Managing Risk in Clinical Research. Dr Martha J Wrigley R&D Manager Senior Visiting Fellow University of Surrey

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1 Managing Risk in Clinical Research Dr Martha J Wrigley R&D Manager Senior Visiting Fellow University of Surrey

2 Aim of the session To explore the risks associated with clinical research and understand how these are mitigated Provide an opportunity for discussion and debate concerning how risk for clinical research is identified and accessed Key Objective Link the research assessment to the NHS Litigation Authority (NHSLA)

3 World Health Organization Definition for Clinical Research A clinical trial is any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. Interventions include but are not restricted to drugs, cells and other biological products, surgical procedures, radiological procedures, devices, behavioural treatments, process-of-care changes, preventive care, etc. (

4 What do you think are the risks associated with conducting clinical research? And how could these risks be addressed?

5 NHS Litigation Authority The NHS Litigation Authority (NHSLA) is a Special Health Authority that was set up in The NHSLA handles negligence claims made against NHS organisations and works to improve risk management practices in the NHS.

6 Why have the standards been developed? improve the safety of patients, staff and others; provide a framework within which to focus risk management activities in order to support the delivery of quality improvements in patient care, organisational governance, and the safety of patients assist in the identification of risk contribute to embedding risk management into the organisation s culture (ref: NHSLA Risk Management Standards Version 2 July 2012)

7 NHS Litigation Authority OVERVIEW OF RISK AREAS

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9 Why we need standards for research Safeguard and protect research participants Risk reduction Quality data Excellent research Good science Trustworthy findings

10 Central philosophy: Protection of the rights, safety and well-being of our patients and participants

11 Standard 1 Governance Risk Management Strategy Policy on Procedural Documents Risk Management Committee Risk Register Dealing with external recommendations

12 Governance Three tiers of approval for research: Medicines and Health Care products Regulatory Agency (MHRA) Independent ethics review Trust review (R&D approval / NHS Permission)

13 MHRA Established in 2003, bringing together the medicines Control Agency and the Medical Devices Agency The UK competent authority responsible for the regulation of medicines, including the regulation of clinical trials, and devices and equipment used in healthcare

14 National Research Ethics Service (NRES) Studies submitted to the UK Integrated Research Application System (IRAS) An independent body of medical and lay members The rights, safety and well-being of the trial subject are the most important consideration and should prevail over interests of science and safety Health Research Authority newly established Dec Coordination and streamlining ethics processes.

15 R&D Departments Research Governance Framework Issued by the Department of Health in April 2001 to provide a framework from which health and social care organisations can host and support safe, high quality research. Implemented by 2004, R&D Departments established Identifies responsibilities to be adopted by NHS organisations hosting the research Must be adhered to for all trials conducted within the NHS in England

16 Standard 2 Learning from experience Clinical Audit Incident Reporting Concerns and Complaints Investigations Being open

17 Nuremberg Trials The Doctors Trial considered the fate of twenty-three German physicians who either participated in the Nazi program to euthanize persons deemed "unworthy of life" (the mentally ill, mentally retarded, or physically disabled) or who conducted experiments on concentration camp prisoners without their consent. The Doctors Trial lasted 140 days. Eighty-five witnesses testified and almost 1,500 documents were introduced. Sixteen of the doctors charged were found guilty. Seven were executed.

18 Nuremberg Code 1947 Voluntary consent Results for the good of society, unprocurable by other means Avoid unnecessary suffering Based on scientific principles Conducted by scientifically qualified persons Interests of subject prevail over those of science and society Adequate information about risks and benefits Subjects are free to withdrawn Written informed consent obtained

19 Declaration of Helsinki (1964) Forms the ethical basis for all clinical research involving human subjects The guiding principle is that the physician must safeguard the health of their people

20 Why the need? Prior to 2004 the standards were guidelines and dual standards existed for pharmaceutical companies working to ICH GCP and academic institutions and the NHS working to MRC and GCP standards After 2004 ethical and scientific standards for the set-up and conduct of clinical research involving human subjects receiving medical products, became subject to the law

21 UK Regulations for Clinical Research Set of interwoven laws, guidelines and frameworks which govern UK clinical research Research Governance Framework The EU Directives and Statutory Instruments (GCP) ICH GCP Medicines for Human Use (Clinical Trials) Act 2006 The Mental Capacity Act (2005) Human Tissue Act (2004)

22 Learning from experience - Thalidomide First developed as an anticonvulsant drug. Had sedative properties, overdose simply caused prolonged sleep. Mid 1950s no guidelines for the development, production and marketing of medicinal products First marketed in Germany in 1957 as Contergral, in the UK in 1958 as Distaval Between 1958 and 1961 it was used by expectant mothers to control morning sickness

23 Learning from experience - Thalidomide Tragically many babies were born often with severe physical disabilities Estimated that 10,000 people worldwide were affected 1965 the first European Community Directive (65/65/EEC) was issued, in order to prevent a recurrence of this disaster which shook the health authorities and general public No medicinal product was ever to be marketed again without prior authorisation Medicines Act 1968

24 Standard 3 Competent and Capable Workforce Induction Risk management training Risk awareness training Supporting staff involved in an incident

25 Good Clinical Practice (GCP) is an international ethical & scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects 14 principles Legal requirement that everyone involved in clinical research has GCP training Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki and that the clinical trial data are credible

26 Responsibilities Clear delineation of responsibility: Sponsor Initiation, management and financing Initiation, management and financing, quality assurance, trial design, data, insurance or indemnity, safety reporting Chief Investigator One per member state. Ethics application Principal Investigator At individual sites Delegation of duties, safety reporting Sub-investigator Delegated responsibilities by the PI

27 Induction and Training Training logs CVs GCP certificates Set-up meetings Confidentiality Agreements Financial Disclosures

28 Delegation of duties Only perform activities in a clinical study which are delegated to them Identifies the individuals who have been delegated by the Principal Investigator, to carry out specific duties Competent and qualified Individuals are informed of their involvement and their required duties Delegation log signed by the Principal Investigator

29 Standard 4 Safe Environment Secure environment The deteriorating patient

30 Phases of drug development Phase 1: Usually paid volunteers Often healthy people, but can be patients Small numbers of participants Specialist units or hospitals Short term follow-up Intensive investigations

31 Phases of drug development Phase 2: Small numbers of patients Mainly in hospitals or specialised units Aim is to evaluate the dose and regimen for further studies Looking at the application of the drug Follow-up usually weeks may be months

32 Phases of drug development Phase 3: Evaluating new treatments in terms of use and safety Large numbers of patients 100s and 1,000s Patient group will have multiple problems Multi-centred Follow up usually 12 months or more Results should change or challenge practice

33 Phases of drug development Phase 4: Product has how been licensed by the regulatory authorities Continued monitoring and safety evaluation Extension of product license Usually long term

34 Key features of a clinical trial EudraCT (European Union Drug Regulating Authorities Clinical Trials)EU database for all clinical trials Study protocol Design of the study States, in detail, how the study is to be conducted Central research question defines the population Inclusion and exclusion criteria Reporting and reviewing procedures Safety monitoring committee

35 Safety Reporting Pharmacovigilance Continuous process of monitoring, evaluating and improving the safety of investigational medical products Adverse events Untoward medical occurrence Adverse reactions Untoward or unexpected adverse reaction Serious adverse events Resulting in, death, life threatening, hospitalisation, prolonged hospitalisation, disability or incapacity, congenital adnormality, other Serious unexpected adverse reaction Not listed in the investigational brochure

36 SAE Reporting Investigators responsibility to report all serious adverse events to sponsor and host organisation Sponsor responsible for ongoing evaluation Report immediately upon knowledge of event Not need to report non-serious and serious reactions identified in the protocol Ongoing safety issues still reported after study termination

37 Standard 5 Acute, Community and Non-NHS Providers Patient Information Consent Maintenance of equipment Record keeping Medicines management

38 Essential documents Study protocol amendments Investigator brochure Patient information sheet (version control) Consent form Regulatory applications, responses and approvals Delegation log Training log Correspondence Safety reporting

39 Patient Information Patient Information Sheet (PIS) Outlines all the details of the study Identifies potential hazards Contact details Can be 6 to 12 pages in length (!) Amendments Ensuring all information is shared with patients (rats!) Changes made to protocol - consent renewed (eg additional blood pressure readings) Version Control MHRA finding

40 Informed Consent A statutory requirement for clinical research Given freely May be in writing or orally in the presence of a witness Recorded - date and signature by authorised personnel The Mental Capacity Act 2005 states that every adult has the right to make his or her decisions, and must be assumed to have capacity to do so unless it is proved otherwise

41 Informed Consent Patients must have given informed consent to be included in a study No study procedures can take place until consent is obtained aims and methods of the study potential hazards know that involvement is voluntary can withdraw at any time information sheet

42 Source Data / Documentation All data collected for the study is verified in the source data medical notes Source data verification Double entry Case report form and the medical notes Investigations are reviewed and signed by a doctor eg blood tests, ECGs Archiving requirements If it is written down it didn t happen!

43 Medicines Management Standard Operating Procedures (SOPs) completed by pharmacy for every study Separate pharmacy file Prescribed via central system Checked against study ID and randomisation number Accountability log for all medications Returns carefully calculated

44 Safety Monitoring Internal checks External monitoring Data queries Source data verification Compliance checks

45 Food for thought 57,000 NHS litigation claims 6 claims associated with clinical research 2 claims successful Oncology studies (very complicated) Mistake regarding dosage calculation Cost less than ¼ million Conclusion: problem in the conduct of the study not the design (Reference: CLRN Conference 12 th March 2012)

46 Thank you!