Ensuring FDA Compliance of Foreign Clinical Trial Data. Kelsey Miller-Torchia

Transcription

1 Ensuring FDA Compliance of Foreign Clinical Trial Data Kelsey Miller-Torchia 1

2 Background: Globalization of Clinical Trials In 2007 over 60% of pivotal studies submitted to CDER contained data from one or more ous sites From October 2007-Septmber 2008, 6,500 foreign sites were conducting clinical trials 60% Western Europe 11% Eastern Europe 10% Asia-Pacific 8% Canada 8% Central/South America 2

3 3 Background: Use of Foreign Data to Support Marketing Applications Governed by 21 CFR , , Data will be acceptable if FDA is able to validate data Competent clinical investigators Conducted in accordance with GCPs, including independent ethics board review, approval, continuing oversight Data is applicable to the US population and medical practice U.S. Department of Health and Human Services Challenges to FDA s Ability to Monitor and Inspect Foreign Clinical Trials/

4 Background: Intrinsic Therapeutics 21 sites in Northwest Europe Austria Belgium France Germany The Netherlands Switzerland 554 patients enrolled between, Dec 2010 and October 2014

5 Overview Financial Resources SOPs/Org Chart Protocol Creation Site Selection Training Monitoring FDA/CA Inspections 5

6 Financial Resources Does it cost more to run a trial ous and is it worth it? Sometimes Sometimes Is it worth running a trial, not controlling for regulatory compliance, and jeopardizing $$ or perhaps the company? Never 6

7 Financial Resources Overall Clinical Trial Costs: The cost of conducting clinical research in Russia, Argentina, China & India is about half the cost to the US ( manpower, rental, IT & operational costs) Dr. Ken Kaitin, Tufts Center for the Study of Drug Development (2008) Germany Ireland Singapore UK US South Africa Taiwan Israel Poland Hungary Czech Republic Brazil India China Argentina Russia

8 Financial Resources: Understanding the Commitment Understand the goal of the study Commercial Marketing Reimbursement Marketing approval Would a registry be a better idea do you need to do a fullblown study? How would the study/registry stand up to FDA inspection? Budget accordingly and communicate with departments/bod/executive committee 8

9 SOPs/WIs/Documents Company/Departmental SOPs/WIs/documents Ensure that they are written with appropriate FDA guidance and understand that foreign ECs and CAs may request changes that are against guidance ICH EU GCP Directive EU Clinical Trial Directive ICF and CTAs vital that language regarding FDA is included 9

10 SOPs: Clinical Sites ONLY if sites are trained to and follow SOPs should they have them Provide templates Informed Consent Process Protocol Training Device Accountability 10

11 Organization Chart US-oUS representation CRO: managed where? Cost Communication Travel Skype Managed team dynamics and cultural sensitivities 11

12 Protocol Creation Endpoints Will they require additional approval than just EC? Patient Selection: Inclusion/Exclusion Cultural sensitivities Pregnancy HIV/AIDs Patient Privacy Follow-up Protocol Expectation realistic? 12

13 Site Selection Location, Location, Location Tier 1 countries Geographic ease If it s difficult to get to, sponsor is less likely to oversee Enrollment suffers Compliance suffers Experience Prior clinical trials With FDA/US Sponsor experience FDA disbarment list/warning letter? Any medical training in the US? Language difficulties? 13

14 Training: Sites Assume nothing May have experience in clinical trials, not per FDA guidance CGP training (for ALL study staff) Set expectations Consider including clarification of CFR in part of SQV so that sites understand what s demands Training must include CFR guidance Investigator and Coordinator responsibilities 14

15 Training: CRO Not all CROs have training modules for CFR If not trained Will not monitor per guidance ICF requirements different Control of CE-marked vs investigational device FDA may not be able to validate data 15

16 Training: Sponsor Are all ous (and US) Clinical Employees trained to CFR? External 1-2 training sessions/year Invite senior staff Develop company culture where external guidance governs company s boundaries 16

17 Monitoring Set expectations clearly and early with CMP Regulations are being followed US only? US-EU? SOPs are being used Co-monitor frequently US oversight US review monitoring reports US Internal CRA 17

18 Monitoring Investigator Site Files Define who is responsible EARLY Communication Files Source documentation Define EARLY Regularly meet with CRO and internal monitoring staff Face-to-face Investigator/coordinator meetings CRO/Sponsor mgmt 18

19 External/Independent Audits Site should prepare for local federal inspection External independent mock-inspection Identify sites most likely to be inspected US-based FDA experience Local Additional buy-in but must be managed Sponsors should conduct internal audit of all sites annually 19

20 FDA ous Site Inspections: Before Sites will be contacted by FDA shortly after clinical module is submitted Put sites on alert s from FDA often go in hospital spam if you hear from one site that FDA has contacted, send out the alarm to everyone Sites should feel prepared Sites should feel assured that the Sponsor will be partner 20

21 FDA ous Site Inspections: During Expect to be involved in day-to-day inspection management Pre-, mid-day, and end-of day meetings with site should be scheduled Sponsor should try to attend all FDA/site meetings Opportunity to control tempo of inspection Site Monitor should be available does the CRO allow them to be on hand? Do they have SOPs available? 21

22 FDA ous Site Inspection: After Sponsor may expected to complete all postinspection work 483 response Payment for room rental/extra time from site staff Training/SOP creation As a CRO/Sponsor, remember what you re protecting and in what order Site Sponsor Study CAPA site/sponsor 22

23 FDA Sponsor Inspection: Before Review FDA BIMO inspection checklist TMF/Central files reconciled Document translations ICF CTAs AEs/SAEs Review date formats ICF content 23

24 FDA Sponsor Inspection: During ous Study Staff should be represented Language Professional growth Introduction should include overview by sponsor of study scope Know the regulations and be willing to push back (gently) 24

25 FDA Sponsor Inspection: After Share with teams and sites all findings CAPA Retrain Prepare for ous federal inspections 25

26 Conclusion Governed by 21 CFR , , Data will be acceptable if FDA is able to validate data Competent clinical investigators Conducted in accordance with GCPs, including independent ethics board review, approval, continuing oversight Data is applicable to the US population and medical practice Preparation is the key 26