Financial model for reimbursment at Karolinska University Hospital

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2 Clinical trial Clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subjects that are designed to answer specific questions about biomedical or behavioral interventions generating safety and efficacy data. Planning Planning The ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor, but any or all of the sponsor's trial-related duties and functions can be transfered to a CRO. Examples of cell therapy study flow Cardiopoietic mesenchymal stem cells Autologous stem cells Oral mucosal epithelial cells Allogeneic NK cells Financial model for reimbursment at Karolinska University Hospital Financial model for reimbursment at Karolinska University Hospital When conducting a clinical trial Karolinska university Hospital need to be reimbursed for the study specific costs which are additional to conventional treatment. Financial Model Template for calculation of study specific costs Application Competent Authority Application Competent Authority Need for an clinical trial application All trials with a purpose to evaluate or prove clinical efficacy and/or safety should be approved by MPA, other European NCA or FDA. Application form The first step in an application is to obtain a EudraCT number. This is a unique identifier which is required for all trials conducted with an investigational medicinal product in any EU Member 2

3 State. It can only be obtained from the EudraCT pages of the EMA website.the application form can then be completed and downloaded using EudraCT website. Once completed the clinical trial application form should be saved as an EudraCT XML file. Signatures The signature page of the application form must be signed before submission. Either insert a signature image prior to conversion to PDF, or print, sign, scan and then merge the signature page with the relevant PDF. Please note that digital signatures are currently not accepted. XML file An XML file is the data format of the saved clinical trial application form information. It is created via the EudraCT website. The XML file of the completed clinical trial application form information is required to enable the authorities to enter the details of the trial into the EudraCT website as they are obliged to do by the Clinical Trials Directive. Eudra-CT application Eudra-CT application Who will recieve the Eudra-CT number? The Eudra-CT number will be sent to the provided and shown on the screen. Can I receive help with my application? MPA can provide help with questions regarding Clinical trial applications. Fill in the Eudra-CT application form Remember to save When you fill in the electronic application it is important to continously save the form otherwise the information will be gone. We advice to save the form each 10 minutes to be sure all information included are saved. Only insert treatments that are to be tested The celltherapy to be tested and any reference substances such as placebo or a comparator should be inserted. Concomitant medication is a drug or biological product, other than a study drug, taken by a subject during a clinical trial and should not be inserted in the Eudra-CT application form. All investigators and sites In the form all investigators and sites that will participate in the study should be filled in. Create a XML and PDF file When all the requested information is filled in and the form validated a PDF and XML file should be created. Versions of the XML file should be stored locally to complete, validate, compare, or to prepare for submission to a National Competent Authority. Both the PDF and XML file should be attached when the application is sent electronically. 3

4 Review time at Medical Products Agency (MPA) NOTE: Make sure to always use the latest version of XML-file to avoid that outdated information is sent to authorities, for example when an amendment is submitted. Required documentation Required documentation Application documents Application document should be placed in different folders as separate pdf-files according to the following structure: General information Clinical Study protocol (CSP) Investigator's broschure (IB) Investigational Medicinal Product Dossier (IMPD) Additional info Scientific advice or Pediatric Investigational Plan (PIP) NOTE: Reference Safety Information (RSI) shall be submitted with the application for all investigational medicinal Products. For approved Products the Summary of Products Characteristics (SmPC) could be used and for non approved Products the information should be provided according to the same structure as the SmPC. Please indicate in your cover letter where the RSI is located. Review time at Medical Products Agency (MPA) Turnaround time for application Medical Products Agency (MPA) follow the EU procedure for Review and after a validation period of max 10 days (additional missing documentation will be required) the Review process will start. The Review time is normally 60 days for medical products however for advanced therapies the Review time will take up to 90 days and even longer for gene therapy products. NOTE: The sponsor is responsible that all approvals are in place before any patients can be screened. This include authorisation from Ethics Committee as well as the Radiation Safety Committee (if applicable). A m e n d m e n t s Amendments The sponsor should notify the Competent Authority and/or Ethics Committee of amendments that are substantial/significant. Amendments are substantial when they are likely to have a significant impact on the safety or physical or mental integrity of the clinical trial participants and/or the scientific value of the trial. It is up to the sponsor to assess whether an amendment is to be regarded as substantial. Non-substantial amendments do not need to be submitted to Competent Authority and/or Ethics Committee. The review time is approximately 4

5 35 days. Voluntary Harmonisation Procedure (VHP) VOLUNTARY HARMONISATION PROCEDURE (VHP) What is VHP? A harmonised procedure for assessing multinational clinical trials in EU proposed by Clinical Trials Facilitation Group (CTFG). The assessment is conducted and coordinated between the National Competent Authorities (NCA) of the member states in which the trial take place. When can you apply with VHP? If you are conducting a trial in two or more member states in EU. Why apply to VHP instead of national competent authorities? Allows for a single initial application for the conduct of multi-national clinical trials and the sponsors can obtain a harmonised assessment from all NCA in the member states participating. The actual trial must still be authorised at national level, and it is therefore not a centralised authorisation. VHP procedure The VHP comprises three phases: Phase 1 Request for VHP and validation of the application (5 working days) Phase 2 Review of CTA by the NCA of the participating MS (30 calendar days) resulting in approval or grounds for non-acceptance (GNA) Response to GNA submitted (within 10 calendar days) NCA review and harmonised opinion (maximum 20 calendar days), which may be: Unanimous decision that CTA approvable Unanimous decision that CTA not approvable CTA considered approvable in some MS, with names of MS with unresolved GNA forwarded to applicant NOTE: Phase 1 and 2 are actually composing the submission phase to the CTFG. Phase 3 is the formal submission of a clinical trial to each NCA. Phase 3 National step (formal CTA, following approval at either day 30 or day 60) 5

6 Submit CTA to all concerned NCA who consider VHP approvable (within 20 calendar days). In the covering letter for the Clinical Trial to the NCA, the sponsor should remind the NCA that this Multi National Clinical Trial has undergone the VHP and add the with the VHP approval. NCA approval (within 10 calendar days) If VHP assessment reaches consensus, the scientific content of the application must not be changed when submitted to the national competent authorities. However, it may be adapted to meet national requirements. NOTE: These timelines do not apply for Member States with unresolved GNA following VHP assessment. Substantial amendments All substantial amendments shall be submitted via VHP otherwise the clinical trial are not harmonised anymore which implies that each NCA can do different assessments. After approval from VHP the national submission should explicitly state in the covering letter that the information provided is the same as that has been approved by the VHP. Fee There is no fee for the VHP process, but you pay the ordinary fee to each NCA for a formal approval. Application Ethics Committee Application Ethics Committee Application to Ethics Committee in Sweden can be submitted to one of the six regional committees. Only one application for all centers in Sweden. Required documents For information about required documents see last page of the application form. Note that only applicable documents needs to be attached. Turnaround time for application Turnaround time for Ethics Committee application concerning somatic cell therapy or medicinal products containing genetically modified organisms is 180 days after a complete application has been received. NOTE: Applications must be made in Swedish and layman language. Number of copies aquired will differ for each ethics committee, see link to EPN homepage for more information. S t u d y d o c u m e n t s b e f o r e s t u d y Study documents before study Documents required to follow regulatory, legal and ICH-GCP requirement. Investigational Medicinal Product Dossier (IMPD) Investigational Medicinal Product Dossier 6

7 (IMPD) What is IMPD? The Investigational Medicinal Product Dossier is the basis for approval of clinical trials by the competent authorities in the EU. The IMPD includes summaries of information related to the quality, manufacture and control of the Investigational Medicinal Product, data from non-clinical studies and from its clinical use. An overall risk-benefit assessment including Reference Safety Information (RSI), critical analyses of the non-clinical and clinical data in relation to the potential risks and benefits of the proposed study have to be part of the IMPD. Authorised Medicinal Product In certain situations when the Investigational Medicinal Product has already been authorised as a medicinal product in one of the EU Member States or clinical studies where the IMPD have been approved by a Member State, a Summary of Product Characteritics (SmPC) will be sufficient as Reference Safety Information. NOTE: The applicant may either provide a stand-alone IMPD or cross-refer to the IB for the preclinical and clinical parts of the IMPD. Labelling Labelling Investigational Product label A copy of the Investigational Product label should be included in the Investigational Medicinal Product Dossier (IMPD) and sent in together with the Clinical Study Protocol to Medical Products Agency (MPA). NOTE: The label need to be in the local language. Investigator Brochure (IB) Investigator Brochure (IB) What is IB? The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. NOTE: The sponsor should update the Investigator's Brochure as any new information becomes available. The recommendation is an annualy review. Clinical Study Protocol (CSP) Clinical Study Protocol (CSP) What is a CSP? The clinical study protocol should contain scientific, regulatory, statistical and ICH-GCP requirements. 7

8 What should the CSP contain? The protocol describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these data could also be provided in referenced documents. NOTE: The Study Drug in cell therapy studies consist of living cells which are fragile and difficult to handle compared to conventional medicine. It is therefore vital to describe a detailed Cell Therapy Product flow in the Clinical Study Protocol. P a t i e n t I n f o r m a t i o n a n d I n f o r m e d C o n s e n t F o r m ( I C F ) Patient Information and Informed Consent Form (ICF) Patient Information It is important that the information for the subject is given in mother tongue in a simple and clear language. The written information should be a complement to the information given orally. There should alway s be given a opportunity for the subject to ask questions. What should the Patient Information contain? See link Ethics Committee advice for Patient Information and Informed Consent. Informed Consent Form (ICF) Freely given informed consent should be obtained from every subject prior to any study procedures. where the patient confirms his/her willingness to participate in the study, after having been informed of all aspects that are relevant to the subject s decision to participate. The consent form may be separate, but a copy of it, as well as a copy of the information form and any annexes, is to be kept by the person participating in the research. NOTE: The ICF should be signed by both the patient and physcian, prefereably at the same occasion. The physcian should never sign the ICF before the patient. Resource Certificate Resource Certificate What is a Resource Certificate? After that the Investigator had been able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of suitable subjects within the agreed recruitment period, had sufficient time, staff and adequate facilities allocated for the Study. The Head of Department should sign a certificate to ensure adequate resources. NOTE: A resource certificate for each centre participating in the Study should be included in the Ethics Committee Application. Curriculum vitae evidencing qualifications of investigator(s) Curriculum vitae evidencing qualifications of investigator(s) 8

9 Who can conduct a Clinical Trial? According to statues of Medical Products Agency, a clinical trial can only be conducted by a licensed physician or dentist. What should the CV contain? The regulations state that the investigator(s) and sub-investigator(s) must have knowledge and experience in clinical trials of the same type. This refers to documented training in GCP (Good Clinical Practice, GCP), a track record of previous participation in clinical trials together with good knowledge of the study drug. Evidence of qualifications should be provided through up-todate curriculum vitae and/or other relevant documentation requested by the sponsor, the IRB/IEC, and/or the regulatory authority(ies). NOTE: It is recommended to have a breif update of the GCP training annualy. Instructions for handling Investigational Product(s) and trial related materials Instructions for handling Investigational Product(s) and trial related materials The sponsor should ensure that written procedures include instructions for the handling, storage, destruction and documentation of investigational product(s) that should followed in the trial. This can be done in the Clinical Study Protocol or in a seperat instruction (refered to in the CSP). What should the instruction contain? The procedures should address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of unused investigational product(s) to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirement(s)). Documentation It is important to document the cell therapy product flow from ordering to destruction to maintain an audit trail. Release of cell therapy product In case of cell therapy products the pharmacy will not handle these at current time. GMP facilities can get permission to release cell therapy products instead of the pharmacy. NOTE: The Study Drug in cell therapy studies consist of living cells which are fragile and difficult to handle. It is therefore vital to describe Cell Therapy Product flow in detail. Trial Master File (Investigator and Sponsor) Trial Master File (Investigator and Sponsor) What is Trial Master File? 9

10 A binder to maintain documentation specified by regulatory requirements and Good Clinical Practice (GCP). Trial master files should be established at the beginning of the trial, both at the investigator site and at the sponsor's office. A final close-out of a trial can only be done when the monitor has reviewed both investigator and sponsor files and confirmed that all necessary documents are in the appropriate files. NOTE: Sponsor is responsible for sending updated information regarding study documents to investigator(s). The investigator(s) is responsible for informing involved staff and uppdating the Investigator Study File. Pre-trial and Trial Initiation Monitoring report Pre-trial and Trial Initiation Monitoring report Monitoring in clinical trials Monitoring is the act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s). The sponsor should determine the appropriate extent and nature of monitoring. In general there is a need for on-site monitoring, before, during, and after the trial. Pre-Trial Monitoring Report To document feasibility of the site (e.g. suitablity for participating in the trial). Trial Initiation Montoring Report Trial procedures and documents are reviewed with the investigator and the investigator's trial staff. Shipping records for Investigational Product(s) Shipping records for Investigational Product(s) What should shipping records contain? Documents of shipment dates, batch numbers and method of shipment of investigational product(s) and trial-related materials. NOTE: The purpose is to enable tracking of product batch, review of shipping conditions, and accountability. Signature and delegation list Signature and delegation list What is a signature and delegation list? A list of appropriately qualified staff to whom the investigator has delegated significant trialrelated duties. The list should include signatures and initials of all staff involved in the trialrelated duties. Origin of source data Origin of source data 10

11 What is source data? All information in original records (e.g. patient records) and certified copies of clinical findings, including laboratory assessments, observations or other activities in a clinical study. Access to source data/documents The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data/documents. NOTE: The purpose is to enable reconstruction and evaluation of the study. Master Randomisation List Master Randomisation List Documents that describes the method for randomisation of trial population.the randomisation schedule of a clinical trial documents the random allocation of treatments to subjects. Different trial designs will require different procedures for generating randomisation schedules. The randomisation schedule should be reproducible (if the need arises). Decoding procedures for blinded trials Decoding procedures for blinded trials In case of emergency the unblinding procedure must be documented before first patient in. The documentation should include how identity of blinded investigational product can be revealed without breaking the blind for the remaining subjects' treatment. NOTE: It is recommended that the person(s) that can unblind is stated in the patient record and CSP for emergancy situations. Study samples and procedures Study samples and procedures Certificate/Accreditation/Validation of Medical/Laboratory/Technical procedures Make sure to use accredited and certified service and equipment suppliers. If not using an accredited method be sure to obtain validation documents and describe the procedure in the clinical study protocol. It is important to use comparable methods and equipment for the same analysis. NOTE: File the accreditations and validation documents in the Trial Master File at site. Reference Values for Medical/Laboratory/Technical procedures Dated and signed reference value(s) and ranges for the laboratory, medical and technical procedures used in the trial. Change of reference values and ranges that during the trial should be documented. How do you obtain Reference value(s)? 11

12 Contact the service provider for the laboratory, medical and technical procedures to obtain appropriate documentation. Labelling of study samples Important to label the study samples with study code and to pseudomize the patient data and use a code list for indentification. No personal data on the sample tubes. Application Biobank Application Biobank The Swedish Biobank Act The Swedish Biobank Act allows biological samples collected and / or stored in healthcare can be used for research and clinical trials if patient/ donor consented to this. Collection and/or use of human samples for research purposes require approval by a Swedish Ethics Review Board for each specific project/clinical trial. Single center application Single centre research study involving sampling at one health authority. Information and applications for research where the application is submitted to the custodian of the biobank. For contact information about specific biobanks, please contact the regional coordinators (see link). Multi center application Application is done to a Regional Biobank Centre (see link). This procedure is used in studies with more than one responsible research body (multi-centre studies), where the samples are: newly collected, and shall be released to a recipient biobank Application Radiation Safety Committee Application Radiation Safety Committee When to apply to the Radiation Safety Committee? All studies where the study subject is exposed to radiation in addition to conventional treatment requires an application. Radiation safety application The application to the Radiation Safety Committee is done locally per study center. NOTE: Remember that the Clinical trial can not start until authorisation from Ethics Committée as well as the Radiation Safety Committee approval (if applicable) is received. I n s u r a n c e Insurance Purpose 12

13 To document that compensation to subject(s) for trial-related injury will be available. In the application to Ethics Committee the insurance must be specified. Study drug owned by external company Contact the company and make sure to get a written certificate of their insurance for the patients. Study drug owned by researcher At Karolinska University Hospital Karolinska Trial Alliance (KTA) is responsible for the pharmaceuticel insurance that Karolinska University Hospital has signed for clinical trials. There are a limited number of patients who can be insured every year. At Karolinska Institute Responsible for clinical trials directed by the Karolinska Institute (KI), have their own insurance through the Legal. Hospital exemption The Swedish Patient Insurance Scheme is applicable since patients are treated under an individual investigator responsibility. S e t u p c o n t r a c t s Set up contracts Purpose A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and if appropriate on financial matters. For exampel with clinic, GMP facility, pharmacy and CRO. Contract with GMP facility With an authorised GMP facility that can manufacture the cell therapy product according to regulations. Vecura at Karolinska University Hospital is approved by the Swedish Medical Products Agency as a manufacturer of cell- and gene therapy products for clinical trials. Contract with Pharmacy Swedish regulation states that there should be a pharmacy who releases a clinical trial drug to clinic. In case of cell therapy products the pharmacy will not handle these at current time. GMP facilities can get permission to release cell therapy products instead of the pharmacy. If you combine the cell therapy with other medicinal product(s) a contract to define responsibilities and costs with a pharmacy can be nessecary. Release of cell therapy product In case of cell therapy products the pharmacy will not handle these at current time. Therefore you need to contact the local GMP cell manufacturer to discuss how release can be done. 13

14 Contract with clinic A contract with clinic(s) who participate in the Study to decide responsibilities and financial aspects of the trial. Contract with Clinical Trial Support Organisation A contract with statement of which sponsor's trial-related duties that will be transferred to Contract Reasearch Organisation (CRO) or equivalent organization. Note: ICH-GCP says: "A sponsor may transfer any or all of the and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor." Contract with pharmaceutical company (LIF) and health care Agreement between the SKL, Sveriges Kommuner och Landsting (The Swedish Association of Local Authorities and Regions) and LIF (the research-based pharmaceutical industry in Sweden) concerning clinical trials of medicines. Valid from Data handling Data handling What is data handling? Includes, record-keeping and handling of data. The purpose is to record, store, transfer and, where necessary, convert efficiently and accurately. The information gathered on each trial subject should contain data that can be analyzed according to Clinical Study Protocol and/or statistical analysis plan. Note: Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly. What is audit trail? The maintenance of an audit trail is essential to ensure that changes to the data are traceable. Any changes to the data should be captured by the audit trail. Case Report Form (CRF)- electronic or paper The CRF is a printed, optical, or electronic document designed to record all of the protocol required information on each trial subject to be reported to the sponsor. The sponsor designs the contents of the forms and distributes them in paper or electronic format to all locations where the clinical trial is being conducted. Note: The CRF (electronic or paper) should be done in a validated system. It is advisable to contact a statistician before construction of the Case Report Form. What is data management? Data management is a general term that covers a broad range of data applications. It may 14

15 refer to basic data management concepts or to specific technologies. Including following data applications: Data design Data storage Data security What is included in a Data Management Plan (DMP)? The data management plan describes the activities to be conducted in the processing of data. Key topics are clinical data management system (electronic or paper) to be used, description of data sources, data handling processes, data transfer formats and process, and quality control procedures to be applied. It also includes roles and responsibilities of study personnel and agreed timelines for the study. Notification to register personal data at Karolinska University Hospital Notification to register personal data at Karolinska University Hospital Notification of register for personal data is required for all records that contain personal information. The notification should be done in Karolinska University Hospitals IT system "PUH". Statistics Analysis Plan (SAP) Statistics Analysis Plan (SAP) What is a statistical analysis plan? A statistical analysis plan is a document that contains a more technical and detailed elaboration of the principal features of the analysis described in the protocol, and includes detailed procedures for executing the statistical analysis of the primary and secondary variables and other data. What should be included? The number of subjects planned to be enrolled. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification. The level of significance to be used. Criteria for the termination of the trial and Statistical method to be used. Procedure for accounting for missing, unused, and false data. Procedures for reporting any deviation(s) from the original statistical plan. The selection of subjects to be included in the analyses (e.g. all randomized subjects, all dosed subjects, all eligible subjects, evaluable subjects). NOTE: It is important that the study is powered to show statistic significance in the primary objective. If you do not set up a seperate Statistical Analysis Plan? If the study do not set up a statistical analysis plan it is important to describe the diffrent 15

16 components of the plan in clinical trial protocol. NOTE: The sponsor should utilize appropriately qualified individuals to conduct the statistical analyses. Any deviation(s) from the original statistical plan should be described and justified in protocol and/or in the final report. Randomization/ registration procedures Randomization/ registration procedures Randomized studies (not blinded) Randomizations lists needed in the Study which should be provided by the sponsor. Randomized blinded studies The sponsor should provide the coding system in blinded trials for the investigational product(s). Unblinding of Investigational Product(s) Sponsor should describe the unblinding procedures that permits rapid identification of the Investigational Product(s) in case of a medical emergency and do not permit undetectable breaks of the blinding. This procedure should only be performed when applicable according to Clinical Study Protocol and/or other written instructions from the sponsor. Registration Studies The sponsor will provide registration list(s) with sequential patient numbers if the study design do not aquire randomization of subjects. 16

17 Conduct Conduct The conduct phase starts with the first patient in (FPI) after receiving approvals from applicable authorities. Handling and notification of adverse events Handling and notification of adverse events Flow chart for safety reporting Safety evaluation Safety evaluation should be done during the whole study and the follow up period stated in the Clinical Study Protocol. Adverse Event (AE) Any untoward medical occurrence in a patient/subject that have received Invesigational Product(s). An adverse event (AE) can be any unfavourable and unintended sign (objective findings done by physcian during physical examination or laboratory results), symptom (subjective experiences reported by patient), or disease temporally associated with the use of Investigational Product(s), whether or not considered related. Adverse Drug Reaction (ADR) Any noxious and undesired reaction related to an experimental drug or an experiment, whatever the dose of the drug. This implies that it exists a relationship between the drug or the experiment and the untoward effect. The difference compared with AE is the relationsship to the drug, thus all adverse drug reactions are adverse events but the opposite is not the case. Serious Adverse Event (SAE) The following events consistute a "serious" adverse reaction, according to the EU: Death A life threatening episode requiring immediate intervention An event resulting in hospitalization or that prolongs existing hospitalization Events resulting in persistent or significant incapacitation or disability A congenital anomaly or birth defect Serious adverse events should be reported to the sponsor within 24 hours after the investigator received knowledge of the event. The investigator shall assess the relationship to study medication and follow up the serious adverse event regarding progress and the impact on the subject. Serious Adverse Reaction (SAR) The same criterias as for SAE but there are a relationship between the drug or the experiment 17

18 and the untoward effect. Suspected Unexpected Serious Adverse Reaction (SUSAR) Unexpected If its nature and severity are not consistent with the information about the medicinal product in question set out: in the case of a product with a marketing authorisation, in the summary of product characteristics for that product, in the case of any other investigational medicinal product, in the investigator's brochure relating to the trial in question. Serious See definition of Serious adverse event (SAE) above. Adverse Any untoward and unintended response in a subject to an investigational medicinal product which is related to any dose administered. Sponsor's responsibility to report SUSAR:s that are life threatning or resulted in death to authorities: The sponsor shall report Suspected Unexpected Serious Adverse Reactions that is life threatening or resulted in a test subject death to the MPA and the Ethics Review Board. Within 7 days: Reporting shall be done as soon as possible after the sponsor became aware of the incident. Within 15 days: Additional relevant information on the implications surrounding after the sponsor became aware of the incident. Sponsor's responsibility to report other SUSAR:s to authorities: The sponsor should report to the MPA and the Ethical Review Board any other suspicious unexpected serious adverse reactions that are not life threatning or resulted in death. Within 15 days: After the date the sponsor first became aware of the incident. Reporting format for SUSAR:s Reporting to the MPA shall be made in the european pharmacovigilance database, EudraVigilance. The sponsor or the organization that has been delegated the SUSAR reporting need to be a user in the EudraVigilance database which requires a continuous payment of license. 18

19 How to apply for assistance with reporting SUSAR:S to the EudraVigilance database For non-commercial sponsors studying an EU-approved drug with insufficient financial resources and who have exhausted all other opportunities for SUSAR reporting to the EudraVigilance database can make an agreement with MPA to report SUSARs on CIOMS (Council for International Organization of Medical Sciences ) form. MPA will then report the information in the CIOMS form to the EudraVigilance database. Sponsors wishing to use this possibility should in the application to MPA apply for assistance which should include a report of efforts made to establish a functioning SUSAR reporting to the EudraVigilance database. Sponsors Responsibility to report SUSAR:s to investigators In cases where the trial is conducted in more than one trial site, the sponsor shall as soon as possible inform all investigators of suspected unexpected serious adverse reactions that have occurred. Annual Safety Reporting Annual Safety Reporting What is Annual Safety Reporting? Once a year throughout the clinical trial, the sponsor shall provide the Member States in whose territory the clinical trial is being conducted and the Ethics Committee with a listing of all suspected serious adverse reactions which have occurred over this period and a report of the subjects' safety. Trial conducted with IB as reference safety information If the investigational product has an IB as safety reference the sponsor shall send an annual safety report on the tested investigational medicinal product to the Medical Products Agency and the Ethics Review Board. The format of the annual safety report should be consistent with the ICH Guideline Development Safety Update Report (DSUR). Trial conducted with SPC as reference safety information For trials with approved drugs when a Summary of Product Characteristics (SPC) is used as reference safety information it is sufficient that the annual security report includes a list of all serious adverse events during the past year in for investigational products in the trial and the assessment of the subjects' safety. Annual safety summary shall be sent to the Medical Products Agency and the Ethics Review Board. Obligation to submit annual safety update resolves when the study has been completed in Sweden. Study documents during study Study documents during study Documents required to follow regulatory, legal and ICH-GCP requirements. 19

20 Investigational Products accountability at the site To document that investigational product(s) have been used according to the protocol. The records should contain product's delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial subjects. Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor. Accountability log will not be applicable for the cell therapy product which is delivered by the GMP facility per patient. NOTE: There must be an audit trail for the Investigational product from ordering to destruction. Record of blood and/or tissue samples All samples taken from patient stated in the protocol (not routine samples). For example biomarkers, genetics, urine, biopsies and tumour tissue. The purpose is to document location and identification of retained samples.there should also be a log of how the samples have been handled and where they are stored. NOTE: Handling of samples should be done according to instructions in Clinical Study Protocol and/or sample handling instructions from sponsor. Subject screening log and identification code list What is a Subject screening log? Identification of all subjects who entered pre-trial screening. The log should not contain any personal data except name or initials. What is Subject identification code list? A document that investigator keeps a confidential list of names of all subjects allocated to trial numbers on enrolling in the trial. Allows investigator to reveal identity of any subject. NOTE: The allocation of subject number should be done before any study treatment is started. What is a donor log? A log which make it possible to trace allogenic cell therapies back to donor. NOTE: The cell therapy must be traceble for 30 years according to the Swedish Health and Welfare Board. Revision or update of study documents Documentation of revisions and updates of trial related documents that take effect during trial should be done. The sponsor should notify the Competent Authority and/or Ethics Committee of changes that are substantial/significant. Amendments are substantial when they are likely to have a significant impact on the safety or physical or mental integrity of the clinical trial participants and/or the scientific value of the trial. It is up to the sponsor to assess whether an 20

21 amendment is to be regarded as substantial. Non-substantial amendments do not need to be submitted to Competent Authority and/or Ethics Committee. NOTE: All document(s) should be identify by a version number and date. Monitoring Monitoring Purpose of monitoring The act of overseeing the progress of a clinical study and ensuring that it is conducted, recorded and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP) and the applicable regulatory requirement(s). Continuous quality control The purposes of trial monitoring is to verify that the rights and well-being of human subjects are protected. But also that the reported trial data are accurate, complete, and verifiable from source documents and the conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s). NOTE: On-site monitoring should at least be done at three occasions: before, during and after the trial. Monitor reports A written report from monitor to the sponsor after each site visit and/or other study-related communications. After taking part of the information from the monitor the sponsor should sign the report. Case Report Forms (CRF) Paper CRF A printed document designed to record all of the protocol required information to be reported to the sponsor on each trial subject. The CRF should be signed to document that the investigator or authorized member of the investigator's staff confirms the observations recorded. All changes/additions or corrections made to CRF after initial data were recorded. Electronic CRF Electronic data designed to record all of the protocol required information to be reported to the sponsor on each trial subject. Important that the ecrf has an audit trail so that all changes are recorded and the login will be the signature that confirms the observations recorded. NOTE: The investigator should ensure the accuracy, completeness, legibility, and timeliness of the trial data. D a t a M a n a g e m e n t Data Management What is data management? 21

22 Data management is a general term that covers a broad range of data applications. It may refer to basic data management concepts or to specific technologies. Some of the notable applications included: Data design Data storage Data security How is Data Management performed in a clinical trial? Quality assurance activities undertaken to verify that the requirements for quality have been fulfilled for all trial-related activities during the whole study (from Clinical Study Protocol to Clinical Study Report). The sponsor should utilize qualified individuals to performe the quality assurance. Data management should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly. Application amendment to Competent Authority and/or Ethics Committee Application amendment to Competent Authority and/or Ethics Committee Amendments The sponsor should notify the Competent Authority and/or Ethics Committee of amendments that are substantial/significant. Amendments are substantial when they are likely to have a significant impact on the safety or physical or mental integrity of the clinical trial participants and/or the scientific value of the trial. It is up to the sponsor to assess whether an amendment is to be regarded as substantial. Non-substantial amendments do not need to be submitted to Competent Authority and/or Ethics Committee. Substantial Amendment Notification Form Amendments to both Competent Authority and/or Ethics Committee are in EU done on a Substantial Amendment Notification Form. Under section F in the Substantial Amendment Notification Form be sure to document all substantial changes by specifying current and new wordings. It is also important to explain the reason for the changes. The approximate time of approval of an amendment to MPA is 35 days. NOTE: Until approval from Competent Authority and/or Ethics Committee has been received the changes done in the amendment shall not bli implemented in the clinical trial. Investigator Brochure updates Investigator Brochure updates Why update the Investigator Brochure? The Investigator Brochure should contain relevant and current scientific information about the investigational product. 22

23 Documentation of updates Any updates to the IB should be documented and provided to the investigator(s) participating in the study by the sponsor. If the Investigational Medicinal Product Dossier (IMPD) is updated be sure to update IB if applicable. NOTE: Versions of the IB should be identified by a version number and date. Randomization/registration during a clinical trial Randomization/registration during a clinical trial Randomized studies The investigator should follow the trial's randomization procedures stated in the clinical study protocol and/or instructions from sponsor. Randomized blinded studies In blinded trials, the coding system for the investigational product(s) should be provided by the sponsor and include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding. NOTE: The investigator should promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational product. Registration studies Registration with sequential patient numbers according to clinical study protocol and/or instructions from sponsor. Audit Audit What is an audit? A systematic and independent examination initiated by the sponsor of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analysed and accurately reported according to the protocol, sponsor s standard operating procedures (SOP), Good Clinical Practice (GCP), and the applicable regulatory requirement(s). Audit Report The observations and findings of the auditor(s) should be documented. Regulatory authority(ies) may seek access to an audit report when evidence of serious GCP noncompliance exists, or in the course of legal proceedings. Audit certificate 23

24 The auditor should prepare an audit certificate at the request of the sponsor. The sponsor should attach the audit certificate to a clinical trial/study report of the targeted trial. The audit certificate should contain the following information: Information that identifies the trial, such as the chemical name or identification code of the investigational drug, the trial title, and the protocol number. The date of issuing the audit certificate. The contents of the audit (e.g., subjects and date of the audit, and date of issuing the audit report). The name(s), title and address of the auditor (s)(and the auditing department manager). The name and workplace address of the auditee. The sponsor should when required by applicable law or regulation provide an audit certificate. Inspection Inspection Risk-based inspections It uses a combination of information provided to the CA on the Compliance Report, internal information about previous inspection history, organizational changes and other compliance reports with the results of intelligence gathering to determine an organization s control of their risk. Organizations selected for inspection under the risk-based inspection program are notified of the inspection in advance. The notification includes a request for information, in the form of a GCP inspection dossier and clinical trials spreadsheet, to be submitted within 30 days of the request. This dossier requests a list of clinical trials, organization charts, standard operating procedure (SOP) lists, key contact details, overview of facilities, key service providers and clinical trials activities. Systems Inspections GCP Systems Inspections examine the systems used by your organization in the conduct of clinical trial research. This will involve a brief tour of facilities, review of documentation and interviews with key personnel. The inspectors will select a number of clinical trials to review in order examine how the organization s trial procedures are applied. Study Specific Inspections Study specific GCP Inspections assess a particular clinical trial which has been completed and reported. This may be a pivotal or key decision making trial, although this is not always the case. This will involve a detailed review of the trial master file, final clinical study report, selected review of clinical trials and pharmacovigilance databases, interviews with key staff, review of contracts and agreements and review of selected case report forms. Triggered inspections 24

25 These are ad-hoc inspections that may be triggered as a result of CA licensing requests or reports received by the CA on suspected violations of legislation relating to the conduct of clinical trials. In rare circumstances the organization may not be notified of these inspections in advance and a plan may not be shared with the organization. CHMP can request GCP inspections in relation to marketing authorization applications made using the EU centralized procedure. EMA coordinates these inspections, which are conducted by inspectors from the EU Member States. Pre-Inspection An inspection plan will be provided to the organization in advance of the inspection. Any comments or questions relating to this plan can be discussed with the Inspector at this time. The organizations should ensure that all documentation requested as part of the inspection plan is available at the start of the inspection. During the inspection The inspections consist of site visits to the organization and, where appropriate, selected investigator sites. The inspection will start with an opening meeting where the Inspector will outline the scope and purpose of the inspection, confirm the inspection plan. During the inspection, the inspector will request additional documentation and the organization should be prepared to provide this promptly during the inspection. At the end of the inspection there will be a closing meeting where the findings are verbal feedback on any non-compliances are provided to the organization and the plans for any further sites to be inspected are discussed, as well as the timescales for issuing the inspection report. Post inspection Inspection Fees Following the inspection the inspected organization will receive an invoice from the MPA. Inspection Report, Responses and Statement The grading of findings found during inspection or subsequent to post-inspection review are classified as 'Critical', 'Major' and 'Other' findings. In addition, the inspectors may include observations and recommendations in the Inspection Report. The inspected organization is requested to provide a response to the Inspection Report in the form of a corrective action and preventative action (CAPA) plan. Once adequate responses have been received from the organization, a GCP Inspection Statement is issued (except where there are unresolved critical findings or enforcement issues arise). The outcome of your inspection will be taken into consideration and in part determine the frequency and scope of subsequent inspections. 25