
4. Multidisciplinary Collaboration
Adding to this we incorporated
these experts into our research team
Clinical Pharmacologists: To manage
drug interactions and dosing strategies during the trial.
1. Behavioural
Scientists: If lifestyle interventions or behavioural changes are part of the
protocol.
2. Bioinformaticians:
For handling large datasets, especially in genomic or proteomic studies.
3. Regulatory
Experts: To navigate the complex approval landscape and ensure compliance with
evolving laws.
5. Ethical Considerations
Multiple interactions with the
ethics committee are often required. To expand:
Risk-Benefit Analysis: A detailed
analysis should demonstrate that the potential benefits outweigh the risks.
Independent Reviewers: Ethics
committees often include independent reviewers who are not affiliated with the
institution to ensure impartiality.
Cultural Sensitivity: The study
design and consent process must respect cultural norms and values, particularly
in diverse populations like in Malaysia.
6. Informed Consent
We made it a point to explain
clearly to our participants the aims and objectives of our study and ask them
to sign a letter of consent if they agree to participate. Before signing the
consent form, participants could be tested on their understanding of the study
to ensure they fully grasp its implications.
7. Managing Adverse Events
My medical and scientific I was
leading have discussed how to handle participants falling sick is a critical
one. My thoughts then were:
1. Predefined
Withdrawal Criteria: Clear criteria should be established for when a
participant is withdrawn from the study due to adverse events.
2. Non-Pharmacological
Interventions: I suggested, naturopathic or non-pharmacological treatments can
be explored. However, their efficacy and safety must also be evidence-based to
avoid confounding results.
3. Consultation
with a Pharmacologist: Absolutely necessary, especially when participants are
on concurrent medications or supplements.
8. Lifestyle Protocol Compliance
Ensuring participants adhere to
strict lifestyle protocols is essential. To build on this:
1. Monitoring
Mechanisms: Use digital tools such as wearable devices, food diaries, or
smartphone apps to track participant adherence in real time.
2. Regular
Check-Ins: Weekly or bi-weekly check-ins with participants can help identify
and address compliance issues early.
3. Educational
Sessions: Informing participants about the importance of adhering to the study
design can foster better cooperation.
Additional Considerations
1. Data Integrity and
Confidentiality
a. Establish
secure systems to ensure data confidentiality and compliance with data
protection laws like GDPR (Europe) or HIPAA (US).
In Malaysia we lack of this system
b. Include
a data monitoring committee to regularly review the data for consistency and
adherence to the protocol.
2. Statistical Power
Adequately power the study to
detect clinically meaningful differences between groups. Underpowered studies
risk generating inconclusive results.
3. Interim Analysis
We planned for interim analyses to
evaluate safety and efficacy during the trial. These analyses can inform
decisions about continuing, modifying, or halting the study.
4. Post-Trial Access
Participants, especially in
low-resource settings, should have access to the drug or intervention if it
proves successful during the trial.
5. Publication and Dissemination
Predefine how results will be
shared, including negative or null findings, to contribute to the broader
scientific community.
Closing Thoughts
The way I planned these when I led
my team in clinical trials, I believe was comprehensive.
My ethical concerns regarding drug
interactions and lifestyle compliance reflect the care and responsibility
needed in clinical trials. These touches, coupled with rigorous planning and
collaboration, ensure that clinical trials not only generate reliable data but
also respect the dignity and safety of participants.
I believe this design also
applies to both cross-sectional and longitudinal study which would be more an
epidemiological study than a clinical study with new drugs, a new therapy, or a
nutrition study. All fit exactly into the same rigorous demands and ethical and
legal requirements.
At the Institute for Medical
Research where I was asked by my former Director to lead a team of doctors and
scientists in a few clinical trials, me and my team must face the Medical
Ethics Committee, some 30 of them including ironically my own Director who
asked me to do study, but sat there asking me why I wanted to conduct the
study? How ironic?
The Medical Ethics Committee also
‘unfortunately’ included one of my best friends, the late Professor MP
Deva, Head of the Department of Psychological Medicine, University Hospital,
University of Malaya whom we knew each other since our college days who also
sat there questioning me twice with a stern face and voice in the Director’s
Board Room at IMR. “Fortunately,after the interview lasted at least 2 hours we
both went out together as friends for dinner. The ironical is, friends are
friends, but when work and medical and scientific ethics is concerned, we are
no friends - in opposition.
In the Medical Ethical Committee,
me and my team must face twice, was also the Attorney General who also sat
there to ensure that everything we did was legally protected by the government
as well as the government itself was protected should there be any death among
the participants because we experimented on them. The AG was there to ensure
legal safety for all parties as it was a government project under the Ministry
of Health
Medical research is very
challenging with high risks involved for all parties for sure!
I think this essay too is a
challenging one for me to write about my past working experience
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