Principles of drug trial in cardiology

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


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.


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


• 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 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


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


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


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.


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


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


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 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


• 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 blindingFocus on hard end pointsGrowing preference for large simple trials


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


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-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.


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


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


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


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 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”


Barriers to participationLack of

knowledgeTime

constraintsFinancial

considerationsNeed for

recognitionLegal liability


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.


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


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


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


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


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 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


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 valueTime to an event-kaplan-mier curvesRisk of an event-odds ratio


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.


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


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 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


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


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 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.


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 targetACE inhibitors-ventricular remodellingMibefradil-heart failure, heart block, and

sudden deathPrinciple-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 combinationsEnhance interaction of clinical community

with manufacturers to avoid missing important information from postmarketing surveillance.


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


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 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


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 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


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


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


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


Principle 9: Applying the Results of ClinicalTrials Is BeneficialSystematic 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 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


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


Role in evidence-based decision making


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.


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

Health & Medicine

Transcript of Principles of drug trial in cardiology