Principles of drug trial in cardiology

Introduction
Designed to help find out how to give a new
treatment safely and effectively to people.
Clinical trials provide information on the
effectiveness and risks of the new treatment.
Advances in medicine and science are the result of
new ideas and approaches developed through
research.

principles of conduct of drug trials in cardiology

 There are various types of clinical trials of which
RCTS are the gold standard for testing any molecule
Conduct of drug trial involves two broad set of
principles:
1.Principles in design
2.Principles in analysis


Cost and scope
Worldwide, the average cost of developing one
molecule costs about $282 million and takes about
seven years to complete.
According to industry estimates, the cost of phase I
trial is 50% cheaper in India and for phase II it is 60%
less.


Evolution of clinical trials in
India
Relatively new in India
Initially small uncontrolled trials-evaluate tolerability
of available medication in Indian population
Mid 90’s MNC started including India in regulatory
trials
CRO ‘s brought outsourced trials to India
Since early 2000’s academic trials were started


• Around 25 contract research organisations (CROs)
and almost all multinational pharmaceuticals
companies have started full-fledged clinical trials in
India since last three years.
• Further, the amendment to Schedule Y of the Drugs
and Cosmetics Act in February 2005 , now allows
MNC s to conduct simultaneous trails in India and
abroad


Hurdles in Indian drug trial
Approvals-DCGI-conduct a trial and import licence-
form 11
Ethical approval from IRB’S or IEC in Mumbai
Drug import- approval from ADC in
Chennai,Mumbai,Delhi,Kolkata
Academic studies need additional clearance from
ministry of health screening committee


Objectives of clinical trial
Cure for a disease
Palliation where cure is not possible
Relief of symptoms
Risk of recurrence of disease
Prevention of disease or disability
Comparitiive efficacy in relation to other alternatives
Relative safety of intervention
Relative impact of demographic profiles
Impact on socio economic parameters

Types of studies
• Observational studies-
• descriptive-case series
• analytical-cohort
• case control
• cross sectional
• Experimental-
• RCTS
• NON -RCTS


TYPES OF REVIEWS
Systematic review - study that addresses a focused
research question, has explicit eligibility criteria, and
undertakes an extensive search of the literature to
identify studies that fulfill the eligibility criteria
Meta-analysis -pooling of data across two or more
studies . High quality meta-analyses only pool data
from systematic reviews.


Types of studies
case report:
most basic type of study
observational report of the course of a single subject
building block of the case series, accumulated data
from several case reports


Case registry:
Collects data on similar patients without specifying
an intervention.
Does not evaluate a new therapy in a randomized
fashion
Does serve to develop a body of data on a new
technique, disease or treatment strategy that may
help formulate hypotheses and guide the
development of new RCT’s.
Permits the evaluation of treatment strategies over
time and may be particularly useful in an institution’s
own quality-improvement program.
IRB review is necessary
Consent only if individual will be exposed

Nonrandomized clinical trial-
known as a single-arm study, in which study
participants are simply assigned a known therapy and
monitored.
The “control” for this type of study is either historical
data or a concurrent single-arm study
Recruitment easier than in randomized trials,
because prospective subjects face no uncertainty
about the therapy they may receive
But lack of proper control lessens credibility


Randomised clinical trials
Fifty-five years ago, the publication of the British
Medical Research Council trial of streptomycin in
patients with pulmonary tuberculosis formally
heralded the arrival of the randomized controlled trial
(RCT) into medical research


• Initially in field of infectious diseases,were successful
as they evaluate large treatment effects
• In fields like cardiology where multifactorial disorders
were evaluated were disappointing because whilst
they excluded large treatment effects, they could not
reliably detect or exclude moderate but important
effects


Trial conduct has changed over last few years mainly
due to greater understanding of key criteria that were
critical to the conduct of a reliable trial-
Ensuring proper blinding
Focus on hard end points
Growing preference for large simple trials


Large simple trial
Eschew detailed data collection and extensive
screening processes in favor of rapid enrollment and
the ability to detect modest differences in hard
clinical end points between treatments
reduction in complexity and per-subject cost allows
rapid enrollment of very large numbers of subjects—
often tens of thousands—with the idea that
subgroups of participants will respond similarly so
that less detailed baseline characterization is
necessary


Blinding
Gold standard.
Single-blinded study is one in which the investigator
knows what the study allocation is, whereas the
patient does not
Double blind-one in which neither the subject nor
the investigator knows what treatment has been
assigned
Double blinding adds expense and complexity to a
trial, it eliminates biases that might be introduced by
patient or investigator expectations, which improves
the reliability of the results

Phase-I
determine the metabolic and pharmacological actions
of the drug in humans
The total number of subjects included in Phase 1
studies is in the range of 50-100.

Phase-II
evaluate efficacy and short-term safety of the drug in
selected populations.
A dose range for the drug is established. Optimal
dose of the drug is also established. Phase 2 studies
involve several hundred people.


Phase-III
These trials are conducted in several hundred to
several thousand people. The objective of these trials
is to confirm efficacy of the study drug and to
establish its safety profile
Phase-IV
Post-marketing surveillance studies are carried out in
order to detect previously unknown adverse events
and risk factors


steering committee: usually is made up of a study
chair and other selected (or elected) representatives
from the investigators and sponsor.
Steering committee members develop the protocol,
lead the trial, and publish the results when the trial
is complete
Data coordination center is responsible for the
management and quality control of the trial data, as
well as for interim or final analyses of the results and
monitoring safety, and efficacy data


DMC monitors the trial for evidence of relative harm
or convincing evidence of benefit, track the trial’s
progress, adherence to protocol, and the quality of the
data
Definitive largescale, randomized trials with an
irreversible outcome (death) and a serious morbidity
outcome (myocardial infarction or stroke) are most
likely to appoint a DMC
Responsibility of assuring a high quality trial rests
with DMC as well as local IRB


Investigator
Increasing number of trials overall has generated a
need for interested and qualified investigators, as well
as for the patients they can recruit
• Fulfill the commitment to advancement of scientific
knowledge.
• Clinical research is losing its attractiveness in the US
due to the shortage of investigators.
• Center Watch estimated that against a demand for
56,000 investigators, only 48,000 will be available, a
shortfall of 15 percent

Problems in India
• India has over 572,000 doctors, 43,322 hospitals and
dispensaries and about 8.7 lakh beds including both
private and public.
• Majority of the doctors are graduates with little or no
knowledge about clinical trials and hence would not
qualify as investigators for complex international
clinical trials.
• Identifying and attracting potential investigators is
the biggest challenge, requiring innovative
approaches.

Why do a drug trial
Pool controlled observations in an objective and
scientific way, allowing clinicians to decide with the
best available data what therapy will work best for
each patient.
Allows the clinician to remain at the cutting edge of
research in a specific area in medicine
Provide an opportunity to Coauthor an article in a
scientific journal
High quality patient care and “trial effect”


Barriers to participation
Lack of
knowledge
Time constraints
Financial
considerations
Need for
recognition
Legal liability


Areas of conflict-placebo arm
Placebo arms should not be used in clinical trials if
there is already an effective standard treatment for
the condition.
In 2002, the world medical association revised the
declaration of helsinki to allow exceptions to this rule
- minor conditions in which the temporary omission
of the treatment would not cause serious harm to the
patient
If there were “compelling and scientifically sound
methodological reasons” to use a placebo.

Areas of conflict-patient interest
Blurring of the roles of physician as caregiver and
physician as investigator- patient clearly understands
that the intervention is not simply a part of his or her
continuing care.
Always obtain proper informed consent while
ensuring the patient of adequate care even if he
choses not to participate
Avoid coercion by utilising the confidence a patient
places in a physician


Areas of conflict-finances
Large trials usually offer adequate reimbursement
Financial interests may lead to-
 improper recruitment
 unjudicious experimentation
 tampering of records to show success
Conflict of interest can be avoided by-
 not allowing inventors into recruitment process
 strict monitoring of entire process by IRBS and
DMC

Role of IRB
Composed of healthcare professionals and non
clinicians
2 medical scientists,2 non medical scientists,one lay
person,one legal expert.
Aim to protect human subjects involved in research
at their particular institution
Review the ethics,monitor the safety
Recommend changes to study protocols or terminate
trial


Role of a coordinator
Liaison between the study site and the trial
coordinating center
Is usually a nurse but may be a nurse practitioner, a
physician’s assistant, or a trained individual with a
medical background.
Meticulous about data, responsive to deadlines,
familiar with the clinical issues, and aware of relevant
regulations,
Timely recording and submission of data and
reporting of adverse events
Special bond with patients


Statistical concepts
Intention-to-treat principle: To minimize any bias
introduced by patients crossing over into unassigned
treatment groups, each subject is analyzed as part of
the group to which he or she was assigned, rather
than by what therapy he or she actually received.
Secondary analyses might also compare results for
actual versus assigned treatment.


Descriptive stastistics-
Reporting of sample characteristics
Central value for a collection of data, eg, a mean, or
average value of the data, along with some indication
of the range or spread of values
Directly expressed as the actual range of values (eg,
average age 64 years, range 18 to 81 years), or, more
commonly, expressed as a mean with a standard
deviation (64+_25 years); the larger the standard
deviation, the greater the spread of data


Sample size:
Larger the sample size (the larger the n), the more
confident we will be in trusting the conclusion
Effect of a particular intervention being studied is
very small, a large n would be needed to be certain of
detecting it.
Calculation of sample size-anticipated event rates in
study population and clinically relevant differences in
rates anticipated between two arms of trial


Comparision of two characters-correlation
coefficient- -1,0 or +1
relationships among multiple variables uses
multivariable analysis, whereas the use of data from
multiple variables to arrive at a likelihood of an
outcome involves multiple regression analysis
Results of two groups-probability value
Time to an event-kaplan-mier curves
Risk of an event-odds ratio


Concealment of randomisation
most common is the sealed envelope system
clinicians are given randomly generated treatment
allocations within sealed opaque envelopes.
 Once a patient has consented to enter a trial an
envelope is opened and the patient is then offered the
allocated treatment regimen.


Problems:
 Prior opening of envelopes
Postpone trial recruitment until a patient with cer-
tain characteristics presents, thus preferentially
recruiting patients with certain characteristics into a
given treatment arm
Trials which did not adequately conceal
randomisation from the investigators demonstrated,
on average, a 41% increase in effect for the active
treatment compared with an adequately concealed
trial


Distance randomisation-involves the investigator, on
recruiting a patient, telephoning a central
randomisation service which notes basic patient
details and then issues a treatment allocation
Can be done across internet


‘Ascertainment bias: distortion of results
 Systematic imbalances in endpoint evaluations and
effective concomitant cointerventions
Use un disputable end points
 Proper blinding
 Completeness of follow up: patients who were not
accounted for at the end of the trial may have
experienced the outcome of interest
Intention to treat:damage the balance in prognosis
between the two groups which is the underlying
purpose of randomization
Avoid undue emphasis on sub group results


Surrogate end points
End point of clinical trial could be definitive or
inferential/surrogate
Evaluation of definitive endpoint needs access to
pathology of interest which is not possible
Surrogate endpoints-alternate markers that corelate
with clinically relevant features of pathology of
interest
Like the proverbial scent which may or may not lead
to the real object


Uses of surrogate markers
Permit evaluation when more definitive marker is
beyond reach
Unacceptable risk of alternate approach
Limit cost of clinical trials
Reduce time required for the trial
Replication of trial is easier


Should be evaluated rigorously, and this evaluation
should employ modern statistical assessment in the
context of current pathophysiological thinking
Distinguish between the correlation of a biomarker
with outcome and the causation of a relevant clinical
outcome difference
Proposed surrogate was determined to be valid for
one class of treatments, it may be invalid for another
class of treatments
Surrogate may not accurately predict outcome for
another drug or biologic in the same general class


Principles in analysis
Treatment Effects Are Modest
patient’s outcome is determined more by the natural
history of the disease than by the treatments we
deliver, and that multiple combined treatments will
be needed in most cases to achieve the best possible
outcome.
chronic therapies designed to prevent events -
anticipated treatment effect is so small that a
response to treatment is difficult to differentiate from
random fluctuations in the natural history of the
disease.


more thought to the degree of benefit it considers to
be a “clinically meaningful difference.”
small effects in epidemic diseases deserve serious
consideration because of the overall impact of the
treatment
Principle-1-clinically meaningful difference
identified will be small.


Qualitative Interactions Are Uncommon, but
Quantitative Interactions Are Usual:
Treatment effect observed in a population is
maintained across most sub groups
Therapy shown to be beneficial for patients with a
clinical condition, the therapy can be applied
systematically to the population in clinical practice


Quantitative interaction –benefit of treatment may be
more in certain sub groups
Important is to select patients in whom the outcome
with therapy is most favorable compared with what
would have happened without the therapy
Under represented groups like females and elderly
should be properly represented
Post marketing survelliance does not make up for
under representation
Principle-2- results of population can be applied
across all sub groups. Trials should be designed with
proper representation of all groups of patients

Unintended Targets Are Common:
Treatment affects an array of biological targets
broader than the intended target
ACE inhibitors-ventricular remodelling
Mibefradil-heart failure, heart block, and sudden
death
Principle-3-Always watch out for effects other than
primary end point.


assumptions by clinicians about untested
combinations of potent therapies may not only be
incorrect, but they could also lead to widespread
negative outcomes.
Examples include combining gp2b3a inhibitor with
heparin in EPIC trial-increased mortality
Observational studies which stated that aspirin and
ACE inhibitors could nullify each others effects.


Principle 4-conduct more trials with the use of a
proper design so that such interactions can be sorted
out
Avoid testing unknown drug combinations
Enhance interaction of clinical community with
manufacturers to avoid missing important
information from postmarketing surveillance.


Long-Term Effects Deserve Evaluation
Therapies have different effects in the short term
than in the long term.
Diet combination phenfluramine dexpheneramine
(fen phen) is a classic example.
 In small clinical trials performed over short periods
of time, the combination caused weight loss.
Only longer-term clinical observations raised the
issue of valvular insufficiency


 LIPIDS study demonstrates the benefit of monitoring
patients even when the randomized portion of the
trial is stopped early for benefit.
In this case, the event-rate curves have continued to
diverge, enabling the investigators to have more
power to look at key subgroups and ancillary
questions and to add important extra data to support
the benefits of pravastatin therapy


Principle-5-Develop more long-term evidence about
the effects of chronically administered therapies
too little research support is oriented towards
understanding how to conduct long-term studies in a
rapidly changing medical care environment.


Class Effects Can Be Uncertain
Class effect has been used to describe the effect of
drugs with the same biological target
But drugs can differ with regard to some qualities
Antiplatelet Trialists’ Collaboration made the point
that antiplatelet drugs generally reduce ischemic
events-but in CAPRIE trial clopidogrel did better than
aspirin in group with PVD
Similar results have been seen with gp2b3a inhibitors
where tirofiban and eptifibatide are better than
abciximab in ACS

Principle-6- be wary about substituting less
expensive drugs taking class effect for granted.
clinician must perform the difficult task of weighing
that uncertainty against the likelihood of compliance
with more affordable medicine for the patient


Adequate postmarketing
surviellance
Report adverse events observed in the post-marketing
period.
Such adverse event reporting played the critical role
in identifying cisapride as a cause of sudden death
and recognizing that mibefradil caused intolerable
toxicity when combined with a variety of other
medications
Principle-7-always ensure good post marketing
surveillance by regular interaction between
manufacturers and caregivers

Most Beneficial Therapies Do Not
Save Money, but They Are Incrementally
Cost-Effective
Development of new therapies almost invariably add
cost, even when the therapies are highly effective,
because the therapies are usually not curative: the
patients eventually succumb or have progression of
disease


GUSTO-I) trial- alteplase would reduce the risk of
death by 15% on a relative scale or by 1% on an
absolute scale, compared with a standard infusion of
streptokinase.
cost $2000 more
The trial found almost precisely the hypothesized
benefit, yielding an increase in life expectancy of 0.15
years per patient.
 Cost per year of life saved was approximately $30 000


coronary stents –though costly have reduced the need
for repeat revascularization
cost-effectiveness studieshave also
found them to be within the realm of
acceptable incremental costs in the
United States.

Principle-8- conduct of prospective cost studies
simultaneously with definitive, pragmatic clinical
outcome trials allows the clinical community to
place therapeutics in perspective


Principle 9: Applying the Results of Clinical
Trials Is Beneficial
Systematic administration of therapies demonstrated
to be effective in clinical trials leads to better patient
outcomes


Principle-9-following guidelines derived from
clinical trials not only ensures better health care but
also can provide new concepts


Principle 10: Some Areas of Cardiovascular
Medicine are Underserved
In the history of pediatric cardiology,< 30 randomized
clinical trials have been completed
primary pulmonary hypertension had extensive
treatment recommendations supported by very little
information derived from randomized clinical
outcome trials
Contrast this to the increased benefit produced by
strong willed organised government backed research
in paediatric cancer-good increase in longevity


Principle 11: Participation Is
Imperative
overall conclusion found in the lessons from clinical
trials and clinical practice is that practitioners and
patients need to play as great a role as possible in
generating the evidence for evidence-based medicine


Role in evidence-based decision
making


conclusions
Clinical trials advance both scientific progress and
help in improving patient care
 double blind randomised control trial is the gold
standard for conduct of any drug trial
selection of appropriate patients,properly defining
end points and ensuring safety of patients is
paramount to success of trials
Ensuring proper blinding both at randomisation and
stastical analysis gives greater reliability.


fair balance needs to be maintained to improve
adherence to ethical norms while not paralyzing
efforts to make progress in clinical research.
Completely dependent on the volunteer, altruistic
spirit of patients and the willingness of busy doctors
to engage in clinical trial efforts


Principles of drug trial in cardiology

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