Dr.P.V.Nishanth
IntroductionDesigned to help find out how to give a new treatment safely and effectively to people.Clinical trials provi...
 There are various types of clinical trials of which RCTS are the gold standard for testing any moleculeConduct of drug ...
Cost and scopeWorldwide, the average cost of developing one molecule costs about $282 million and takes about seven years...
Evolution of clinical trials inIndiaRelatively new in IndiaInitially small uncontrolled trials-evaluate tolerability of ...
• Around 25 contract research organisations (CROs)  and almost all multinational pharmaceuticals  companies have started f...
Hurdles in Indian drug trialApprovals-DCGI-conduct a trial and import licence- form 11Ethical approval from IRB’S or IEC...
Objectives of clinical trialCure for a diseasePalliation where cure is not possibleRelief of symptomsRisk of recurrenc...
Types of studies• Observational studies-• descriptive-case series•     analytical-cohort•                case control•    ...
TYPES OF REVIEWSSystematic review - study that addresses a focused research question, has explicit eligibility criteria, ...
principles of conduct of drug trials in cardiology
Types of studiescase report:most basic type of studyobservational report of the course of a single subjectbuilding blo...
Case registry:Collects data on similar patients without specifying an intervention.Does not evaluate a new therapy in a...
Nonrandomized clinical trial-known as a single-arm study, in which study participants are simply assigned a known therap...
Randomised clinical trialsFifty-five years ago, the publication of the British Medical Research Council trial of streptom...
• Initially in field of infectious diseases,were successful  as they evaluate large treatment effects• In fields like card...
Trial conduct has changed over last few years mainly due to greater understanding of key criteria that were critical to t...
principles of conduct of drug trials in cardiology
Large simple trialEschew detailed data collection and extensive screening processes in favor of rapid enrollment and the ...
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 ...
principles of conduct of drug trials in cardiology
Phase-I determine the metabolic and pharmacological actions of the drug in humansThe total number of subjects included i...
Phase-III These trials are conducted in several hundred to several thousand people. The objective of these trials is to c...
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 investig...
DMC monitors the trial for evidence of relative harm or convincing evidence of benefit, track the trial’s progress, adher...
InvestigatorIncreasing number of trials overall has generated a  need for interested and qualified investigators, as well...
Problems in India• India has over 572,000 doctors, 43,322 hospitals and  dispensaries and about 8.7 lakh beds including bo...
Why do a drug trialPool controlled observations in an objective and scientific way, allowing clinicians to decide with th...
Barriers to participation     Lack of      knowledge     Time constraints     Financial      considerations     Need f...
principles of conduct of drug trials in cardiology
Areas of conflict-placebo armPlacebo arms should not be used in clinical trials if there is already an effective standard...
Areas of conflict-patient interestBlurring of the roles of physician as caregiver and physician as investigator- patient ...
Areas of conflict-financesLarge trials usually offer adequate reimbursementFinancial interests may lead to-            ...
Role of IRBComposed of healthcare professionals and non clinicians2 medical scientists,2 non medical scientists,one lay ...
Role of a coordinatorLiaison between the study site and the trial coordinating centerIs usually a nurse but may be a nur...
principles of conduct of drug trials in cardiology
Statistical conceptsIntention-to-treat principle: To minimize any bias introduced by patients crossing over into unassign...
Descriptive stastistics-Reporting of sample characteristicsCentral value for a collection of data, eg, a mean, or avera...
Sample size:Larger the sample size (the larger the n), the more confident we will be in trusting the conclusionEffect o...
Comparision of two characters-correlation coefficient- -1,0 or +1relationships among multiple variables uses multivariab...
principles of conduct of drug trials in cardiology
Concealment of randomisationmost common is the sealed envelope systemclinicians are given randomly generated treatment a...
Problems: Prior opening of envelopesPostpone trial recruitment until a patient with cer- tain characteristics presents,...
Distance randomisation-involves the investigator, on recruiting a patient, telephoning a central randomisation service wh...
‘Ascertainment bias: distortion of results Systematic imbalances in endpoint evaluations and effective concomitant coint...
Surrogate end pointsEnd point of clinical trial could be definitive or inferential/surrogateEvaluation of definitive end...
Uses of surrogate markersPermit evaluation when more definitive marker is beyond reachUnacceptable risk of alternate app...
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...
Principles in analysisTreatment Effects Are Modestpatient’s outcome is determined more by the natural history of the dis...
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 ...
Qualitative Interactions Are Uncommon, but Quantitative Interactions Are Usual:Treatment effect observed in a population...
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 ...
Unintended Targets Are Common:Treatment affects an array of biological targets broader than the intended targetACE inhi...
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 ...
Principle 4-conduct more trials with the use of a proper design so that such interactions can be sorted outAvoid testing...
Long-Term Effects Deserve EvaluationTherapies have different effects in the short term than in the long term.Diet combi...
 LIPIDS study demonstrates the benefit of monitoring patients even when the randomized portion of the trial is stopped ea...
Principle-5-Develop more long-term evidence about the effects of chronically administered therapiestoo little research s...
Class Effects Can Be UncertainClass effect has been used to describe the effect of drugs with the same biological target...
Principle-6- be wary about substituting less expensive drugs taking class effect for granted.clinician must perform the ...
Adequate postmarketingsurviellanceReport adverse events observed in the post-marketing period.Such adverse event reporti...
Most Beneficial Therapies Do NotSave Money, but They Are IncrementallyCost-EffectiveDevelopment of new therapies almost i...
GUSTO-I) trial- alteplase would reduce the risk of death by 15% on a relative scale or by 1% on an absolute scale, compar...
coronary stents –though costly have reduced the need for repeat revascularization  cost-effectiveness studieshave also  ...
Principle 9: Applying the Results of ClinicalTrials Is BeneficialSystematic administration of therapies demonstrated  to ...
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 ne...
Principle 10: Some Areas of CardiovascularMedicine are UnderservedIn the history of pediatric cardiology,< 30 randomized ...
Principle 11: Participation IsImperativeoverall conclusion found in the lessons from clinical trials and clinical practic...
Role in evidence-based decisionmaking        principles of conduct of drug trials in cardiology
principles of conduct of drug trials in cardiology
conclusionsClinical trials advance both scientific progress and help in improving patient care double blind randomised c...
fair balance needs to be maintained to improve adherence to ethical norms while not paralyzing efforts to make progress i...
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Principles of drug trial in cardiology

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Drug trials in cardiology

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Principles of drug trial in cardiology

  1. 1. Dr.P.V.Nishanth
  2. 2. 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
  3. 3.  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 principles of conduct of drug trials in cardiology
  4. 4. 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. principles of conduct of drug trials in cardiology
  5. 5. Evolution of clinical trials inIndia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 principles of conduct of drug trials in cardiology
  6. 6. • 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
  7. 7. 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 principles of conduct of drug trials in cardiology
  8. 8. 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 principles of conduct of drug trials in cardiology
  9. 9. 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
  10. 10. 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. principles of conduct of drug trials in cardiology
  11. 11. principles of conduct of drug trials in cardiology
  12. 12. 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 principles of conduct of drug trials in cardiology
  13. 13. 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 principles of conduct of drug trials in cardiology
  14. 14. 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
  15. 15. 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 principles of conduct of drug trials in cardiology
  16. 16. • 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
  17. 17. 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 principles of conduct of drug trials in cardiology
  18. 18. principles of conduct of drug trials in cardiology
  19. 19. 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 principles of conduct of drug trials in cardiology
  20. 20. principles of conduct of drug trials in cardiology
  21. 21. 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
  22. 22. principles of conduct of drug trials in cardiology
  23. 23. 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. principles of conduct of drug trials in cardiology
  24. 24. 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 principles of conduct of drug trials in cardiology
  25. 25. principles of conduct of drug trials in cardiology
  26. 26. principles of conduct of drug trials in cardiology
  27. 27. principles of conduct of drug trials in cardiology
  28. 28. principles of conduct of drug trials in cardiology
  29. 29. 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
  30. 30. 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
  31. 31. 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 principles of conduct of drug trials in cardiology
  32. 32. 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
  33. 33. 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” principles of conduct of drug trials in cardiology
  34. 34. Barriers to participation Lack of knowledge Time constraints Financial considerations Need for recognition Legal liability principles of conduct of drug trials in cardiology
  35. 35. principles of conduct of drug trials in cardiology
  36. 36. 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. principles of conduct of drug trials in cardiology
  37. 37. 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 principles of conduct of drug trials in cardiology
  38. 38. 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 principles of conduct of drug trials in cardiology
  39. 39. 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 principles of conduct of drug trials in cardiology
  40. 40. 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 principles of conduct of drug trials in cardiology
  41. 41. principles of conduct of drug trials in cardiology
  42. 42. 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
  43. 43. 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 principles of conduct of drug trials in cardiology
  44. 44. 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
  45. 45. 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 principles of conduct of drug trials in cardiology
  46. 46. principles of conduct of drug trials in cardiology
  47. 47. 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. principles of conduct of drug trials in cardiology
  48. 48. 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 principles of conduct of drug trials in cardiology
  49. 49. 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
  50. 50. ‘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 principles of conduct of drug trials in cardiology
  51. 51. 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 principles of conduct of drug trials in cardiology
  52. 52. 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 principles of conduct of drug trials in cardiology
  53. 53. principles of conduct of drug trials in cardiology
  54. 54. principles of conduct of drug trials in cardiology
  55. 55. 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
  56. 56. 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. principles of conduct of drug trials in cardiology
  57. 57. principles of conduct of drug trials in cardiology
  58. 58. 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
  59. 59. 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
  60. 60. principles of conduct of drug trials in cardiology
  61. 61. 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
  62. 62. 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. principles of conduct of drug trials in cardiology
  63. 63. principles of conduct of drug trials in cardiology
  64. 64. 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
  65. 65. 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. principles of conduct of drug trials in cardiology
  66. 66. 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 principles of conduct of drug trials in cardiology
  67. 67.  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
  68. 68. 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
  69. 69. 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 principles of conduct of drug trials in cardiology
  70. 70. 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
  71. 71. Adequate postmarketingsurviellance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 principles of conduct of drug trials in cardiology
  72. 72. Most Beneficial Therapies Do NotSave Money, but They Are IncrementallyCost-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 principles of conduct of drug trials in cardiology
  73. 73. 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 principles of conduct of drug trials in cardiology
  74. 74. 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 principles of conduct of drug trials in cardiology
  75. 75. Principle 9: Applying the Results of ClinicalTrials Is BeneficialSystematic administration of therapies demonstrated to be effective in clinical trials leads to better patient outcomes principles of conduct of drug trials in cardiology
  76. 76. principles of conduct of drug trials in cardiology
  77. 77. 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
  78. 78. Principle 10: Some Areas of CardiovascularMedicine 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 principles of conduct of drug trials in cardiology
  79. 79. Principle 11: Participation IsImperative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 principles of conduct of drug trials in cardiology
  80. 80. Role in evidence-based decisionmaking principles of conduct of drug trials in cardiology
  81. 81. principles of conduct of drug trials in cardiology
  82. 82. 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. principles of conduct of drug trials in cardiology
  83. 83. 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

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