Harmonization - ICH Robert J. Temple, MD Deputy Center Director for Clinical Science FDA/Center for Drug Evaluation and Research SACHRP March 9, 2010

2 ICH - History ICH originated in the early 90’s in recognition of the need to harmonize, where possible, critical elements of drug development to, develop common standards, avoid waste, and develop databases that could serve all regulators and, one hopes, all patients. It was designed to reflect the views of the 3 main drug developing regions (US, EU, Japan) and their corresponding pharmaceutical organizations. I can tell you there was initial anxiety about moving to the “LCD” (lowest common denominator) but, as someone heavily involved in the effectiveness part (ICH also dealt with toxicology, quality), that fear was not realized. The guidance documents, developed by regulators and manufacturers (the final version is developed by the regulators), have been ambitious and broad-ranging.

3 ICH History ICH initially covered (for effectiveness) E-1: Safety database E-2: (general) safety reporting pre and post marketing pre and post marketing E-3: Reporting on a clinical trial E-4: Dose-response E-5: Ethnic differences, using foreign data E-6: GCP E-7: Studying the elderly E-8: General considerations E-9: Statistics E-10: Choice of control groups E-14: QT evaluation M: Common technical document

4 ICH History Note particularly E-10, a very good discussion of all potential kinds of controls, including historical, and a thoughtful consideration of use of placebos when there is existing treatment that the World Medical Association (Declaration of Helsinki) would have done well to appropriate in Because of it, the regulated industry and the regulators have been well ahead of most others in understanding non-inferiority studies. ICH E-6 (GCPs) describes expectations for the conduct of clinical studies that facilitates a global standard. We regularly use data obtained in the EU under such standards and the standards are increasingly global (E. Europe, Latin America, China, India).

5 ICH E-6 It describes many aspects you would expect: 1. General principles – origin in D of H and tracks that document, demanding − Rights, safety, well-being of subjects are highest priority − Potential benefits must justify risks (beneficence) − Studies must be scientifically sound, with a clear protocol − Freely given consent − Prior review by IRB/IEC − Good handling of data − Assure quality of all aspects of trial It then gives a great detail of detail about responsibilities of IRB/IEC, investigators, study sponsors, certainly as detailed, or more detailed than what we have written for US trials.

6 ICH E-6 2. IRB/IEC Tasks and purpose is the same for both but IRB composition not Identical to IEC, so that foreign investigators could not sign FDA form We have arranged for simple waiver so they can sign 1572; in that event the trial can be done under an IND. We have long-accepted central IRB’s so that the EU system, becoming less local than US, is not a problem. As ICH E-10 says, locales can differ on whether placebo is acceptable. We believe we are helping lead to greater understanding of what is needed for a credible non-inferiority study.

7 ICH E-6 3. Safety reporting by investigator Flexible: all serious ADEs except those agreed on in protocol or elsewhere. This flexibility is important. We’ve been plagued by reports to us by Sponsors of study endpoints, adverse outcomes common in population. We are looking at our own rules and E-6 clearly provides flexibility. We are also looking at what sponsors need to report to us.

8 ICH E-6 4. Extent and Nature of Monitoring An area of particular interest to CTTI, as well as to FDA is the extent and nature of study monitoring. As Dr. Califf will tell you, few matters are more critical to the conduct of the large outcome trials we need than controlling the amount of data we collect and the extent of monitoring study monitoring. CTTI is examining various monitoring practices and it is striking that practices in industry (every site, every 4 weeks), NHLBI/VA (far less) and NCI (site assessment, not really trial monitoring) are so different.

9 ICH E-6 4. Extent and Nature of Monitoring E-6 is very flexible. Sponsor is responsible for adequate monitoring and determines the appropriate extent and nature of monitoring. This is based on the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. “In general there is a need for on-site monitoring, before, during, and after the trial; however, in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators’ training and meetings, and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sample may be an acceptable method for selecting the data to be verified.” This flexibility is very important and CTTI is highly focused on monitoring practices. A recent meeting suggested a need for FDA guidance in this area.

10 ICH E-6 We accept as a basis for approval studies done abroad, [21 CFR ] if the data are “applicable to the US population and US medical practice.” This has long been true with respect to trials in Western Europe, with little distinction from US data, and increasingly we see data from the rest of the world. Under , which refers to foreign studies not done under an IND, the applicant must document I.C., IRB/IEC review, and provide a description of steps taken to follow GCP (not necessarily ICH E-6 version), and FDA must be able to inspect the study. The IEC’s decision must be documented; the IC must be the described; training of investigators to comply with GCPs must also be described.

11 ICH E-6 ICH E-6 represented a very valuable consensus on the expectations and duties of all parties to a clinical investigation. Fully based in past expressions of standards, it has been particularly pertinent, I think, in the present era, where trials are moving into new locales. So even though ICH E-6 was developed by the familiar countries with established sites for trials, it applies broadly to anywhere that trials are carried out. As I noted ICH E-6 has appropriate flexibility on just how its principles are implemented, but it reflects the principles all accept very well.