Research Methodology 2


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Interventional studies
Clinical Trials

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Research Methodology 2

  1. 1. Methodology (II) Tamer Hifnawy MD. Dr.PH Associate Professor P u b l i c H e a l t h & C o m m u n i t y M e d i c i n e F a c u l t y O f M e d i c i n e – B S U - E g y p t C o l l e g e O f D e n t i s t r y T a i b a h U n i v e r s i t y - K S A V i c e D e a n F o r Q u a l i t y , D e v e l o p m e n t & I n t e r n a t i o n a l A f f a i r s C e r t i f i e d T r a i n e r F o r I n t e r n a t i o n a l R e s e a r c h E t h i c s
  2. 2. What is a Clinical Trial? A prospective study comparing the effect and value of intervention (s) against a control in human being. Friedman, 1998
  3. 3. Intervention studies Objective To measure the effect of a particular intervention (a drug, other treatment, a vaccine or a health promotion program)
  6. 6. What Is The RCT ?  It is one of the simplest, most powerful, revolutionary tools of research in which ;  Participants  are allocated at Random  into 2 or > groups (one of them is Control)  to receive one or more Interventions, then  Followed up in time, and  Outcomes are compared
  7. 7. Clinical Trials  A research study to test new treatments in people for specific illnesses or conditions (Malaria, HIV, Cancer, etc).  Clinical Trials are the fastest and safest way to find out which treatments work
  8. 8. Definition of Clinical Trials  Pre-Planed usually Controlled studies of the Safety, Efficacy, or Optimum Dosage schedule of one or more Diagnostic, Therapeutic, or Prophylactic drugs in humans selected according to pre-determined criteria of Eligibility and observed for pre-defined evidence of Favorable and Unfavorable effects.
  9. 9. Goals of Clinical Trials Finding Drugs or Treatments that WORK Those that do NOT WORK
  10. 10. Uses of Clinical Trials  Treatment: test experimental treatments, combinations of drugs, new approaches.  Prevention: look for better way to prevent disease or its recurrence.  Diagnostic: develop better tests.  Screening: to detect diseases or health conditions.  Quality of Life (or Supportive Care): improve comfort and QOL in chronic disease states.
  11. 11. Common Clinical Trial Terms  CONTROLLED STUDY: A study in which a test article is compared with a treatment / placebo  A test drug is given to one group of people. This group is often called the “treatment group.”  Another drug, or no drug, is given to a second group of people with the same illness. This is often called the “control group.”  Then the results of the two groups are compared.
  12. 12. PLACEBO  A pill, liquid, or powder that contains no drug and has no treatment value.  A placebo looks just like the real drug.
  13. 13. Control arm WHY? Spontaneous cure Side effects HOW? Criteria Historical Ethical
  14. 14. Examples of control arm  Standard care.  Placebo.  Careful follow-up.  Early or late application of same intervention.  Higher or lower dose level.
  15. 15. Randomized Clinical Trials Participants RandomlyAssigned Follow - Up Follow - Up OutcomesCompared Intervention Group (New Drug) Control Group (Old Drug) Intervention Group Control Group
  16. 16. Randomization Means that subjects recruited from the study population are allocated to either intervention or control arm by chance. Random procedure = haphazard procedure
  17. 17. Why Randomization  Ensures comparability of the two arms regarding known and unknown factors.  Avoid selection bias.  Provides basis for standard statistical analysis. Differences in baseline characteristics of the study arms indicate break in randomization.
  18. 18. Why Randomization is difficult Any randomization technique must insure: 1. Every new subject has an equal chance to be allocated to either arms (alternation?!) 2. Nearly equal number of subjects in each arm (coin toss?!).
  19. 19. Randomization techniques  Fixed allocation randomization: 1. Simple randomization. 2. Blocked randomization. 3. Stratified randomization.  Outcome adaptive designs: Play the winner.  Others.
  20. 20. Simple Randomization 1. Sealed envelopes. 2. Random number tables. 3. Computer generation.
  21. 21. Blocked Randomization  Blocks containing specific number of participants are generated ( 5 blocks each containing 4 participants for a study with total of 20 participants).  Within each block, participants are randomly allocated to either arms. TCTC CCTT TTCC TCCT CTCT
  22. 22. Stratified Randomization Control Age<40 Test Enrolled Control Age>40 Test
  23. 23. Baseline measurements Useful to check that comparability has been successfully achieved.
  24. 24. Design of the trial Methodology section should include the following: 1-Patient inclusion criteria. 2-Time of patients inclusion in the study. 3-Presence of a comparison group. 4-Matching criteria of the two groups. 5-Method used for randomization.
  25. 25. Blindness Means ensuring that a person remains unaware of which arm a subject has been allocated to.
  26. 26. Why Blindness(continued):  To reduce selection bias.  to avoid bias in outcome measures. Blinding is not possible in all studies so, one needs to consider how important it is, and to what extent it can be achieved.
  27. 27. Trials are often described as:  Single-blind: subject  Double-blind: subject & investigators (clinician, interviewers, laboratory personnel).  Triple blind: subject, investigators & Statistitian. Blindness (continued)
  28. 28.  Compliance: 1. Questioning 2. Observing 3. Check drug  Complications.  Completeness of follow-up. Observe the following
  29. 29. Complex designs 1- Multiple treatment groups More than 2 different treatments (or doses) may be compared with a control group. Sample population Control Drug A Drug B Drug C
  30. 30. Complex designs 2- Cross-over trial Each subject receives both the active and control treatments during two periods separated by a wash-out period.
  31. 31. Outcome No outcome Outcome No outcome Cross-Over Enrolled Population Wash-out period Drug APlacebo Outcome No outcome Outcome No outcome Drug APlacebo
  32. 32. Complex designs for clinical trials 3- Factorial design used to evaluate the separate and combined effects of two different factors: 1. Group 1: Placebo. 2. Group 2:. Iron 3. Group 3: Folate. 4. Group 4: Iron + Folate Sample population Control Surgery Radiotherapy Surgery+Radio
  33. 33. Outcome variables Continuous variables: hypertension Dichotomous variables: dead/alive. Time-to-event variables: time to remission. Ordered variables: mild, moderate, severe. Repeated measures: visual acuity. Composite measures: score, cost-benefit.
  34. 34. Losses to follow-up •One of the most important sources of bias, since those lost may be different from those seen. •Compare drop-outs to non-drop-outs. •Perform sensitivity analysis.
  35. 35. Interpretation of trial 1- Reporting the data. 2- Statistical methods. 3- Statistical analysis. 4- Power. P < 0.05 ??
  36. 36. Good RCT should report Clear definition of patients. Comparison group. Randomization and blindness. Outcome criteria and variables. Compliance and completeness. Complications of treatment. Statistical manipulation.
  37. 37. Risks and Benefits of Clinical Trials  Risks:  Unpleasant or serious side effects  You may receive a placebo  No guarantee that the experimental drug will be an effective treatment for you.  Benefits:  May experience health benefits from a new treatment  Free lab tests and expert treatment  Contributing to the development of a new medication
  38. 38. Statistics  Only 1 in 10,000 of the compounds synthesized for potential drug use ever reach market  Of all drugs tested in human beings, only 1 in 10 becomes a new medicine  Only 33% of all drugs that are marketed make profits that exceed the costs of development  The average cost of bringing a drug to market is $800 million  The average number of studies conducted on a new drug prior to market approval are 64 Did you know that...
  39. 39. PhRMA Pharmaceutical Industry Profile 2006
  40. 40. The Drug Development Process
  41. 41. Goals and Objectives  Basic understanding of drug development process as a whole, i.e.  How a drug goes from test tube to market  Connections between preclinical testing, chemistry and clinical research as they relate to drug development  Understanding of what goes into an Investigational New Drug Application (IND) and New Drug Application (NDA), including FDA involvement  Know how GLP, GMP, and GCP regulations and guidelines fit into the drug development picture
  42. 42. PRECLINICAL The Pipeline Concept of Drug Development APPROVAL $$$ PIPELINE
  43. 43. The Pipeline Concept of Drug Development Drug Discovery Period (Pre-Clinical) Drug Development Period Commercialization Idea for New Drug Synthesis & Purification Specific Biological Activity Found Animal Testing Candidate Compound Chosen and More Testing Compound Evaluated to Project Status IND Plan Set IND Filed With FDA Clinical Studies Planned and Started NDA Prepared and Submitted to FDA NDA Approval Drug Launched Post- Marketing Studies Begun New Clinical Uses Pursued Activities to Support Market New Dosage Forms and Formulas Developed Clinical Trials Phases I, 2, & 3 Clinical Trials -- Phase 4 3.5 Years 8.5 Years 8 Years Left on Patent (patent applied for)
  44. 44. The Pipeline Concept of Drug Development While in the pipeline, the drug could be halted for several reasons. Pre-Clinical Marketed Lack of Safety Lack of Funds Lack of Efficacy Unethical Conduct
  45. 45. Pre-Clinical Research  Why?  Per FDA requirement, a sponsor must first submit data showing that the drug is reasonably safe for use in initial, small- scale clinical studies  Therefore:  Preclinical research must be initiated prior to submission of Investigational New Drug application (IND)
  46. 46. Pre-Clinical Drug Discovery Period (Pre-Clinical) Idea for New Drug Synthesis & Purification Specific Biological Activity Found Animal Testing Candidate Compound Chosen and More Testing
  47. 47. Animal Testing  Provide sufficient information to support selection of initial human dose and safe duration of exposure  Evaluate drug’s toxic and pharmacologic effects  Toxicology: predicts potential hazards in man  Pharmacology: investigates action of drug  Pharmacokinetics  Pharmacodynamics
  48. 48. Animal Testing (cont.) Pharmacodynamics The effect the drug has on the body. Looks at bodily responses to pharmacological, biochemical, physiological, and therapeutic effects: ED50, LD50 Pharmacokinetics The effect the body has on the drug: ADME.
  49. 49. Drug Development Drug Development Period Compound Evaluated to Project Status IND Plan Set IND Filed With FDA Clinical Studies Planned and Started NDA Prepared and Submitted to FDA NDA Approval Drug Launched Clinical Trials Phases I, 2, & 3
  50. 50. Clinical Studies Phases 1, 2, 3  Ultimate premarket testing ground for unapproved drugs  Investigation drug administered to humans and evaluated for its safety and effectiveness  Results from trials decide approval or disapproval of drug  Involves three phases of clinical studies (21 CFR 312.21)
  51. 51. Phase 1 Objectives  Main purpose: assessing safety of drug  Human Pharmacology (PK and PD –e.g. ADME)  Typically non-therapeutic objectives  Determine tolerability of dose range expected to be needed for later trials (Maximum tolerated Dose -MTD)  Determine nature of adverse reactions that can be expected  Assess clearance of drug and to anticipate possible accumulation of parent drug or metabolites and potential drug-drug interactions
  52. 52. Phase 1 Demographics  Usually healthy volunteers or certain types of patients (e.g. new chemotherapeutic agent for cancer patients with end stage disease)  Often conducted in a medical setting  20-100 patients  Trials can last up to several months  Open label –everyone knows what they are getting.  70% of drugs successfully complete Phase 1 and continue on to Phase 2
  53. 53. Phase 2 Objectives  Therapeutic Exploratory  Main purpose: assessing efficacy for particular indication (Efficacy-A product's ability to produce beneficial effects on the course or duration of a disease)  Initial evaluation:  Safety (side-effect profile-AE / SAE)  Well-controlled, closely monitored studies  Active or placebo controlled -- double blind  Includes dose-response and/or dosing schedule studies  Determine dose and regimen for Phase 3
  54. 54. Phase 2 Demographics  200-300 (up to 1000) patients with targeted indication  Diseased patients; selected by relatively narrow criteria  Trials last from several months to 2 years  Experienced physicians in the specialty  Early Phase 2 trials may be called Phase 2a or pilot studies  33% of drugs successfully complete Phase 2 and continue on to Phase 3
  55. 55. Phase 3 Objectives  Therapeutic Confirmatory  Main purpose: safety, effectiveness - confirm therapeutic benefit for use in intended indication and recipient population  Effectiveness-The desired measure of a drug's influence on a disease condition as proved by substantial evidence from adequate and well- controlled investigations such as clinical trials.  Evaluate overall benefit-risk relationship  Provide adequate basis for marketing approval  Extrapolate results to put in labeling  25-30% of drugs complete Phase 3 trials
  56. 56. Phase 3 Demographics  Several hundred to several thousand patients  Patients with the disease; more diverse population  Inclusion/Exclusion criteria less restrictive  Trials last from 1-4 years  Less experienced investigators - Approaches general use (the “real world population)  Overall: on average, 20% of drugs ultimately gain FDA approval to market
  57. 57. Conducted after submission for marketing but prior to approval Phase 3b
  58. 58. Commercialization/Post Marketing Commercialization Post- Marketing Studies Begun New Clinical Uses Pursued Activities to Support Market New Dosage Forms and Formulas Developed
  59. 59. Phase 4- Post Marketing Trial  Post Marketing trials are studies (other than routine surveillance) performed after drug approval and related to the approved indication(s).  These trials go beyond the prior demonstration of the drug’s safety, efficacy and dose definition.  These trials may not be considered necessary at the time of new drug approval but may be required by the Licensing Authority for optimizing the drug’s use.  They may be of any type but should have valid scientific objectives.
  60. 60. Phase 4  Increases patient experience  Safety in practice environment  Information to support marketing claims / change labeling  Pharmacoeconomics, quality of life, Pediatric patent extension trials
  61. 61. Post Marketing Surveillance  Continued evaluation of adverse events after marketing  FDA reporting required  May result in labeling changes or restrictions or in extreme cases withdrawal from market