Practical Issues in the Planning and Conduct of Clinical Research. Study feasibility. Start up activities 9/16/2010

Transcription

1 Practical Issues in the Planning and Conduct of Clinical Research Clinical and Translational Research Boot Camp September 20, 2010 Ann J. Melvin MD, MPH Co-Director ITHS Regulatory Support and Bioethics Core Study feasibility Population Procedures Collaborations Staff Budget Resources 2 Start up activities Write a protocol Why, who and what of the study Communication tool with IRB, staff, other sites, monitoring group Basis of all other study documents Read the protocol Make sure everyone on the research team reads the protocol 3 1

2 If you are writing the protocol Make it simple, clear and easy to understand Think about the inclusion/exclusion criteria Build in appropriate flexibility Write a good data safety and monitoring plan Determine which procedures can be done by non-physician staff 4 Protocol templates SCH IRB website - s-policies/irb/other-forms/ ITHS website Study start-up activities Financial planning UW Clinical Research Budgeting and Billing Support SCH Clinical Research Support Office and_education.asp FHCRC Office of Sponsored Research 6 2

3 Study start-up activities Review committees Institutional Review Board ITHS Scientific Review Committee FHCRC Scientific Review Committee Radiation Safety Committee Institutional Biosafety Committee 7 8 Institutional Review Boards UW Human Subjects Division Biomedical Committees: A, B, D Social/Behavioral Committees: C, G, J Biomedical & Social/Behavioral Committees: V & V2 FHCRC Institutional Review Office SCH Institutional Review Board 9 3

4 Additional IRBs Western IRB (WIRB) Reviews industry sponsored clinical trials for the UW Cancer Consortium IRB (CC-IRB) Reviews cancer research from consortium members. UW Cooperative Agreements HSD policies for WIRB and other institutional cooperative agreements 10 Working with the IRB Fill out all aspects of the application form completely don t leave sections blank and include all necessary documents Use at least 10pt font and write clearly Present information clearly bulleted lists, tables, diagrams, flow charts when applicable Proof for cut and paste errors 11 What the IRB will look for Risk/benefit Are the risks minimal? Are the risks minimized? Who benefits from the research? Confidentiality Is the data confidential/anonymous Is there a plan for data maintenance, storage, sharing, destruction? Consent process Does the consent include all the required elements? Is it written in a way that subjects can understand? 12 4

5 Training requirements Human Subjects Protection Training Required by all IRBs Provided periodically by SCH IRB and FHCRC IRB Or on-line at CITI Collaborative Institutional Training Initiative 13 Training requirements Good Clinical Practice Required by some NIH consortia Required by FHCRC On-line at CITI HIPAA ipaa.html 14 Other important offices UW Office of Sponsored Programs UW Clinical Research Budget and Billing dgetbilling/ SCH Clinical Research Support Office FHCRC Clinical Trials Support Office

6 Other start-up activities Investigational Drug Service ITHS Clinical Research Center 16 Develop all study materials Regulatory Binder Case report forms Eligibility checklist Adverse event report forms Protocol deviation report forms Screening logs Training logs Standard Operating Procedures (SOPs) Are a reference and guideline as to how research will be conducted within the clinical site Identify the responsible person for each task. Describe actions (what is to be completed). Monitor site performance. Staff training 18 6

7 Completing case report forms Use standard data entry conventions Never erase, or white-out single line through, initialed and dated Use ballpoint pen Every piece of data needs a source document If the CRF is to serve as the source document this needs to be noted at start of trial and the CRF should be initialed and dated Complete CRF in a timely fashion 19 Understanding investigator responsibilities Federal Regulation of Clinical Research Department of Health and Human Services (DHHS) NIH FDA 45 CFR 46, CFR 11, 50, 54, 56, 312, 314, 600, 803, 812,

8 Clinical Trials Oversight: FDA vs. OHRP FDA oversight Sponsors, monitors, clinical investigators, contract research organizations involved in IND/IDE studies IRBs reviewing clinical research involving any FDAregulated product (IND/IDE and non-ind studies) OHRP oversight Institutions where clinical research is conducted or supported by HHS or Institutions that agree to assume responsibility for the research in accordance with 45 CFR 46 regardless of the funding source 22 Who is the responsible investigator? IND trials signs FDA form 1572 IDE trials submits investigator statement Other - Investigator of record Institution signs the IRB application 23 Excerpts of DHHS Form

9 Investigator Responsibilites 1. Personally conduct or supervise the investigation 2. Ensure that all associates, colleagues, and employees assisting in study conduct are informed about their obligations 3. Conduct the study in accordance with the protocol 4. Comply with all requirements regarding obligations of clinical investigators [21CFR 312] 5. Inform subjects drugs are being used for investigational purposes and ensure informed consent and IRB requirements are met FDA Form Investigator Responsibilites 6. Obtain initial and continuing review and approval from the IRB. Promptly report to the IRB all changes in the research activity and all unanticipated problems and make no changes in the research without IRB approval 8. Maintain adequate and accurate records 9. Report Adverse Events to the sponsor/irb 10. Read and understand the investigator s brochure FDA Form Lack of adequate trial supervision results in: Poor data Frustrated staff Study delays Risk to subjects Risk for audit by IRB/OHRP/FDA 27 9

10 Blame for Poor Trial Conduct Investigator s Report 9% 4% 4% 39% FDA/IRB/Institution Position 100% 9% 9% P.I. Study Coordinator P.I. Nurse 9% 17% n (parties blamed) = 23; n (cases) = 20 Woollen, S.W., CDER, FDA, So what does it mean to personally conduct or supervise the investigation I can t do it all! How can this be done? Appropriate delegation Adequate training Adequate supervision FDA guidance for industry: Investigator responsibilities - protecting the rights, safety and welfare of study subjects

11 What is appropriate delegation of studyrelated tasks? The investigator should ensure that any individual to whom a task is delegated is: qualified by education, training State licensure (where applicable), and experience to perform the delegated task. FDA guidance for industry: Investigator responsibilities - protecting the rights, safety and welfare of study subjects How can this be documented? Maintain a list of qualified persons to whom the study-specific task has been delegated Describes the delegated tasks Identifies the qualifying training Identifies the dates of involvement in the study 32 Dr. Right PRINCIPAL INVESTIGATOR Heads the team Dr. Smart SUB-INVESTIGATOR Assists with consents and performs physicals RN/Coordinator Manages the study, paper flow, and administers drug Coordinator Regulatory functions Helps with recruitment EVERYONE ELSE Lab techs X ray techs etc. Generate an organization chart for yourself Identify the people you need to get the job done Put their specific responsibilities on paper and give it to them Review responsibilities and adherence at set intervals When someone leaves make sure all new credentialing/training is done 33 11

12 Examples of inappropriate delegation of study-related tasks Assessment of inclusion/exclusion criteria conducted by individuals with inadequate medical training Physical examinations performed by unqualified personnel Evaluation of adverse events by individuals lacking appropriate medical training or knowledge of the clinical protocol or study agent Assessments of primary study endpoints by individuals lacking appropriate medical training and knowledge of the protocol Informed consent obtained by individuals who lack the medical training and knowledge of the protocol needed to be able to discuss the risks and benefits of a clinical 34 trial What is adequate training? Have a general familiarity with the study and the protocol Have a specific understanding of the details of the protocol and the investigational product (if applicable), relevant to the tasks they will be performing Are competent to perform the tasks that they are delegated FDA guidance for industry: Investigator responsibilities - protecting the rights, safety and welfare of study subjects What is adequate supervision of study conduct? Conduct regular meetings with staff Review basic science and clinical issues Review trial progress Update staff on any changes to the protocol or other procedures Review adverse events set plans Review deviations/violations FDA guidance for industry: Investigator responsibilities - protecting the rights, safety and welfare of study subjects

13 What is adequate supervision of study conduct? Establish procedures for ensuring that the consent process is being conducted in accordance with what was approved by the IRB and that study subjects understand the nature of their participation, risks, etc. FDA guidance for industry: Investigator responsibilities - protecting the rights, safety and welfare of study subjects Assuring proper informed consent procedures Review recruitment and approach procedures Assure that anyone who obtains consent* thoroughly understands the protocol Use of consent tools to document process *consent can only be obtained by personnel with the training necessary to adequately explain procedures, risks, benefits, etc. 38 Study number Version number IRB date stamp Date consent was signed Time 1. Information about the study, including all available options, was provided in a language that the subject can understand. 2. The subject was given ample opportunity to consider all available options. 3. Questions were elicited and all answers given prior to signing consent. 4. The investigator or sub-investigator is comfortable that by providing adequate information to the subject there is no likelihood of coercion. 5. Verification of comprehension was done in one of the following ways (select at least one of the following): A) The subject asked relevant questions during the informed consent process. B) The clinician asked the subject specific questions about the study. C) The clinician asked the subject to repeat information discussed. 6. The following items were covered when discussing the informed consent for a study with the subject: a) The study involves research. b) Participation is voluntary c) Subjects can decide not to participate or withdraw at any time without penalty or loss of benefits. d) The purpose, duration of study, and issue of randomization/blinding e) The number of screening, pre-entry, entry and on-study visits. f) The length of follow up, what happens in case of early withdrawal, and the reasons for which a subject might be involuntarily discontinued from the study. g) Risks of study treatments and procedures, including psychosocial ones. h) Possible benefits, and if none, this should be stated. i) Reimbursement to subjects, if any. j) Costs to subject. What happens in case of research-related injury or side effects. k) What happens in case of pregnancy, if applicable. l) New findings will be communicated to them. m)confidentiality of data. n) Phone numbers for questions at a later time, including research questions, questions related to subject s rights, and research-related injuries. 7. Copy of consent given to subject. 8. HIPAA consent signed, if required. Comments: Clinician signature Date 39 13

14 What is adequate supervision of study conduct? Establish procedures for ensuring study staff comply with the protocol, adverse event assessment and reporting, and other medical issues that arise during the course of the study. Establish procedures for correcting problems Establish procedures for documenting the performance of delegated tasks FDA guidance for industry: Investigator responsibilities - protecting the rights, safety and welfare of study subjects Protecting the Rights, Safety, and Welfare of Study Subjects During and following the trial, ensure adequate medical care is provided for any adverse events related to the trial. Clinical investigators should be available to subjects during the conduct of the trial at their site. FDA guidance for industry: Investigator responsibilities - protecting the rights, safety and welfare of study subjects Protecting the Rights, Safety, and Welfare of Study Subjects Failure to adhere to the protocol may be considered a failure to protect the rights, safety, and welfare of subjects. Non-compliance with inclusion/exclusion criteria Failure to perform safety assessments in a timely manner FDA guidance for industry: Investigator responsibilities - protecting the rights, safety and welfare of study subjects

15 Tools and Templates Standard Operating Procedures Study Start-up Checklist Study Implementation Checklist Study Team Meeting Minutes Adverse Event Log Protocol Deviation Logs Training logs ITHS Forms Clinical Trials Registration Registration is required for any research study that prospectively assigns human participants or groups of humans to one or more healthrelated interventions to evaluate the effects on health outcomes As of 2007 includes Phase I studies Purely observational studies do not require registration 44 Who registers the trial NIH sponsored trials normally the institute Industry sponsored trials the company PI is responsible Investigator initiated trials Trials where the investigator holds the IND/IDE If the sponsor does not register the trial 45 15

16 Who can help? UW - Clinical Trials Administrator in the HSD - hsdinfo@uw.edu FHCRC- ClinicalTrials.gov administrator in the Protocol Office - ml SCH Resources Institute for Translational Health Sciences (ITHS) Additional education UW Clinical trials handbook ITHS Regulatory Support and Bioethics Core and rsbcore@u.washington.edu Translational Research Toolkit UW Healthlinks Toolkits Translational ResearchToolkit PRIMER toolkit Additional resources UW Research Coordinator Core SCH Clinical Research Staff Support Core FHCRC Clinical Trials Support Office ITHS Clinical Research Center All linked from

17 Questions? 17