principles of drug trial in cardiology
DESCRIPTION
Drug trials in cardiologyTRANSCRIPT
Dr.P.V.Nishanth
IntroductionDesigned 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 design2.Principles in analysis
principles of conduct of drug trials in cardiology
Cost and scopeWorldwide, 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.
principles of conduct of drug trials in cardiology
Evolution of clinical trials in IndiaRelatively 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 IndiaSince early 2000’s academic trials were
started
principles of conduct of drug trials in cardiology
• 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
principles of conduct of drug trials in cardiology
Hurdles in Indian drug trialApprovals-DCGI-conduct a trial and import
licence-form 11Ethical approval from IRB’S or IEC in
MumbaiDrug import- approval from ADC in
Chennai,Mumbai,Delhi,KolkataAcademic studies need additional clearance
from ministry of health screening committee
principles of conduct of drug trials in cardiology
Objectives of clinical trialCure for a diseasePalliation where cure is not possibleRelief of symptomsRisk of recurrence of diseasePrevention of disease or disabilityComparitiive efficacy in relation to other
alternativesRelative safety of interventionRelative impact of demographic profilesImpact on socio economic parameters
principles of conduct of drug trials in cardiology
Types of studies• Observational studies-• descriptive-case series• analytical-cohort• case control• cross sectional• Experimental-• RCTS• NON -RCTS
principles of conduct of drug trials in cardiology
TYPES OF REVIEWSSystematic 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.
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
Types of studiescase report:most basic type of studyobservational report of the course of a single
subjectbuilding block of the case series,
accumulated data from several case reports
principles of conduct of drug trials in cardiology
Case registry:Collects data on similar patients without
specifying an intervention. Does not evaluate a new therapy in a
randomized fashionDoes 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 necessaryConsent only if individual will be exposed
principles of conduct of drug trials in cardiology
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
principles of conduct of drug trials in cardiology
Randomised clinical trialsFifty-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
principles of conduct of drug trials in cardiology
• 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
principles of conduct of drug trials in cardiology
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 blindingFocus on hard end pointsGrowing preference for large simple trials
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
Large simple trialEschew 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
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
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
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
Phase-Idetermine 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.
principles of conduct of drug trials in cardiology
Phase-IIIThese 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
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
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
principles of conduct of drug trials in cardiology
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
principles of conduct of drug trials in cardiology
InvestigatorIncreasing 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
principles of conduct of drug trials in cardiology
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.
principles of conduct of drug trials in cardiology
Why do a drug trialPool 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”
principles of conduct of drug trials in cardiology
Barriers to participationLack of
knowledgeTime
constraintsFinancial
considerationsNeed for
recognitionLegal liability
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
Areas of conflict-placebo armPlacebo 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.
principles of conduct of drug trials in cardiology
Areas of conflict-patient interestBlurring 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
principles of conduct of drug trials in cardiology
Areas of conflict-financesLarge trials usually offer adequate reimbursementFinancial interests may lead to- improper recruitment unjudicious experimentation tampering of records to show successConflict of interest can be avoided by- not allowing inventors into recruitment process strict monitoring of entire process by IRBS and
DMC
principles of conduct of drug trials in cardiology
Role of IRBComposed of healthcare professionals and
non clinicians2 medical scientists,2 non medical
scientists,one lay person,one legal expert.Aim to protect human subjects involved in
research at their particular institutionReview the ethics,monitor the safetyRecommend changes to study protocols or
terminate trial
principles of conduct of drug trials in cardiology
Role of a coordinatorLiaison between the study site and the trial
coordinating centerIs 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
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
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.
principles of conduct of drug trials in cardiology
Descriptive stastistics-Reporting of sample characteristicsCentral 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
principles of conduct of drug trials in cardiology
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
principles of conduct of drug trials in cardiology
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 valueTime to an event-kaplan-mier curvesRisk of an event-odds ratio
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
Concealment of randomisationmost common is the sealed envelope systemclinicians 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.
principles of conduct of drug trials in cardiology
Problems: Prior opening of envelopesPostpone 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
principles of conduct of drug trials in cardiology
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
principles of conduct of drug trials in cardiology
‘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 resultsprinciples of conduct of drug trials in cardiology
Surrogate end pointsEnd point of clinical trial could be definitive
or inferential/surrogateEvaluation 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
principles of conduct of drug trials in cardiology
Uses of surrogate markersPermit evaluation when more definitive
marker is beyond reachUnacceptable risk of alternate approachLimit cost of clinical trialsReduce time required for the trialReplication of trial is easier
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
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 of conduct of drug trials in cardiology
Principles in analysisTreatment Effects Are Modestpatient’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.
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
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.
principles of conduct of drug trials in cardiology
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
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
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
principles of conduct of drug trials in cardiology
Unintended Targets Are Common:Treatment affects an array of biological
targets broader than the intended targetACE inhibitors-ventricular remodellingMibefradil-heart failure, heart block, and
sudden deathPrinciple-3-Always watch out for effects
other than primary end point.
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
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.
principles of conduct of drug trials in cardiology
Principle 4-conduct more trials with the use of a proper design so that such interactions can be sorted out
Avoid testing unknown drug combinationsEnhance interaction of clinical community
with manufacturers to avoid missing important information from postmarketing surveillance.
principles of conduct of drug trials in cardiology
Long-Term Effects Deserve EvaluationTherapies 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
principles of conduct of drug trials in cardiology
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
principles of conduct of drug trials in cardiology
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.
principles of conduct of drug trials in cardiology
Class Effects Can Be UncertainClass effect has been used to describe the effect
of drugs with the same biological targetBut drugs can differ with regard to some
qualitiesAntiplatelet 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
principles of conduct of drug trials in cardiology
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
principles of conduct of drug trials in cardiology
Adequate postmarketing surviellanceReport 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
principles of conduct of drug trials in cardiology
Most Beneficial Therapies Do NotSave Money, but They Are IncrementallyCost-EffectiveDevelopment 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
principles of conduct of drug trials in cardiology
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 moreThe 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
principles of conduct of drug trials in cardiology
coronary stents –though costly have reduced the need for repeat revascularizationcost-effectiveness studies have 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
principles of conduct of drug trials in cardiology
Principle 9: Applying the Results of ClinicalTrials Is BeneficialSystematic administration of therapies
demonstrated to be effective in clinical trials leads to better patient outcomes
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
Principle-9-following guidelines derived from clinical trials not only ensures better health care but also can provide new concepts
principles of conduct of drug trials in cardiology
Principle 10: Some Areas of CardiovascularMedicine are UnderservedIn the history of pediatric cardiology,< 30
randomized clinical trials have been completedprimary 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
principles of conduct of drug trials in cardiology
Principle 11: Participation Is Imperativeoverall 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
principles of conduct of drug trials in cardiology
Role in evidence-based decision making
principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
conclusionsClinical 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 trialselection 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.
principles of conduct of drug trials in cardiology
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 conduct of drug trials in cardiology