Interdisciplinary Aggregate Assessments for IND Safety Reporting The

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Interdisciplinary Aggregate Assessments for IND Safety Reporting: The Spirit of the Final Rule 2018

Interdisciplinary Aggregate Assessments for IND Safety Reporting: The Spirit of the Final Rule 2018 ASA Stat Workshop September 2018 Greg Ball, Amit Bhattacharyya, Susan Duke and Liang For the DIA-ASA Interdisciplinary Safety Evaluation

ASA Biopharm Safety Monitoring Working Group Interdisciplinary Safety Evaluation † • • • •

ASA Biopharm Safety Monitoring Working Group Interdisciplinary Safety Evaluation † • • • • • • Statistical Methodology Greg Ball (co-lead, Merck) • Amit Bhattacharyya (ACI Clinical) Jim Buchanan (co-lead, Covilance LLC)* • Brian Cohen (ACI Clinical)∆ • Susan Duke (co-lead, FDA) • Michael Fries (CSL Behring) Mary Furnari (Celgene)* • Robert (Mac) Gordon (Janssen) • Frank Harrell (Vanderbilt)∆ Barbara Hendrickson (Abb. Vie)* • ∆ Rebbeca Krouse (Rho) • Juergen Kuebler (Qscicon) Raffael Kurek (Lilly) • Mengchun Li (co-lead, TB Alliance)* • Dennis O’Brien (Boehringer-Ingelheim)* Jonathan Seltzer (ACI Clinical)* • Mat Soukup (FDA)∆ • Sheryl Treichel (Amgen) Lothar Tremmel (CSL Behring) • Wenquan Wang (Sanofi) • William Wang (Merck) Jeremy Wildfire (Rho)∆ Eugene Zalmover (Sanofi)* Michael Colopy (UCB) Bridging Real World Evidence and Randomized Controlled Trials Rositsa Dimova (FDA) • Dimitri Bennett (Takeda) Michael Fries (CSL Behring) • Rima Izem (co-lead, FDA) Lan Huang (FDA) • Judy Li (Regeneron) Judy Li (co-chair, co-lead, Celgene) • Li An Lin (Merck) Melvin Munsaka (co-lead, Abb. Vie) • Yong Ma (FDA, CDER) Satrajit Roychoudhury (Pfizer) • Olga Marchenko (Bayer) • Melvin Munsaka, (Abbie) • Krishan Singh (GSK) • William Wang (co-chair, co-lead, Merck) • Ed Whalen (Pfizer) • Richard Zink (SAS/JMP) Matilde Sanchez-Kam (FDA) Sourav Santra (Cytel) Wenquan Wang (Sanofi) William Wang (Merck) Brian Waterhouse (Abb. Vie) Sammy Yuan (Merck) Kefei Zhou (Theravance) † DIA-ASA scientific working group: 2 * Clinical scientists, ∆ Safety graphics taskforce

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final Rule – Developmental Safety Management Team • Lilly (Brenda Crowe, 2016 DIA PV) – Aggregate Analysis by Anticipated Event Analysis Team • J&J (Mac Gordon) – Blinded Ongoing Aggregate Safety Evaluation • Abb. Vie (Barbara Hendrickson, 2018 FDA Workshop; Brian Waterhouse, 2017 JSM) • Merck (Greg Ball) – Smaller Company Perspective • Shionogi (Bruce Binkowitz) • Summary • Panel Session

Safety Reporting Requirements for INDs: Guidance for Industry • To improve the overall quality

Safety Reporting Requirements for INDs: Guidance for Industry • To improve the overall quality of safety reporting and to comply with requirements for IND safety reports based on data in the aggregate, “the sponsor should have in place a systematic approach for evaluating the accumulating safety data” • “Reasonable possibility” for IND safety reporting A. “A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure” (examples include angioedema, blood dyscrasias, rhabdomyolysis, hepatic injury, anaphylaxis, and Stevens. Johnson Syndrome) B. “One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug” (examples include tendon rupture or heart valve lesions in young adults, or intussusception in healthy infants) C. “An aggregate analysis of specific events observed in a clinical trial that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group” 4

Safety Assessment for IND Safety Reporting: Draft Guidance for Industry • Sponsors should periodically

Safety Assessment for IND Safety Reporting: Draft Guidance for Industry • Sponsors should periodically review accumulating safety data – Integrated across multiple studies (completed and ongoing) – Provide a quantitative framework for measuring evidence of: • An association for unexpected events (especially “anticipated” events) • A clinically important increase for expected events – Make a judgment about “reasonable possibility” for IND safety reporting 5

Safety Assessment for IND Safety Reporting: Draft Guidance for Industry • FDA’s preferred approach:

Safety Assessment for IND Safety Reporting: Draft Guidance for Industry • FDA’s preferred approach: Safety Assessment Committee (SAC) should regularly perform unblinded comparisons across treatment groups – Serious anticipated AEs and previously recognized ADRs – Appropriate steps should be taken to maintain overall study blinding • Alternative approach: Only perform unblinded comparisons if the overall rate of an SAE is substantially higher than a predicted rate; need to prespecify: – Predicted rates of anticipated and expected events – Guidelines for determining when an observed rate has exceeded 6

Key Terms • Suspected Unexpected Serious Adverse Reactions (SUSARs) – All adverse events with

Key Terms • Suspected Unexpected Serious Adverse Reactions (SUSARs) – All adverse events with a reasonably possible causal relationship that are both serious and unexpected, which are subject to expedited reporting (ICH E 2 A) • Reasonable Possibility – There is evidence to suggest a causal relationship between the drug and the adverse event (2015 FDA draft guidance) • Unexpected Events – The nature or severity is not consistent with information in the relevant source documents (ICH E 2 A) – “Hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis” – “Cerebral thromboembolism and cerebral vasculitis would be 7

Key Terms • Anticipated Events: Certain serious adverse events can be anticipated to occur

Key Terms • Anticipated Events: Certain serious adverse events can be anticipated to occur in the study population independent of drug exposure (2015 FDA draft guidance) – Known consequences of the underlying disease or condition under investigation (eg, symptoms, disease progression) – Events unlikely to be related to the underlying disease or condition under investigation but common in the study population independent of drug therapy (eg, cardiovascular events in an elderly population) Note: For events “anticipated” or “expected” to occur in one or more trials, determining “reasonable possibility” would require an assessment of increased frequency based on aggregate data 8

What Are We Looking for (Where’s the Gap)? • SUSARs – Concerns that we

What Are We Looking for (Where’s the Gap)? • SUSARs – Concerns that we would want the investigators to know about • Primarily anticipated and expected events – Where an aggregate assessment is needed and useful • In ongoing blinded trials – Can assess treatment differences in unblinded trials* • For bigger trials and/or effects – Have cumulative meta-analysis of completed unblinded trials for smaller effects • Not rare events – Have medical safety review/medical monitoring for single cases/small clusters *Janet Wittes, Brenda Crowe, Christy Chuang-Stein, et al. The FDA's Final Rule on Expedited Safety Reporting: Statistical Considerations. Stat Biopharm Res. 2015; 9 7(3): 174– 190.

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final Rule – Developmental Safety Management Team • Lilly (Brenda Crowe, 2016 DIA PV) – Aggregate Analysis by Anticipated Event Analysis Team • J&J (Mac Gordon) – Blinded Ongoing Aggregate Safety Evaluation • Abb. Vie (Barbara Hendrickson, 2018 FDA Workshop; Brian Waterhouse, 2017 JSM) • Merck (Greg Ball) – Smaller Company Perspective • Shionogi (Bruce Binkowitz) • Summary • Panel Session

Used existing structure: Developmental Safety Management Team (DSMT) and Developmental Safety Surveillance Team (DSST)

Used existing structure: Developmental Safety Management Team (DSMT) and Developmental Safety Surveillance Team (DSST) DSMT Multidisciplinary team that includes the safety physician from DSST Safety physician Surveillance scientist, epidemiologist 11

High-level process Developmental Safety Surveillance Team (DSST)—these are part of the Safety organization Frequently

High-level process Developmental Safety Surveillance Team (DSST)—these are part of the Safety organization Frequently reviews all SAEs (blinded, individually and in aggregate--by preferred term (PT) and clusters of PTs for prespecified events). If a B or C event deemed important, bring it to DSMT. Routes for Communication Routes for Escalation Safety Internal Review Committee (SIRC) Determines if the event is reportable Developmental Safety Management Team (DSMT) • Reviews blinded cases for consistency, confounders, alternative causes, timing, dechallenge; considers biological plausibility • Decides if an important maldistribution between treatment groups disfavoring drug will establish a suspected adverse reaction/signal 12

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final Rule – Developmental Safety Management Team • Lilly (Brenda Crowe, 2016 DIA PV) – Aggregate Analysis by Anticipated Event Analysis Team • J&J (Mac Gordon) – Blinded Ongoing Aggregate Safety Evaluation • Abb. Vie (Barbara Hendrickson, 2018 FDA Workshop; Brian Waterhouse, 2017 JSM) • Merck (Greg Ball) – Smaller Company Perspective • Shionogi (Bruce Binkowitz) • Summary • Panel Session

3 Stage Approach STAGE 1: BLINDED Identify & Define Protocol: Updated to include anticipated

3 Stage Approach STAGE 1: BLINDED Identify & Define Protocol: Updated to include anticipated events (An. Es) An. E Safety Monitoring Plan (ASMP): Co-led by clinician and statistician STAGE 2: UNBLINDED Analyze Aggregate Analysis by An. E Analysis Team (AAT) Summary and Output Internal safety monitoring tool to evaluate threshold rules through simulation Study Team / SMT / Others AAT / Data Mgmt / Rand Vendor Identify An. E, thresholds and fill out ASMP Set up sequestered area, perform analysis 14 STAGE 3: As needed Review and Report Medical Review and Decision Summary Report and Reporting SMT / SAC / Reporting Review output, summary, reporting

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final Rule – Developmental Safety Management Team • Lilly (Brenda Crowe, 2016 DIA PV) – Aggregate Analysis by Anticipated Event Analysis Team • J&J (Mac Gordon) – Blinded Ongoing Aggregate Safety Evaluation • Abb. Vie (Barbara Hendrickson, 2018 FDA Workshop; Brian Waterhouse, 2017 JSM) • Merck (Greg Ball) – Smaller Company Perspective • Shionogi (Bruce Binkowitz) • Summary • Panel Session

A contour plot can be generated prior to the trial. . . In order

A contour plot can be generated prior to the trial. . . In order to maintain study integrity while still benefiting from the project team’s expertise, blinded methodologies of safety signal detection are needed. Contour plots and interactive graphics can help teams further explore assumptions before deciding whether an unblinded assessment is required. 4 events have happened at 240 PY exposure Prob(RR>1 | data) is about 70% x x 2 more events have happened with 60 additional PY exposure Prob(RR>1 | data) is > 80% Need to look closer When to Alert SAC? 2017 JSM, Baltimore, MD 02 August 2017 16

Safety Assessment Committee – Abb. Vie Pilot Execution of IND safety report submission Day

Safety Assessment Committee – Abb. Vie Pilot Execution of IND safety report submission Day 0= Day Product Safety Team endorses need to submit IND report SSP -> Anticipated Events for Review Routine Safety Review* (blinded) Referred Safety Event Continuous Ongoing Monitoring • • • Blinded Recommendation: No IND report needed No IND report at this time; request future re-reviews Submit IND Report Safety Review (unblinded) SAC Charter Ad Hoc or at Specified Intervals Designated Contact DMC Charter Review (unblinded) Notification of any Recommendations For IND safety reports Recommended Safety Actions (communicated as per DMC Charter) *Quantitative assessment of safety data from ongoing studies using historical event rates PPS | PPT Template 17

Merck: Leveraging the Scientific Expertise and Medical Judgment of the Multi-Disciplinary Risk Management Safety

Merck: Leveraging the Scientific Expertise and Medical Judgment of the Multi-Disciplinary Risk Management Safety Team (RMST) in the Aggregate Safety Assessment Planning (Ag. SAP) Process and Ongoing Aggregate Safety Evaluations (OASE) RMST Blinded-OASE (ongoing studies) Unblinded-OASE (completed studies) Ag. SAP Process Drives the Overall Planning DMC or CSO (Any potential safety concerns identified by the RMST could be referred for an unblinded assessment) DMC: Data Monitoring Committee; CSO: Chief Safety Officer 18 Other Data Sources Feedback to RMST (if action required)

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final Rule – Developmental Safety Management Team • Lilly (Brenda Crowe, 2016 DIA PV) – Aggregate Analysis by Anticipated Event Analysis Team • J&J (Mac Gordon) – Blinded Ongoing Aggregate Safety Evaluation • Abb. Vie (Barbara Hendrickson, 2018 FDA Workshop; Brian Waterhouse, 2017 JSM) • Merck (Greg Ball) – Smaller Company Perspective • Shionogi (Bruce Binkowitz) • Summary • Panel Session

Smaller Company Perspective • The DIA-ASA Interdisciplinary Safety Evaluation scientific working group has an

Smaller Company Perspective • The DIA-ASA Interdisciplinary Safety Evaluation scientific working group has an impressive list of contributors and is a wonderful example of crosscompany collaboration. – It is also an excellent example of a heavy “big” pharma representation. – Was this done purposefully? – I ask because in this case it is likely appropriate since the guidelines we are discussing in this section apply to large groups of trials that are not often capable of being funded by small pharma. • The entire paradigm assumes there are multiple studies in a chronological order, or at least simultaneous studies with enough sample size to drive signal detection. – A smaller program, perhaps in a rare disease, or in a smaller target population, may have a single phase 2 and single phase 3 trial. This happens in infectious disease, for example. 20

Smaller Company Perspective So the paradigm is not likely to apply to small programs.

Smaller Company Perspective So the paradigm is not likely to apply to small programs. • BUT, the thinking still applies for monitoring the studies, including as per ICH E 6 R 2, but integration across multiple studies can't happen without multiple studies. • FDA's preferred approach is likely covered in a small program, especially for a potentially life threatening disease, because there will be DMC on the single phase 3 trial, and the DMC will be familiar with the phase 2 results. So no SAC needed. Again, the thinking applies but the execution is for much larger programs. If no DMC, then beyond GCP, the numbers don’t lend themselves to this paradigm. But program level DMCs bring their own challenges. • The alternative approach is unlikely to have a sufficient sample size to give rules for signal detection with reasonable precision, even after an additional post-marketing trial. 21

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final Rule – Developmental Safety Management Team • Lilly (Brenda Crowe, 2016 DIA PV) – Aggregate Analysis by Anticipated Event Analysis Team • J&J (Mac Gordon) – Blinded Ongoing Aggregate Safety Evaluation • Abb. Vie (Barbara Hendrickson, 2018 FDA Workshop; Brian Waterhouse, 2017 JSM) • Merck (Greg Ball) – Smaller Company Perspective • Shionogi (Bruce Binkowitz) • Summary • Panel Session

Interdisciplinary Aggregate Assessments for IND Safety Reporting • Safety monitoring during clinical development requires

Interdisciplinary Aggregate Assessments for IND Safety Reporting • Safety monitoring during clinical development requires a partnership between clinical and statistical scientists – A thorough understanding of existing safety data, the target population and relevant sub-populations, and risk factors for particular Adverse Events (AEs) – A meta-analytic review should routinely be part of the process in order to more readily detect differences in Adverse Drug Reaction (ADR) rates • A special challenge in ongoing aggregate evaluation of safety data is applying appropriate statistical techniques with a safety mindset – Medical judgment and decision-making within a quantitative framework – As opposed to strict statistical inference (testing and confirming) 23

Interdisciplinary Aggregate Assessments for IND Safety Reporting • FDA is calling for – A

Interdisciplinary Aggregate Assessments for IND Safety Reporting • FDA is calling for – A multidisciplinary approach – Frameworks around aggregate review and level of evidence (not statistical decision rules) – Assessments that are product specific and decisions that are driven by medical judgment 24

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final

Agenda • FDA IND Safety Reporting Final Rule • The Spirit of the Final Rule – Developmental Safety Management Team • Lilly (Brenda Crowe, 2016 DIA PV) – Aggregate Analysis by Anticipated Event Analysis Team • J&J (Mac Gordon) – Blinded Ongoing Aggregate Safety Evaluation • Abb. Vie (Barbara Hendrickson, 2018 FDA Workshop; Brian Waterhouse, 2017 JSM) • Merck (Greg Ball) – Smaller Company Perspective • Shionogi (Bruce Binkowitz) • Summary • Panel Session

Interdisciplinary Aggregate Assessments for IND Safety Reporting: A Dialog among Colleagues from Industry, Academia

Interdisciplinary Aggregate Assessments for IND Safety Reporting: A Dialog among Colleagues from Industry, Academia and the FDA • Organizer: Liang Fang, Ph. D, Senior Director, Biostatistics, Myo. Kardia • Chair: Greg Ball, Ph. D, Senior Principal Biostatistician, Merck Research Labs • Panelists: – Amit Bhattacharyya, Ph. D, Vice President, Biometrics, ACI Clinical – Bruce Binkowitz, Ph. D, Vice President, Biometrics Shionogi – Jacqueline Corrigan-Curay, JD, MD, Director, Office of Medical Policy, CDER, FDA – Susan Duke, MS, Mathematical Statistician, CDER, FDA – Jay Herson, Ph. D, Senior Associate, Biostatistics, Johns Hopkins Bloomberg SPH – Frank Rockhold, Ph. D, Professor of Biostatistics, Duke University – Estelle Russek-Cohen, Ph. D, Senior Advisor, Office of Biostatistics, 26

Interdisciplinary Aggregate Assessments for IND Safety Reporting: A Dialog among Colleagues from Industry, Academia

Interdisciplinary Aggregate Assessments for IND Safety Reporting: A Dialog among Colleagues from Industry, Academia and the FDA 1. For AEs “anticipated” or “expected” to occur in a trial, determining “reasonable possibility” would require an assessment of increased frequency based on aggregate data. a) Could a two-staged approach (using the examples from Lilly, J&J, Abb. Vie and Merck) meet the spirit of the final rule? b) The FDA has placed the responsibility squarely on sponsors to judge reasonable possibility before sending an expedited report. The EMA and other regional regulatory agencies want to be more involved in the assessments. Could a two-staged approach help harmonize how safety reports are handled globally? 27

Interdisciplinary Aggregate Assessments for IND Safety Reporting: A Dialog among Colleagues from Industry, Academia

Interdisciplinary Aggregate Assessments for IND Safety Reporting: A Dialog among Colleagues from Industry, Academia and the FDA 2. Could the DMC be modified in such a way as to be able to make recommendations to the sponsor about safety reporting (rather than constituting a new and resource-intensive SAC)? a) Program vs trial level (multiple trials) b) Safety vs benefit-risk mindset (ignoring efficacy) c) Higher vs lower frequency of review (adhoc meetings) d) Larger vs smaller number of members (expertise) e) Training (for IND safety reporting) f) Communication and trial integrity (who gets unblinded and when) 28

Interdisciplinary Aggregate Assessments for IND Safety Reporting: A Dialog among Colleagues from Industry, Academia

Interdisciplinary Aggregate Assessments for IND Safety Reporting: A Dialog among Colleagues from Industry, Academia and the FDA 3. What do we do when there isn’t much to aggregate? Is ICH E 6 R 2 sufficient for a small program when it states that the clinical trial protocol should discuss the specification of safety parameters: a) Methods and timing for assessing, recording, and analyzing safety parameters b) Procedures for eliciting reports and reporting of AEs and intercurrent illnesses c) Type and duration of the follow-up of subjects after AEs 29

Interdisciplinary Aggregate Assessments for IND Safety Reporting: A Dialog among Colleagues from Industry, Academia

Interdisciplinary Aggregate Assessments for IND Safety Reporting: A Dialog among Colleagues from Industry, Academia and the FDA 4. Is there a formal statistical framework in which we can view the review and analysis aspects of the Final Rule? 30

Thank You

Thank You

Sources of Safety Information • The sponsor should exam data from all sources, some

Sources of Safety Information • The sponsor should exam data from all sources, some examples include: – Animal studies or in vitro studies – Clinical or epidemiological investigations – Reports in the scientific literature – Unpublished scientific papers – Information presented at scientific meetings – Reports from foreign regulatory authorities – Reports from commercial marketing experience – Safety information presented at a professional meeting – Foreign spontaneous reports 32