CRA training Balakireva Vera

1. CRA training Balakireva Vera

2. Welcome & Introductions Overview of Cromos Pharma company What a clinical trial is? Project team Feasibility process Kick off meeting Site Selection Contract Process Essential Documents Maintenance Travel and expenses Site Initiation Site Monitoring AE/SAE Site Closure Audit Training Plan

3. Welcome & Introductions • Please introduce yourself by telling us: • Your name • Where do you work • Your position • How many years in this industry • What you would like to get out of this training

4. Overview of Cromos Pharma company

5. CEO & President Overview of Cromos Pharma company Managing Director Associate Director RA QA Finance BD Clinical Operations (20) Covering Russia, Ukraine, Belarus, Finland, Bulgaria, Estonia, Hungary, Latvia, Lithuania, Project Managers (2) 3C Alliance members Senior CRAs (4) COREX (depot in Moscow) CTS (Clinical Trial Support) CRAs (9) CT Assistants (4) Logistics Manager (1) KREARA(DM & BS)

6. What a Clinical Trial is?

7. What a Clinical Trial is? Pre-Clinical Clinical Phase III Phase IV Phase I Phase II Phase 0 Registered medications Decision development in man First administration in man Administration in diseased people New drug application

8. What a Clinical Trial is? • Phase I trials – • First Exposure to Man • Healthy volunteers (20-80 pat.) • Decision about drug’s safety (tolerability, pharmacokinetics, doze ranges) • Duration 0,5 - 1 year • Phase II trials – • Subjects with specific disease area • Patients (100-200 pat.) • Clinical potential of a medical product (safety in diseased people, safety, tolerability) • Duration 1 - 2 years

9. What a Clinical Trial is? • Phase III trials – • Efficacy and Safety • Patients (hundreds-thousands) • Focus on regulatory approval issues • Duration 2 - 3 years • Phase IV trials – • Post Marketing, Post Approval • General target population (1000s) • Comparative/observational design • Market positioning • Cost evaluation

10. What a Clinical Trial is? • Clinical trial/study • Any investigation in human subjects using Investigational Medical Product (IMP) • Goals: • to discover/verify the clinical, pharmacological, other pharmacodynamics effects of IMP • to identify any adverse reactions • to ascertain safety and/or efficacy

11. What a Clinical Trial is? • Clinical trial design • Control groups • Randomization • Blinding

12. Project team

13. SPONSOR Project team Project Manager Monitor Clinical Trial Administrator Business Development Laboratory Quality Assurance DM and Statistics Regulatory Affairs Safety Drug Supplies Medical Writing

14. Project Manager Provides the overall leadership to the project team Project team • Responsible for: • Compliance • Timelines • Overall budget • Customer contact • Operational experience

15. Clinical Trial Administrator A person who supports the Clinical Project Team in carrying out their activities Project team • Responsible for: • Serves as a main assistant of • a CRA • Serves as a central coordinator of all communications/ correspondence regarding Clinical aspects of a project

16. Monitor Project team A clinical research associate ensures compliance with the clinical trial protocol, checks clinical site activities, makes on-site visits, reviews Case Report Forms (CRFs) and communicates with clinical research investigators.

17. Project team CRA – who is he? • CRA’s competencies: • Excellent verbal and written communication skills

18. Project team • CRA’s competencies: • Excellent organizational, record retention, time • management, decision making, customer service, and interpersonal skills

19. Project team • CRA’s competencies: • Good command of written and spoken English language

20. Project team • CRA’s competencies: • Focus on quality, precision, and punctual delivery of results

21. CRA’s competencies: • Willing to perform additional activities outside own area of expertise Project team

22. CRA’s tasks: • Completes study start-up activities (feasibility) • Performs clinical trial selection, initiation, monitoring and close out activities while adhering to all applicable regulatory and Standard Operating Procedures (SOPs) and Project Specific Operating Procedures • Develops and implements innovative approaches for site selection, and pre-study activities to identify and evaluate potential investigators • Completes site evaluation and reports to Project Manager as appropriate • Completes submission of documents to the Regulatory Authority, when required • Collects, reviews and tracks regulatory documents when required. • Manage and track investigator grants with study sites when required • Assists with the development of study specific monitoring plan, annotated CRFs, monitoring conventions, tracking forms, and other study related documents • Participates in study specific training • Actively participates in the preparation and coordination of investigator meetings and attends when required Project team

23. CRA’s tasks: • Reviewing regulatory requirements, collecting outstanding documents, reviewing patient screening/randomization procedures, reviewing SAE reporting requirements, and reviewing drug storage and accountability procedures. • Develops patient enrollment strategies with the project team and study sites. • Ensures proper storage, dispensation, and accountability of all Investigational Product(s) and trial-related materials. • Ensures the integrity of clinical data and appropriate follow up procedures, including source document verification and SAE reporting in accordance with the project plan. • Completes in-house monitoring activities as appropriate, such as updating in-house site files, and completing visit reports. • Maintains tracking records for assigned sites such as tracking of status and source document review per patient. Project team

24. CRA’s tasks: • Conducts and assists with Project specific administrative activities as a member of the project team. • Provides study site evaluation through consultation with senior staff and if appropriate ensure site registration in investigator database. • Responsible for representation of Cromos Pharma in a professional manner. • Continues to increases knowledge of drug development process, therapeutic areas, Good Clinical Practices, and any applicable local regulatory requirements. • If appropriate, maintains home-office set-up to include computer, fax/copier printer, appropriate filing system, adequate telephone lines, and voice mail system when applicable. • If appropriate, maintain appropriate lines of communication and use of mail and delivery services if applicable • Accurately completes Cromos Pharma administrative activities in a timely manner Project team

25. Feasibility process

26. Feasibility: A determination that a process, design, procedure, or plan can be successfully accomplished in the required time frame Feasibility study: An investigation which attempts to clearly establish whether a project will be successful and achieve its expected results (is it possible to meet the requirement targets with the number of sites/countries suggested by Sponsor). Feasibility process

27. Why do we conduct feasibility assessments? Critical part of the successful planning for any study • Determine if the trial is possible • Determine the optimum countries / site distribution strategy • Assist with project planning/contingency planning • Assist with finalizing feasible protocol designs • Assist with establishing appropriate site budgets Selling tool Improve internal knowledge Feasibility process

28. Before Feasibility Study Sponsor/client: • Is sponsor capable of performing the feasibility study? • Has sponsor conducted studies in this country before? • Does the sponsor have enough time/money? Cromos Pharma: • Have we worked with country/site before? • Are we unfamiliar with study? • Do we have enough resources? __________________________________________________ Study may not be conducted if: • We know country population/demographics • We know sites are available • We have experience with the study/indication Feasibility process

29. Feasibility process • Determining value of feasibility data • Detail of information provided to the investigators • • Timing - how close the feasibility assessment is done • compared to when the actual trial starts • • The accuracy of the answers provided by the • investigators • CRAs can help improve the quality of answers

30. Outcomes of Feasibility Study • What decisions will be made as result of contacting investigators? • Which countries will be used • Whether or not the Protocol needs to be changed • Which sites will be used Feasibility process

31. Positive feedback contributes to: • Cromos Pharma being awarded new business • Sensible country/site distribution & recruitment strategy • Ability to meet and hopefully exceed timelines • Building relationship with clients for repeat business • Constructive negative feedback: • Supports correct decision-making on country/site distribution strategy • No feasibility feedback: • Country not chosen/selected, no new business for that country • Feasibility and SSV are key to the trial success especially when Cromos Pharma is responsible for selecting sites Feasibility process

32. CRA responsibilities in Feasibility Studies: Ensure you understand the purpose of the feasibility study and the protocol Send out and obtain Confidentiality Agreements signed by investigators Send out the feasibility questionnaire/protocol synopsis to the investigators Discuss the prospective study requirements with investigators & ensure investigators understand the study design Obtain realistic enrolment estimates, screening failure rates & withdrawal rates from investigators Follow up regularly with investigators (via phone/fax/email) Feasibility process

33. Review completed feasibility questionnaires for completeness Provide regular status updates to assigned Sponsor’s representative Email the completed Feasibility Responses spreadsheet to assigned Sponsor’s representative within specified deadline Summarize recommendation about whether trial is feasible in that particular country and/or any key issues to consider Follow up with a thank you letter/email/fax (or as appropriate) to investigators Inform investigators of outcome of feasibility using template follow-up letters Feasibility process

34. What could potentially occur if investigators misunderstand the study design? • Incorrect decisions made on feasibility of country/site • potential study delays in getting protocol approved • affects Cromos Pharma integrity • What could potentially occur if investigators overestimate numbers of patients they can recruit and underestimate screening failure/withdrawal rates? • Incorrect decisions made on country/site distribution strategy & recruitment strategy • timelines not met • potentially affects new business with same client Feasibility process

35. How can you help drive the feasibility process? • Ensure you understand purpose of the feasibility • Speak to the investigators • Ensure they understand the study design & the purpose of the feasibility • Encourage them to provide realistic enrolment rates, screening failure rates & withdrawal rates • Provide any relevant constructive negative feedback • Review the answers to the questionnaires critically before • sending the information to the assigned Sponsor’s • representative Feasibility process

36. What additional information could you provide to help drive the feasibility process? • Summary recommendation about whether you feel that country is feasible/suitable • How many suitable sites could be used in that country • Additional key information about country (incidence, treatment practices, study design likely to be approved/accepted, etc.) • Additional key information about investigator/site (Opinion Leader (OL), very experienced, problems with site, etc.) Feasibility process

37. Next steps after Feasibility Studies: • 'Hand-over' process from CRA, who performed feasibility to PM assigned to the study • Each CRA assigned to initiate sites/monitor sites should ask the PM for relevant feasibility information • CRAs assigned to conduct selection/monitoring visits may be different from CRAs assigned to do the feasibility assessment Feasibility process

38. Kick off meeting

39. Customer sends Request for Proposal (RFP) to Cromos Pharma Kick off meeting • BD meet to review relevant information • Review proposal and scope of work requested by customer • Develop strategic approach to the opportunity • Identify missing information/questions for customer • Determine input needed from functional areas Proposal Development

40. Sign off by the Managing Director Kick off meeting Submission of Proposal and Budget to Customer Defense Meeting with Customer End Project awarded Kick off meeting

41. Internal kick off meeting • To ensure that everyone understand and will be running the project in the same way • Update Cromos Pharma project team members on study-specific details: • Study focus and design • Start up timelines • Enrollment timelines • Project deliverables and owners • To address potential issues before the project starts • To promote relationship building within the Cromos Pharma project team Kick off meeting

42. External kick off meeting* • To discuss with Sponsor key points of study and processes • To also discuss questions related to Vendors that may attend this meeting (Central laboratory, Electronic diary vendor, etc.) • Review study timelines • Finalize needed processes(the flow of SAE reports, sponsor-required timelines for study progress updates, etc.) • Serves to promote relationship building between Cromos Pharma and the Sponsor • ______ • * optional Kick off meeting

43. Site Selection

44. Site Selection • The investigator selection process consists of several steps: • Developing List of potential Investigators • Identifying investigators • Contacting potential Investigators • Conducting Site Selection Visit

45. Site Selection • List of potential Investigators • Sponsor provided investigator lists • Investigators that Cromos Pharma has worked with in the past • Recommendations from CRAs • Recommendations from PM • Feasibility results • Websites, societies, other external sources

46. Site Selection • Identifying Sites and Investigators • Who is being targeted? • Target more investigators than needed (2 x number of sites needed) • Not every site that is sent a Confidentiality Agreement will complete and return it • Not every site that sends a Confidentiality Agreement will sign the Contract • Not every site that signs the Contract will be recruit the patients

47. Site Selection • Contacting potential Investigators • Obtain Confidentiality Agreement • Fax/mail study information

48. Site Selection Conducting Site Selection Visit Definition: The site visit that verifies the suitability of an investigator, the site and staff for the duties and responsibilities required to conduct a clinical study. Which documents/sources should be reviewed prior to performing SSV: Protocol, Sponsor Specific Requirements, Project Management Plan, Monitoring Plan, Training recommendations, Regulatory Authority Requirements, SSV report template, all the necessary documents to take to the site (also checking all documents to be retrieved from the site)

49. Before each visit CRA should: • confirm the scheduled appointment in writing (letter, fax or e-mail) highlighting the visit agenda details and maintain documentation as per monitoring plan • follow the documentation of study specific training and routing of study specific training records • all project-related telephone communication with the site should be documented using “Telephone Contact Log” form. These forms should be kept in project file Site Selection

50. Which documents are suggested to be taken to the Site? * • Protocol, IB, CRF (if available) • Copy of agenda and confirmation letter • Names of contacts for questions • Map/Directions • SSV report template • ______________ • Confidentiality Agreement should have been signed • by the Investigator in advance Site Selection