Clinical Trials (General Talk)

Transcription

1 Clinical Trials (General Talk) Liz Clark, EBMT CTO London London 9 th April

2 Agenda Definitions and acronyms Clinical trial process Regulations, Ethics and Pharmacovigilance Quality Trial Coordination Further information 2

3 Definitions and Acronyms 3

4 Definitions A clinical trial = Investigation in human subjects To discover or verify the clinical, pharmacological and/or pharmacodynamic/pharmacokinetic (PD/PK) effects of one or more medicinal products To identify adverse reactions CTIMP Clinical Trial of an Investigational Medicinal Product CTIMP is a legal definition 4

5 Definitions Prospective clinical trials Investigate future events, following a clinical trial protocol. Prior ethics committee and regulatory approval are needed. For drugs without a marketing approval or for a new indication. Non-interventional prospective studies Investigate future events, following standard hospital practice (no protocol). Data collection does not interfere with the choice of treatment, sample collection, procedures, or the treatment itself. Retrospective studies Use information on past events (from the registry plus requests for new data on past events). Algorithm - 5

6 Definitions Prospective clinical trials Investigate future events, following a clinical trial protocol. Prior ethics committee and regulatory approval are needed. For drugs without a marketing approval or for a new indication. Non-interventional prospective studies Investigate future events, following standard hospital practice (no protocol). Data collection does not interfere with the choice of treatment, sample collection, procedures, or the treatment itself. Retrospective studies Use information on past events (from the registry plus requests for new data on past events). Algorithm - 6

7 Common jargon / terms Randomised: which arm depends on chance Placebo-controlled or gold standard treatment Treatment blinding: Double-blind: neither doctor nor patient know Single-blind: the patient does not know Open: everyone knows Study design: Crossover: subjects receive all arms sequentially Parallel group: different groups receive different arms Pharmacovigilance: safety reporting Investigator initiated trials (IIT) / post-marketing trials 7

8 Common Acronyms (S)AE (serious) adverse event CRA clinical research associate (monitor) CRF case report form CRO contract research organisation CSR clinical study report DSMB data safety monitoring board / committee (IDMC) IB Investigator s Brochure ICF information and consent form / patient information leaflet (PIL) IEC independent ethics committee / IRB institutional review board IMP investigational medicinal product GCP good clinical practice (GLP, GMP, GxP) SMO site management organisation TMF trial master file (essential documents) 8

9 The Drug Development Process License approved 9

10 Trial Phases Phase Aim Subjects Preclinical In vivo and in vitro tests to determine toxicity profile and effective doses of an NME 0 Initial PK micro-doses (radiolabeled) select drug candidates Reduced data package needed for regulatory No safety or tolerability 1 Safety and tolerability (pharmacology) Dose range selection (FTIM, SAD, MAD) Identify side effects 2 Effectiveness (exploratory) Dose response Safety 3 Effectiveness (confirmatory) Compare to common treatments Safety and side effects 4 Post-marketing surveillance Effectiveness and safety in general population Optimising treatment protocols N/A healthy volunteers (not oncology = patients) patients 100s-1000s patients <100 patients 10

11 Clinical Trial Process 11

12 So what s involved in a clinical trial? 12

13 The Clinical Trial Process Turn the idea into a research question discuss ideas review the literature Design the study and develop methods statistics guidelines Write the proposal Peer review internal & external Funding Obtain approvals Senior management Competent Authority Ethics Committee Research Governance Archive documents Publish data Analyse data Collect data Review lessons learnt Presentations Manuscripts Guidelines Results reporting Statistics Impact on clinical practice Recruit patients Monitoring and data cleaning Pharmacovigilance Data protection 13

14 a useful guide 14

15 Regulations, Ethics and Pharmacovigilance 15

16 EU Regulations EU directives Transposed into country laws (differences, complex) Data protection laws Listing of clinical trials and reports Clinicaltrials.gov and clinicaltrialsregister.eu 16

17 The UK Clinical Trials Regulations EC GCP Directive (2005/28/EC) Also Phase 1 accreditation scheme Source: UK Clinical Trials Toolkit 17

18 This is what needs to be done in the UK Similar lengthy processes are needed for each country Significant costs per country In the UK, also EC and R&D approvals Source: UK Clinical Trials Toolkit

19 EU Regulation - the future The EU Directives will be superseded by an EU Regulation in 2016 This will streamline the approval process (between countries and CA/EC), reducing costs and time No transposition into country laws, faster review times Low interventional trials to be introduced Note that the MHRA already has a notification scheme for Type A trials: related to the licensed indication and dose or they involve off-label use that is established practice and supported by sufficient published evidence and/or guidelines Reduced data package and notification only (14 days can go ahead) Still need EC approval 19

20 Regulatory/Competent authorities EMA European Medicines Authority MHRA UK ANSM France BfArM/PEI Germany... FDA Food and Drug Administration (US) 20

21 Research Ethics Committees All CT must be approved by a REC Protocol, IB, ICF, emergency contact card, adverts, CV, insurance In the UK, submission is done via IRAS Main REC reviews favourable opinion? Site Specific Assessment also required SUSARs and Annual Progress Report 21

22 Pharmacovigilance Drug safety collection related to risk/benefit and prior knowledge Immediate reporting of SAEs to the sponsor (24h) Expectedness assessment by Sponsor SUSAR reporting to CA, EC and Investigators 7 days for fatal or life threatening 15 days for other SUSARs Longer trials may need an IDMC/DSMB Annual DSUR with line listings of safety data 22

23 Quality 23

24 How to ensure quality? Quality is a systems property that must be built into an enterprise and cannot be achieved by oversight or monitoring alone FDA monitoring guidance document (2011) You need: Well designed protocol & CRF Include safety monitoring plan table (mitigation) Site training (TC, webcasts, e-learning) Real-time central monitoring Ideally Quality Manager (& good document management system) 24

25 How to ensure quality? SOPs standard operating procedures QC quality control QA quality assurance (auditing) Monitoring to ensure : The rights and well being of the patient Data quality through source document verification (SDV) Trial conduct is in line with protocol and regs Auditing sites, documents, procedures 25

26 Trial Coordination 26

27 What does a CTC do? Job description: To manage and co-ordinate all aspects of clinical studies on behalf of the Sponsor: ensuring that all procedures are performed in line with the protocol and global regulatory standards and that financial and timeline targets are met. Qualified to degree level (science) and experience of managing trials. 27

28 The CTC key relationships CTMS / IT Chief Investigator / Writing Committee Sites DSMB CTC EC/CA Statistician Pharma co Monitors Hold regular trial meetings and ensure information flows 28

29 What does trial coordination involve? Coordination of trial team during: Trial set-up Recruitment Maintenance / Follow-up Close-out and reporting Data management Trial Master File Management of budget Risk management GCP, EU clinical trials directive, SOPs 29

30 Trial set-up Trial feasibility and costing Point of contact for Sponsor/Investigator Contracts Ethics Committee and Regulatory submission Writing or reviewing the ICF Review/design protocol, CRF, other documents Management of third parties (CRO, consultants) costs, contracts, timelines Develops timeline and milestones Insurance 30

31 Initiation / recruitment phase Site initiation visit (SIV or TC) Ensure enough drug is delivered on time, after approvals in place Patient randomisations Internal and external meetings (minutes) Liaise with centres Monitoring visits Data Management 31

32 Maintenance phase/ Follow-up Patient visits Data management Audits Protocol amendments Manage changes to CRF, ICF, contract etc File notes Protocol deviations Monitoring visits 32

33 Close out and reporting Close out visits Audits Preparing files for statistical analysis Coordination of review of: Tables, figures and listings Manuscript / Clinical Study Report End of trial notifications (ethics, regulatory) Results posting 33

34 Data Management From trial feasibility to clinical study report Coordination of review of: CRF, CRF completion guidelines Data Management Plan, Edit Check Plan Statistical Analysis Plan CRF collection and Data Queries Tables, figures and listings Manuscript / Clinical Study Report Regular meetings Audits 34

35 Data Management Process Forms entered by data manager (or site) Publication Statistical analysis CTMS Data cleaning (automatic and manual queries) Database lock Queries to sites and corrections Interim analysis 35

36 Filing Trial Master File (TMF) This is kept by the Sponsor or CRO All essential documents Need to document the whole trial If it s not written down, it didn t happen! Kept for 5-15 years Investigator Site File (ISF) All essential documents according to GCP 36

37 Essential Documents Before the study: IB, protocol and amendments, ICF, adverts, written info to subjects Contract, insurance, CVs, laboratory normal ranges and certification Ethics Committee and Regulatory Authority approval, local approvals IMP example labels, IMP instructions, shipping records, certificates of analysis, randomisation code, initiation report During the study Updates to any of the above documents Monitoring visit follow-up letters Signed ICFs and source documents (at site), completed CRFs, screening and enrolment log, delegation of authority log Dose escalation documentation, IMP accountability SAEs, notification of SUSARs to RA and EC, safety updates After the study IMP accountability (destruction/return), audit certificates, end of trial notification to EC and regulatory, final clinical study report (if applicable). 37

38 Further Information 38

39 Useful links Institute for Clinical Research CTA manual useful descriptions and acronyms goo.gl/mshpc ICH EMA ABPI MHRA NIHR CTN NIHR Clinical Trials Toolkit KHP clinical trials office The Compliance Healthcheck 39

40 Useful publications Invaluable ( 45) And Canary Books GCP, Regulations 40

41 Any questions? / Meet the Team! liz.clark@ebmt.org Liz Clark CTOM CTOM = Clinical Trials Operations Manager CTC = Clinical Trials Coordinator DM = Data Manager IT = IT manager Ruzena Uddin CTC Janette Zarev CTC Fernando Bautista IT Alain Barrois CTC Marleen van Os CTC Menno van den Bosch DM London Leiden 41

42 Back-up Slides 42

43 EBMT Recent Trial publications Trial Chief Investigator Publications RATGAA07 J Marsh Blood 2012 VOD-DF S Corbacioglu Lancet 2012 MMVAR L Garderet CLL M Michallet Blood 2011 Flagship AA A Tichelli Blood 2011 JCO 2012 (+ editorial) EBMT 2011, ASH 2010, 2011 IMW 2011 Lym-1 R Pettengell JCO 2013 (+ editorial) ASTIC ASTIS Chris Hawkey D Farge / J van Laar EBMT 2012, DDW 2012, UEGW 2012 Manuscript in preparation EBMT 2012, ACR Nov 2012, ASH Dec 2012 Manuscript in preparation 43

44 7 Golden Rules for Clinical Trials 1. Ensure that the protocol is complete, clear and correct (avoid amendments) 2. Be clear in the questions that will be answered by the trial and design the CRF well 3. Ensure that all inclusion and exclusion criteria are warranted 4. Choose your centres wisely 5. Have contingency plans for poor recruitment (back up centres/countries, advertising). 6. Ensure that you plan the budget fully 7. Have systems for safety, monitoring and quality management to protect the rights, safety and well-being of subjects, and to ensure that the data generated are reliable and robust 44

45 Good Clinical Practice 45

46 What is ICH-GCP? Good Clinical Practice (GCP) is a standard for: the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that ensures that: the rights, integrity and confidentiality of trial subjects are protected the data and reported results are credible and accurate 46

47 Why is GCP important? Nazi war crimes / Nuremburg Trials Despite German Medicine Regulations Tuskegee Trial, Alabama, USA In 1932, recruited 399 impoverished African-American farmers with syphilis By 1947, penicillin had become the standard treatment for syphilis However, the trial continued until 1972, when a leak to the press resulted in its termination Victims included numerous men who died of syphilis, partners contracted the disease, and children born with congenital syphilis 47

48 GCP Good Clinical Practice, Ethical studies (Declaration of Helsinki, regulations) 2. Risk-benefit must be acceptable 3. Rights, safety and well-being of subjects are paramount and prevail over science and society 4. Data should support the study (pre-clinical, clinical) 5. Protocol needed must be scientifically sound 6. Prior ethics committee approval of protocol 7. Qualified doctor (or dentist) is responsible for treatment and decisions 8. Staff must be adequately trained and qualified 9. Freely given informed consent before participation 10. Data should be properly recorded, handled and stored (5 years) 11. Confidentiality and privacy should be maintained 12. Drugs should be manufactured according to GMP and follow the protocol 13. Quality procedures should be applied throughout the trial process 48

49 Informed consent process ICH GCP states freely given informed consent must be obtained from every subject prior to trial participation. During informed consent Patients must be given sufficient information and ample time to decide whether or not they want to take part. Use the Patient Information Leaflet (PIL) approved by the EC All questions must be answered to the satisfaction of the potential research subject or patient. Documentation PIL signed by the patient or representative and Investigator Investigator must sign after the patient Also note discussion in patient notes Give copy to patient and file in ISF 49

50 Governance CT2 - EBMT CT2-EBMT objectives Advise the Board to enable it to deliver trials that are: Relevant and feasible Advise CTO so it can better manage the CTs Remit: All EBMT sponsored prospective clinical trials All EBMT labelled trials Non-interventional studies are outside remit 50

51 CT2 Operational structure Science Statistics Board CT2- proposal WP chair Finance/Legal Operations 51

52 CT2-EBMT members Scientific Advice Hermann Einsele (chair), Franco Locatelli (vice chair), Per Ljungman, Jan Cornelissen Appointed by the board (3y + 1y) Legal and Financial Advice Andreu Gusi By position Clinical Trial Operations Advice Liz Clark By position Statistical Advice Ariane Boumendil By position Accountable to the EBMT board Meet at least once per year (face to face at annual Congress) TC as required 52

53 Contracts and costs 53

54 Clinical Trial Agreements Complex blend of business, law and regulations Requires negotiation and time Roles and responsibilities (table is best) Sponsor, CRO, centre, pharma, other organisations Oversight is vital as although delegated, responsibilities remain the sponsor s Publication and Intellectual Property Confidentiality Indemnification and insurance NHS templates (Industry/non-commercial) Also costing templates 54

55 Roles and Responsibilities Task Sponsor CRO Pharma co Centres Sponsor X Contracts X (x) x X Insurance X (x) x Trial Master File X (x) x Patient recruitment X SAE reporting X (x) X Monitoring X (x) Data management X (x) x Quality X (x) x Statistical analysis X (x) Publication X x X 55

56 Clinical Trial Costs?? $$$ Item Investigator payments (per patient), most hospitals include an overhead. Pharmacy may be extra. Phase 1 unit costs Volunteer fees Ethics Committee and Regulatory Submissions Cost 2,000-5,000 (Phase 2-3) 2-300,000 (for volunteers) 3000 per volunteer (for 2 week stay) 5,000 per country (fees) Insurance 10,000 per country (Phase 2-3), Phase 1 depends on risk (set rules for cover now) Monitoring and auditing Staff costs 25-50,000 (depends on number of patients and centres) Trial manager, Project Manager, Medic A typical Phase 1 trial will cost 3-500,000 A typical Phase 2 trial will cost million A typical Phase 3 trial will cost many millions 56

57 What are the differences between academic and pharmaceutical sponsored trials? Objectives: Pharma - new drug to market / new indication Academia - improving standard treatment protocols to increase response rates Innovative ideas, not necessarily any commercial use Operational differences: size funding level of monitoring/audits no of staff - eg country managers, CRO support and payments to centres timelines - more aggressive centralised procedures (eg labs, drug supply, labelling) relationship with centres 57