Clinical Trials


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the ppt describes in detail the translational research and path of the drug from lab to bed side, CONSORT guidelines, DCGI guidelines, CTR-I, the GCP principles, medical ethics, sample size estimation for RCT, RCT designs including cross over design and factorial design, Randomized permuted blocks, blinding and matching.

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Clinical Trials

  1. 1. ClinicalTrials Dr Menaal Kaushal JR II Department of S.P.M. S. N. Medical College Agra 16-05-2014
  2. 2. Types of Studies Epidemiological Studies Observational Descriptive Analytical Interventional/ Experimental RCT FieldTrial Community Trial 16-05-2014 2
  3. 3. Why ClinicalTrials?  Gold standard with aTotality of Evidence:  Lab Study- High Precision  Epidemiological Study- High Relevance  Designed to elucidate Most Appropriate Treatment for the FUTURE PATIENTS  Should be done only in existence of CLINICAL EQUIPOISE  So, during enrollment the researcher must ensure Absence of THERAPEUTIC MISCONCEPTION among the participants.  Also ensure the non-existence of Oxymoron: THERAPEUTIC RESEARCH 16-05-2014 3
  4. 4. From Lab to Clinics to Community- the Developmental Process Funnel Drug Discovery Pre clinical Phase I FIH Phase II POC Phase III Post approval Trials- Phase IV 10,000 compounds 10- 15 yrs $ 1 billion 1 compound Bench to Bed SideTranslational Blocks T0- Discovery Science T1 Phase Clinical/Translational Research NOT ClinicalTrial BorderlineTrial ClinicalTrial T2 T3 16-05-2014 4
  5. 5. Pre Clinical Phase  Safety Testing- Toxicity and Physiological Response to the new Compound is assessed  Organs targeted include:  Cardio- vascular  Neuro- muscular  Respiratory  + Other Organs and systems depending on the compound’s action  Dose Dependence  Potential for Reversibility16-05-2014 5
  6. 6. Toxicity studies  AcuteToxicity: determine overdose effects  Repeated Dose Toxicity: maximum duration of clinical trial 16-05-2014 7
  7. 7. MRSD Determination  HED= animal’s NOAEL (mg/kg)* Wt (Animal) 1-0.62  A 10 fold Safety margin is usually used, so:  MRSD= HED/ Safety factor  Maximum tolerated Dose (MTD) needs to be estimated where the Dose limiting toxicity has a certain probability ( )Wt (Human) 16-05-2014 8
  8. 8. Dose Response Curve Increasing Dose (mg/kg)------------> Probabilityofadverseevents P(DLT)----------> 0 1 0.33 MTD 16-05-2014 9
  9. 9. Phase I- FIHTrial  Healthy volunteers are given a single dose in a controlled environment (In- patient settings)  Volunteers usually paid  Risks are kept to be minimum  What needs to be assessed is:  Safety  Pharmacokinetics  Pharmacodynamics  Route and Rate of administration  Fixing up the end points  Physiologic effects in humans16-05-2014 10
  10. 10. POC Study  Patients having the disease of interest, are enrolled  Volunteers not paid  Moderate (or even serious) risks are acceptable  Done to assess:  The Dose response  Safety  Pathophysiology  Limited observation about efficacy 16-05-2014 11
  11. 11. Steps in Conducting a Phase III Clinical Trial  Design Phase  Research Question- FINER Criteria, PICOT style  Study Designs  Ethical Considerations& GCP Guidelines  Registering with CTRI  Latest DGCA Guidelines-Video Record Every Consent  Sample Size, Clearly defined Inclusion- Exclusion criteria 16-05-2014 12
  12. 12. Steps in Conducting a Phase III Clinical Trial  Implementation Phase  Randomization v/s Random Allocation  Blinding  Control- StandardTreatment v/s Placebo  Monitoring& DSMB- InterimAnalysis  Analytical Phase  ITT v/s Per protocol analysis  CONSORT Guidelines 16-05-2014 13
  13. 13. Research Question  FINER; PICOT  Following need to be considered:  Effect Size  Composite endpoints  Surrogate End Points  Study duration  Secondary Questions  Sub group Hypothesis  Natural History Studies 16-05-2014 14
  14. 14. Study Designs  Two group parallel design-The Look ahead trial (T2DM obese pts on Diabetes support& education v/s active, intensive lifestyle modification)  Multi group parallel design-The Re-ly trial (Atr Fib pts on warfarin v/s dabigatran 110mg v/s dabigatran 150 mg)  Factorial design-The SUPPORTTrial (very premature neonates were randomized into Early surfactant v/s early CPAP and O2 Saturation 85% v/s 95%)  Cross over design- Pts can be compared on themselves. E.g. Hemophilia trial. No carry over between the two treatment periods- Rest period is needed16-05-2014 15
  15. 15. The History Behind Ethics Nuremberg Code- 1946 Declaration of Helsinki- 1964 Council for International Organizations of Medical SciencesCIOMS- 1982 International Conference on Harmonization – Good clinical practice (ICH-GCP)- 1996 16-05-2014 16
  16. 16. Historical Perspectives  Council for International Organizations of Medical Sciences (CIOMS) and WHO (1982) – International ethical guidelines for biomedical research involving human subjects  Revised – 1993, 2002  International Conference of Harmonization – Good clinical practice (ICH-GCP)-1996)  International ethical and scientific quality standard for designing, conducting, recording and reporting trials involving human subjects. 16-05-2014 18
  17. 17. 13 Principles of GCP 1. Ethics (Declaration of Helsinki) 2. Risk Benefit analysis 3. Trial subjects (rights and safety) 4. Investigational product (Information support study) 5. Scientifically sound 6. Compliance (IRB review)16-05-2014 19
  18. 18. 7. Qualified physician to provide medical care 8. Trial staff (trained in protocol) 9. Informed consent 10. Data (reporting, interpretation, verification) 11. Confidentiality 12. Good manufacturing practice of the investigational product 13. QualityAssurance of all aspects of protocol 16-05-2014 20
  19. 19. 7 Components of the Ethics: 1. Social or Scientific value 2. ScientificValidity 3. Fair Subject Selection 4. Favorable risk- benefit ratio 5. Independent review 6. Informed Consent 7. Respect for potential and enrolled subjects 16-05-2014 21
  20. 20. Ethics in Trials  During Phase I Trials, 95% of the times, participating patients do not benefit from theTrial  The probability (chance) of having any benefit 5%  Risk of fatal complication 5%  While there may be a significant chance of benefit in Phase IIITrial 16-05-2014 22
  21. 21. Risk- Benefit Ratio 16-05-2014 23
  22. 22. Risk- Benefit Ratio 16-05-2014 24
  23. 23. Informed Consent - Elements  Information  Patient/subject information sheet  Comprehension  Simple and understandable language  Local language translations  Voluntariness  Consent 16-05-2014 27
  24. 24. Informed Consent  Community studies – Consent needed from  Community – group consent  Individuals  Children  Parent/guardian  Assent of child to his/her capability  Mentally Ill  Close biological relative  Legally authorized person  Certificate from psychiatrist 16-05-2014 28
  25. 25. Importance Of Clinical Trials Registration  To ensure transparency , accountability and to increase public trust in the conduct of clinical research.  Clinical trial registration and results reporting would help ensure unbiased public records on safety and efficacy of drugs.  All clinical trials should be registered before the enrolment of the first patient and all results made publicly available. 16-05-2014 29
  26. 26. Registration of Trials Globally  At the 58th WHA held on 25th May 2005 WHO had set up of an International Clinical Trial Registry Platform (ICTRP), a one-stop search portal for searching registers worldwide.  The ICTRP recommended 20 key points as Trial Registration data Set that need to be publicly declared before the enrolment of the first patient.  In the 59th General Assembly of the World Medical Association, 2008, in its revision of the Declaration of Helsinki among other modifications, specifies that:  “Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject.” 16-05-2014 30
  27. 27. CTR- I  Till 2006, there was no national registry of clinical trials in India  On July 20, 2007, ICMR through its National Institute of Medical Statistics (NIMS) formed Clinical Trials Registry – India (CTRI) with financial support from DST andWHO.  The CTRI has additional data points over the ICTRP’s recommended 20 point data set:  Later these additional points were borrowed from CTR- I and were inculcated in the WHO’s ICTRP. 16-05-2014 31
  28. 28. Registration Data Set of the CTRI 1. Public Title of Study 2. Scientific Title of Study, Acronym, if any 3. Secondary IDs, (UTN, Protocol No etc) 4. Principal Investigator’s Name and Address* 5. Contact Person (Scientific Query) 6. Contact Person (Public Query) 7. Source/s of Material or Monetary Support 8. Primary Sponsor 9. Secondary Sponsor 10. Countries of Recruitment 11. Site/s of study 12. Name of Ethics Committee and approval status 13. Regulatory Clearance obtained from DCGI * Optional fields 14.Health Condition/Problem studied 15.Study Type 16.Intervention and Comparator agent 17.Key inclusion/Exclusion Criteria 18.Method of generating randomization sequence* 19.Method of allocation concealment* 20.Blinding and masking* 21.Primary Outcome/s 22.Secondary Outcome/s 23.Target sample size 24.Phase of Trial 25.Date of first enrollment 26.Estimated duration of trial 27.Status of Trial 28.Publication details* 29.Brief Summary Additional items of CTRI 16-05-2014 32
  29. 29. ClinicalTrial Registry-India 16-05-2014 33
  30. 30.  It is housed at the National Institute of Medical Statistics, ICMR, New Delhi.  Trial registration is purely online, paperless process and free of charge  The CTRI software application was modified and implemented on 15th March 2011. Clinical Trials Registry – India 16-05-2014 34
  31. 31. Objectives of CTRI  To establish a public record system by registering all clinical trials on health products including:  Drugs  Devices  Vaccines  Herbal drugs  It makes the information available to both public and healthcare professionals in an unbiased, scientific and timely manner.  To create a complete, authentic and readily available data of all ongoing and completed clinical trials. 16-05-2014 35
  32. 32. Objectives of CTRI  To provide a corrective system against “positive results bias” and “selective reporting” of research results to peer review publication.  To increase awareness and accountability of all the participants of the clinical trials and also for public access:  Trial registration empowers the public and offer patients the choice of enrolling in a clinical trial to gain access to latest breakthrough treatment options.  To promote training, assistance and advocacy for clinical trials by creating database and modules of study for various aspects of clinical trials and its registration. 16-05-2014 36
  33. 33. Registration of clinical trials under CTR- I is recommended by: 1. Drugs Controller General (India): Made mandatory since June 2009 2. Editors of Indian Biomedical Journals; 3. Ethics Committees of various institutions, AIIMS, CMC, Sir Ganga Ram Hospital etc. 16-05-2014 37
  34. 34. DCGI Notification 16-05-2014 38
  35. 35.  CTRI currently accepts registration of:  Prospective trials  Ongoing  Completed trials  Terminated trials  Registered trials are flagged as:  Trial registered prospectively  Trial registered retrospectively  Terminated trial registered 16-05-2014 41
  36. 36. 16-05-2014 Empowering patients 42
  37. 37. Registering Trials during PG Thesis CTRI encourages registration of trials being conducted as part of post- graduation thesis work  This would help  Ensure ethical standards  Prevent unnecessary duplicate research  Raise the standard of research  Enable better exchange of data and ideas 16-05-2014 47
  38. 38. PG Thesis registration 16-05-2014 48
  39. 39. Methodology Enrollment Criteria Ascertainment of Primary End Point Treatment A (Test) Treatment B (Control) Quality: Adherence Missing Data 16-05-2014 53
  40. 40. Sample Size Calculations n= 2 ṕ (1-ṕ) (Zα/2+Zβ)2/ Δ2 Where: Δ= pc- pt ṕ= (pc+ pt)/ 2 At α= 0.05, Zα/2= 1.96 At β= 0.20, Zβ= 0.84 16-05-2014 54
  41. 41. Sample Size Calculations n= 2 (Zα/2+Zβ)2/ log (λc/λt)2 Where: λ= survival probability At α= 0.05, Zα/2= 1.96 At β= 0.20, Zβ= 0.84 16-05-2014 55
  42. 42. Randomization  Unrestricted Randomization: may produce treatment groups of different sizes  Randomized Permuted Block  Stratified Randomized Permuted Block  Cluster Randomization 16-05-2014 56
  43. 43. Unrestricted Randomization Probability--------------------- Number of heads from 20 tosses--------------------16-05-2014 57
  44. 44. Relativeefficiency Proportion allocated toTreatment A 50%0% 100% Relative Efficiency of Unbiased Allocation 16-05-2014 58
  45. 45. Randomized Permuted Blocks ABAB AABB BBAA BABA ABBA BAAB 16-05-2014 59
  46. 46. Blinding Single BlindTrial Double BlindTrial Triple BlindTrial 16-05-2014 60
  47. 47. Analysis  Intent to treat  Modified Intent to treat  Per protocol Analysis  On assignedTt  Fully compliant with study domain  As treated Analysis Best Active- Interventional Compromised Observational 16-05-2014 61
  48. 48. Analysis to Study Outcome  Binary (HTN or Normotensive)  Measurable (BP reading)  Time to event (at what time during the follow up, has the event occurred)  Other outcomes: No. of episodes (e.g. no of exaggeration episodes of asthma, while on treatment) 16-05-2014 62
  49. 49. CONSORT (Con solidated S tandards o f R eportingT rials) statement Section/Topic Item No Checklist Reported on Pg no Title& Abstract 1a Identification as a randomised trial in the title 1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) Introduction 2a Scientific background and explanation of rationale Background& Objectives 2b Specific objectives or hypotheses Method Trial Design 3a Description of trial design (such as parallel, factorial) including allocation ratio 3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons 16-05-2014 63
  50. 50. Section/Topic Item No Checklist Report ed on Pg no Participants 4a Eligibility criteria for participants 4b Settings and locations where the data were collected Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were actually administered outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed 6b Any changes to trial outcomes after the trial commenced, with reasons Sample size 7a How sample size was determined 7b When applicable, explanation of any interim analyses and stopping guidelines16-05-2014 64
  51. 51. Section/Topic Ite m No Checklist Reported on Pg no Randomization Sequence 8a Method used to generate the random allocation sequence Generation 8b Type of randomisation; details of any restriction (such as blocking and block size) Allocation Concealment mechanism 9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned Implementatio n 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how 16-05-2014 65
  52. 52. Section/ Topic Item No Checklist Reported on Pg no 11b If relevant, description of the similarity of interventions Statistical Method 12a Statistical methods used to compare groups for primary and secondary outcomes 12b Methods for additional analyses, such as subgroup analyses and adjusted analyses Results Participants (a flow diagram strongly recommende d) 13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome 13b For each group, losses and exclusions after randomisation, together with reasons Recruitment 14a Dates defining the periods of recruitment and follow-up 14b Why the trial ended or was stopped16-05-2014 66
  53. 53. Section/ Topic Item No Checklist Reported on Pg no Baseline data 15 A table showing baseline demographic and clinical characteristics for each group Number analyzed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was by original assigned groups Outcomes& estimation 17a For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) 17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended Ancillary analysis 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) 16-05-2014 67
  54. 54. Section/ Topic Item No Checklist Reported on Pg no Discussion Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses Generalizabili ty 21 Generalisability (external validity, applicability) of the trial findings Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence Other information Registration 23 Registration number and name of trial registry Protocol 24 Where the full trial protocol can be accessed, if available Funding 25 Sources of funding and other support (such as supply of drugs), role of funders16-05-2014 68
  55. 55.  Flow chart 16-05-2014 69
  56. 56. References:  Textbook of Preventive and Social Medicine by K. Park   ClinicalTrials by Stuart J Pocock  harvard 16-05-2014 70
  57. 57. 16-05-2014 71 ThankYou