Working with Pharma Sponsors in Research

1. Working with PharmaSponsors in Research Becky Hubbell, PharmD, MBA Sr Ex Dir, Clinical Research Operations

2. Background • 10 years hospital pharmacy practice • Assistant Professor KU School of Pharmacy • 20 years pharmaceutical industry • 13 years Marion labs -> Aventis • 6 years Pharmion -> Celgene • Clinical development • Outcomes Research • Therapeutic areas—last 6 years oncology • KUCC—Clinical Research Operations

3. Pharmaceutical Industry: Drug Development • 1999: 1,800 compounds in development • 2009:  2,900 medicines in development • 2008: Food and Drug Administration approved 31 drugs and biologics  • 2006: cost to develop a drug $1.3 billion dollars and takes between 10 and 15 years 

4. Research Relationship with the Pharma Industry • Many of the research projects undertaken at academic medical centers are part of the drug development process  • The pharmaceutical industry can be a funding source for innovative ideas through investigator-initiated trials (IITs)

5. Objective • Briefly discuss the process of drug approval from the pharmaceutical industry perspective • Discuss how to optimize and improve our working relationship with our partners in the pharma industry around clinical research • Disclaimers: • Overview for discussion and thought • Not complete review of regulatory activity/responsibility for clinical trials • Not complete review of internal processes

6. Pharmaceutical Companies • Wide variations • Global or local • Therapeutic focus—single area, e.g., oncology or broad • Size—start ups vs. mega corporations • Publically or privately held • Culture • Etc.

7. Points of contact with Pharma • Sales and marketing • On label discussions • You can request material off label—information usually will come from medical information department • Medical science liaison • Medical departments, provide scientific information • Contact for IITs • May or may not be involved in studies • Clinical development • CRAs, Scientists, Operations • Research/study specific • Contract Research Organizations • Others as well

8. New Drug Application (NDA) • Drug is safe and effective in its proposed use and the benefits outweigh the risk • The drug’s proposed labeling (package insert) is appropriate • The methods used in manufacturing the drug are adequate to preserve the drug’s identity, strength, quality and purity • Documentation is supposed to tell the drug’s whole story • 100,000 pages and more • Outcome: Approval, Approvable, Not Approved

9. Drug Development • International Conference on Harmonization (1990) – ICH guidelines • USA, Europe, Japan • Preclinical -> IND • Clinical • Phase I • Phase II • Phase III: NDA requires studies • NDA (Advisory Panel) • Phase IIIb, IV

10. Planning Drug Development • Product development plan • Shortest path to marketing (NDA, MAA) • Plan should target the labeling • Least number of studies • Each study results in more information • Meetings and guidance from regulatory authorities (FDA, EMEA, etc) • Budget • Time to market is crucial • Marketing success • Will additional studies be required to provide additional information

11. Labeling: Package Insert

12. Off Label Marketing: Pfizer Pays $2.3 Billion to Settle Marketing Case • Published New York Times: September 2, 2009 • WASHINGTON — The pharmaceutical giant Pfizer agreed to pay $2.3 billion to settle civil and criminal allegations that it had illegally marketed its painkiller Bextra, which has been withdrawn. It was the largest health care fraud settlement and the largest criminal fine of any kind ever.

13. Off Label Marketing: Pfizer Pays $2.3 Billion to Settle Marketing Case • Bextra was approved in 2001 by the Food and Drug Administration to treat arthritis and menstrual cramps. The drug was not approved for the treatment of acute pain, nor was it shown to be any more powerful than ibuprofen. But Pfizer instructed its sales representatives to tell doctors that the drug could be used to treat acute and surgical pain and at doses well above those approved, even though the drug’s dangers — which included kidney, skin and heart risks — increased with the dose, the government charged. The drug was withdrawn in 2005 because of its risks to the heart and skin.

14. Drug Development—Preclinical • Drug discovery (5,000–10,000) • Preclinical (250) • 3–6 years • File Investigational New Drug application (IND) • Includes a protocol • 30 day wait

15. Drug Development: Clinical • Clinical Trials • Phase 1: Assesses safety and evaluates how the compound affects the body • Small number of healthy subjects • May evaluate dose (dose escalation) • Role of biomarkers • Food effects • Phase II testing of the compound in patients • Safety • IIa Dosing • IIb initial efficacy

16. Drug Development • Clinical trials • Phase III (Pivotal) • Large scale trials (2 or more) • Multicenter • Randomized, double blind, placebo controlled • Basis of drug approval • Efficacy • Safety including more rare events • Target population (elderly, disease state, etc…) • Submission of NDA: Indication and PI will be defined by data from clinical trials, especially pivotal

17. Pharma Sponsored Trial designs • FDA input into drug development • Trial design, especially phase I and phase III, FDA should have extensive input • May not be the most scientifically interesting • Issues encountered • Comparator agent: approved vs. most current thought • Treatment plan may be a compromise • Patient numbers • Inclusion, exclusion

18. Increasing Complexity of Studies

19. Becoming a Study Site • Patient Recruitment • Support for the number of patients who qualify; how many will enroll, competing studies—be realistic, have data to support • Adequate resources to conduct the study • Study start up • 1572 • Contract • IRB • Study budget • Pre study or qualification site visit

20. Study Conduct • Recruitment • Quality work • Data entered in timely fashion, respond to queries • Regulatory compliance • Study deviations • Study endpoints • Adverse event reporting • Monitoring visits • Personnel to support including PI availability • Collaborative working relationship

21. Study Monitoring • Ensures the trial is conducted and documented properly • Communication • Study drug • Verify protocol adherence • Patient eligibility • Verify source documents • Checking accuracy and completeness of CRF • Adverse events • Maintaining essential documents • Etc. • Monitoring report

22. Monitoring—Contract Research Organization • CRO • Can perform any of the responsibilities of the sponsor (TOR) • Quality and integrity of the trial data always rests with sponsor • Can facilitate or hinder communications • Feedback to the sponsor as necessary

23. Auditing • Independent of monitoring, to evaluate trial conduction and compliance with the protocol, SOPs, Good Clinical Practices (GCPs) and regulatory compliance • Audit plan guided by the importance of the trial to the submission to regulatory authorities, number of subjects in the trial, level of risk to subjects and identified problems • Auditing or monitoring that identifies serious and/or persistent non compliance, sponsor should terminate the trial and report to regulatory authorities and IRB

24. Study Closure • Final patient visits: endpoints, safety data • Study close out visit • Final monitoring • Study drug • Records retention • FDA (or other regulatory authority) audits • Will audit phase III study sites, and other studies as they deem appropriate • Generally select high enrolling sites • Always contact the sponsor for support

25. Support of IITs • Pharma motivation: • Support their product: Might be part of their product development plan • Will not lead to product approval, but will be cited as “supportive” in the NDA • Hypothesis generating • Publication, presentations • Less costly than internally conducted trials

26. Support of IITs • You have a great idea for a trial, now what? • Regulatory responsibility: • Sponsor • Filed to IND • Data integrity • 1572 • Idea • Well-thought-out hypothesis • Reasonable scope • Patients • Resources

27. Pharma Support for IITs • Identify logical funding source • Approach about interest and process • Contact? Probably the medical science liaison, sales rep may locate the contact • Format • Budget • Is the idea of interest; if not what similar ideas are of interest?

28. Pharma Support for IITs • Budget • Funding cycle • Level of support • Include all areas of support • Indirect expenses • Internal process for IITs • When in place submit the idea and budget to the sponsor

29. Hybrid • A pharma-sponsored trial, that is a collaborative effort with a PI • Idea must be central to the PDP • Requires a close working relationship • Will be conducted as part of the NDA • You probably will lose some scientific creativity

30. Questions?