1. Changing Scene of Clinical Research Judy Stone, MD www.conductingclinicalresearch.com © Creative Commons Attribution- Noncommercial-Share Alike

2. Background on Changing Scene Globalization of Clinical Trials

3. Background: What % of Sites are Outside the US? 10 % 20 % 40 % 60 %

4. Background: What % of Sites are Outside the US? 10 % 20 % 40 % 60 %

5. Open Phase 3 Clinical Trials, 2007 56% of trials are outside of US 1/3 of trials done solely outside US

6. Open Phase 3 Clinical Trials, 2007 Open Phase 3 Clinical Trials, 2007 19952005 19952005 # Countries 33 70 large incr in countries US % of trials 54 43 10% decr in trials # Pts/trial215 661 large incr in # trial asubjects Glickman, Seth et al. Ethical and Scientific Implications of the Globalization of Clinical Research. NEJM 360 (8): 816-823, 2009

7. Non-US Clinical Investigators Tracked by FDA

8. Increase in Overseas Trials http://www.financialexpress.com/news/huge-growth-in-clinical-trials-in-country-official/389956/,

9. Shift in Clinical Investigators Submitting INDs hybrid slide of data from Centerwatch Analysis 2009 and Tufts CSDD Impact Volume 1, 2009

10. Access to patients # of pts needed for trials rose: 2.8 million people in 1999 to 19.8 million in 2005 only 1-2% participation rate in trials in US http://www.boston.com/news/nation/articles/2007/12/29 What is Driving the Shift Overseas?

11. Distribution of World Population # of pts needed for trials per yr-19.8 million

12. What is Driving the Shift Overseas? Need for: Large numbers with a specific condition* Specialized centers Phase 2 supercenters with up to 9000 outpt visits/day** Treatment naive patients Different ethnic/racial groups e.g., Iressa effective in Asia, not US lg Japanese pop in Brazil; less competition **http://www.dddmag.com/clinical-trials-on-the-move.aspx

13. Bureaucracy delays in protocol development phase III ECOG trial protocols require about 800 days from conception to activation* contracts and grants negotiation now the longest part of starting a study at one institution, 87 steps and 29 signatures were required to launch a trial *Sandler, Alan in http://www.cancernetwork.com/display/article/10165/1382200, 09http://www.cancernetwork.com/display/article/10165/1382200 What is Driving the Shift Overseas?

14. Availability of patients Slow recruitment causes 85-90% of delay in trials 80% of studies run over by 30-42%, or avg. 6 mo* Recruitment speed may be 25 x or more higher** Cost Need to shorten development time… Trials in the Fast Lane: Accelerating Clinical Trials: Budgets, Patient Recruitment, and Productivity, Cutting Edge Information **www.ngpsummit.com/pdf/Clinstar.pdf What is Driving the Shift Overseas?

15. Costs of Delay direct cost of delay $37,000 per day in out-of-pocket expenses. indirect cost for a billion dollar drug is 83 million/month or 2.8 million/day* (another estimate is $15.6 million/day**) *Excel-China CW **www.ngpsummit.com/pdf/Clinstar.pdf

16. Relative Costs of Trials

17. Grooming markets in developing countries Huge population of potential buyers Reduce regulatory barriers What is Driving the Shift Overseas?

18. Difficulty recruiting patients in US Low volunteer rate, <5% even for cancer trials Liability Mistrust of pharma Less risk-tolerant patients More competition for pts as more drugs in development restrictive inclusion-exclusion req req for larger trials HIPAA Problems in US Trials

19. Costs higher employee benefits 30% administrative costs higher designated person to reconcile billing, to ensure that Medicare or third party payers are not inadvertently billed Cost of finding pts higher due to increased screening req HIPAA Cost to site of obtaining HIPAA consent $5/per subject =>10 million/yr Unique Problems in US Trials Goldfarb, N Association of Academic Health Centers (AAHC), The HIPAA Privacy Rule: Lacks Patient Benefit, Impedes Research Growth, Johnson, Guy GW

20. Fewer feel need to participate higher standard of care Insurance precluding participation Unique Problems in US Trials

21. Costs are 50+ % lower outside of US More readily available naïve patients More compliant patients Less regulatory oversight Less litigious climate What is Driving Move to Conduct Clinical Trials in Developing Countries? Summary

22. a) 2 % b) 5 % c) 10% d) 20 % How Profitable are Clinical Trials for a Site?

23. a) 2 % b) 5 % c) 10% d) 20 % How Profitable are Clinical Trials for a Site?

24. Where Does the Clinical Grant Dollar Go? Hidden Costs incl managing Adv Event, Travel to req Inv Meeting, Supervision, review of CRF, attending initiation meeting, CRA interactions-Ken Getz

25. Sponsor-Site Relationships

26. Sponsor site relationships Less friendly; no longer personal relationships Now computer data-base driven Cross-indemnification clauses CROs/CRAs: More use of CROs rather than in-house team High turnover in CRAs Costly for site to train CRAs Inconsistency in CRFs, etc.

27. Sponsor site relationships New clinical trials startshas declined by 40 % since mid-2008. Numerous programs have also been halted and cancelled. Investigators have to hedge their bets may be left with expensive infrastructure expenses if trial is cancelled

28. Decline in # PIs New PIs declined 10% betw 2000-07, while the # of studies has incr ~15% 45% of all PIs in 2000 decided to quit after their studies ended, compared to a 27% turnover rate during the early 1990s. Lack of exposure in training; Enormous time commitment Increasing difficulties recruiting pts HIPAA, insurance restrictions, incl-excl criteria Liability issues

29. Decline in # PIs Financial incentives diminishing 2% profit now investigator compensation per procedure has declined 3 percent annually since 1999 while the sites work burden increased 10.5 percent annually. Financial Disclosure requirements offend many

30. Problems with Recruitment, Retention: Incr competition for pts Incl-Excl criteria are more complex and rigid=> Ave eligibility criteria have increased by 58%* More screening Expectation of <1 pt/mo Smaller pool of potential volunteers Enrollment rates dropped from 75% between 1999 - 2002 to 59% between 2003 - 2006. Retention rates fell by 30%. Mistrust: increased from 28% to 75% from 1996 to 2002 Getz, Ken. Chasing Veteran US Sites Out of the Enterprise. Why investigative sites are at financial risk and how it may effect sponsors and CROs. Applied Clinical Trials, Nov. 2010

31. Retention Incr complexity and # of procedures 6.5% annual growth in # unique procedures per protocol 8.7% annual growth in the frequency of the protocol activities (1999-2005) (1999-2005) Volunteer retention dropped from 69 percent to 48 percent between 2003 and 2006 Ave number of procedures required rose from 89.8 to 150.5. Mistrust: OIG noted a tenfold increase in complaints against sites.

32. Less publicized impediments: CRF size; e-crfs (with dedicated computer/line) CRF size; e-crfs (with dedicated computer/line) HIPAA HIPAA Staffing at hospitals declining and rapid turnover of staff => Staffing at hospitals declining and rapid turnover of staff => inability to do trials without errors; no longer a dedicated unit for trials Utilization Review Utilization Review Revolving door Insurance denials of stay/investigative Rx Standard order sets Standard order sets e.g. Pneumoniacall Dr. Stone re drug study was not an option

33. Contract Issues

34. Grant payment schedules Back-loaded favored by sponsor Front-loaded advantageous for site

35. Contract Issues--Tips Start-up $ when contract is finalized rather than enrollment of 1st pt Grant broken down by patient and Insist that payments include a remittance advice, or detailed breakdown of what the funds are for, to avoid a bookkeeping nightmare.

36. Contract Issues--Tips Be wary of milestones like payment after every 5th pt might end up floating a loan to sponsor if enrollment is slow

37. Contract Issues--Tips Require the monitor to visit the site within 2 weeks of your having enrolled your first patient. close monitoring on complex studies ensures that you are enrolling patients appropriately and performing all the study evaluations correctly. avoids costly unevaluable pts

38. Contract Issues--Start-ups Complete a financial review of the sponsor or CRO, and have clauses for: Recovery of all attorney fees and costs, in case of nonpayment Ability to withhold data for nonpayment Retrieval of CRFs at specified intervals and interim $ if not retrieved Insurance for the sponsor-min of $5 million

39. Contract Issues--Warnings Publication clauses Publication clauses Patent and Inventions Patent and Inventions Cross-indemnification clauses Cross-indemnification clauses insist on receiving a draft contract prior to investing a lot of time in the protocol. Insurance Insurance indemnification clauses do not cover alleged physician error most malpractice insurance policies exclude coverage for clinical trials Be sure to limit indemnification to limits of your coverage

40. Conflict of Interest

41. IOM definition: …creates a risk that professional judgment or actions regarding a primary interest will be unduly influenced by a secondary interest.

42. Conflict of Interest-History 1980s pressure to translate basic bench research into Rx for patients => research collaborations between the government (NIH) and industry became acceptable Bayh-Dole Patent and Trademark Laws Amend. Act of 1980 academic institutions gained intellectual property rights when carrying out government-funded research=> receiving the patent and licensing funds and ongoing royalties

43. Conflict of Interest-History NIH 1995, Dr. Harold Varmus rescinded policies prohibiting investigators from accepting consulting fees or stock from industry/sponsors Annual limits on work and revenue from outside the NIH were also removed. Pendulum swings back: NIH now requires reporting of salary or stocks totaling more than $10,000 for a related company

44. Conflict of Interest-History To what degree should financial interests by investigators be disclosed to prospective research participants?

45. Conflict of Interest-History 5 percent of volunteers said they would not participate because of an investigators equity interest vs investment as a plus, feeling the PI would work harder or believed more strongly in the potential benefit of the intervention.

46. Conflict of Interest-Physician Pressure re enrolling their own patients--trust, coercion Pressure to enroll borderline patients: financial, for overhead and salary expenses (bonuses for goals) sites prospects for future trials prestige, coauthorship on publications rank and tenure

47. Conflict of Interest-Physician Does participation in trial influence: hospitals formulary decisions? alter a physicians prescribing patterns?

48. Pt-Prompted Ethical Issues Patients who lie about their medical histories or problems to gain access to medical therapies that would not otherwise be available to them to gain access to medical therapies that would not otherwise be available to them Make reasonable payments to cover patients time and trouble in participating (e.g., gas, parking, taxi fare), rather than excessive participation fees that might be unduly tempting or coercive.

49. Pt-Prompted Ethical Issues Occur when: the PI is also the patients personal physician. Sometimes MD so intensely wants to help their pt that they bend the enrollment criteria for a trial so a patient can have access to a potentially lifesaving drug…

50. Pt-Prompted Ethical Issues ~64% of respondents thought that PIs should deviate from the protocol to improve subjects care. 22% recruited an ineligible patient anyway if they believed the trial would be beneficial to the pt of 36% who said one of their pts had met termination criteria but seemed to benefit medically from the trial, 9% reported that they kept the subject in the trial.

51. Pt-Prompted Ethical Issues dual role/relationship [of physician and investigator] may confuse research with clinical care and puts the investigator in a position to heavily influence the patients/subjects decisions.

52. Conflict of Interest: IRBs Commercial IRBs are paid directly by the drug company sponsor Presumably, they dont want to bite the hand that feeds Other nonfinancial ethical conflicts may be due to excessive personal involvement or prejudgment or when there is a personal or collaborative relationship between the investigator and the IRB member. Increasingly, competition may exist between the PI and IRB members.

53. IRB Impracticality: Form FDA 1572 obligations place this responsibility on a PI: I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation.

54. 2007 Guidance: Supervisory Responsibility of Investigators contains 2 critical points: When tasks are delegated by the investigator, the s/he is responsible for providing adequate supervision and is accountable for regulatory violations from failure to do so to be able to discuss the risks and benefits of a trial

55. 2007 Guidance: Supervisory Responsibility of Investigators Inappropriate delegation includes: medical histories screening evaluations conducted by individuals with inadequate medical training (e.g., a medical assistant). assessment of inclusion/exclusion criteria informed consent obtained by individuals who lack the medical training, knowledge of the Protocol or Inv. Product needed to be able to discuss the risks and benefits of a trial

56. So, Why Do Studies? Basic physiologic Income and safety needs and safety needs need for love, sense of membership belonging need for esteempublication and recognition intellectual challenge higher needs of self-actualization and transcendencealtruism, wanting to develop a medicine or device that will help others medicine or device that will help others

57. Cutting Edge Information Trials in the Fast Lane: Accelerating Clinical Trials: Budgets, Patient Recruitment, and Productivity, 2004 Getz, Ken. Chasing Veteran US Sites Out of the Enterprise. Why investigative sites are at financial risk and how it may effect sponsors and CROs. Applied Clinical Trials, Nov. 2010 Glickman, Seth et al. Ethical and Scientific Implications of the Globalization of Clinical Research. NEJM 360 (8): 816-823, 2009 Goldfarb, Norm Clinical Research Terminology Codes: What We Do and How Much It Costs, 2006 What is Killing Off the Investigators? A Clinical Research Mystery, 2005 Steinberg, Mindy. Association of Academic Health Centers (AAHC), The HIPAA Privacy Rule: Lacks Patient Benefit, Impedes Research Growth 2009 Selected References

58. Thank you! Questions? jstone@conductingclinicalresearch.com