Global Clinical Trials: Best Practices & Common Pitfalls to Avoid

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WATCH THE WEBINAR ON-DEMAND HERE: http://www.imperialcrs.com/resources/podcasts-webinars/best-practices-common-pitfalls-to-avoid-in-planning-global-clinical-trials/ 45% of clinical trials are conducted exclusively in non-U.S. countries, and only 6% are registered in both the U.S. and rest of the world. The globalization of clinical trials demands deeper knowledge and greater efficiencies in planning and execution. Melynda Geurts, Dan McDonald, and Gwen Welty of DAC Patient Recruitment Services explore actionable solutions to real-world multinational clinical trial challenges.

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Best Practices & Common Pitfalls to Avoid in Planning & Conducting Global Trials Focus on: Study Feasibility, Regulatory Considerations, Site Selection and Patient Recruitment:

Best Practices & Common Pitfalls to Avoid in Planning & Conducting Global Trials Focus on : Study Feasibility, Regulatory Considerations, Site Selection and Patient Recruitment Prepared for

Speaker Introductions:

2 Speaker Introductions As director of project operations, Gwen is responsible for identifying new business opportunities, building strategic partnerships, and managing existing client relations. A seasoned biopharmaceutical professional, she brings more than 16 years of regulatory, preclinical, clinical, and sales experience to the DAC team. Dan works from DAC’s Boston office identifying income opportunities, building strategic partnerships, and managing contract negotiations. He re-joined the team in 2013, having previously served in the area of strategic and business development under DAC’s former brand moniker, D. Anderson & Company, from 2006 to 2007. Dan has authored many articles for industry publications, is a popular presenter at industry conferences, and has conducted numerous workshops on patient recruitment for clinical trials.

Going Global: Lots of Choices:

Going Global: Lots of Choices A.T. Kearney

Critical Attributes in Country Selection:

A.T. Kearney Patient Pool (30%) Size and availability of suitable patient pool Cost Efficiency (20%) Cost efficiency of labor Cost efficiency of facilities and travel Regulatory Conditions (20%) Food and Drug Administration visibility Country’s regulatory laws Strength of intellectual protection Relevant Expertise (15%) Number of clinical research organizations Number of clinical trials Size and availability of labor force with relevant skills Infrastructure and Environment (15%) Protection of intellectual property Health-care infrastructure Country infrastructure Country risk factors Country Attractiveness Index Criteria and Weighting Critical Attributes in Country Selection

Echoes from Global Project Managers:

Echoes from Global Project Managers The local ethics c ommittee rejected my r ecruitment strategies. The regulatory agency responded w ith a single question and no d etails! Our c linical t rial materials are baking in a hot locker s omewhere inside customs. My highest-enrolling i nvestigator is d emanding the latest iPad to keep enrolling. Patients living only 10 miles away have a 2-hour drive time to the site! Sure, that country enrolled like gang- busters. Too bad the data had more holes than Swiss cheese!

Lions, Tigers & Bears ─ Oh My!:

What can go wrong, very well may!!! Unreasonable and under-vetted protocol design Poor timing of country/site activation; countries never activated Incomplete and/or inaccurate feasibility data Patient pools dry up after study start Poor communication channels with sites Cultural differences and communication gaps Lack of risk mitigation strategies Lack of customized patient recruitment plan Scope and budget creep Unmotivated or angry investigators Delays, delays, delays Sure, go ahead, leave it to chance! Lions, Tigers & Bears ─ Oh My!

Pitfall #1: Study Feasibility & Planning:

Pitfall #1: Study Feasibility & Planning Realistically evaluate protocol for availability of patients. Does the target population exist? Analyze disease prevalence & incidence. Filter site enrollment projections through local representative & data sources. Determine threat of competing studies. Cl early understand the standard of care and presentation of disease. Build in buffers for unexpected time and costs Protocol should be fully vetted globally before finalization & regulatory submissions: Complete internal review Review by outside TA consultants Full investigator review and feedback Review by local country representatives Leverage “big data” to understand prevalence Consider Socio-economic Profile : Does your protocol require subjects who have completed 3 rd line chemo-therapy , but you have sites in location’s where most patients can afford such treatment

Pitfall #2: Regulatory Submissions:

Pitfall #2: Regulatory Submissions Develop strategic regulatory plan with steps and timelines. Stagger submissions if needed to ensure all countries activate ASAP and enrollment can begin. Pre-submission due diligence discussions with regulatory agency Create a checklist and examples of required documents. Understand country-specific data acceptance policies. Major changes will cause major delays. Apply for more patients and sites than needed. Hurried submission resulting in missed requirements… Your application just went to the bottom of the pile!

Pitfall #3: Inadequate Local Analysis:

Local details are the key to global study success Options: Local Experience; Local Personnel; Local Partner Logistics: Transportation routes and access points Customs clearance, taxation, licenses, documentation Languages spoken and communication channels Religious , cultural and socio-economic considerations Familiarity with sites and PI, their experience and reputation Ethics Committee structure and approval timelines Customs clearance in countries like Brazil, India and s everal Eastern European countries require hands-on payment and r eceipt of materials by local r epresentative ! Pitfall #3: Inadequate Local Analysis

Pitfall #4: Site Feasibility:

Ensure mix of KOLs with lesser-known, competent, enthusiastic PIs Consider location in country: PI’s in Tier 2 and 3 cities often perform better Some markets justify an on-site visit and inspection Verify facilities, equipment and drug storage facilities. Consider availability of critical support resources, departments and personnel (IRB, local lab, diagnostics; etc.) Capture metrics on past performance for similar studies. Ensure no participation in competing studies. Consider catchment area of subjects around site. Determine subject referral network and process in advance. Determine sites willingness to implement certain recruitment procedures. Consider accessibility and convenience factors for subjects. Pitfall #4: Site Feasibility Re-conduct site feasibility if there is 3+ month delay from site selection to activation.

Pitfall 5: Patient Recruitment:

Critical to develop expertise in regards to the recruitment landscape Consider developing a proactive recruitment plan – Every country is unique Which recruitment materials require EC approval & approval timelines Typical utilization rates for the various recruitment strategies by sites The ways in which patients can be engaged at the investigative site Understand how patients first learn about clinical trials Identify common stakeholders in the consent decision process Which types of initiatives prove successful when supporting sites – only gained from hands on experience Engage CRAs, as they provide a critical link with the investigative site Involve local expertise and network of various groups to enhance recruitment and increase effectiveness Pitfall 5: Patient Recruitment

Pitfall #6: Investigator Relations:

Pitfall #6: Investigator Relations Proactively address investigator concerns with protocol. CTAs should be performance-driven. Consider need for local representation. Ensure fair allocation of site grant to PI. Be sensitive to regional compensation differences. In-person sponsor visits have many benefits. Consider critical site support personal availability. Determine availability of onsite CRC or through contract. Be wary of investigator leveraging and strong-arming: Establish performance incentives up front. Determine if sites are open to training. Gauge willingness of PI s to refer patients. Set aside funds for investigator recognition. Consider mid-study rejuvenation meetings. Have backup sites contracted, approved and ready. Re-conduct site feasibility if there is 3+ month delay from site selection to activation.

Metrics Support a Data-Driven Approach:

Access to Patients Predicts Success 53% of investigators were highly successful if their number of matching patients was high. High matching was defined as 6% or more of their insured patient population. 13 Metrics Support a Data-Driven Approach Experience Helps Predict Success 52 % of investigators were very successful if they conducted a high number of trials. The percentage of successful investigators was sharply lower if trial count was low/medium.

Case Study: Pitfalls Re-shape a Study:

Feasibility (graphic) Indication: Ovarian Cancer Institution Type: Public & Private Enrollment Period: 10 months Phase: III Countries: 5 incl. Brazil and India Sites: 7 in Brazil and India Patients Per Mo: +500 Est. Enrollment: 160-180 Initial feasibility based on the draft protocol was encouraging to the Sponsor. Brazil and India would carry 40% of target, reducing timeline by 3 to 4 months. The sponsor program manager planned country visits to inspect sites. Following receipt of the full protocol, several challenges became apparent: Subjects must have completed 2 nd line chemo and be platinum-resistant. Subjects required to take home study drug requiring temperature control. Subjects were to complete a specialized quality of life survey Case Study: Pitfalls Re-shape a Study

Case Study: Pitfalls Reshape a Study:

Actual Study Institution Type: Private Only Enrollment Period: 9 months Phase: III Countries: 12 Sites: 6 (Brazil, India) Patients Per Mo: 95-100 Est. Enrollment: 60-70 Requirement to maintain cold chain: Extreme high temperatures are common in both countries. Specialized temperature-controlled boxes would be supplied to subjects Patients would need to have refrigerators in their residence (or AC) Temperature loggers or visits from social workers to monitor compliance The Sponsor was unaccustomed to some sensory elements of both countries. Private centers more aesthetically appealing to Sponsor despite fewer patients. QOL questionnaire translations were both time consuming and costly. Challenges Emerge: 2 nd line chemo requirement inappropriate for some cities Large OC population Diagnosis poor Socioeconomic challenges severely limit patient pool While care at government centers is free, chemo is usually not Case Study: Pitfalls Reshape a Study

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