Changing Scene of Clinical Research

Judy Stone, MD

www.conductingclinicalresearch.com

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Background on Changing SceneGlobalization of Clinical Trials

Background:

What % of Sites are Outside the US?10 %20 %40 %60 %

Background:

What % of Sites are Outside the US?10 %20 %40 %60 %

Open Phase 3 Clinical Trials, 2007

56% of trials are outside of US

1/3 of trials donesolely outside US

Open Phase 3 Clinical Trials, 2007

1995 2005

# Countries 33 70 large incr in countries

US % of trials 54 43 10% decr in trials

# Pts/trial 215 661 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

Non-US Clinical Investigators Tracked by FDA

00

2,000

4,000

6,000

8,000

10,000

12,000

14,000

16,000

80-84 85-89 90-94 95-99

# of investigators

Increase in Overseas Trials

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

Shift in Clinical Investigators Submitting INDs

hybrid slide of data from Centerwatch Analysis 2009 and Tufts CSDD Impact Volume 1, 2009

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?

Distribution of World Population

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00

2007

# of pts needed for trials per yr-19.8 million

What is Driving the Shift Overseas?

Need for:Large numbers with a specific condition*

Specialized centersPhase 2 “supercenters” with up to 9000 outpt visits/day**

Treatment naive patients

Different ethnic/racial groupse.g., Iressa effective in Asia, not USlg Japanese pop in Brazil; less competition

**http://www.dddmag.com/clinical-trials-on-the-move.aspx

Bureaucracydelays 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, 09

What is Driving the Shift Overseas?

Availability of patientsSlow recruitment causes 85-90% of delay in trials80% of studies run over by 30-42%, or avg. 6 mo*

Recruitment speed may be 25 x or more higher**

CostNeed 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?

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

Relative Costs of Trials

0.000

0.200

0.400

0.600

0.800

1.000

1.200

1.400

Fast track, 2006: Amretechpharma.com

Germany US China India Russia

Grooming markets in developing countriesHuge population of potential buyersReduce regulatory barriers

What is Driving the Shift Overseas?

Difficulty recruiting patients in USLow volunteer rate, <5% even for cancer trialsLiabilityMistrust of pharma Less risk-tolerant patients

More competition for pts as more drugs in developmentrestrictive inclusion-exclusion reqreq for larger trialsHIPAA

Problems in US Trials

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

HIPAACost 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

Fewer feel need to participatehigher standard of care

Insurance precluding participation

Unique Problems in US Trials

Costs are 50+ % lower outside of USMore readily available “naïve” patientsMore compliant patientsLess regulatory oversightLess litigious climate

What is Driving Move to Conduct Clinical Trials in Developing Countries?Summary

a) 2 %

b) 5 %

c) 10%

d) 20 %

How Profitable are Clinical Trials for a Site?

a) 2 %

b) 5 %

c) 10%

d) 20 %

How Profitable are Clinical Trials for a Site?

Where Does the Clinical Grant Dollar Go?

63%18%

6%2%

4%7%

Salaries Overhead TrainingProfit Operating CostsHidden Costs

Hidden Costs incl managing Adv Event, Travel to req Inv Meeting, Supervision, review of CRF, attending initiation meeting, CRA interactions-Ken Getz

Sponsor-Site Relationships

Sponsor site relationshipsLess friendly; no longer personal relationshipsNow computer data-base drivenCross-indemnification clauses

CROs/CRAs:More use of CROs rather than in-house teamHigh turnover in CRAs

Costly for site to train CRAsInconsistency in CRFs, etc.

Sponsor site relationshipsNew clinical trials starts—has 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

Decline in # PIsNew 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 ptsHIPAA, insurance restrictions, incl-excl criteria

Liability issues

Decline in # PIsFinancial 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

Problems with Recruitment, Retention:

Incr competition for ptsIncl-Excl criteria are more complex and rigid=>Ave eligibility criteria have increased by 58%*More screening

Expectation of <1 pt/moSmaller 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

RetentionIncr complexity and # of procedures6.5% annual growth in # unique procedures per protocol8.7% annual growth in the frequency of the protocol activities

(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.

Less publicized impediments: CRF size; e-crfs (with dedicated computer/line) HIPAA Staffing at hospitals declining and rapid turnover of staff =>

inability to do trials without errors; no longer a dedicated unit for trials

Utilization ReviewRevolving doorInsurance denials of stay/investigative Rx

Standard order setse.g. Pneumonia—call Dr. Stone re drug study was not an

option

Contract Issues

Contract Issues

Grant payment schedulesBack-loaded favored by sponsorFront-loaded advantageous for site

Contract Issues--Tips

Start-up $ when contract is finalizedrather than enrollment of 1st pt

Grant broken down by patient andInsist that payments include a remittance advice, or detailed breakdown of what the funds are for, to avoid a bookkeeping nightmare.

Contract Issues--Tips

Be wary of milestones like payment after every 5th ptmight end up floating a loan to sponsorif enrollment is slow

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

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

Contract Issues--Warnings

Publication clauses Patent and Inventions Cross-indemnification clauses

insist on receiving a draft contract prior to investing a lot of time in the protocol.

Insuranceindemnification 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

Conflict of Interest

Conflict of InterestIOM definition: “…creates a risk that professional judgment or

actions regarding a primary interest will be unduly influenced by a secondary interest.”

Conflict of Interest-History1980s 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

Conflict of Interest-HistoryNIH 1995, Dr. Harold Varmus rescinded policies prohibiting

investigators from accepting consulting fees or stock from industry/sponsorsAnnual 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

Conflict of Interest-HistoryTo what degree should financial interests by investigators be

disclosed to prospective research participants?

Conflict of Interest-History5 percent of volunteers said they would not participate because of

an investigator’s equity interestvsinvestment as a plus, feeling the PI would work harder or believed

more strongly in the potential benefit of the intervention.

Conflict of Interest-PhysicianPressure re enrolling their own patients--trust, coercion

Pressure to enroll borderline patients:financial, for overhead and salary expenses(bonuses for goals)site’s prospects for future trials

prestige, coauthorship on publicationsrank and tenure

Conflict of Interest-PhysicianDoes participation in trial influence:

hospital’s formulary decisions?

alter a physician’s prescribing patterns?

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

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.

Pt-Prompted Ethical IssuesOccur when:the PI is also the patient’s 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…

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.

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 patient’s/subject’s decisions.

Conflict of Interest: IRBsCommercial IRBs are paid directly by the drug company sponsor

Presumably, they don’t 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.

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.”

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

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

So, Why Do Studies?Basic physiologic Income

and safety needs

need for love, sense of membership

belonging

need for esteem publication and recognition

intellectual challenge

higher needs of self-actualization

and transcendence altruism, wanting to develop a

medicine or device that will help others

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

Thank you!

Questions?

jstone@conductingclinicalresearch.com