Critical Considerations for Clinical Research in “Emerging Regions” (ERs)

1. Critical Considerations for Clinical Research in “Emerging Regions” (ERs) Craig A. Metz, PhD Vice President, Regulatory GlaxoSmithKline

2. Key Points to Consider • Data Integrity • Generalizability • Ethics

3. What’s Being Said AboutStudies in ERs

4. Notable Quotes In addition to manufacturing challenges, Dr. Woodcock explained that FDA has to interpret and extrapolate data from clinical trials conducted overseas. “We have to figure out how to deal with...intensified in recent years...extrapolating findings from one population, maybe a Third World-type of population, to our population and making sure the drug could still be safe and effective...under the conditions of the United States.”

5. Notable QuotesJohn Jenkins Jenkins, who spoke on the audience-submitted question with CDER associate director for medical policy Robert Temple, said the trend has also caused FDA to have “concerns about the local standards of medical practice and how that may influence the ability to extrapolate and interpret the data that are brought back for consideration for the U.S. population.”

6. Notable QuotesRobert Temple • “I’m more worried about depression studies. We’ve had some fairly stunning examples of at least one drug that looked pretty good in studies in South America and Eastern Europe, and we’re finding them not replicable in Western Europe and the U.S. We have no idea what that means. We have no reason to think anybody cheated.” • “it’s extremely common to accept data that’s collected from a wide variety of places in the world. Usually there’s fair consistency and it’s not a particular problem. I have to say we’ve not seen studies from India yet. We’ve seen a couple of giant Chinese studies that could very well figure in favorable actions — but not India yet, although we all know people who are moving there. When you talk to companies about what they encounter, they’re well aware that there are differences in delving through protocols that are different by region ...”

7. Notable QuotesSenator Grassley According to an FDA official interviewed by HHS OIG, about 20% to 25% of the trials for products that FDA oversees occur outside the U.S., and this number is growing. Because FDA’s regulations generally do not apply to trials conducted outside of the U.S., the agency’s oversight of foreign trials is limited. What steps, if any, is FDA taking to ensure the quality and integrity of data from foreign clinical trials, and what is FDA doing to improve its monitoring of such trials?

8. Notable QuotesEMEA Reflection Paper Clinical trials are now increasingly being conducted in countries outside the EU and the relevance of the data for EU patients is not always clear. In addition, there are now also examples of results of trials conducted globally, for which interpretation of the data for the EU was difficult.

9. Data Integrity • Each FDA Division may have a different philosophy regarding data from ERs • Are appropriate sensitivity analyses being conducted to evaluate the potential for regional effects? • How/when do you obtain regulatory authority concurrence with your analytical plan? • When are the regulatory authorities apprised of your proposed enrollment balance across regions for the primary efficacy studies?

10. Data Generalizability • Potential for unknown/poorly understood regional differences in medical practices/standard of care • Potential impact of culture/language on the effective deployment of PROs in ERs • Placebo response rates may be higher in ERs for certain disease settings which could decrease study power and lead to failed trials • The more subjective the primary registration endpoint is the more regulatory risk is invoked with a development program involving significant recruitment from ERs

11. Ultimate Goal APPROVAL NOT submission