Division of Pharmacometrics, Reviewer Observations from the Antiviral Information Management System (AIMS) Database Jeffry Florian, Ph.D. CDER/OTS/OCP Division of Pharmacometrics, Reviewer The opinions and information in this presentation are those of the author, and do not represent the views and/or policies of the U.S. Food and Drug Administration.

Overview of the Antiviral Information Management System (AIMS) Outline Overview of the Antiviral Information Management System (AIMS) Observations and analyses from AIMS EOP2 NDA Trial design Future project considerations with the database

Project started in 2008 – Critical Path Initiative A system to archive data and assist analysis for new anti-HCV agents is needed to inform dose selection. With more than forty new anti-HCV drugs in the pipeline, we must keep pace with development. BOTTLENECK: Lack of available database & data standards 40+ HCV drugs in development Modeling and simulation can help inform dosing and trial design issues for efficient development. Systematic archival of data and analysis will help leverage prior knowledge in this emerging therapeutic area. Project started in 2008 – Critical Path Initiative Dr. Gobburu and Dr. Jadhav

Modeling codes and analyses AIMS database relies on : (1) Database standards, (2) Data requests (3) Internal analysis codes, and (4) Shared experience AIMS Database Standards Analysis Data Mean viral load : 1a 1b log10 HCV RNA time (weeks) Modeling codes and analyses Fraction achieving SVR Time (weeks) 0 12 24 48 1.0 0.5

Relationship Diagram: Implementation of the relational database structure, data templates and controlled terms requires forward thinking and planning. AIMS Database Relationship Diagram: Relational structure supports efficient queries Sponsors will receive a data template and a list of controlled terms to guide data submission. Templates: definitions and examples for all data fields. Controlled Terms: specific listing of acceptable inputs for each data field to ensure identical formatting for all sponsors. CM CM EX EX concomitant meds exposure PC PC pharmacokinetics DRUG DRUG STUDY STUDY DM DM MB MB demographics virology VS VS Analysis data specific for HCV vital signs Raw data in abbreviated CDISC format EP EP LB LB endpoints lab measures

The available information depends on the active and willing collaboration of sponsors developing HCV drugs Original information request was issued in July 2010 to all companies with an active HCV IND New data request issued whenever a sponsor submits a new IND Voluntary data submission of completed trials according to the provided data standard. Request data at the time of End-of-Phase 2, End-of-Phase 2A, or other key early development meetings

Every day is like drinking from a fire hose http://www.phdcomics.com/comics/archive.php?comicid=820

Recent Phase III trials were submitted according to AIMS standard. The AIMS database contains demographic, PK, virologic, and treatment data from previous, recent, and ongoing trials. 9 drug development programs 29 studies 10K+ subjects Legacy data were converted using internal resources to include in the database. Recent Phase III trials were submitted according to AIMS standard. Many EOP2 meetings have accompanying AIMS datasets Multiple treatment regimens (PR, PR+DAA) and durations were included in the dataset.

Archive data from sponsors without additional formatting. The AIMS database assists reviewers in analyses across all HCV submissions In addition ... Use archived HCV data to generate research hypotheses across multiple studies and drugs. Archive data from sponsors without additional formatting. Generate analysis datasets, plots and reports using automated scripts. Archive analysis results (data, models, plots, reports). Access historic data to inform decisions about new submissions.

Outline Overview of the Antiviral Information Management System (AIMS) Observations and analyses from AIMS EOP2 NDA Trial design Future project considerations with the database

AIMS database has aided reviewers in dose selection and treatment duration during early drug development. DRUG REVIEW QUESTION RESULT Drug X (EOP2) What dose/duration to use in Phase III? Explore different regimens in two proposed later trials Drug Y (EOP2) Does the loading dose improve efficacy? Later trials removed loading dose Drug Z (EOP2) Is the proposed dosing regimen reasonable? Is the proposed duration for reasonable? Longer treatment durations were explored in later phase trials. Involved in 16+ EOP2/EOP2A/Type C meetings

AIMS datasets have been provided for ~50% of early phase meetings Sponsors are submitting materials to support and justify doses, treatment durations, and patient population A majority of EOP2 submission packages are accompanied by modeling and simulation results Supportive analyses for regimen(s) selected for registrational trials Viral kinetic modeling including resistance and viral subtypes Predictions of SVR using studied and/or exploratory regimens Exposure-response safety analyses for key signals identified in Phase II AIMS datasets have been provided for ~50% of early phase meetings Data conversion and standardization is time consuming not commonly performed until later in drug development Sponsors provide datasets for modeling and simulation whenever available

General observations over multiple EOP2 submissions As regimens are becoming better (↑SVR, ↓treatment duration), the need for earlier assessments increases Intrinsic patient factors remain important for treatment outcome (e.g., IL28B, cirrhosis, baseline HCV RNA) Genotype subtype is becoming more important (ref: Dr. Harrington) P/R-regimens: time to HCV RNA not detected remains predictive of response The impact of shortening treatment duration may require even earlier metrics (eRVR or even ‘Week 1’VR) IFN-free regimens: antiviral activity ≠ SVR Predictive factors based on viral kinetics remain to be identified Much easier to identify when something is not optimal

Outline Overview of the Antiviral Information Management System (AIMS) Observations and analyses from AIMS EOP2 NDA Trial design Future project considerations with the database

Two programs, same story Two new HCV therapies characterized by drastically different drug development programs REGISTRATIONAL TRIAL DESIGNS BOCEPREVIR TELAPREVIR Lead-in Phase YES NO Response Guided Therapy All trials Only treatment-naïve patients Treatment-experienced trial Excludes null responders Include relapsers, partial responders, and null responders Two programs, same story

“Bridging” Observations Through Interferon Responsiveness Similar response with first or second round of P/R treatment Data for previously treated subjects are “bridged” with data from untreated subjects Previously treated subjects are represented within untreated subjects P/R treatment for HCV is unlike HIV treatment which frequently leads to resistance and does not yield similar virologic response on subsequent courses of treatment

Similar Virologic Response at Week 4 with First or Second PR treatment (pooled analysis) 1416 468 597 219 507 112 548 Liu et al. CID 2012

Standardized datasets facilitated similar analyses and led to novel dosing recommendations. EXAMPLE REVIEW QUESTIONS RESULT Telaprevir Pivotal trials did not evaluate shorter treatment durations in relapse patients Additional study deemed unnecessary. Shorter treatment duration included in label for prior relapsers Boceprevir Prior null responders not included in Phase III Different regimens for treatment-naïve (TN) and treatment-experienced (TE) trials Evidence of effectiveness for prior null responders Dosing recommendations for TN late responders A successful trial in TE subjects can serve as evidence of effectiveness to support dosing and approval in TN subjects.

Outline Overview of the Antiviral Information Management System (AIMS) Observations and analyses from AIMS EOP2 NDA Trial design Future project considerations with the database

Endpoint is assessed 24 weeks after the end of treatment SVR24 was the surrogate endpoint used in original Peg-IFN/RBV and recent DAA+Peg-IFN/RBV trials TREATMENT Follow-up Wk 24 8 24 16 40 32 48 60 72 WEEK 60-70% 30-40% Endpoint is assessed 24 weeks after the end of treatment Follow-up duration may be as long as treatment SVR12 (HCV not detected at 12 weeks post treatment) is evidence of effectiveness in Phase II Can a similar assessment be used in Phase III?

Concordance was observed between SVR12 and SVR24 for all Peg-IFN/RBV and DAA+Peg-IFN/RBV treatments SVR 24 Assessment ‘Y’ ‘N’ SVR12 Assessment 5428 93 56 4617 ~2% of patients with SVR12 relapse by SVR24 assessment (false positive) PPV: 98% NPV: 99% Sensitivity: 99% Specificity: 98.0% SVR 24 Assessment ‘Y’ ‘N’ SVR4 Assessment 4239 412 53 3002 Less agreement between SVR4 and SVR24 SVR4 may be useful for guiding dose selection PPV: 91.1% NPV: 98.2% Sensitivity: 98.7% 21 Specificity: 87.7% 21

Sensitivity analyses support that SVR12 and SVR24 are concordant for Peg-IFN/RBV containing regimens  SVR 24 Assessment PPI SVR 12 ‘Y’ (P/R Arms - all) 98.1% SVR 12 ‘Y’ (DAA Arms) 98.8% RGT (DAA Arms) 98.9% No RGT (DAA Arms) Overall 2% No matter how the analysis was performed 1-3% of patients relapse between SVR12 and SVR24

The analysis of SVR12/SVR24 for genotype 1 subjects motivated similar analyses for other populations and different regimens Subsequent application of the same analysis demonstrated concordance for Pediatrics Genotype 2/3 G2/3 IFN-free regimens: Additional data is required Provide all available SVR12 and SVR24 data from drug development program and discuss (all regimens)

Outline Overview of the Antiviral Information Management System (AIMS) Observations and analyses from AIMS EOP2 NDA Trial design Future project considerations with the database

Compatible with AIMS datasets submitted by sponsors eDISH (Evaluation of Drug-Induced Serious Hepatotoxicity) – FDA reviewer tool eDISH is a tool developed to assist reviewers in analyzing/explaining DILI in an IND/NDA Compatible with AIMS datasets submitted by sponsors http://www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/ucm076777.pdf

eDISH includes time plots of key laboratory values eDISH (Evaluation of Drug-Induced Serious Hepatotoxicity) – FDA reviewer tool (cont.) eDISH includes time plots of key laboratory values Data is linked to individual patient narratives May assist in the safety analyses for IFN-free regimens 26 http://www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/ucm076777.pdf

Conclusions Sponsors are submitting datasets for AIMS These datasets are assisting in the review of submissions at EOP2 meetings Information from these submissions has provided insight regarding subsequent HCV trial design Future projects will continue to be evaluated as additional data becomes available

Acknowledgements Division of Antiviral Products Critical Path Initiative and ORISE Lauren Neal Jianmeng Chen OCP (Division of Clinical Pharmacology IV) John Lazor Kellie Reynolds Sarah Robertson Vikram Arya Stanley Au Ruben Ayala Shirley Seo Jenny Zheng OCP (Division of Pharmacometrics) Joga Gobburu Pravin Jadhav Yaning Wang Ying Chen Division of Antiviral Products Debra Birnkrant Jeff Murray Many supportive medical reviewers and project managers DAVP Clinical Virology Team Patrick Harrington Jules O’Rear Lisa Naeger NCTR Steve Hodge Edward Bearden OTS Chuck Cooper Office of Biometrics Ted Guo Many subjects, investigators, and sponsors who have provided data

Questions