Modernization of ICH E8 Sholeh Ehdaivand, President and CEO LMK Clinical Research Consulting 27 April 2017 Page 1

Agenda ICH E8 “General Considerations for Clinical Trials” Overview Proposed Revisions GCP-QA Comments Questions

ICH E8 – Overview General Considerations for Clinical Trials finalized in 1997 Plan for other ICH Clinical Trial Guidelines (e.g. E6 Good Clinical Practices) General Considerations for Clinical Trial: Design Plan Management Conduct

ICH E8 – Details Four main objectives: Describe internationally accepted principles and practices in the conduct of both individual clinical trials and overall development strategy for new medicinal products; Facilitate the evaluation and acceptance of foreign clinical trial data by promoting common understanding of general principles, general approaches and the definition of relevant terms; Present an overview of the ICH clinical safety and efficacy documents and facilitate the user's access to guidance pertinent to clinical trials within these documents; Provide a separate glossary of terms used in the ICH clinical safety and efficacy related documents that pertain to clinical trials and indicate which documents contain them.

ICH E8 – Details Protection of Human Subjects Scientific approach to design and analysis Classification of Clinical Studies according to objective Special considerations (e.g. special populations) Objectives Conduct Analysis Study Reporting

ICH E8 – Details

Proposed Revisions – Background February 2016, a group of research organizations and international consortium of health researchers wrote a letter to ICH. Some of their concerns included: Current ICH E6 guideline fails to “sufficiently recognize variations in the level of risk for participants in different types of trials and allow corresponding flexibility and managing of risks”; Limited scope of E6, which should aim to address the planning and conduct of clinical trials more holistically.

Proposed Revisions – Overview Data quality fundamentally depends on the quality of the study that generates the data and many aspects of the study design affect the reliability of the study conclusions. ICH Reflection on “GCP Renovation”, January 2017

Proposed Revisions – Overview Fast Facts: First update since 1997 ICH released a Reflection Paper in January 2017 on GCP Renovation (E6 and E8) Public comment period ended 11 March 2017 Will begin late 2017 or 2018 Attempt to modernize the guideline to keep pace with the diversity in clinical research related to study type diversity and data sources.

Proposed Revisions – Details Subsequent renovation of ICH E6 through a set of annexes Address study quality: Trial aspects that are critical to generating reliable data Strategies and subsequent actions to effectively and efficiently support clinical trial quality. Quality by Design and Critical to Quality are not just buzz words Updating to cross-referenced sections Expert Working Groups (EWGs) to conduct a series of guidelines

Proposed Revisions – Details Recognition by ICH of emerging data sources: Electronic Health Records/Electronic Medical Records Hospital Discharge Summaries Patient/Disease Registries Technology Regulations

Proposed Revisions – Steps Modernization of E8 by the EWG (clinical, statistical, data science, patient-reported outcome/clinical outcome assessment experts and others as needed). Output: Guideline Effort 1 E6 Renovation by the EWG (clinical trial conduct and GCP compliance) Output: Guideline Effort 2 (E6 Overarching Principles) Guideline Effort 3 (Annex 1 – Traditional Interventional Trials) Guideline Effort 4 (Annex 2 – Non-Traditional Interventional Trials) Guideline Effort 5 (Annex 3 – Non-Traditional Trials)

GCP – QA Feedback On 07 February 2017, the GCP-QA DIA Community opened the feedback period to all members. The individual comments were submitted anonymously. Comments were consolidated and sent to DIA for final review/comments.

GCP – QA Comments Section Comment General - It would be desirable to address some emerging trends in treatment, which affect protocol design, inclusion/exclusion criteria, and fine-tuning of patient populations.   For example, DIA GCP-QA recommends language around utilizing genetic marker data or other health care data to refine the population that would be targeted by a new treatment or regimen. A second area of recommendation includes adding reference to the now common use of adaptive trials and accelerated trials, instead of the classic development progression through design phases. - The forthcoming EU Clinical Trial Regulation (http://ec.europa.eu/health/human-use/clinical-trials/regulation_en), currently due to be implemented in October 2018, introduces the term “low intervention clinical trial” that will have less stringent requirements in terms of monitoring, TMF content, informed consent process and investigational medicinal product traceability than “normal” interventional clinical trials. DIA GCP-QA recommends that ICH consider this new trial category, and harmonize with EMA, FDA, and PMDA in establishing a common terminology. - The October 2018 EU Clinical Trial Regulation also differentiates between Clinical “Trial” and Clinical “Study” whereas those terms have in practice been interchangeable. If unilaterally adopted, the EU approach would be divergent from the remaining members of the tripartite, and DIA GCP-QA recommends adoption of a common terminology. - Quality by design is definitely needed as stated in the reflection paper.  The DIA GCP-QA asks the ICH committee to consider including information beyond Electronic Medical Records, such as data from mobile devices, including consumer-grade (fitness trackers) as well as ePRO and regulatory-agency approved devices.

GCP – QA Comments Section Comment General - Quality by design would also benefit from ICH E8 referencing independent oversight, such as Data Monitoring Committees and Institutional Review Boards.   - DIA GCP-QA agrees with comments inferred in the reflection paper on including topics on risk assessed monitoring, based on Transcelerate’s Position Paper: Risk-Based Monitoring Methodology (2013), http://www.transceleratebiopharmainc.com/wp-content/uploads/2013/10/TransCelerate-RBM-Position-Paper-FINAL-30MAY2013.pdf, and Defining a Central Monitoring Capability, Therapeutic Innovation and Regulatory Science vol 48, no 5. DIA GCP-QA recommends also including discussion on the value of statistical investigation of multi-regional consistency (eg, Buyse, Centralized Statistical Monitoring As a Way to Improve the Quality of Clinical Data, Applied Clinical Trials (2014), and Buyse, A statistical approach to Risk Based Monitoring, J of Clinical Research Best Practices (2014). - Standards of quality are currently different in Controlled Clinical Trials intended for Registration vs Early Stage probe studies.  With expansion to Low or No Intervention trials, pragmatic and observational trials, and data mining trials, it is suggested that ICH provide some guidance on acceptability in different scenarios. - With the proposed revisions to interventional studies, clarifying the criteria for use of surrogates would be welcome. - Revision of ICH E8 is welcome.  While the proposal was also to simultaneously revamp E6, with the recently released E6(r2) already covering modern approaches, another E6 revision would hold a lower priority.

GCP – QA Comments Section Comment E8 3.1.3 DIA GCP-QA suggests including adaptive trials in the discussion of trials and the phases they fall into. ICH E8’s Figure 1 and Section 3 are predicated on the historic progression from phase 1 to phase 4.  With the adoption of adaptive designs and accelerated P1/2 and P2/3 designs, a change to the current paradigm is in order.   E8 2.2. and Table 1 It would be helpful to include some language about current industry trending in the area of Early Efficacy or Preliminary Efficacy types of studies that are scaled to provide an initial confirmation of a primary efficacy endpoint before scaling to larger studies. E8 3.2.2.2 As the Industry continues to develop more complex drugs and regimens for difficult diseases, it would be helpful if this section would address some rules-of-thumb for using different types of control comparators in cases where placebo control would be unacceptable to the patient population.