Post on 28-Mar-2015
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