Controlling The Action

Transcription

1 Clinical Trial Administrator Manual Controlling The Action TM

2 Contents SOME USEFUL WEBSITES INTRODUCTION ACRONYMS CTA ROLE STUDY TEAMS PHASES OF CLINICAL TRIALS Blinding / Randomisation STUDY START UP Feasibility Set Up Ethics Trial Master File (TMF) STUDY CONDUCT Distribution of Study Material to Sites Study Supplies Filing Tracking Spreadsheets Other Tasks STUDY CLOSE DOWN MEETINGS FINANCE ARCHIVING SUMMARY SOME USEFUL WEBSITES IRAS MHRA UKCRN NHS R&D Forum NRES ICH Clinical Trials.gov FDA ICR NICE INTRODUCTION This manual has been written by Clinical Trial Administrators (CTAs) for Clinical Trial Administrators to help them understand their role within a Study Team within a Clinical Research Department. It has been written informally and provides a general guide for working. It is impossible to cover every aspect of the CTA role and assistance should be sought as and when required. This manual is written as a guideline and not as a replacement or addition to any SOPs or Working Instructions. Authors: The ICR CTA Specialist Interest Group The CTA SIG are grateful to the delegates who attended the CTA Forum in November 2008 for their valuable contributions to the content of this manual and to the ICR PM Specialist Interest Group for their advice & guidance December 2009 Clinical Trial Administrator - Manual December Page 2

3 ACRONYMS ABPI Association of British Pharmaceutical Industry ADR Adverse Drug Reaction AE Adverse Event CA Competent Authority CHAI Commission for Health Audit and Inspection CHMP Committee of Medicinal Products for Human use (EU) CI Chief Investigator COV Close Out Visit CPU Clinical Pharmacology Unit CRA Clinical Research Associate CRF Case Report Form CRO Contract Research Organisation CSR Clinical Study Report CTA Clinical Trial Administrator also known as Clinical Trial Assistant or Clinical Trial Associate CTA Clinical Trial Agreement CTA Clinical Trial Application CTM Clinical Trial Manager CTIMP Clinical Trial of an Investigational Medicinal Product CTMS Clinical Trial Management System (eg IMPACT) CTP Clinical Trial Protocol DM Data Manager DRA Drug Regulatory Affairs ecrf Electronic Case Report Form EDC Electronic Data Capture EC Ethics Committee EMEA European Medicines Agency EU CTD European Union Clinical Trial Directive EUDRACT European Union Drug Regulating Authorities Clinical Trials FDA Food and Drug Administration (USA Government) FIH FIM FPI GCP GLP GMP IB ICF ICH First in Human First In Man First Patient In Good Clinical Practice Good Laboratory Practice Good Manufacturing Practice Investigator Brochure Informed Consent Form International Conference on Harmonisation ICH-GCP International Conference on Harmonisation- Good Clinical Practice (ICH Guideline E6) ICR Institute of Clinical Research IEC Independent Ethics Committee IFPMA International Federation of Pharmaceutical Manufacturers and Associations IMP Investigational Medicinal Product IND Investigational New Drug IRAS Integrated Research Application System (on line Ethics application system) IRB Institutional Review Board (another name for an Independent Ethics Committee, commonly used in the USA) ISF Investigator Site File LREC Local Research Ethics Committee LRN Local Research Networks LPLV Last Patient Last Visit LPO Last Patient Out MAA Marketing Authorisation Application MHRA Medicines & Healthcare products Regulatory Agency (United Kingdom) MREC Multi Research Ethics Committee MV NDA NIHR Monitoring Visit New Drug Application National Institute for Health Research NIHRCRN National Institute of Health Research (NHS) Clinical Research Network NICE National Institute for Health and Clinical Excellence NRES National Research Ethics Service OREC Office of Research Ethics Committee PI Principal Investigator PIS Patient Information Sheet PM Project Manager PSF Pharmacy Site File PV Pharmacovigilance QA Quality Assurance QC Quality Control R & D Research & Development REC Research Ethics Committee SAE Serious Adverse Event SDV Source Document Verification SIV Site Initiation Visit SOP Standard Operating Procedure SQV Site Qualification Visit SSA Site Specific Assessment SSI Site Specific Information SUSAR Suspected Unexpected Serious Adverse Reaction TMF Trial Master File UKCRC United Kingdom Clinical Research Collaboration UKCRN United Kingdom Clinical Research Network UKECA United Kingdom Ethics Committee Authority Clinical Trial Administrator - Manual December Page 3

4 CTA ROLE Definition of a Clinical Trial Administrator (CTA) There is no standard definition of a Clinical Trial Administrator however a useful description might be: someone who administers, maintains and co-ordinates various logistical aspects of clinical trials in accordance with standards such as ICH (International Conference on Harmonisation) GCP (Good Clinical Practice) and relevant SOPs (Standard Operating Procedures) and who acts as a pivotal point of contact for clinical development colleagues. The CTA role is principally to support the Study or Project Team and complete tasks assigned to enable the Team to meet study timelines and deliverables for all phases of the clinical trial process. Tasks may include but are not limited to the following: Creating study start-up tools. Assisting with ethics and/or regulatory/or R&D submissions and filing necessary supportive documentation. Tracking of site contract approvals, invoices and payments relating to sites and subjects/patients. Assisting with the ordering and distribution of study related supplies and/or co-ordinating local supplies and vendors. Reconciling and tracking essential documents necessary for the Trial Master File (TMF), Investigator Site Files (ISF) and Pharmacy Site Files (PSF), if applicable. Co-ordinating internal study processes to meet safety and regulatory requirements as outlined in the SOPs. Provide assistance in meeting planning, preparation of agendas, presentations and minute taking. Planning/assisting with the organisation of Investigator Meetings to include sourcing venue, arranging travel, creation and collation of meeting materials, joining instructions, attendance records, expense forms etc. Developing and maintaining functional knowledge of ICH-GCP, SOPs, local regulations and therapeutic area(s) through continued training. Clinical Trial Administrator - Manual December Page 4

5 STUDY TEAMS The roles and responsibilities within Study Teams vary hugely and for example might consist of a Project Manager (PM) who has overall responsibility for the study, Clinical Research Associates (CRAs), a Data Manager (DM) responsible for processing clinical trial data, a Statistician responsible for contributing to the study design, a Regulatory Affairs Officer responsible for R&D submissions, the licensing, marketing and the legal compliance of the study and the CTA who will support some or all of these functions within the Study Team. Other members may join the Team as and when required, for example Pharmacovigilance (PV) and Medical Writing representatives. Study Team membership will vary from company to company, dependent upon its hierarchy, from Pharma to CRO and to site, and may also be dependent upon the study design and the phase of the study. The Project Manager (PM) The PM is usually accountable for the effective and efficient delivery of operational aspects of the study or studies. The PM role varies by company but usually they provide the leadership to the Study Team(s) to include local strategic planning and organisation to achieve successful study completion, within timelines and budgets. Their principal responsibilities might be to: Oversee the project, protocol, site feasibility and provide feedback and recommendations to the Study Team. Develop and manage the study budget/financial plan and forecasts, using appropriate tools to ensure sufficient resources are available to effectively deliver high quality results on time and within budget. Ensure studies are performed and conducted in compliance with ICH-GCP guidelines, SOPs and all applicable regulatory requirements. Co-ordinate investigational medicinal product (IMP) supplies. Lead and/or organise local or regional meetings and training sessions (i.e. study team meetings, investigator meetings, CRA workshops). Liaise with the CRAs regarding site monitoring activities. Attend co-monitoring visits with the CRAs. Organise study close down activities. Oversee the timely production of the final Clinical Study Report (CSR) in collaboration with Medical Writing. Clinical Trial Administrator - Manual December Page 5

6 Clinical Research Associate (CRA) Study monitoring is a requirement of ICH-GCP and is conducted by CRAs. For larger studies there is often a Lead CRA (LCRA) with overall responsibility for individual CRAs who are allocated to individual sites. CRAs are responsible for performing study site management activities relating to study start up, regulatory compliance, patient enrollment, protocol adherence, Case Report Form (CRF) completion and data quality for clinical trials to meet specified scientific, medical, regulatory and commercial needs, as well as developing and maintaining investigator relationships. Their principal responsibilities might be to: Contribute to site and investigator selection process for their area of responsibility. Perform and facilitate study start-up activities with the site to ensure all necessary arrangements are in place prior to study conduct and the required essential documentation is obtained and filed for a site to start the study on time and according to plan. Ensure adherence to ICH-GCP guidelines, SOPs, local regulations and the reporting of protocol changes to the relevant ECs/Regulatory Board/Health Authorities. Ensure that the reported trial data is accurate, complete and verifiable from source documents. Perform site monitoring activities according to the Monitoring Plan. Assess study progress; raise/close monitor discrepancies and follow-up monitoring visit action items. Perform site-level drug accountability and reconciliation activities to ensure proper handling, storage, administration, record keeping and disposition of study drug(s) as per ICH-GCP, local regulations and the protocol. Ensure all activities in relation to Site Close Out are carried out at the end of the study. Reconcile and submit essential documents to archive. The Data Manager (DM) The Data Manager and/or members of their team are responsible for processing clinical trial data using computerised applications and database systems. The data may be collected in multiple sources, and reconciled and reviewed for completeness and consistency, whist maintaining adherence to quality standards. Their principle responsibilities might be to: Contribute to the design of study protocols from a data collection perspective. Contribute to the design of Case Report Forms. Build, test and maintain the study database. Raise data queries to site or CRAs to resolve identified data inconsistencies or omissions, and maintain an audit trail of data changes in compliance with ICH-GCP. Ensure identified database items are coded using specified dictionaries for analysis and reporting. Provide support to site or monitoring staff regarding recording of collected data. Work with vendors e.g. central laboratory, to define acceptable formats for transfer of clinical data results in compliance with ICH-GCP and FDA 21CFR-11. Reconcile data from vendors e.g. central laboratory data and integrate with clinical database. Reconcile Serious Adverse Event (SAE) details with Safety Database, prior to database lock. Review Statistical Output (Tables, Listings and Figures) to ensure they reflect the locked database. Clinical Trial Administrator - Manual December Page 6

7 The Statistician The Statistician is responsible for contributing to the design of a trial and ensuring that data are collected, analysed and interpreted correctly. The Statistician will also determine the number of patients to be enrolled into a trial in order to achieve the best results. Their principle responsibilities might be to: Operate in collaboration with study personnel to provide input into the study design and protocol. Assist or be accountable for selecting statistical methods for data analysis, authoring the corresponding sections of the protocol, and conducting the actual analysis once a reporting database is created. Collaborate with data management in the planning and implementation of data quality assurance plans. Maintain accuracy with respect to statistical methodology, maintain proficiency in applying new and varied methods, and be competent in justifying methods selected. Collaborate with team members to write reports and communicate results. Assist with, or be responsible for, communicating study results via regulatory submissions, manuscripts, or oral presentations in group settings, as well as communicating one-on-one with key customers and presenting at scientific meetings. Respond to regulatory queries and interact with regulators. Regulatory Affairs The Regulatory Affairs Officer/Administrator ensures the appropriate licensing, marketing and legal compliance of pharmaceutical and medical products and assists with Regulatory & Ethics Submissions for approval of the study. Their principal responsibilities might be to: Ensure that a company s products comply with local regulations. This would be those of the Medicines and Healthcare products Regulatory Agency (MHRA) for studies in the UK. Prepare submissions of license variations and renewal approvals. Set timelines for license variations and renewal approvals. Write clear, accessible product labels and patient information leaflets. Advise on regulatory requirements and submissions to Competent Authorities for regulatory approval of studies. Complete / update Eudract Form via IRAS website. Keep abreast of international legislation, guidelines and customer practices. Clinical Trial Administrator - Manual December Page 7

8 The Medical Writer The Medical Writer may be responsible for writing the Protocol at the beginning of the study, including any amendments necessary during study conduct and/or may be responsible for writing and producing the Clinical Study Report (CSR) at the end of the Study. They may also assist with preparation of, for example, informed consent documents, Investigator s Brochures and publications. Their principal responsibilities might be to: Prepare documentation for medical communications programmes (e.g website, abstracts, manuscripts). Provide project management with writing-only projects. Ensure all documents are well-organised, accurate, consistent and in compliance with applicable company SOPs and regulations. Summarise data from clinical studies. Work precisely according to procedures, rules and regulations. Approach all issues from a number of perspectives, summarising data in order to draw conclusions. The Pharmacovigilance (PV) Officer The PV Officer is responsible for safety surveillance of the study drug, the reconciliation and assessment of Serous Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions (SUSARs) and monitoring the risk/benefit profiles throughout the clinical trial and post-marketing phases essential for the protection of patients. Their principal responsibilities might be to: Report AEs, SAEs and ADRs in a timely and accurate manner in accordance with ICH-GCP Guidelines, SOPs and legal reporting requirements in the countries in which the trial is being conducted. Prepare spreadsheets for reconciliation, monitoring and tracking of SAEs. Follow up information received from patients and healthcare professionals in a timely manner. The PV Officer might also be asked to: Represent pharmacovigilance on clinical study teams. Be involved with protocol reviews. Prepare SAE reporting procedures. Assist with providing pharmacovigilance training to other PV Officers and members of the Study Team. Perform quality control of safety reporting. Clinical Trial Administrator - Manual December Page 8

9 PHASES OF CLINICAL TRIALS Before a drug can be given a licence to treat patients on a day-to-day basis, it needs to go through a series (or phases) of clinical trials to test whether it is: safe has side effects (toxicity) works better than the current standard treatment helps people feel better (has an affect on quality of life) is cost effective A single clinical trial cannot answer all these questions at once, therefore different aspects of a treatment s effect are tested in different phases. Phase I Phase I clinical trials test the safety of a new treatment. This will include examining the side effects (toxicity) of a treatment for example, does a subject develop headaches or vomit? If the treatment results in too many side effects it will not progress any further in development in that form. Each Phase I clinical trial may involve only a small number of people (possibly as few as 15-20). Depending on the type of disease being studied, patients in Phase I trials are usually healthy volunteers or they may be patients with advanced stages of a disease, such as cancer, where existing standard treatments are no longer considered to be of benefit. If the treatment is considered safe in a Phase I trial, it will progress to a Phase II clinical trial. Phase II Phase II clinical trials test whether the treatment works in people who have the disease that the drug is intended to treat. These studies are larger than Phase I trials, involving a larger number of subjects, and could take place in a number of hospitals/investigator sites in a number of countries. Phase II clinical trials also collect information about safety in this larger group of subjects and what dose is appropriate. Treatments only move into a Phase III clinical trial if Phase II is successful. Phase III The objective of Phase III clinical trials is to test the new treatment in an even larger group of subjects. Several hundred to a few thousand subjects could be involved in a Phase III clinical trial. Due to the large number of subjects participating, this phase could involve many hospitals/investigator sites and many countries. These clinical trials examine how well the treatment works often by comparing it with the best treatment currently available, or, occasionally with a placebo (a dummy drug, which resembles the drug being tested). In Phase III trials, and frequently in Phase II trials, patients are allocated their treatment using a process called randomisation. As Phase III trials are examining long term treatment effects they can sometimes last for many years. Phase III trials are also used to collect more information about any side effects and safety of the treatment. Clinical Trial Administrator - Manual December Page 9

10 Blinding / Randomisation Blinding A single-blinded trial is where the subjects taking part do not know which treatment they are receiving, however, the investigator/prescribing physician does know. The subject could be receiving the new treatment or the standard treatment or a placebo (dummy treatment), depending on the design of the trial. All patients receive identical injections or tablets, so they cannot tell which treatment they are receiving. A double-blinded trial is where neither the subject nor the investigator knows which treatment they are receiving. The computer gives each patient a code number and the code numbers are then allocated to treatment groups, thus neither the patient nor the Investigator is aware of which treatment is being administered. Members of the study team are also unaware of the treatment assigned, The list of subjects and their code numbers are strictly confidential until the end of the trial. In an emergency, researchers would be able to find out which treatment group a subject was allocated to (this is referred to as unblinding ), but generally no-one would know until the trial had finished. Randomisation Most Phase III trials and some Phase II trials are randomised. This means that there are at least two different treatment groups in the trial and subjects taking part are put into one or the other group at random. This randomisation process is usually determined by a computer-generated list which contains the treatment allocation for each subject. Each group in the trial has a different treatment. For example, if there are two groups, one group might receive the new treatment being tested and the other group will receive a standard treatment that is already on the market or a placebo. Subjects having the standard treatment or placebo are called control groups. Trials are randomised to ensure that the results are correct and are not biased. Open-Label Studies An open study (or open-label study) is one in which both the subject and the investigator are aware of the identity of the treatment given and may often follow a blinded Phase III study to provide the investigational medicinal product to subjects until Regulatory Authorities grant licence approval. Open studies are appropriate where knowledge of the treatment received does not enable the subject or investigator to influence the results. Open-label studies can be randomised in the same way that other phases of studies are randomised. Open studies can also compare a new treatment with an existing treatment. Phase IV (sometimes known as Post Marketing Trials) Phase IV studies may be required by regulatory authorities or may be undertaken by a pharmaceutical company for competitive (eg finding a new market for the drug) or other reasons (eg the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women). This phase of safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. It may uncover effects not known about before the drug was given a marketing licence. Harmful effects discovered by Phase IV trials may result in a drug no longer being sold, or restricted to certain uses. The main reasons pharmaceutical companies run Phase IV trials are to find out : more about the side effects and safety of the drug the long term risks and benefits how well the drug works when it is used more widely than in clinical trials Clinical Trial Administrator - Manual December Page 10

11 STUDY START UP Feasibility Set Up There are two types of feasibility: 1. At the Protocol level to assess the feasibility of carrying out the study in particular countries. The CTA may help collate responses. 2. At site level to assess that those sites identified have the experience, resources and facilities to participate in the trial. The CTA may issue questionnaires and track responses. Ethics Independent Ethics Committees (IECs), or IRBs as they are frequently referred to in the USA, have a duty to consider and give an ethical opinion on any ethical issue relating to a clinical trial of an investigational medicinal product. An application to the EC may be made either at the same time as, or in sequence to, the Clinical Trial Authorisation (CTA) being made depending on the country in which the trial is being conducted. The application, once submitted, will be reviewed and, if in their opinion, the trial is considered to be ethical, a favourable opinion will be given thus allowing the study to begin. IRAS (Integrated Research Application System) In the UK a single system (known as IRAS) is currently used for applying for the permissions and approvals for health and social care/community care research and some CTAs may be asked to help with these applications, with guidance from the CRA or PM. IRAS enables you to enter the information about your project once instead of duplicating information in separate application forms, by using filters to ensure that the data collected and collated is appropriate to the type of study, and consequently the permissions and approvals required, thus meeting regulatory and governance requirements. IRAS captures the information needed for the relevant approvals from relevant review bodies, for example Gene Therapy Advisory Committee (GTAC) Medicines and Healthcare products Regulatory Agency (MHRA) NHS / HSC R&D offices NRES/ NHS / HSC Research Ethics Committees Visit for more information. Research and Development (R&D) In addition to requiring ethics approval, trials may also need institutional (R&D) approval. In the UK, applications for this can be made at the same time as applying for ethics approval and Clinical Trial Authorisation. R&D offices are responsible for approving Site Specific Information (SSI) applications for all research and all types of studies. If the trial has been adopted onto the National Institute for Health s Research (NIHR) Portfolio, then the Co-ordinated System for Permissions will coordinate the R&D and SSI approvals. Under the guidance of the PM/CRA, the CTA may assist with the completion of an Ethics/R&D Submission. Clinical Trial Administrator - Manual December Page 11

12 Regulatory (Competent Authority) Regulatory Agencies are responsible for regulating all medicines (and medical devices) by ensuring they work and are acceptably safe. The regulatory body for the UK is the MHRA. This is achieved through: authorising clinical trials before medicines are marketed, taking both their safety and effectiveness into account; ensuring clinical trials meet robust standards and safeguard patients interests. Once approvals have been received from Regulatory, Ethics and R&D, the original correspondence and approval documentation are filed in the TMF by the CTA, copies are filed in the ISF by the CTA or CRA and sites can be initiated and the trial can begin. Trial Master File (TMF) Composition of the Clinical Trial Master File The documents that demonstrate that the trial is conducted in accordance with regulatory requirements and ICH-GCP are held in the Trial Master File (TMF). The TMF is set up at the start of a study before any subjects/patients are recruited and is archived at the end of the study. The files may take the form of various media, e.g. electronic and/or paper. The content of the TMF consists of essential documents which enable both the conduct of a clinical trial and quality of the data produced to be evaluated. It may be inspected during the study by auditors and regulatory bodies. Further reference on the composition and contents of the TMF may be found in the following documents: EU Directive 2001/20/EC EU Directive 2005/28/EC ICH GCP E6 Medicines for Human Use (Clinical Trials) Statutory Instruments (UK only) Each Sponsor/CRO will have their own Standard Operating Procedure (SOP) that details the process for collecting and filing the study essential documents. The TMF is made up of various components dependent on the phase of the study and all the documents are brought together at the end. During the study these various components may be held in different locations, one example might be : Trial Master File Centre Study File Investigator Site File Other ancillary study files eg Pharmacy File. As a guide, example descriptions of these files for a particular study are given below: Trial Master File (TMF) The TMF resides with the Sponsor or CRO in secure fire-resistant conditions and holds all study specific documentation. If the TMF is paper-based, the files are created and maintained by the Sponsor/CRO and contain study documents relevant to the study at country-specific and global level. The Sponsor s/cro s SOP(s) and/or Working Practice(s) should provide a list of what documentation essential documents - needs to be retained in the TMF. Clinical Trial Administrator - Manual December Page 12

13 Contents may include for example: Protocol and Amendments Ethics and Competent Authority submissions/approvals Investigator Brochures Insurance/Indemnity Investigational Medicinal Product (IMP) information Master CRF Centre Study File (CSF) The CSF is again retained by the Sponsor or CRO in secure fire-resistant conditions and deemed to be a sub-file of the Trial Master File. This file is created and maintained by the Sponsor/CRO and contains study material pertinent to an individual site. The Sponsor s/cro s SOP(s) and/or Working Practices should provide a list of what documentation needs to be retained in these files. Contents may include for example: Patient information sheets/informed consent forms on hospital headed paper Signed Protocol/Amendment pages Visit Reports Site Correspondence Subject status Contracts/Agreements (signed) Investigator Site File (ISF) The ISF is study site/centre specific file and is located at the investigational site and deemed to be a sub-file of the Trial Master File. This file is created and issued to the site by the Sponsor/CRO and contains study material pertinent to that site, which is jointly maintained by the Sponsor/CRO and site. The contents will heavily overlap with the in-house TMF/CSF. The Sponsor s/cro s SOP(s) and/or Working Practices will provide a list of what documentation needs to be retained in these files. Contents may include for example: Protocol and Amendments Investigator Brochure Insurance/Indemnity Authorised Signature Log/Delegation Log Site Staff CVs Other Ancillary Site Files Some studies require additional study related files to be provided to the site by the Sponsor/CRO and again these files will be deemed to be part of the TMF and can include for example, a Pharmacy File, amongst others, dependent upon the study. The content of these files are determined locally by the Sponsor/CRO on a study by study basis and are created by the Sponsor/CRO and maintained jointly by the Sponsor/CRO and site. Filing Responsibility It is the responsibility of the CRA and/or PM to ensure that all correct, accurate and relevant documents are sourced and filed in the relevant sections of clinical study files (i.e. TMF, CSF, ISF and other study related files). The CRA and/or PM may delegate filing-related tasks (see list below). A review of the files is performed by the CRA/PM to ensure accuracy and completeness throughout the duration of the study and prior to study/site close. Clinical Trial Administrator - Manual December Page 13

14 Any gaps in a file section need to be explained with a file note in accordance with the Sponsor s/cro s procedure. CTA Involvement Creation of study files both site and in-house (in conjunction with the CRA/PM) in accordance with the relevant SOP(s) and/or Working Practice(s). Issue study files to sites (under the instruction of the CRA/PM). Undertake filing, which should be coded (under the instruction/ guidance of the CRA/PM) in accordance with the company s SOP(s) and/or Working Practice(s). Assisting with file reviews in conjunction with CRA/PM. Photocopying thermal paper (to prevent fading). File splitting (in order to create additional filing space as and when required throughout the duration of the study). Archiving activities. Clinical Trial Administrator - Manual December Page 14

15 STUDY CONDUCT Distribution of Study Material to Sites The CTA is usually involved in distribution of study material to sites eg ISFs, PSFs, ICFs, CRFs, patient diary cards, if applicable, and other study related materials. Every study is different and study materials may also include lab kits, hospital supplies, etc. Study Supplies The CTA may be responsible for the ordering, tracking, control and distribution of study supplies/study aids. Re-printing or re-ordering of study supplies/aids can be organised as appropriate. Filing The CTA, under the guidance of the PM/CRA, usually ensures that relevant documents are filed in the TMF and CSF see section TMF. Tracking Spreadsheets Spreadsheets may be used to track a variety of items across the different studies depending on the clinical trial management system in use at the Sponsor or CRO. Below is a list of some of the spreadsheets that may be updated/maintained by the CTA: Drug Ordering IB Tracking Document Receipt Tracking eg IB receipts Essential Document Tracking Invoices/Investigator and subject payments Study and site approvals (EC and R&D) SAEs/SUSARs Other Tasks The CTA may be responsible for maintaining study information on a variety of databases e.g. Corporate Clinical Trials Registry. The CTA may prepare Study Status Reports. The CTA may review documents for completeness, accuracy and compliance with the protocol. The CTA may order drug supplies and CRFs to be sent direct to site(s). The CTA may create a mail merge for each study, in order to distribute Newsletters, recruitment updates or safety information quickly and efficiently to sites. The CTA may create and issue Newsletters under the guidance of the Sponsor/PM/CRA. The CTA may be asked to perform a QC check of the TMF from time to time to ensure the completeness and accuracy of the documents filed. The CTA may be asked to organise archiving of the TMF in accordance with company SOPs after study close-down. The CTA may also be asked to arrange travel, create presentation slides and to perform many other study related tasks, not listed in this manual. Clinical Trial Administrator - Manual December Page 15

16 STUDY CLOSE DOWN The CTA may be asked to assist with Study Close Down activities. This could involve co-monitoring with the CRA in order to: Check that the ISFs (and PSFs, and any other study related files, if applicable) contain all essential and relevant documentation. Assist the CRA with the collection and photocopying of CRFs. Assist with drug reconciliation. Assist with off-site archiving. Provide other assistance the PM or CRA may require. During and after Study Close Down, the CTA may be asked to assist with the review of all essential documents and all other relevant documentation filed in both the TMF and CSFs for completeness. The TMF can then be archived which the CTA may organise. This activity usually happens after the CSR has been finalised. MEETINGS Study Team Meetings may be held periodically (weekly, fortnightly, monthly depending on the study design) and are usually chaired by the PM with the CTA taking minutes. The CTA may be responsible for organising the meeting room, sending out invitations and taking, transcribing and distributing the minutes in a timely manner to enable actions to be dealt with promptly. The CTA may also help with the organisation of Investigator Meetings by liaising with meeting planners, helping to coordinate the logistics and distributing relevant materials. FINANCE The PM is usually responsible for the study finance however the CTA may be asked to track invoices, investigator and subject payments and other study related costs. This would be discussed at study start up with the PM. For investigator-led studies, the CTA may be involved in assisting the PM to apply for funds for running the trial and could be asked to monitor study expenditure e.g. tracking invoices and subject payments. The CTA could also be responsible for ensuring all invoices and payments are presented on time prior to the trial funding ceasing. At the end of the study the PM could ask the CTA to assist with the submission of end of study financial reports to the funder(s) in accordance with their terms and conditions. Clinical Trial Administrator - Manual December Page 16

17 ARCHIVING The Sponsor/CRO must appoint named individual(s) within the organisation to be responsible for archiving the documents which are, or have been, contained in the TMF and access to those documents should be restricted to those appointed individual(s). In the UK, compliance with ICH-GCP guidelines 4.9.4/5, relevant EU Directives 2001/20/EC and 2005/28/EC and UK Statutory Instruments, together with company/site guidelines/global/local SOPs/ Working Instructions regarding archiving and the handling of confidential data to prevent accidental or premature destruction of essential documents, must be maintained. The CTA may have Responsible Archivist (RA) responsibilities and may be required to undertake archiving activities after study close down. This is a responsible role with legal implications and training must be undertaken in order to perform this role competently. Responsibilities The ultimate responsibility for archiving usually lies with the head of the clinical research department, i.e. the Clinical Director or equivalent. The PM or the CRA are usually responsible for ensuring that clinical trial documents are archived in accordance with guidelines listed above. A Sponsor/CRO will usually appoint a Responsible Archivist (RA), which could be the CTA and the CRA will liaise with the CTA/RA to ensure documents are archived appropriately. The CTA/RA may be the appointed authorised signatory for deposit of new archive boxes into and retrieval of boxes from off-site storage. The following is a guide to archiving, dependent upon the organisation: Documents to be Archived The Sponsor s/cro s Trial Master Files (TMF), Investigator Site Files (ISF) and other study-related files are archived once a study has come to an end. The contents of these files are usually outlined in the relevant Sponsor s/cro s Global/Local SOP(s)/Working Instructions. These documents could be in paper form or stored as electronic records or on other media. Location and Management of the Archive If a company does not have their own adequate archive facilities, a Service Level Agreement (SLA) would be set up with an external archive provider, appropriate for the archiving of clinical trial documents in accordance with legislative requirements. In order to ensure the archiving facility remains suitable for the storage of clinical trial documents, it would be recommended that the archive should be visited by a Sponsor/CRO representative at least once a year. During these visits, a review of the archive facilities should be performed. It is recommended that a checklist/report is completed covering the following suggested elements (non exhaustive): disaster recovery plan to document the archiving process and the actions to be taken in the event of an unforeseen occurrence which results in the loss of, or damage to, documents; all archived documents are stored appropriately and securely but can be easily and quickly accessed and retrieved; the archive is environmentally controlled to ensure extremes of temperature and humidity do not occur; provision is in place to prevent damage to documents from other external factors (e.g. fire, flood, vermin etc.); Clinical Trial Administrator - Manual December Page 17

18 safety and security measures are in place regarding transportation of archive boxes; relevant insurances/slas are in place and current for third party providers; bar coding system and inventory procedure is robust. Following each inspection, the completed checklist/report should be issued for review by the head of department and should then be filed in the appropriate archiving file held at the Sponsor s/ CRO s offices. This should be readily available and produced on request during audits/inspections by authorised personnel. Preparation of Documents for Sponsor/CRO/Site Clinical Study Archiving Before any documents are sent to archive, the TMF and other study related files will be reviewed in accordance with Sponsor s/cro s procedures by the responsible CRA/PM to ensure all documents are complete, legible, accurate and unambiguous. These files will not normally be archived until the final clinical study report has been issued. If, during this pre-archiving file review, any incomplete or missing documents are noted, these will either be completed or collected or their absence documented in a File Note with a reason. The RA/CTA may ensure that all trial related documents have subject identifiers removed or blanked out. Plastic wallets and paperclips should be removed and thermal paper photocopied to prevent deterioration. Once the responsible CRA/PM is satisfied that the files are complete, they will be transferred into appropriate archiving boxes by the responsible CRA/PM and / or the RA/CTA, following the instructions as outlined in the Sponsor s/cro s Global/Local SOP/Working Instructions. Transferring Documents to the Archive Once documentation has been transferred into the archive boxes and relevant paperwork completed as outlined in the Sponsor s/cro s Global/Local SOP/Working Instructions and filed appropriately, a mutually convenient time and date should be arranged for collection of the boxes by the archive provider for storage at their premises. Details of all documents sent to the archive (barcodes, content, date transferred to archive etc.) should be documented on the Sponsor s/cro s electronic inventory. Retrieval of In-House Documents from Archive If documents from the TMF or CSF need to be retrieved from the archive, the RA/CTA may be required to assist with this request as outlined in relevant Sponsor s/cro s Global/Local SOP(s)/Working Instructions. A documented dated record should be maintained listing the number of boxes re-called, their contents, the reason for the recall and details of the requestor, which should be by a PM. The retrieved boxes should remain the responsibility of the requestor until they are ready to be returned to the archive. Once the boxes are ready to be returned to the archive, the RA/CTA may be requested to check the box contents in conjunction with the requestor/pm to ensure that all documents that were retrieved are returned. This process should be documented and signed off by the PM, or designee, authorising what is being returned to the archive. Archiving of Investigator Site Files All efforts should be made to archive the Investigator Site Files (ISF) at the investigational site; however, in the event that suitable archiving facilities are not available at the site, the files may be archived by Sponsor s/cro s archive provider. If the latter is the case, the Sponsor/CRO should provide the site with archive boxes, barcodes, manila document wallets, relevant archiving instructions and other necessary stationery to perform this exercise successfully. The procedure for preparing the ISF for archiving is the same as that described in Preparation of Documents for Sponsor/CRO/Site Clinical Study Archiving above. Clinical Trial Administrator - Manual December Page 18

19 The RA/CTA may be asked to assist with the archiving activities as requested by the CRA/PM at the investigational site. Once the boxes containing the ISFs are ready for collection, they will be collected directly from the site for storage by the archive provider as outlined in the Sponsor s/cro s Global/ Local SOP/Working Instructions. Only the Investigator or designated site staff will be able to request retrieval of their ISF and this can only be shipped back to the site to ensure confidentiality is maintained. The Sponsor/CRO must not have access to, or have control over, archived ISFs. The Sponsor/CRO will document on an archiving electronic inventory where off-site archiving facilities are used to archive the ISF. In addition, relevant Sponsor/CRO groups should be notified by the PM that the ISF has been archived with details of the archive location. Document Retention and Media Used All clinical trial paper documents, electronic records and other media (i.e. both in-house files and the ISF) must be archived for the time period specified in the study protocol or as per Sponsor/ CRO Global/Local SOP(s)/Working Instructions. If any institution cannot retain their documents for this length of time they must inform the Sponsor/CRO of this, so that provision can be made for alternative appropriate archiving. The Sponsor/CRO will notify investigators in writing when they can destroy their clinical trial documents. No documents can be destroyed without the written approval of the Sponsor/CRO. Media used to store clinical trial documents (paper/electronic/other) shall be such that they remain complete and legible throughout the retention period. Any alterations to the documents should be traceable. Clinical Trial Administrator - Manual December Page 19

20 SUMMARY A Clinical Trial Administrator is a critical link between all parties involved in Clinical Trials. Controlling The Action! In summary, an empowered CTA will drive a study forward within the appropriate organisational framework. The CTA can be the nucleus for administration and communication for the clinical trial team. An experienced CTA will instinctively apply their knowledge and implement current SOPs and processes to provide the solid framework for the conduct of their trials. Study teams should be encouraged to draw on this knowledge, along with their wealth of administrative skills when working on, or transferring to new studies. They can be relied upon by others in being an instrumental team player to ensure the smooth, timely and successful running of a clinical trial. If you would like to find out more about the role of a CTA, we recommend that you have a look at the ICR website - and attend the following courses, run by the ICR, aimed at CTA s: Introduction to Clinical Trials Beyond the Basics Clinical Trial Administrator - Manual December Page 20