The Science of Drug Discovery: The Intersection of Clinical Trials and Drug Development. Rich Whitley March 2, 2017

Transcription

1 The Science of Drug Discovery: The Intersection of Clinical Trials and Drug Development Rich Whitley March 2, 2017

2 The Many Faces of Clinical Research n Natural History Study n The impact of congenital cytomegalovirus infection on hearing n Evaluation of a Diagnostic n Assessment of an Intervention n Benefits of drug eluting stent placement n Appraisal of a Drug n Placebo controlled n Drug Drug Comparison n Open label evaluations

3 Who is the Sponsor? n Industry n Goal is to license the intervention (make money) n An Academic Institution n Goal is to generate new knowledge n Add value to intervention n Establish proof of principle n An Individual n Goal is to establish proof of principle and value n Advance a career

4 Components of a Clinical Trial n What hypothesis do you wish to test? n Grounded in a literature search n Outcome A exceeds Outcome B by what percent? n Usually 25-50% margin n Non-inferiority (within 10% variability) n Is it ethical? n How does that translate to endpoints? n Primary n Secondary n Toxicity n Exploratory

5 First Steps n Data Management Plan n Where will the data go? n How is verified? n How is it protected n Biostatical Design n Sample size n Randomization n Data Safety and Monitoring Board Reports n Analysis Plan

6 What Happens Behind the Scenes? n Statistical Review n Design of Case Record Forms n Review Board Approvals n Institutional Review Board n UAB/SRI n Western Review Board n Conflict of Interest Review Board n Gene Therapy Review n Universal IRB n Investigator s Brochure

7 The Protocol n n n n n n n n n n n Background and Significance Approaches to the Problem Relevant Data n Cell and Animal Experiments n If a drug, adsorption, distribution, metabolism and excretion n Toxicity Endpoints Inclusion/Exclusion Criteria Details of Evaluation (when, where and what) Sample size determination, including statistical methodology Adverse Event Monitoring Literature Cited Appendices, including Case Record Forms Compiled Investigator Brochure

8 Institutional Review Boards n Review Informed Consent versus Assent n Understandable to a teenager n Accurate and without bias n Evaluate mechanism by which consent will be obtained n Equipose n Conflict of Interest n Marginalized Study Populations n Children n Women n Under represented minorities

9 Conflict of Interest Review n Goal: to insure that all parties have no vested interest in the outcome of the study n Financial n Non-monetary gifts in kind n Investigators as well as family members n Ghost Writing n Does the Institution have a conflict of interest (i.e. hold a patent)?

10 Federal Approvals n Is an IND required? n Performed within the state of origin (i.e. does not cross state lines) n NDA directed n Registration of Federally funded clinical trials n Compliance requires adherence to Code of Federal Regulations (CFR)

11 Funding n Government n Industry n Foundation or Philanthropy n Institution n Health Service Foundation n Departmental

12 Stages of Clinical Development n Phase 0 n Phase I n Phase II n Phase III n Phase IV

13 Phase 0 Clinical Trials n Phase 0 clinical trials are intended to expedite the clinical evaluation of new molecular entities. n An exploratory IND supports the performance of first-in-human testing of new investigational agents at subtherapeutic doses based on reduced manufacturing and toxicologic requirements (drug-target effects, PK, PD)

14 Phase I n Goal: to define distribution and potential effects of intervention n Phase IA n Pharmacokinetics and Toxicity in Normal Volunteers n Entails sequential blood draws and collection of select biologic fluids n Phase IB n Pharmacokinetics, Pharmacodynamics and Toxicity in patients with disease

15 Protocol Design

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17 Median GCV Concentrations Following IV Dosing at Days 4 and 34 GCV Concentraion (mg/l) Time (h) Day 4 Day 34

18 Median GCV Concentrations Following PO Dosing at Days 6, 35, and 36 GCV Concentration (mg/l) Time (h) Day 6 Day 35 Day 36

19 Ganciclovir Clearance vs. Age Following IV Dosing 50.0 Clearance vs. Age R 2 = r = 0.65 Clearance (ml/min) Age (days)

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21 Whole Blood Viral Load Blood VL Day 53 56

22 Phase II n Goal n Phase IIA n Performed in target population n Proof of Principle n Usually three doses of medication n N= per cell n Phase IIB n Performed in target population n Expanded sample size to guarantee Proof of Principle

23 Ganciclovir Evaluation in Congenital CMV Conduct of Study Congenital CMV (culture proven) With CNS Involvement Informed Consent Ganciclovir vs. No Treatment x 42 days 12 mg/kg/day Monitoring Clinical/Virologic Serology Toxicity Follow-up (Months 6, 12, 24, 36, 48, and 60) Escape: Hematologic, Renal, Liver Toxicity Clinical Decline

24 Study Endpoints n Primary Endpoint n Improved BSER by one gradation (or remains normal) between baseline and 6 month followup n Biologic assessment (total ears) n Functional assessment (best ear) n Second Endpoint n Laboratory improvement by 2 weeks n Clinical improvement

25 Change in Hearing Between Birth and 6 Months of Age Ganciclovir Recipients No Treatment Group Worse 100% Improved or Unchanged 59% 41% P < 0.01 > 36.7 db

26 Change in Hearing Between Birth and 1 Year of Age Ganciclovir Recipients No Treatment Group 79% 21% * Worse Improved or Unchanged 32% 68% * 25 db P < 0.01 > 30.6 db

27 Phase III n Goal: Registrational Trial n Controlled and Randomized n Monitored by DSMB n Usually patients per arm n Two required for licensure n Results must be filed whether positive or negative n FDA demands adequate numbers of volunteers to determine safety

28 Shingles Prevention Study n A double-blind, placebo-controlled trial n Oka/Merck VZV strain n Live, attenuated vaccine n Median dose = 24,600 pfu (19K-60K)] n 18-fold greater than childhood vaccine n Age of subjects (38,500 subjects) n years = 20,750 n 70 years = 17,800 n 80 years = ~2500

29 Background - Endpoints n Burden of Illness (BOI) n Sum of all severity of illness scores for each of two treatment groups - vaccinees and placebo recipients n Post-herpetic neuralgia (PHN) n Significant pain ( 3 on ZBPI) n 90 days after rash onset n Herpes Zoster (incidence/1000/year)

30 Shingles Prevention Study: Endpoints n Endpoints = BOI and PHN n Severity-of-illness (component of BOI) n Measured severity of HZ pain with a validated method (ZBPI; scale = 0 to 10) n Recorded severity at defined intervals n Plotted severity vs time after rash onset n Determined area under the curve n Score = 0 if no HZ

31 HERPES ZOSTER AUC of ZBPI Worst Pain Scores* over Time Hypothetical Example of AUC for One Subject With HZ 10 Worst Pain Score First ZBPI Evaluation at Day 5 End of 1 st AUC Recurrent pain, 2 nd AUC starts End of 2 nd AUC End of Follow-up Days Since Rash Onset * ZBPI per Coplan et al. The Journal of Pain 5: , 2004

32 Shingles Prevention Study n Subjects 38,500 (17,800 = 70 years) n Completed study = >95% n Suspected HZ 1308 (V=481; P=827) n Confirmed HZ (V=322; P=662) n Diagnosis n PCR = % n Culture = % n Clinical = %

33 Shingles Prevention Study: Efficacy n Burden Of Illness n 61.1% ( %) n Post-Herpetic Neuralgia n 66.5% ( %) n Incidence of Herpes Zoster n 51.3% ( %)

34 Vaccination Reduces Herpes Zoster Incidence Cumulative incidence of HZ (%) P<.001 Placebo Years of follow-up Zoster vaccine Placebo: n=19,247 Zoster vaccine: n=19,254 Oxman M et al. N Engl J Med. 2005;352:2271-2

35 Vaccination Reduces PHN Incidence Cumulative incidence of PHN (%) P<.001 Years of follow-up Placebo Zoster vaccine Placebo: n=19,247 Zoster vaccine: n=19,254 Oxman M et al. N Engl J Med. 2005;352:2271-2

36 ZOSTER VACCINE EFFICACY HZ BOI Score years 70 years Incidence of PHN years 70 years Incidence of HZ years 70 years 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% Relative Vaccine Efficacy (1-Vaccine/Placebo)

37 Role of the Data Safety and Monitoring Board n Guarantee the well-being of volunteers who participate in the trial n Interim analyses for efficacy or undue toxicity n Lan Demets n O Brien Fleming n Monitor temporal changes in therapy to make sure the trial design remains contemporary and ethical

38 Phase IV n Goal: Verification of Phase III data n Guarantee safety n Usually a few thousand patients

39 Outcome n Hopefully, improved outcome of patient intervention n At least further insight into the natural history of disease n Results of negative studies must still be reported in the literature n If no benefit, integrity in the results