Acceleration of clinical trials Dr jani


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Acceleration of clinical trials Dr jani

  1. 1. Best practices & Techniques to Accelerate the Trial Process Dr. Rajendra H Jani Senior Vice President, Clinical R&D Cadila Healthcare Limited Zydus Cadila House TPS 5, Plot 360, Service Road Vile Parle (E) Mumbai- 400057 E-mail:,© Dr. R.H.Jani E-mail: 1, 15-Apr-11
  2. 2. Accelerate the Trial Process • Examining the current trends in Clinical trials • Analyzing trials for different phases of a project • Deploying dynamic research approaches – Clinical trial designs & systematic and random errors • Best Practices to accelerate in Clinical trial -Implementing global technique© Dr. R.H.Jani E-mail: 2, 15-Apr-11
  3. 3. Examining the current trends in Clinical trials© Dr. R.H.Jani E-mail: 3, 15-Apr-11
  4. 4. Comparison of Clinical Trial Density Numbers of Region Country Studies Global 103914 100% America 60734 58.44% Canada 7979 7.68% USA 57464 55.29% Europe 26228 25.24% Germany 7134 6.86% France 6132 5.90% UK 5301 5.10% Asia 16975 16.33% China 2043 1.96% India 1546 1.48% 6th March 2011© Dr. R.H.Jani E-mail: 4, 15-Apr-11
  5. 5. Density of Clinical Trials Density of actively recruiting clinical sites, on 6th March 2011© Dr. R.H.Jani E-mail: 5, 15-Apr-11
  6. 6. Clinical Trial Density in India Density of actively recruiting clinical sites in India, on 6th March 2011© Dr. R.H.Jani E-mail: 6, 15-Apr-11
  7. 7. Clinical Trial Density in China© Dr. R.H.Jani E-mail: 7, 15-Apr-11
  8. 8. Clinical Trial Density in China© Dr. R.H.Jani E-mail: 8, 15-Apr-11
  9. 9. Analyzing trials for different phases of a project© Dr. R.H.Jani E-mail: 9, 15-Apr-11
  10. 10. Clinical studies: Phases of development • Phase 0: A new concept of Micro-dosing • Before the permission to market, a potential new drug candidates passes through three well defined clinical development phases; Phase I, II and III. – Phase I is the earliest study usually conducted in healthy humans volunteers and divided into early and late phase I studies – Phase II studies are conducted in patients with the target disease and are also known as Proof of Concept or exploratory studies usually. – Phase III also known as confirmatory trials and aim at conclusively proof of efficacy and safety – Phase IV are conducted in patients, usually at the post-marketing stage, to assess long-term safety and/or investigate rare adverse effects.© Dr. R.H.Jani E-mail: 10, 15-Apr-11
  11. 11. Clinical trials: Phase I • Early Phase I – Single dose escalation – Multiple dose escalation – Pharmacokinetics – Pharmacodynamic (sometimes) – Maximum tolerated dose (MTD), – gender effects and – food effects.© Dr. R.H.Jani E-mail: 11, 15-Apr-11
  12. 12. Clinical trials: Phase I • Late Phase I trial- – Definitive pharmacokinetics / pharmacodynamic – Bioavailability with range of formulations – Interaction studies with • Drug - food and • Drug – drug – Metabolic disposition – Drug PK/PD/Metabolism in • Hepatic impairment • Renal impairment – Pharmacokinetic in special groups; children and elderly© Dr. R.H.Jani E-mail: 12, 15-Apr-11
  13. 13. Clinical trial: Phase II – Phase II studies are conducted in patients with the target disease and are also • known as Proof of Concept or • exploratory studies • First in patient trials – Objectives of phase II studies is to- • determine appropriate dose levels, • investigate safety, and • assess any signs of efficacy. • The studies usually are relatively small in terms of sample size, and they may or may not include randomization, double-blinding, and control groups.© Dr. R.H.Jani E-mail: 13, 15-Apr-11
  14. 14. Clinical trials: Phase III • Phase III studies are - – Conducted in large numbers of patients to confirm the efficacy and safety – Confirmatory studies for PoC – Sample size are determined from PoC results – Statistical power – Comparative© Dr. R.H.Jani E-mail: 14, 15-Apr-11
  15. 15. Clinical trials – a case study Exenatide (Eli Lilly / Liraglutide Amylin (Novo Nordisk) Industry sponsor 93 32 Sponsored By originator 68 32 Phase 1 Total 7 6 Healthy Volunteers 3 3 India 0 0 Diabetes 5 3 Phase 2 Global 12 6 India 0 1 Phase 3 Global 31 19 India 7 6 Phase 4 Global 7 1 India 1 0 Compiled from on 6th March 2011© Dr. R.H.Jani E-mail: 15, 15-Apr-11
  16. 16. Dynamic qualitative & quantitative research approaches© Dr. R.H.Jani E-mail: 16, 15-Apr-11
  17. 17. Qualitative vs quantitative research • Qualitative research is concerned with finding the answer to questions which begin with – why? – how? – In what way? • Quantitative research is concerned with questions about: – how much? – How many? – How often? – To what extent?© Dr. R.H.Jani E-mail: 17, 15-Apr-11
  18. 18. Qualitative Vs Quantitative Research • Qualitative: • Quantitative – Participant observation – Randomized clinical trial – Case study – Cohort – Structural observation – Case-Control study – Content analysis of documents – performance data – Focus groups – Example: – Example: • What proportion of • What stops people smokers have tried to giving up smoking? give up?© Dr. R.H.Jani E-mail: 18, 15-Apr-11
  19. 19. Qualitative Vs Quantitative Research • Qualitative • Quantitative – Title: • Title: • Pregnancy outcomes in – The acceptability of injectable foreign-born and US-born contraceptive by women in women. India – Objective: – Objective: • To compare pregnancy • To find out the reasons outcomes between why there is such a low foreign-born women and acceptability of methods of women born in the United injectable contraception States. – Method: – Method: • The project will be • Retrospective cohort study conducted as a survey of all deliveries at Grady and some focal group hospital in Atlanta discussions will be held. between 1991 and 2000. • A total of 1200 women will – *Authors: Forna F, Jamieson DJ, Sanders D, be interviewed, 600 will be Lindsay MK. Int.J.Gynecol.Obstet.2003;83:257-65 of the urban area and 600 from the rural areas.© Dr. R.H.Jani E-mail: 19, 15-Apr-11
  20. 20. Acceleration of Clinical trials through Clinical trial designs© Dr. R.H.Jani E-mail: 20, 15-Apr-11
  21. 21. Clinical trials: Various designs • Open comparative • Comparative: – Open or double blind – Randomized – Crossover – Parallel – Prospective – Observer blind© Dr. R.H.Jani E-mail: 21, 15-Apr-11
  22. 22. Clinical trials: Blinding • CLINICAL TRIALS – BLINDING (MASKING): – Blinding refers to the situation in which the patients do not know the treatment identity. – A double-blinded study: • the investigators and patients are blinded to treatment identity, which eliminates assessment bias. – An observer blind study: • It is not possible to design a masked trial in some situations, e.g., surgical trials. • In such situations, the researchers who administer the treatments should be distinct from those who collect the data.© Dr. R.H.Jani E-mail: 22, 15-Apr-11
  23. 23. Clinical trials: Crossover design • Some trials may invoke a crossover design in which patients serve as their own controls. For example, – subjects may undergo an experimental therapy for six weeks and then “cross over” to the control therapy for another six weeks (or vice versa). • Crossover designs are appealing because – the patients serve as their own controls. – require a much smaller sample size than a “parallel” design. • Crossover designs is suitable for chronic diseases or pharmacokinetics studies in healthy volunteers • sample of patients, so that variability will be lower.© Dr. R.H.Jani E-mail: 23, 15-Apr-11
  24. 24. Clinical trials: Crossover design Limitations: • Not suitable for an acute condition e.g., common cold, where condition may resolve itself within a short period of time, so there is nothing that the second treatment can do. • A disadvantage of a crossover design is the potential for “carryover” effects, i.e., the treatment administered during the first period may carry over into the second treatment period. • Criteria that are more restrictive will yield a homogeneous • This will require a smaller target sample size, but recruitment will be difficult. • Another drawback is that the results of the study may not be generalizable to other types of patients with the disease (lack of external validity).© Dr. R.H.Jani E-mail: 24, 15-Apr-11
  25. 25. Active Control Trials • Many clinical trials compare two or more active therapies, rather than comparing an active therapy with placebo. • Issues that need clarifying include: – How should the confidence interval for demonstrating non- inferiority be determined? – What data should be used to estimate the effect of the control agent (e.g., all prior studies?) – How should they be weighted? – What drugs should be included as the active control? – How should inconsistent results (i.e., size of treatment effect) from prior studies of the active control be approached? – What are appropriate sample size requirements in non-inferiority and active-controlled studies?© Dr. R.H.Jani E-mail: 25, 15-Apr-11
  26. 26. Adaptive Trial Designs • Adaptive trial designs allows modifications aspects of the trial after its initiation – It allows the rectification of inappropriate assumptions – Examples of the modifications are- • Sample size re-estimation • Early stopping due to efficacy or futility • Adaptive randomization • Dropping inferior treatment group • Consensus and clarification is needed on questions such as: • When can extra trial arms be dropped? • When can an early marker be used to choose • which treatment to carry forward or to choose a subset for analysis? • When is it valid to modify randomization based on results, for example, in a combined phase 2/3 cancer trial? • When is it valid and under what situations can one stage or phase of a study be combined with the second stage or phase?© Dr. R.H.Jani E-mail: 26, 15-Apr-11
  27. 27. Biomarkers : Enrichment Clinical Trial Designs© Dr. R.H.Jani E-mail: 27, 15-Apr-11
  28. 28. How do we know that a Biomarker is valid? • What is a valid biomarker? – A biomarker that is measured in an analytical test system with well established performance characteristics and for which there is an established scientific framework or body of evidence that elucidates the physiologic, toxicologic, pharmacologic, or clinical significance of the test results. – http:// www. fda. gov/ cder/ guidance/ 6400fnl. pdf© Dr. R.H.Jani E-mail: 28, 15-Apr-11
  29. 29. First Wave of Biomarkers • Galactomannan detection in- – broncho- alveolar lavage fluid as marker for invasive pulmonary aspergillosis. – blood as a biomarker for invasive aspergillosis. • Preclinical Biomarkers of Nephrotoxicity (PSTC) • Circulating Tumor Cells as biomarkers to aid in therapeutic decision- making in metastatic breast cancer.© Dr. R.H.Jani E-mail: 29, 15-Apr-11
  30. 30. Biomarkers for Oncology Drug Theraputic Area Biomarker Label Sections PML/RARα Boxed Warning, Clinical Pharmacology, Indications Arsenic Trioxide Oncology translocation and Usage, Warnings Philadelphia Busulfan Oncology chromosome Clinical Studies Capecitabine Oncology DPD Contraindications, Precautions, Patient Information Indications and Usage, Warnings and Precautions, Cetuximab (1) Oncology EGFR Description, Clinical Pharmacology, Clinical Studies Indications and Usage, Clinical Pharmacology, Cetuximab (2) Oncology KRAS Clinical Studies Philadelphia Indications and Usage, Clinical Studies, Patient Dasatinib Oncology chromosome Counseling Information Erlotinib Oncology EGFR Clinical Pharmacology Gefitinib Oncology EGFR Clinical Pharmacology Indications and Usage, Dosage and Administration Imatinib (1) Oncology C-Kit Clinical Pharmacology, Clinical Studies Philadelphia Indications and Usage, Dosage and Administration, Imatinib (2) Oncology chromosome Clinical Pharmacology, Clinical Studies© Dr. R.H.Jani E-mail: 30, 15-Apr-11
  31. 31. Biomarkers for Oncology Drug Theraputic Area Biomarker Label Sections Dosage and Administration, Warnings, Clinical Irinotecan Oncology UGT1A1 Pharmacology Indications and Usage, Clinical Pharmacology, Lapatinib Oncology Her2/neu Patient Counseling Information Dosage and Administration, Contraindications, Precautions, Adverse Reactions, Clinical Mercaptopurine Oncology TPMT Pharmacology Philadelphia Indications and Usage, Patient Counseling Nilotinib (1) Oncology chromosome Information Nilotinib (2) Oncology UGT1A1 Warnings and Precautions, Clinical Pharmacology Indications and Usage, Warnings and Precautions, Panitumumab (1) Oncology EGFR Clinical Pharmacology, Clinical Studies Indications and Usage, Clinical Pharmacology, Panitumumab (2) Oncology KRAS Clinical Studies Rasburicase Oncology G6PD Boxed Warning, Contraindications Indications and Usage, Precautions, Medication Tamoxifen Oncology Estrogen receptor Guide Thioguanine Oncology TPMT Dosage and Administration, Precautions, Warnings Indications and Usage, Precautions, Clinical Trastuzumab Oncology Her2/neu Pharmacology© Dr. R.H.Jani E-mail: 31, 15-Apr-11
  32. 32. Biomarkers : Enrichment Clinical Trial Designs • Trastuzumab: – Enrichment design- • Diagnostic test is used to restrict eligibility for Her 2 + breast cancer patients for the trial • Drug is effective on Her 2+ patients which constitute 15- 25% of the breast cancer population • Standard randomized trials would require large sample size to detect diluted effects of trastuzumab.© Dr. R.H.Jani E-mail: 32, 15-Apr-11
  33. 33. Clinical trial Random and systemic errors© Dr. R.H.Jani E-mail: 33, 15-Apr-11
  34. 34. Clinical trials: Random and systemic errors • Objectives of any trial is to estimate not only intended and unintended effects, but also magnitude of such effects. • Inaccurate estimates prove costly, either through- – discontinuation of a good potential candidates or – selection of wrong • Systemic errors are – reduced through precision and unbiasness – Brought in by- • Literature • Study sample selection • Measurement of exposures, • outcomes (and covariates) analysis • Interpretation© Dr. R.H.Jani E-mail: 34, 15-Apr-11
  35. 35. Clinical trials: Bias What is bias? Systemically wrong estimate of parameter of interest Amount by which an estimate differs from true values Any process tending to lead to results differing systemically from truth© Dr. R.H.Jani E-mail: 35, 15-Apr-11
  36. 36. Clinical trials: Some of possible source of bias Study Design Study conduct Analysis Confounding Selection Bias Measurement Interpretation© Dr. R.H.Jani E-mail: 36, 15-Apr-11
  37. 37. Clinical trials: Bias from study conduct • With any systemic allocation procedure bias is possible, perhaps- – Hospital numbers; outdoor, indoor and emergency – Date of presentations; weekdays vs. holidays – Prognostic factor associated with allocation criteria • The difference in results from any systemic allocation procedures instead of differences in efficacy of treatment • Above confounding factor© Dr. R.H.Jani E-mail: 37, 15-Apr-11
  38. 38. Clinical trials: Bias from confounding Confounding factor is- Associated Correlates with with treatment outcome Exposure (treatment)  Confounder   Disease (Outcome)© Dr. R.H.Jani E-mail: 38, 15-Apr-11
  39. 39. Clinical trials: Bias from analysis Attrition biases Dropouts from the groups before the intervention is completed Losses to follow-up© Dr. R.H.Jani E-mail: 39, 15-Apr-11
  40. 40. Clinical trials: Measurement biases • Invasive Methods • Non invasive Investigations • Governed by ethical issues & cost • Sensitive (Responsive) Methods of • Reliable (Repeatable) Measurement • Practical Surrogated • Provide practicability marker • Validity becomes controversial© Dr. R.H.Jani E-mail: 40, 15-Apr-11
  41. 41. Clinical trial: Bias from interpretation • Preferred, revealed Blinding by pattern of response Non-comparative • Hardly possible trials • Observer blinding? Confusion on • Test of significance statistics • Methods of analysis© Dr. R.H.Jani E-mail: 41, 15-Apr-11
  42. 42. Best Practices to accelerate in Clinical trial© Dr. R.H.Jani E-mail: 42, 15-Apr-11
  43. 43. Regulatory-Trial Process-Technology Regulatory Clinical Trial Influences trial process process Reengineering Emerging Industry Best Practices Technology Improves the performance© Dr. R.H.Jani E-mail: 43, 15-Apr-11
  44. 44. Best Practice and technology for the acceleration of the clinical trials • Project managements – Regulatory approaches – Investigators’ selection – Logistics – Clinical trial management – Electronic Data Capturing – Clinical Data Management© Dr. R.H.Jani E-mail: 44, 15-Apr-11
  45. 45. Investigator Recruitment • Early involvement of investigators to help to shape the protocol for feasibility of recruitment • Agreement • Assessing the site’s ability to meet protocols requirements • Better access to site recruitment – Wider use data mining, assessment and screening • Patient accrual vs cost • Multiple prong approach to patient recruitment- – Data Mining – Local publicity – Collaboration for tracing mobile patients© Dr. R.H.Jani E-mail: 45, 15-Apr-11
  46. 46. Clinical Trial Management • Near real-time visibility of project status across all studies whether in-sourced or outsourced, active or inactive • Warning systems to identify problems or non-compliance early • Better sponsor access to potential project team resources • Continued outsourcing to CROs, using very defined performance metrics© Dr. R.H.Jani E-mail: 46, 15-Apr-11
  47. 47. Clinical Data Management • eCRF, eCTD and CDISC standards are widely accepted leading to “bridge development” to/from legacy systems • Leveraging existing – EDC and electronic patient reported outcomes (ePRO), – expanding eSource collection methods and – improving active analysis of trial and clinical data to identify administrative, safety, or efficacy issues early© Dr. R.H.Jani E-mail: 47, 15-Apr-11
  48. 48. Data Analysis • More near real time reporting and analysis occurring during trials (adaptive designs, patient adoption rates, site selection, etc.) • Workflow tools used to streamline and document the process for easy repeatability and increased reuse of statistical programs© Dr. R.H.Jani E-mail: 48, 15-Apr-11
  49. 49. Clinical Supplies • More use of integrated processes and systems for effective manufacturing, inventory, and distribution of small and large orders • Continued use of IVRS and a growing use of Radio Frequency Identification (RFID) technologies to support better tracking and scheduling© Dr. R.H.Jani E-mail: 49, 15-Apr-11
  50. 50. Regulatory and Safety • Faster and more effective participation via Improved cross- functional workflow • management and database mining – Use of database mining tools – Shortened durations for document preparation and submissions through use of integrated databases/systems • Global pharmacovigilance function that develops and implements risk management systems, including signal detection and signal management© Dr. R.H.Jani E-mail: 50, 15-Apr-11
  51. 51. Thank You This presentation is the property of Dr. Rajendra H Jani, Senior Vice President Clinical R&D, Zydus Cadila Healthcare Limited. Views expressed in this presentation is of the author and not of the company. Under no circumstances the information contained in this presentation should be quoted, distributed, copied, reproduced or retrieved, in part or whole, in any form, written, verbal and/or electronic format without the expressed permission from: Dr. Rajendra H Jani, Senior Vice President & Clinical R&D, Cadila Healthcare Limited, Zydus Cadila House, Service Road, Vile Parle (E),Mumbai-40057, India, Phone: +91-22-26186052, Fax: +91-22-26181735, E-mail: or© Dr. R.H.Jani E-mail: 51, 15-Apr-11