The Product Review Life Cycle A Brief Overview

Transcription

1 Stat & Quant Mthds Pharm Reg (Spring 2, 2014) Lecture 2,Week 1 1 The review process developed over a 40 year period and has been influenced by 5 Prescription User Fee Act renewals Time frames for review and meetings clearly set Communications with sponsors occur and are important Meetings during drug development and during the review process Discipline specific reports Two components to the pre-market review the IND and the NDA 2 Robert O Neill, Ph.D. 1

2 The Investigational New Drug (IND) Review Process Primarily about the evaluation of protocols, their goals and objectives, endpoints, claims, ability to provide evidence, etc. Evaluation of the Statistical Analysis plan: a prospective plan for how the data and resulting analyses will be conducted to distinguish between what is confirmatory objective and what is an exploratory objective 3 The Investigational New Drug (IND) Review Process Planning early studies receive less scrutiny and/or advice except for patient safety (clinical holds) Phase 2, Phase 3 A&WC trials: Protocols reviewed, advice provided Safety data base standards to prepare for integrated safety analysis Complexities of design and development plans involve earlier discussion (eg. adaptive designs) 4 Robert O Neill, Ph.D. 2

3 The FDA Review Process The Medical Product Life Cycle Concept Planning early studies receive less scrutiny and/or advice except for patient safety (clinical holds) Phase 2, Phase 3 A&WC trials: Protocols reviewed, advice provided Safety data base standards to prepare for integrated safety analysis 5 A Reminder of the Clinical Trial Life Cycle that should be considered during planning Planning Conduct Analysis Reporting Protocol Hypotheses (claims) Study design Assumptions Statistical Analysis Plan Bias Dropouts Protocol viol. Uncontrolled variation Model endpoints comparisons covariates subgroups imputation censoring Interpreting results as planned Selective display of data and results - after the fact interpretations Changing the analysis after observing data Changing objectives 6 Robert O Neill, Ph.D. 3

4 Trial Design Considerations (1) Endpoints Treatment effect size - Screening criteria, stratifications Dose(s) Duration of trial Comparison groups Sample size Multiplicity - how many ways to win for multiple endpoints, subgroups, analysis times Controlled and uncontrolled factors 7 Trial Design Considerations (2) Which design to choose and how Parallel, crossover, multi-center, factorial, dose response, two-stage Superiority or Non-inferiority - objectives Group Sequential Designs for serious irreversible morbidity/mortality outcomes Adaptive study designs which may change design features depending upon accumulating data How to choose? Compare them on efficiency (sample size to meet same objectives) 8 Robert O Neill, Ph.D. 4

5 Topic to be revisited later Planning a multi-regional clinical trial relevant to global development and a complex effort ICH E5 issues Statistical design issues Sources of variability in outcomes and treatment effects Assumptions regarding consistency of treatment effects heterogeneity quantitative and qualitative interactions 9 The Statistical Analysis Plan (SAP) A critical component of the protocol that is prospectively planned (see ICH E9) It contains key feature of the study design, sample size, power considerations justification for the chosen design All the hypotheses intended to be proven to support claims, etc. Primary, secondary endpoints Win criteria and type 1 error control for all hypotheses (strong control) It contains the statistical approaches to the analysis of the data that will support the claims; tests of hypotheses, estimation, plans for addressing missing data, censoring, stratification strategies 10 Robert O Neill, Ph.D. 5

6 The Role of Guidances Guidances are a critical component of the regulatory standards framework Guidances have sufficient content on quantitative thinking, planning, study designs and approaches to support topic dedicated courses This lecture will provide an overview of that content 11 FDA Guidances Part of evidence criteria - Usually developed after experience with issues faced in the review process Early guidances during 1970 s and 1980 s established precedents for evidence presentation, as well as scientific focus No books, no CONSORT at the time FDA staff review experience enabled substantive guidance on how to report, what to report, and eventually principles for what to plan for in study designs, how to deal with difficult planning issues, encouragement for new designs, etc. all of this can be considered advancing science and promoting /encouraging innovation 12 Robert O Neill, Ph.D. 6

7 Regulatory Guidances with Statistical and Quantitative Methods Content 13 yinformation/guidances/ucm htm 14 Robert O Neill, Ph.D. 7

8 yinformation/guidances/ucm htm 15 nformation/guidances/ucm htm 16 Robert O Neill, Ph.D. 8

9 Other Guidances relevant to assessing and labeling evidence Labeling guidance - principles When is a single study sufficient? 17 Data Monitoring Committees and Interim Analysis Part of the machinery and infrastructure of modern clinical trials Increasing use in outcome trials and trials for serious and irreversible morbidity/mortality outcomes 18 Robert O Neill, Ph.D. 9

10 19 ICH International Conference on Harmonization Began in the early 1990 s as an effort among Japan, the European Union, and the United States; regulators and the industry 6 parties contributing to process Intended to harmonize standards for pharmaceutical development and regulatory evaluation not necessarily to arrive at the same conclusion (left to local regulators) but to eliminate duplication of effort and facilitate timely access by patients in all regions to new therapies 20 Robert O Neill, Ph.D. 10

11 Nine ICH Documents deal with clinical trial issues, evidence and quantitative concepts E - 3 : Clinical Study Reports E - 4 : Dose - Response E - 5 : Acceptance of foreign data E - 6 : Good Clinical Practice E - 7 : Special populations: Geriatrics E - 8 : General Consideration for clinical trials E 9: Statistical Principles for Clinical Trials E - 10 : Choice of control groups E 14 :Clinical Evaluation of QT/QTc Interval Prolongation 21 The New Drug Application (NDA) Review Process A NDA contains all studies to support the efficacy and safety claims for a new drug. Today, most of the information is electronically submitted for efficiency of review Reviewers focus on confirmatory clinical trials (adequate and well controlled) that are judged for substantial evidence PDUFA timelines for review and decisions including written reviews archived in electronic data base Planning and holding advisory committees to vote on Questions- FDA reviewers and sponsors make Presentations : materials available on FDA website 22 Robert O Neill, Ph.D. 11

12 The New Drug Application (NDA) Review Process What is the NDA? What data is involved? How is it reviewed? Against what standards What is the end result of such a review? Meetings, communications and the process 23 The NDA Review Will be illustrated throughout the course with written reviews and/or presentations extracted from FDA website Statistical aspects Clinical aspects Quantitative Safety Review Access to electronic data sets Amendments to protocols, agreements like SPA Label negotiations what data and what statements go into the label impact on advertising 24 Robert O Neill, Ph.D. 12

13 A Reminder of the Clinical Trial Life Cycle that should be considered during planning Planning Conduct Analysis Reporting Protocol Hypotheses (claims) Study design Assumptions Statistical Analysis Plan Bias Dropouts Protocol viol. Uncontrolled variation Model endpoints comparisons covariates subgroups imputation censoring Interpreting results as planned Selective display of data and results - after the fact interpretations Changing the analysis after observing data Changing objectives 25 The FDA review of clinical trials is unique in that: All data at the patient level is included in the submission, so FDA evaluates patient level outcome data, not summary data Data listings derived from the case report forms Analysis data sets Protocols and any amendments Any agreements on study design or success criteria FDA conducts its own statistical analysis and clinical review of safety data often to confirm sponsor results, sometimes to address issues of potential bias, robustness, sensitivity 26 Robert O Neill, Ph.D. 13

14 The Statistical Review Template what s involved Robert O Neill, Ph.D. 14

15 29 How are all the discipline reviews put together The Division Director decision and memo The Office Director decision and memo The final decision Considers many issues including the input from the advisory committee and all reviewers on the team 30 Robert O Neill, Ph.D. 15

16 31 32 Robert O Neill, Ph.D. 16

17 Protocol review A Schematic of the Life cycle Evaluation of a New Drug NDA review Pre-market Process Advisory Committee Decision to approve or more study FDA communications Passive,Active Surveillance Post-market Process Adverse event reports and signals Clinical, observational studies 33 This course will utilize material derived from FDA s public advisory committee process to illustrate a range of issues involving quantitative and statistical thinking in the regulatory evaluation of evidence of the efficacy and safety of pharmaceuticals and biologics FDA reviewers as well as industry sponsor representatives present their evaluations to the AC members 34 Robert O Neill, Ph.D. 17

18 Case studies that are in the public domain and available as course content Much of the discussion and vetting of evidence is occurs in public advisory committees by independent expert advisers who are special government employees - and this is all documented and archived However, these advisory committees only provide advice which FDA may or may not act on Final decisions are made by FDA scientists Most of FDA s evaluation of evidence is contained in written reviews and available on FDA s website, if a product is approved 35 The Advisory Committee Process: Types of issues generally addressed General policy issues Study designs, clinical endpoints, scientific evidence needed New Drug Applications for which the committee is asked to evaluate evidence and recommend actions to be taken Generally, about subject matter members depending upon the issues two committees may jointly meet 36 Robert O Neill, Ph.D. 18

19 Some background on FDA s advisory committees, their role, make up and operations Advisory committees provide FDA with independent opinions and recommendations from outside experts on applications to market new drugs, and on FDA policies. The marketing applications include data to show the safety and effectiveness of human drugs. 37 Some background on FDA s advisory committees, their role, make up and operations The outside experts receive summary information about the applications and copies of FDA's review of the application documents. Based on this information, advisory committees may recommend approval or disapproval of a drug's marketing application. FDA generally follows an advisory committee's recommendation, but is not bound to do so. 38 Robert O Neill, Ph.D. 19

20 Who are the members and what are their qualifications? Nominations for scientific members, consumer, industry and patient representatives originate from professional societies, industry, consumer and patient advocacy groups, the individual himself or other interested persons. Candidates are asked to provide detailed information regarding financial holdings, employment, research grants and contracts, and other potential conflicts of interest that may preclude membership. 39 Who are the members and what are their qualifications? Persons nominated as scientific members must be technically qualified experts in their field (e.g., clinical medicine, engineering, biological and physical sciences, biostatistics, and food sciences) and have experience interpreting complex data. Candidates must be able to analyze detailed scientific data and understand its public health significance. 40 Robert O Neill, Ph.D. 20

21 CDER has 17 advisory committees 41 Agendas, Briefing Materials, Slides, Transcripts and Webcasts (if held at White Oak) are publically available on FDA s website This course will draw heavily from case studies that come before the advisory committees so that the process and extent of regulatory evaluation of evidence is better understood 42 Robert O Neill, Ph.D. 21

22 The FDA discipline specific reviews contain the results of the NDA review process - reflected both in advisory committee presentations and on FDA s website (Drugs@FDA) if a product is approved Usually, selected members of the FDA review team present to the advisory committee, as do division directors, and office directors as necessary. Sponsors present their own analyses and interpretation of clinical studies Archiving of FDA reviews occurs for all evaluations but the availability of information publically is limited to drugs for which an approval decision has been made: Summary Basis of Approval [email protected] 43 Components of Safety Assessment, pre and post market, and life cycle Clinical trials large studies to rule out risk of prespecified magnitude Monitoring strategies Prospective safety analysis plans (SPERT) for drug development and post - approval Specific guidance on reporting - Diabetes guidance Cumulative meta-analysis that is prospectively planned 44 Robert O Neill, Ph.D. 22

23 Components of Safety Assessment, pre and post market, and life cycle Observational cohort studies concern for reproducibility of research studies (bias) - causal inference methods: Propensity score strategies, inverse probability weighting strategies, instrumental variables Statistical methods to characterize and quantify risk and assess uncertainty of the risk Data mining and signal detection common data model, distributed data models; electronic medical records Mini-Sentinel project OMOP Observational Medical Outcomes Partnership Robert O Neill, Ph.D. 23

24 47 The Emerging Science of Safety 48 Robert O Neill, Ph.D. 24

25 Benefit / risk decisions can the drug be used safely, or with risk evaluation and mitigation strategies Upon completion of review, decide if substantial evidence exists to use the drug where benefits outweigh risks How to label the drug: indications, claims, dose, subpopulations, warnings, contraindications, clinical trial summary data, tables, graphs, descriptive statistics Restrictions on prescribing Benefit/Risk Framework REMS: Risk Evaluation and Mitigation Strategies /PostmarketDrugSafetyInformation forpatientsandproviders/ucm htm Post-Approval Surveillance Safety RCT s, passive reporting, signaling, active surveillance signaling, periodic safety update reports (PSUR) 49 Periodic Benefit-Risk Evaluation Report (PBRER) FDA s structured approach to benefit risk assessment Replaces the Periodic Safety Update Report (PSUR) PSUR around for many years- PBRER is an analytical document covering all available data both interval data and cumulative data. It covers the items in the earlier PSUR but requests more including a review of market uptake and off-label use on/guidances/ucm pdf?source=govdelivery Robert O Neill, Ph.D. 25

26 Periodic Benefit-Risk Evaluation Report (PBRER) FDA s structured approach to benefit risk assessment Change in focus in that it now views risk in the context of benefits and risk is no longer reviewed in isolation (as in the old PSURs), eg. without considering whether the drug is used for a benign set of symptoms (e.g. anti-histamines for seasonal allergic rhinitis) or for deadly diseases (cancer, infections) and without considering the nature of benefits for the drug. New relevant interval data is reviewed in the context of cumulative information and how it impacts on the integrated benefit-risk assessment on/guidances/ucm pdf?source=govdelivery Recap of components of the evidentiary life cycle evaluation process Regulations and standards of evidence for efficacy and safety The evaluation process: reviewing sponsors submissions, prospective protocol plans and completed studies, reports, analyses : INDs, NDA s The decision making process: internal and external role of FDA Advisory Committees Benefit / risk decisions can the drug be used safely and the need for risk mitigation plans 52 Robert O Neill, Ph.D. 26

27 Recap of components of the evidentiary life cycle evaluation process Labeling a drug for use conveying information, instructions for use, fixing the conditions of use and is labeling effective Surveillance of efficacy and safety when on the market: passive and active: post approval review process Regulatory research, responding to crises and promoting collaboration Resources available for course content: documentation, written reviews, approval packages, safety communications 53 Template to be used in the course for case studies as a teaching tool Describe the issue or problem Refer to relevant published guidance that may frame the study design, analysis of interpretation Identify the case study which illustrates the points and collect information as background reading List FDA website resources and links to access information Use resources like written reviews, advisory committee presentations, and webcasts to provide background, readings, in class discussion modules allows for e-learning and e-blending courses 54 Robert O Neill, Ph.D. 27

28 FDA resources available for course content Statistical and Medical Reviews, decisional memos for all approved products available at rugsatfda/index.cfm Advisory Committee Meetings: transcripts, agenda, questions, slides (available on the FDA advisory committee website for CDER), votes, and webcasts if available at tteesmeetingmaterials/drugs/default.htm 55 FDA resources available for course content Drug Safety Communications (available on FDA s website) Guidances that contain scientific policy (available at FDA s website under guidance) Regulatory research: published statistical literature pertinent to regulatory problems 56 Robert O Neill, Ph.D. 28

29 Where and how to get access to FDA resource material? Advisory Committee content Medical and statistical reviews (only if approved product) tfda/index.cfm Scientific guidances gulatoryinformation/guidances/ucm htm 57 Robert O Neill, Ph.D. 29