Statistical analysis of clinical data isi 30 01 07


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Statistical analysis of clinical data isi 30 01 07

  1. 1. Statistical Analysis of Clinical DataA Cancer Trials Perspective Presented at the Indian Statistical Institute, Kolkata on 06.02.2007 Dr. Bhaswat S. Chakraborty VP, R&D, Cadila Pharmaceuticals Ltd.
  2. 2. Contents Research and Regulations of Cancer Trials Pivotal Cancer Trials (Phase III)  Efficacy end points  Merits and demerits  Optimum Study Designs  Superiority  Non-Inferiority and other designs  Sample Size Considerations  Scientific questions  Basics of sample size calculation Statistical Plan for a Cancer RCT Statistical Analysis of Cancer Data Lead Statisticians & DSMB Special Issues Conclusion
  3. 3. Cancer Research Today Research is conducted mainly on  New Drugs  New Combinations  Radiotherapy  Surgery In the West, research is usually done by large co-operative groups, in addition to those mentioned for India In India  Large Pharmaceuticals  Co-operative Groups, e.g., ICON (Indian Co-operative Oncology Network)  Regional Cancer Centres & Govt. sponsored studies  Academia
  4. 4. What does FDA Look for? FDA approves a drug application based on  Substantial evidence of efficacy & safety from “adequate and well-controlled investigations”  A valid comparison to a control  Quantitative assessment of the drug’s effect  (21 CFR 314.126.) The design of cancer trials intended to support drug approval is very important
  5. 5. Study Design: Approaches Randomised Controlled Trials (RCT) most preferred approach  Demonstrating superiority of the new therapy Other approaches  Single arm studies (e.g., Phase II)  e.g., when many complete responses were observed or when toxicity was minimal or modest  Equivalence Trials  No Treatment or Placebo Control Studies  Isolating Drug Effect in Combinations  Studies for Radio- and Chemotherapy Protectants
  6. 6. Randomized Clinical Trials Gold standard in Phase III Single centre CT  Primary and secondary indications  Safety profile in patients  Pharmacological / toxicological characteristics Multi-centre CT  Confirmation of the above  Effect size  Site, care and demographic differences  Epidemiological determination  Complexity  Far superior to meta-analyzed determination of effect
  7. 7. Non-Inferiority Trials New drug not less effective by a predefined amount, the noninferiority (NI) margin  NI margin cannot be larger than the effect of the control drug in the new study  If the new drug is inferior by more than the NI margin, it would have no effect at all  NI margin is some fraction of (e.g., 50 percent) of the control drug effect
  8. 8. Placebo Control Equality Trials No anticancer drug treatment in the control arm is unethical Sometimes acceptable  E.g., in early stage cancer when standard practice is to give no treatment  Add-on design (also for adjuvants)  all patients receive standard treatment plus either no additional treatment or the experimental drug  Placebos preferred to no-treatment controls because they permit blinding  Unless very low toxicity, blinding may not be feasible because of a relatively high rate of recognizable toxicities
  9. 9. Drug or Therapy Combinations Use the add-on design  Standard + Placebo  Standard + Drug X Effects seen in early phases of development  Establish the contribution of a drug to a standard regimen  Particularly if the combination is more effective than any of the individual components
  10. 10. What to Measure? Time to event end points  Survival  Disease free survival  Progress (of disease) free survival Objective response rates  Complete  Partial  Stable disease  Progressive disease Symptom end points Palliation QoL
  11. 11. Cancer Trials – End PointsEndpoint Evidence Assessment Some Advantages Some DisadvantagesSurvival Clinical benefit • RCT needed • Direct measure of • Requires larger and • Blinding not benefit longer studies essential • Easily • Potentially affected by measured crossover therapy • Precisely • Does not capture measured symptom benefit • Includes noncancer deathsDisease-Free Surrogate for • RCT needed • Considered to • Not a validatedSurvival accelerated • Blinding be clinical benefit survival surrogate in most(DFS) approval or preferred by some settings regular • Needs fewer • Subject to assessment approval* patients and bias shorter studies than • Various definitions survival exist
  12. 12. Cancer Trials – End PointsEndpoint Evidence Assessment Some Advantages Some DisadvantagesObjective Surrogate for • Single-arm or • Can be assessed • Not a direct measure ofResponse accelerated randomized in single-arm benefitRate (ORR) approval or studies can be studies • Usually reflects drug regular used activity in a minority of approval* • Blinding patients preferred in • Data are moderately comparative complex compared to studies survivalComplete Surrogate for • Single-arm or • Durable CRs • Few drugs produce highResponse accelerated randomized represent obvious rates of CR(CR) approval or studies can be benefit in some • Data are moderately regular used settings (see text) complex compared to approval* • Blinding • Can be assessed survival preferred in in single-arm comparative studies studies
  13. 13. Design Concepts Difference in Clinical Efficacy (Є) Non-Inferiority Superiority +δ 0 Equivalence -δ Inferiority Non-Superiority Equality δ = Meaningful Difference
  14. 14. Phase III Cancer Trials New Drug (or Regimen) is Compared with a Standard 90 80 New 70 Standard 60 50 40 30 20 10 0 Superiority Trials Survival DFS QoL
  15. 15. Phase III Cancer Trials4035 New30 Standard25201510 5 0 Survival DFS QoL  Non-Inferiority or Equivalence Trials
  16. 16. Understanding Basics μ0 and μA  Means under Null & Alternate Hypotheses σ02 and σA2  Variances under Null & Alternate Hypotheses (may be the same) N0 and NA  Sample Sizes in two groups (may be the same) H0: Null Hypothesis  μ0 – μA = 0 HA: Alternate Hypothesis  μ0 – μA = δ Type I Error (α): False +ve  Probability of rejecting a true H0 Type II Error (β): False –ve  Probability of rejecting a true HA Power (1-β): True +ve  Probability of accepting a true HA
  17. 17. Basics of Sample Size Calculation Answer the scientific questions for the Trial size Understand the distribution and variability of the data Construct correct Null and Alternate hypotheses From the hypotheses derive formula for sample size Also make sure that this size trial has adequate power to establish a true alternate
  18. 18. Five Key Questions1. What is the main purpose of the trial?2. What is the principal measure of patient outcome?3. How will the data be analysed to detect a treatment difference?4. What type of results does one anticipate with standard treatment?5. How small a treatment difference is it important to detect and with what degree of certainty? Answers to all of the five questions above enable us to calculate the sample size and analyze the data with most appropriate test of hypothesis. Pocock SJ: Clinical Trials: A Practical Approach Chichester: Wiley; 1983
  19. 19. Start Planning Reliable or historical data available? No Yes Use conventional methods for analysis Use bootstrap simulation for sample size Normally distributed continuous data? Summary Yes measure: mean & mean μT – μC difference∆normal = Use parametric methods of σ analysis, two sample ‘t’ or ANOVA Effect Size No 2 [Z1-α/2 + Z1-β/2]2 Use non-parametric methods Nnormal = of analysis, Mann-Whitney U ∆2normal or Proportional Odds Model Sample Size
  20. 20. Understanding Sample Size Determination H0: μ0 – μA = 0 HA: μ0 – μA = δ Critical Value S.Error =σ(√2/N) S.Error =σ(√2/N) Power = 1-β β α/2 α/2 0 δ X0–XA 0+Z1-α/2σ√(2/N) δ–Z1-βσ√(2/N)
  21. 21. From the Previous Graph, We have 0+Z1-α/2σ√(2/N) = δ–Z1-βσ√(2/N) Upon simplification, 2 [Z1-α/2 + Z1-β/2]2 Nnormal = ∆2normal
  22. 22. Sample Size: 2-Sample, Parallel Superiority/Non-Inferiority Trial (z+zβ)2 (p1 (1– p1) + p2(1 – p2))N in each arm = (Є – δ)2
  23. 23. Power: 2-Sample, Parallel Superiority/Non-Inferiority Trial Є –δ Φ – z √p1 (1– p1)/n1 + p2(1 – p2)/n2) Where p1 and p2 are true mean response rates from Test & Control & Φ is the cumulative standard normal distribution function
  24. 24. Statistical Plan  Primary outcome considerations  Study Design  Sample size calculation  Randomization  Statistical consideration in Inclusion/Exclusion criteria (Homogeneity within centre and strata)  Accrual of patients  Cleaning of data  Interim Analysis  Go/No go criteria  α Considerations  Final analysis  Final conclusions
  25. 25. Statistical DesignsCrossover Trials A ABaseline B B Parallel Arm Trials A Baseline B
  26. 26. Accrual of Patients Study of the statistical trends in accrual patterns  Seasonal  Planned approaches  Reasons for drop outs and loss to follow up  Motivational factors Monitoring of recruitment progress and strategies  Frequency  Parameters  Duration Understanding natural history and non-cancer, non-intervention deaths Changes in accrual after Interim Analysis
  27. 27. Randomisation Generation of randomisation scheme according to  Centre  Block  Strata  Patient  Investigational Product to be given  Measures of ensuring non-bias Allocations What should go on the labels  Primary, secondary, tertiary packaging
  28. 28. Blinding Often difficult in oncology trials  Test and control are of different characteristics  Different routes of administration  Different schedules New low toxicity oral treatments are relatively easy to blind In other cases the end-point evaluating investigator must be different from the one administering the drugs
  29. 29. Data Capture Manual or Electronic CRF is the main source of raw data capture Data must be quality assured  Integrity, accountability, traceability Data must be validated All production and/or quality system software, purchased or developed in-house  Should document  Intended use, and information against which testing results and other evidence can be compared  To show that the software is validated for its intended use
  30. 30. Data Cleaning & Locking Data are cleaned based on a good plan for interim or final analysis  E.g.,  Hundred percent data are made quality checked and assured  Eligibility criteria for data selection  Correction and editing  Double data entry or other methods of data integrity Data will be locked after cleaning the data and resolving all the queries  SOP for data locking  No change after locking Only locked data are used as input into data analysis program
  31. 31. Interim Analysis of Data 0.05 0.045 0.04 0.035 0.03 0.025 Nominal p 0.02 0.015 0.01 0.005 0 1 2 3 4 Looks
  32. 32. Interim Analysis of Data 2 Looks 3 LooksHow many times 0.05 0.05can you look into Nominal Pvalue Nominal Pvaluethe data? 0.03 0.03 o pocock o ob+fle 0.01 0.01 o fle+har+ob 0.0 0.0 1 2 1 2 3 Look Look 4 Looks 5 Looks 0.05 0.05Type 1 error at kth Nominal Pvalue Nominal Pvaluetest is NOT the 0.03 0.03same as the 0.01 0.01nominal p value 0.0 0.0for the kth test 1 2 3 4 1 2 3 4 5 Look Look
  33. 33. Considerations for IA  Stopping rules for significant efficacy  Stopping rules for futility  Measures taken to minimize bias  A procedure/method for preparation of data for analysis  Data has to be centrally pooled, cleaned and locked  Data analysis - blinded or unblinded?  To whom the interim results will be submitted?  DSMB  Expert Steering Group  What is the scope of recommendations from IA results?  Safety? Efficacy? Both? Futility? Sample size readjustment for borderline results?
  34. 34. Final Analysis and Conclusion Clinically meaningful margins must be well defined in Control trials prospectively  Superiority and non-inferiority margins must not be confused Two or one-sidedness of α should also be prospectively defined Power must be adequate Variance must be analysed using the right model Strategy for dealing with multiple end points must be prespecified  Too many end points ot tests will increase the false positive (α) error Sometimes (e.g., in equality trials) statistically significant results may not be medically significant Data censoring or skewed data  E.g., time to event data
  35. 35. Equality Designs(e.g., 2-Sample, Parallel) H0 : Є = 0 HA : Є ≠ 0 Reject H0 when p1— p2 ˆ ˆ > z/2 √p1(1—p1)/n1 + p2(1— p2)/n2 ˆ ˆ ˆ ˆ Where p1— p2 are true mean response rates ˆ ˆ from Test & Control
  36. 36. Superiority/Non-Inferiority Designs(e.g., 2-Sample, Parallel) H0 : Є ≤ δ HA : Є > δ … Superiority H0 : Є ≥ δ HA : Є < δ … Non-Inferiority Reject H0 when p1— p2 – δ ˆ ˆ > z √p1(1—p1)/n1 + p2(1— p2)/n2 ˆ ˆ ˆ ˆ
  37. 37. Survival Data – The Kaplan-Meier Estimator 1.0 Survival Percentage 0.75 0.50 0.25~40% Patientwill survivebeyond 0.8 year 0.0 Time (Year) 0.0 0.2 0.4 0.6 0.8 1.0
  38. 38. Intent-to-Treat Principle All randomized patients Exclusions on prespecified baseline criteria permissible  also known as Modified Intent-to-Treat Confusion regarding intent-to-treat population: define and agree upon in advance based upon desired indication Advantages:  Comparison protected by randomization  Guards against bias when dropping out is realted to outcome  Can be interpreted as comparison of two strategies  Failure to take drug is informative  Refects the way treatments will perform in population Concerns:  “Difference detecting ability”
  39. 39. Per Protocol Analyses Focuses on the outcome data Addresses what happens to patients who remain on therapy Typically excludes patients with missing or problematic data Statistical concerns:  Selection bias  Bias difficult to assess
  40. 40. Intent to Treat & Per Protocol Analyses Both types of analyses are important for approval Results should be logically consistent Design protocol and monitor trial to minimize exclusions Substantial missing data and poor drug compliance weaken trial’s ability to demonstrate efficacy
  41. 41. Missing Data Protocol should specify preferred method for dealing with missing primary endpoint  ITT  e.g., treat missing as failures  e.g., assign outcome based on blinded case-by-case review  Per Protocol  e.g., exclusion of patients with missing endpoint
  42. 42. Data Safety and Monitoring Board (DSMB) All trials may not need a DSMB DSMB Membership  Medical Oncologist, Biostatistician and Ethicist Statistical expertise is a key constituent of a DSMB Three Critical Issues  Risk to participants  Practicality of periodic review of a trial  Scientific validity of the trial
  43. 43. Practicality of a DSMB If the trial is likely to be completed quickly, the DMC may not have an opportunity to have a meaningful impact In short-term trials with important safety concerns, however, a DMC may still be valuable
  44. 44. Outstanding Issues Problems in ‘discounting’ (raising the hurdle to declare non- inferiority in order to account for inherent weaknesses) when indirectly comparing an experimental treatment to a placebo. Confronting weaknesses due to lack of assay sensitivity and constancy. Selection of the primary analysis population (ITT population vs. per protocol population). Inappropriate selection of analysis population will lead to biased results. The impact of trial quality on the results of active controlled trials – what the regulator will want to see substantiated on trial quality. Ethical issues if placebo controlled trials are used vs. statistical issues if they are not.
  45. 45. Outstanding Issues Selecting and using surrogate endpoints – the determination of statistical significance. Problems of designing clinical trials involving combination therapies. Statistical analysis and interpretation of complex data. Issues with the choice of control group in dose-finding studies – which doses to test and whether to include a placebo dose. Statistical inference with non-randomized controls - Propensity scores - Paired availability design for historical controls Statistical inference with randomized controls - Adjusting for non-compliance - Surrogate endpoints/missing outcome
  46. 46. Conclusions Clinical testing of new Oncology products is very sophisticated and complex A Statistician’s role in Cancer trials is invaluable Statistical considerations must be thoroughly given attention and built in while planning the study design and calculating the sample size Cancer clinical data is very complex (censored, skewed, often fraught with missing data point), therefore, proper hypothesization and statistical treatment of data are required Prospective RCTs are usually the preferred approach for evaluation of new therapies
  47. 47. Conclusions Survival as primary end point is preferred by regulatory agencies Randomisation and blinding offer a robust way to remove bias in end-point estimations Data must be accurately captured without any bias and analysed by prospectively described methods Interim analysis should carefully plan ‘ spending’ function Final analysis should be done carefully, independently and meaningfully (medical as well as scientific) Choose clinically relevant delta Design, conduct, and monitor trials to minimize missing data and poor compliance to drug Analysis  Both intent-to-treat and per protocol analyses should be conducted  Sensitivity analyses There are many oustanding statistical issues in Cancer trials that need no be discussed and solved
  48. 48. Acknowledgements Dr. Nikunj Patel Dr. Sumit Goyal Dr. Manish Harsh Dr. Nilesh Patel Ms. Darshini Shah Thank You Very Much