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Patient recruitment and retention plan:global strategies

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Map of All Studies in ClinicalTrials.gov

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Global Clinical Development The Golden Rules

• Whatever timeline you have planned– IT WILL TAKE LONGER

• Whatever delays you anticipate– THERE WILL BE MORE

• Whatever you have budgeted– IT WILL COST MORE

• However much you know US Trials– THE REST OF THE WORLD IS NOT THE US

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Optimistic Accrual Goals: You Can’t Change the Facts

• Oncology Trials– 2006, 679 trials in all phases for lung, breast and prostate would need 238,000 patients – corresponds to 50% of all cancer incidence

– However, current participation rates in trials are roughly 3-5% NOT 50%

• Currently there are >5,000 oncology clinical trials, >3,000 CNS trials, > 2000 infectious disease trials*.– >600 breast cancer trials– >800 lymphoma trials– >400 NSCLC trials– 300 brain cancer trials– 170 mantle cell lymphoma trials* Based on trials posted on clinicaltrials.gov as of 3/2007

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Current Landscape and Timelines

• % of trials that DON’T meet planned timeline– Phase I: 42%

– Phase II: 31%

– Phase III: 30%

• % of trials with > 1 month enrollment delay– 2001: 57%

– 2005: 70%

• Number of trials has increased 250% in the last 15 years

• Number of patients and investigators has not kept up

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So How Do You Know Where To Go?

• Formal feasibility and site assessment is critical for correct selection of regions/countries/sites

• Key is up-front planning and a detailed questionnaire

• Ask the right questions– A poorly designed tool will lead to useless data– Anticipate potential issues and collect additional data in case of study design changes

– Not just about medical issues – ethical and cultural issues

– Ask for retrospective data as an edit check for prospective data

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Planning and Expectations

• Accurate Timelines Require The RIGHT QUESTIONS UP FRONT

• Is the study as designed feasible in the planned countries?– Standard of Care, Competition, Reimbursement, Availability of prior tx?

– Ethics Issues, Comparator/Placebo, Best Supportive Care

• Country Selection IS THE SECRET!– Public healthcare systems, Developing Countries

• Increase Accrual 2X-10X and decrease timelines

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Pre-planning vs. the Rescue

• Conducting a true feasibility prior to finalizing a study design and development timeline may take 6-8 weeks up-front

• However, waiting until a study is not accruing as planned and trying to add sites mid-stream will take significantly longer

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Feasibility Data Results…Expectations…and Reality

• Therapeutic indication, name recognition, drug class, patient/physician need, result in 20-40% return rate on questionnaires sent – thus 3-4x the number of questionnaires sent

– 300 questionnaires = 100 responses = 30-40 actual sites

• Global feasibility will take 6-8 weeks in total.

• While standard-of-care data, medical data, regulatory and ethical data is relatively accurate, self reported accrual rates are not.

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Feasibility Data Results…Expectations…and Reality

• Typically self-reported accrual rates are inflated by at least 50% in the US – lower ex-US

• Ideally data is cross-referenced with registry data

• Feasibility results need to be analyzed in conjunction with other data points – literature, prior history, experience, etc.

• Trial timelines and assumptions cannot be based solely on feasibility results.

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What Does All This Mean?

• Decline in NA and WEU accrual has resulted in delayed development timelines and increased costs for drug development globally

– Average development time is 9-12 years with 50% of that in Phase II/III

– Average cost is $800M USD

• Lack of understanding by sponsors has resulted in unrealistic expectations of accrual in the US and WEU and ultimately unhappy sponsors, delayed development and budget overages

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So What’s the Solution?

• Access sites and patients in regions outside US and WEU

– Eastern Europe (Russia, Ukraine, Poland, Romania, Bulgaria, Slovakia, Czech Republic, Hungary)

– Latin America (Brazil, Argentina, Chile, Mexico, Peru, Colombia, Costa Rica)

– Asia (China, Taiwan, Hong Kong, Korea, Thailand, Singapore)

– India

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India

• Of all the new regions in the world – India has the greatest potential for rapid accrual, high quality data at a substantially lower cost

• India has 500,000 medical doctors, 162 medical colleges and 17,000 medical graduates each year

• With over 1 billion people located in major city centers – even indications that are rare in western countries can be found at reasonable accrual rates

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India

• Highly centralized system

– Major hospitals such as Tata Memorial and All India Institute have encachement areas of 50-100 million people.

– Results in patient accrual that can be 5-10x the US

• Large population base makes India a key component for many indications:

– CV, respiratory, metabolic, CNS, oncology

• Highly experienced research sites, English as the primary language, access to EDC is routine

– Sites such as Tata Memorial have been doing NIH/NCI research for over a decade with dedicated clinical trials staff.

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Latin America

• Patient accrual is generally 50-75% higher in most indications

• Investigator costs are 60-70% of those in the US/WEU

• Placebo trials as a rule are not acceptable

• To date Latin American sites have been used as a rescue strategy to save programs that have slow/low accrual

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Latin America

• Excellent for seasonal respiratory disorders (asthma, influenza), ID (HIV, TB, tropical diseases), hematology/oncology, cardiovascular, pediatrics and diabetes

• Brazil, Argentina and Chile have been conducting and publishing widely in clinical research for over a decade.

• 80% of the population is on public healthcare with limited access to therapies beyond 1st line or curative intent

• Major public hospitals are in high density areas with populations in the 10-20 million range (Sao Paulo, Buenos Aries, Santiago, Mexico City)

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Social Aspects in Latin America

Disparity ratio between rich and poor in America’s, 2000-2005

Ratio (20% richer/20% poorer)

Source: Human development report 2006, Database from World Bank (2006). World

Development indicators 2006.

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We are not the same!

PRA Intl – Latin America

North toSouth of Brazil

PeruBoliviaColombiaChileArgentina

Central America:MexicoPanamaGuatemalaCosta Rica

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Culture EUA x LA

LINEAR MULTIDISCIPLINAR

•Planning

•Timeline

•Methodic

•Detail

•Privacy

•The “hot” topic of the moment

•Punctuality is relative

•Relationship is everything

•“Talk too much, write too little”

•“Yes” – I hear you!

•“Maybe” – it is no!

•“No” – how dare have you propose something like that?

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Bioethics in Latin America

• “The systematic and profound study of the human conduct in life science and health in the light of values and moral principles” (1)

• Principle perspective (2):- autonomy - beneficence- non harm- justice

• (1) W.T. Reich: Encyclopedia of bioethics. The Free Press. New YorK, 1978, vol I, XIX

• (2) Beauchamp,T. e Childress,J. Princípios da Ética Biomédica. São Paulo. Loyola.2002

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Bioethics in USA

• “The systematic study of moral dimensions - including vision, decision and moral norms – of life science and healthcare , using a variety of ethic methodologies in multidisciplinary context” (3)

• Contractual perspective:

- Autonomy

- Individual

- Plural

- Tolerance

- Rational

- Pragmatic

• (3) W.T. Reich: Encyclopedia of bioethics. Revised edition. New York; Macmillan,1995

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Current regulatory/ethics issues

– ICF language:

- Drug access after the conclusion of the study

- Pregnancy and new born follow up

– Placebo use: need plausible justification- “risk management”

– Genetic studies: the purpose of it should be well defined and a separate Inform Consent is necessary

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Clinical trials

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Clinical trials

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It’s Not All About Accrual

• Many patients in these countries would only have limited access to many of these therapies … if any at all– Public healthcare budgets – curative intent only

• By convincing clients to take trials to these regions we are providing lifesaving access to medications for people that might otherwise have no chance for treatment or a cure

• But there are trade-offs– Getting these patients often requires long-term commitments to drug access and patient care

– HIV, oncology, chronic illnesses, long-term indemnification

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Current regulatory/ethics issueson recruitment

• “There is nothing intrinsically wrong with researchers or institutions making money. The issue is whether making money for The issue is whether making money for enrolling individuals in clinical trials is a conflict of intereenrolling individuals in clinical trials is a conflict of interest that st that requires disclosure as part of the informed consent processrequires disclosure as part of the informed consent process. At present prospective research subjects are rarely if ever told outright that their physician will be paid by the company sponsoring the research study for entering them into the study. There are some who feel that this direct financial benefit, one not widely appreciated by research subjects, represents an ethicallysuspect temptation to the investigator to transgress his or her fiduciary obligation to the patient”

Spiro HM. Mammon and medicine: The rewards of clinical trials. JAMA 1986;255:1174-1175; Shimm DS, Spece RG, Jr. Industry reimbursement for entering patients into clinical trials: Legal

and ethical issues. Annals of Internal Medicine 1991;115:148-151.

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Current regulatory/ethics issueson recruitment

“Two other financial conflicts of interest that have not been adeTwo other financial conflicts of interest that have not been adequately quately addressed are what we refer to as bountyaddressed are what we refer to as bounty--hunting fees and finder's feeshunting fees and finder's fees. We define bounty-hunting fees as large sums of money paid by pharmaceutical houses, manufacturers of medical devices, or other sponsors of research studies to clinical researchers on a per capita basis for the purpose of testing their products. Finder's fees are sums of money paid to a non-researcher (usually house officers, research nurses, other hospital personnel, or other research subjects) who identifies and/or enrolls research subjects for a specific research study. BountyBounty--hunting and hunting and finder's fees differ not only in the magnitude of the monetary efinder's fees differ not only in the magnitude of the monetary enticement, nticement, but also in the level of responsibility of the involved parties.but also in the level of responsibility of the involved parties. BountyBounty--hunting fees involve the primary investigator, who shoulders thehunting fees involve the primary investigator, who shoulders the ultimate ultimate responsibility for the conduct of the research and the procuremeresponsibility for the conduct of the research and the procurement of nt of informed consentinformed consent”

Levinsky NG. Nonfinancial conflicts of interest in research. NEJM2002;347:759-761.

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Current regulatory/ethics issueson recruitment

“ What is important ethically is that individuals recruited to participate in research be provided with the appropriate information to make an informed choice about participation. However, we contend that some fees should not be paid at all. Thus, we offer the following recommendations:

• Under no circumstances should house officers, nurses, staff members, or other hospital personnel be offered or accept a monetary "finder's fee" or other incentives for recruiting subjects or referring them to clinical trials.

•• Researchers must disclose fully to the IRB at the time of submisResearchers must disclose fully to the IRB at the time of submission of a research protocol all sion of a research protocol all financial arrangements and other conflicts of interest and justifinancial arrangements and other conflicts of interest and justify all compensation in terms of fy all compensation in terms of the time and expertise required for the research study.the time and expertise required for the research study.

• The IRB may require the disclosure to research subjects of the financial arrangements between the researcher and sponsor as part of the informed consent process and document.

•• The IRB and individual researchers should encourage the use of bThe IRB and individual researchers should encourage the use of block payments rather than per lock payments rather than per capita payments when negotiating research contracts with sponsorcapita payments when negotiating research contracts with sponsorss.”

Lemmens T, Miller PB. The human subjects trade: Ethical and legal issues surrounding recruitment incentives. Journal of Law, Medicine, & Ethics 2003;31:398-418, p. 401

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“The management skill factor on recruitment and retention plan”

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“The management skill factor on recruitment and retention plan”

Pirâmide de Maslow

Fonte: Mussak E. Metacompetência: Uma nova visão do trabalho e da realização pessoal. São Paulo: Editora Gente, 2003. 145p.

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Strong Foundations

• Timelines should be based on – Feasibility

– Site Recruitment Months

– Appropriate assumptions for start up• Contracts, EC/MOH, Regulatory Questions, Staffing, Holidays, Scientific Meetings, Site Selection, Feasibility, Drug Manufacturing/labeling/packaging/shipping

• Vendor contracts (Central Lab, ECG/QTc, Imaging, IVRS, EDC, clinical supplies, shipping, printing, QP)

• Legal representation

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Expect the Unexpected

• Build in time cushions– Start up should be at least 6 months to all sites up and accruing

– Assume regulatory timelines will be delayed in 25% of the cases

– Understand in detail the patient population, standards of care, competition and reimbursement issues to create an accrual rate BEFORE committing to financial markets or senior management

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No Detail Too Small

• Detailed GANNT chart or tracking program is vital to the successful planning.

• Critical path items that drive where timeline delays will be caused MUST be known and identified early on!

• Guessing is not a strategy – If you don’t have experience in running a global trial, work with a CRO partner that does.

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Innovate Around the Value Chain

right

protocol

right

country

right

investigator

right

subject

right

data

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Were are we going ??

• Private clinical research as a main activity for investigators?

or

• Pure academic investigative participation?

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Thank You!

Gracias / Obrigado

schmidtcharles@praintl.comtel:+55-11 31501165

PRA Intl – Latin America