SOP04: Standard Operating Procedure for Trial Supplies and Labelling

Transcription

1 SOP04: Standard Operating Procedure for Trial Supplies and Labelling Authorship Team: Anne Seagrove & Mair Roberts Joint SOP Group on Trial Administration (viz Angela Evans, Sarah Gaze, Hayley Hutchings, Kathy Malinovzsky, Ian Russell, Marie Thomas) Approved by WWORTH JMG (Ian Russell in chair) Signature Date of Approval 0 Version Record Version Number Effective Date Reason for Change 0 19 Dec 2007 Derived from SOP approved by NWORTH Feb 2009 Reviewed by JSOPG on 19 February Apr 2009 ACS amendments Apr 2009 MR amendments May 2009 ACS amendments May 2009 ACS amendments May 2009 ACS amendments following review at JSOPG 22 May May 2009 ACS amendments following review at JSOPG 22 May Jun 2009 ACS addition of SOPs 1a&1b to Related SOPs section Jul 2009 Addition of Related SOPs Sept 2009 ACS Amendments following JMG review Sept 2009 ACS Amendments following JMG review Sept 2009 ACS Amendments following JMG review Sept 2009 Approved in principle at JMG May 2010 Minor formatting changes Jun 2011 SOP from the perspective of CONSTRUCT, PROBAT and IST-3 Thrombolysis trial. ACS amendments following JSOPG meeting 06 Mar Jun 2011 ACS/ MS amendments following JPSOG meeting 17 Jun July 2011 ACS final amendments July 2011 ACS final amendments July 2011 Approved by JMG June 2013 Update header and formatting amendments May 2014 Remove training log post JSOPG discussion - MS & CS WWORTH-SOP04TrialSuppliesLabellingV Page 1 of 34 Not guaranteed if printed

2 1 Table of Contents 0 Version Record Table of Contents Glossary Introduction Purpose Roles and responsibilities Procedure MHRA approval Drug Costs Prescription charge NHS Treatment Costs Manufacture and Production of the IMP Obligations of a manufacturing authorisation holder Ordering Product Specification File Principles applicable to comparator product Blinding operations Randomisation code Packaging Quality Control Release of Batches Shipping Storage Recalls Returns of IMP Destruction of IMP Trial Supplies Trial supplies considerations and the treatment protocol IMP considerations in different types of trial Trials of EU marketed medicines used in accordance with their MA Labelling Adapted provisions for labelling IMPs used within MA Marketed products to be used outside of its licensed indications in a clinical trial Novel IMPS/placebo products Prescriptions for IMPs Drug Accountability Logs Incident Reporting Training Plan References...27 WWORTH-SOP04TrialSuppliesLabellingV Page 2 of 34 Not guaranteed if printed

3 9 Related SOPs Appendices...29 Appendix 1: Trial Supplies Flowcharts...30 Trial Supplies Flowchart 1 Active Substance Trial Supplies Flowchart 2 New Product Trial Supplies Flowchart 3 Product Supplied in Bulk Appendix 2: Annex 13 labelling requirements...34 WWORTH-SOP04TrialSuppliesLabellingV Page 3 of 34 Not guaranteed if printed

4 2 Glossary The full Glossary is in Swansea University H drive/documents/526- WWORTH/Development Group/Glossary. 3 Introduction This document forms part of the set of standard operating procedures of the West Wales Organisation for Rigorous Trials in Health (WWORTH) and Abertawe Bro Morgannwg University Health Board (ABMU). It describes the roles, responsibilities and actions of individuals concerned with trial supplies and labelling. Not all products used in clinical trials (CTs) are necessarily IMPs although pharmacy or other departmental quality systems may apply in hospitals in respect of such products. Annex 13 of EU Vol 4, Good Manufacturing Practices 1, includes a note about such other products as follows: Products other than the test product, placebo or comparator may be supplied to subjects participating in a trial. Such products may be used as support or escape medication for preventative, diagnostic or therapeutic reasons and/or needed to ensure that adequate medical care is provided for the subject. They may also be used in accordance with the protocol to induce a physiological response. These products do not fall within the definition of investigational medicinal products and may be supplied by the sponsor, or the investigator. The sponsor should ensure that they are in accordance with the notification/request for authorisation to conduct the trial and that they are of appropriate quality for the purposes of the trial taking into account the source of the materials, whether or not they are the subject of a marketing authorisation and whether they have been repackaged. The advice and involvement of a Qualified Person is recommended in this task. Please note that EU Directive 2001/20/EC 3 (Article 14) has adapted provisions relating to labelling for IMPs with a marketing authorisation, if they are prescribed by a doctor, dentist or pharmacist/nurse prescriber, labelled in accordance with the existing UK requirements for medicines dispensed by pharmacists, and are to be used in a CT on patients for which the product is indicated in the authorisation (see Labelling, Section 6.5). EU Directive 2003/94/EC 4 lays down the principles of good manufacturing practice in respect of medicinal products for human use and IMPs for human use. The Directive requires that all IMPs should be produced in accordance WWORTH-SOP04TrialSuppliesLabellingV Page 4 of 34 Not guaranteed if printed

5 with the principles and guidelines of good manufacturing practice (GMP) 2. GMP guidelines are contained in Volume 4 Good Manufacturing Practice Guidelines 2 in the EU with Annex 13 1 providing detailed guidance in relation to the manufacture of IMPs. The GMP guidelines are intended to ensure that trial subjects are not placed at risk arising from unsatisfactory manufacture, and that the results of CTs are unaffected by inadequate safety, quality or efficacy arising from unsatisfactory manufacture. Annex 13 also sets out requirements for labelling IMP supplies, along with guidance on ordering, shipping, and returning such supplies. The Medicines for Human Use (Clinical Trials) Regulations (the Regulations) regulate CTs in the UK since they came into force on the 1 May Contracts should be in place between the organisations involved in the manufacturer and supply of trial supplies and a Clinical Trial Agreement in place between the sponsor and Trusts/Health Boards. 4 Purpose To describe the process of manufacturing, packaging, labelling, distribution, prescription, storage and accountability of trial supplies. 5 Roles and responsibilities The people responsible for utilising and implementing this SOP are as follows: Sponsors hold overall responsibility for all aspects of the clinical trial including arrangements to provide IMPs. However, the sponsor can delegate the responsibility to the CI. Most non-commercial sponsors will usually do this. Chief Investigators (CIs) are responsible to the sponsor for implementing this SOP but will usually delegate most of the tasks specified within it to the TM/TC. Trial Manager / coordinator (TM/TC) is responsible to the CI for all tasks specified within this SOP that are delegated to the TM/TC by the CI; in particular for liaising with manufacturers, PIs and LCTPs to ensure that they comply with this SOP He or she should have a thorough understanding of, and training in, the application of GMP to IMPs, GCP and all clinical trials regulations. Please refer to the WWORTH SOP15 MHRA Approval. Chief Clinical Trials Pharmacist (CCTP) is responsible, if a member of the TMG, for advising the study team in accordance with the relevant Directives, regulations and guidelines and should be involved from an early stage. WWORTH-SOP04TrialSuppliesLabellingV Page 5 of 34 Not guaranteed if printed

6 Principal Investigators (PIs) are responsible to the CI for ensuring that IMPs are provided in accordance with the study protocol. They may delegate some responsibilities and tasks to the LC, LCTP or both; this should be recorded in the local delegation log. Local Clinical Trials Pharmacists (LCTPs) are responsible to the PI for specific pharmaceutical roles and responsibilities at a site, as defined by the study and recorded in the delegation log. Local coordinators (LCs) are responsible for any tasks at their sites delegated to them by the PI Qualified Person is the person responsible for certifying each batch of a finished product before it is released for sale or supply in the EC/EEA or for export to ensure that the batch has been manufactured and checked in accordance with the requirements of its marketing authorisation, the principles and guidelines of EC Good Manufacturing Practice and all other requirements. In the event that a defect needs to be investigated or a batch recalled, the details of the QP who certified the batch and the relevant records are readily identifiable. Cooperation is required between trial sponsors, trial staff, IMP manufacturers and LCTPs. 6 Procedure Please see MRC Clinical Trials Toolkit Trial Supplies Flowcharts 7 in Appendix 2 (or available at MHRA approval The Regulations prohibit anyone from selling or supplying an IMP to those involved in a CT unless certain conditions are met. In particular, the trial must be authorised by the MHRA and products without a UK valid marketing authorisation which are made abroad have to meet certain quality testing requirements. The regulations prohibit the manufacture, assembly or import of an IMP other than in accordance with a manufacturing authorisation (MA) granted for the purpose, unless the product has an MA. It is therefore important to ensure that a Clinical Trial Authorisation (CTA) is obtained from the MHRA (see WWORTH SOP15 MHRA Approval). The MHRA will request detailed information about the IMP. It is vital that a manufacturer with the appropriate authorisations is identified and is willing to provide the trial drugs before any applications are made to the MHRA. It can take time to identify an appropriate manufacturer so it is vital to WWORTH-SOP04TrialSuppliesLabellingV Page 6 of 34 Not guaranteed if printed

7 contact them at the earliest possible stage. It is important to ensure good communication flows between the trial team and the manufacturer, as the manufacturer will have to provide all appropriate information needed about the drug. It is also important that the TM/TC ensure that protocol amendments following MHRA approval are submitted to and approved by the MHRA before implementation. 6.2 Drug Costs Prescription charge In Wales, Northern Ireland and Scotland prescriptions are currently free. Therefore, at the time of writing, the next paragraph refers to England. The CI on behalf of the sponsor (when Swansea University (SU) is the sponsor the CI, or the first applicant on the grant application, must be employed by SU) of a clinical trial should ensure that the IMPs used in the trial, and any devices used for the administration of such products, are made available to the trial participants free of charge if they are not covered by a prescription charge and other NHS charges. The CI may choose to pay all the charges, but this would need to be included in the budget. The charges raised must be handled separately from any clinical trial payments, as per each site s pharmacy department policy. For clinical trials that are placebo-controlled all drugs must be provided free of charge. Thus, it is important to calculate the cost of the supplies accurately and these should be reflected in the budget of any grant application (see WWORTH SOP13 Protocol Development) NHS Treatment Costs These are the patient care costs which would continue to be incurred (by the NHS) if the patient care service in question continued to be provided after the R&D study had stopped. (In determining Treatment Costs, the assumption should be that the intervention/service being tested will continue after the end of the study even if there are no plans in place for it to continue). Where patient care is provided that is either an experimental treatment or a service in a different location from where it would normally be given and it differs from the normal, standard treatment for that condition, the difference between the total treatment cost and the cost of the standard treatment (if any) is called the Excess Treatment Cost (ETC). This cost is nonetheless part of treatment costs and is not an NHS Support of Research Cost. NHS Treatment Costs, including ETCs, related to non-commercial research studies are the responsibility of the NHS and are funded through WWORTH-SOP04TrialSuppliesLabellingV Page 7 of 34 Not guaranteed if printed

8 normal arrangements for commissioning patient care. This is because funding to cover these costs is allocated to Primary Care Trusts (PCTs) as part of their overall revenue allocations. In ideal circumstances, researchers should notify NHS Trusts / Health Boards (via the Trust R&D lead) about planned studies and their associated ETCs well in advance of the study starting date to allow Trusts and their commissioners to build these costs into their financial and commissioning plans. In Wales applications for ETCs should be submitted to the National Institute for Social Care and Health Research (NISCHR) using the current ETC application form. Any correspondence relating to excess treatment costs should be sent to etc@wales.gsi.gov.uk or telephone / See for details. 6.3 Manufacture and Production of the IMP See EU Volume 4, Good manufacturing practices, Annex 13, Manufacture of IMPs, February for full details. In CTIMPs there may be added risk to participating subjects compared to patients treated with marketed products. The application of GMP to the manufacture of IMPs is intended to ensure that trial subjects are not placed at risk, and that the results of clinical trials are unaffected by inadequate safety, quality or efficacy arising from unsatisfactory manufacture. Equally, it is intended to ensure that there is consistency between batches of the same IMP used in the same or different CTs, and that changes during the development of an IMP are adequately documented and justified. The production of IMPs involves added complexity in comparison to marketed products by virtue of the lack of fixed routines, variety of CT designs, consequent packaging designs, the need, often, for randomisation and blinding and increased risk of product cross-contamination and mix up. Furthermore, there may be incomplete knowledge of the potency and toxicity of the product and a lack of full process validation, or, marketed products may be used which have been repackaged or modified in some way. These challenges require personnel with a thorough understanding of, and training in, the application of GMP to IMPs. Cooperation is required between manufacturers and the trial team, including the CI as representative of the trial sponsors, who undertake the ultimate responsibility for all aspects of the CT including the quality of IMPs. Clinical trial supplies should be of a high quality and produced to a high WWORTH-SOP04TrialSuppliesLabellingV Page 8 of 34 Not guaranteed if printed

9 standard. The process of manufacturing can be lengthy particularly if a placebo needs to be manufactured, and any process that may be required to secure blinding. It is important to identify a manufacturer at the same time that the protocol is being developed. You will need to start discussion at an early stage with the manufacturer to ensure that they can provide you with all the supplies that you will need. When approaching manufacturers you should be aware that they cannot manufacture, assemble or import any IMP except in accordance with an MA. The MHRA maintains a list of licensed manufacturers within the UK which includes what activities they are licensed to undertake. Hospital pharmacies are exempt from this MA for reconstitution or repackaging of IMPs provided they are used within the hospital site. Note that although some pharmaceutical companies will provide both the IMP and placebo (or comparator) for blinded trials, this is not always the case. Alternative companies may need to be sourced who can provide the placebo tablets. They will also need to conform to the regulations and will need to provide information to the MHRA before they can manufacture the placebo Obligations of a manufacturing authorisation holder The Regulations require the holder to comply with the principles and guidelines of GMP and the Medicines for Human Use (Clinical Trials) Regulations The MA holder must have the services of a Qualified Person (QP). The QP should have the necessary qualifications and experience which are set out in the Regulations. In particular the person must check production batches of manufactured products and certify that they are of a satisfactory quality. To verify compliance with the provisions on GCP and GMP, the manufacturers will be inspected by the MHRA. They will check the trial site/s, the manufacturing site of the IMP, any laboratory used for analyses in the clinical trial and/or the sponsor's premises. Further guidance on manufacture and production of IMPs can be found in the Medicines for Human Use (Clinical Trials) Regulations document Ordering CI or TM/TC may order the IMPs on behalf of the sponsor. The order should request the processing and/or packaging of a certain number of units and/or their shipping. It should be in writing (paper or ) to the WWORTH-SOP04TrialSuppliesLabellingV Page 9 of 34 Not guaranteed if printed

10 manufacturer, and precise enough to avoid any ambiguity. It should be formally authorised and refer to the PSF (see below) and the relevant CT protocol as appropriate. A CCTP should, as a member of the TMG, advise the study team at this (or preferably earlier) stage in the process. If the TMG has no CCTP, advice should be sought from at least one external pharmacist Product Specification File The PSF should be continually updated as development of the product proceeds, ensuring appropriate traceability to the previous versions. It should include, or refer to, the following documents: Specifications and analytical methods for starting materials, packaging materials, intermediate, bulk and finished product. Manufacturing methods In-process testing and methods Approved label copy Relevant clinical trial protocols and randomisation codes, as appropriate Relevant technical agreements with contract givers, as appropriate Stability data Storage and shipment conditions The above list is not exclusive or exhaustive - the contents will vary depending on the product and stage of development. The information should form the basis for assessment of the suitability for certification and release of a particular batch by the QP and should therefore be accessible to him/her. All correspondence and files to and from the manufacturer should be held by the sponsor or delegated person as these will be requested in an MHRA inspection (WWORTH SOP03 Master Site File) Principles applicable to comparator product If a product is modified, data should be available (e.g. stability, comparative dissolution, bioavailability) to demonstrate that these changes do not significantly alter the original quality characteristics of the product. The expiry date stated for the comparator product in its original packaging WWORTH-SOP04TrialSuppliesLabellingV Page 10 of 34 Not guaranteed if printed

11 might not be applicable to the product where it has been repackaged in a different container that may not offer equivalent protection, or be compatible with the product. A suitable use by date, taking into account the nature of the product, the characteristics of the container and the storage conditions to which the article may be subjected, should be determined by or on behalf of the sponsor. Such a date should be justified and must not be later than the expiry date of the original package. There should be compatibility of expiry dating and CT duration Blinding operations Where products are blinded, systems should be in place to ensure that the blinding has been successful while allowing for identification of blinded products when necessary, including the batch numbers of the products before the blinding operation. In a blinded trial it is vitally important that nothing on the labelling or packaging unblinds the trial drug. However, it is important that in an emergency situation the identification of product can be revealed. Guidance should be in place for all the trial team on how to deal with an emergency code break (see WWORTH SOP28 Statistics, WWORTH SOP19a Pharmacovigilance 19b USMs, WWORTH SOP24 Randomisation) Randomisation code Procedures should describe the generation, security, distribution, handling and retention of any randomisation or identification code used for packaging IMPs, and code-break mechanisms. Appropriate records should be maintained (see WWORTH SOP24 Randomisation and WWORTH SOP03 Master Site File) Packaging The trial supplies should be packaged individually for each patient. The number of units to be packaged should be specified prior to the start of the packaging operations, and should include units necessary for carrying out quality control and any samples that need to be retained. Sufficient reconciliations should take place to ensure the correct quantity of each product required has been accounted for at each stage of processing. For blinded trials, it is important that the IMPs and comparators are packaged identically so as to avoid unintentional unblinding. Likewise, it is important that specifications and quality control checks are in place to guard against unintentional unblinding due to changes in appearance between different batches of packaging materials. Precautions against mis-labelling such as label reconciliation, line clearance, in process control checks by appropriately trained staff should accordingly be intensified. WWORTH-SOP04TrialSuppliesLabellingV Page 11 of 34 Not guaranteed if printed

12 The packaging must keep the IMP in good condition during transport and storage. Any opening or tampering of the outer packaging during transport should be evident Quality Control As CTIMP manufacturing processes may not be standardised or fully validated, testing takes on more importance in ensuring that each batch meets its specification. Quality control should be performed in accordance with the PSF and in accordance with the information in Article 9(2) of Directive 2001/20/EC 3. Samples of each batch of IMPs, including blinded products should be retained for the periods specified in the Directive as amended for IMPs 4. Consideration should be given to retaining samples from each packaging run/trial period until the clinical report has been prepared to enable confirmation of product identity in the event of, and as part of an investigation into inconsistent trial results Release of Batches IMPs should not be released by the manufacturer until the QP has certified that the requirements of Directive 2001/20/EC 3 have been met. Where IMPs are manufactured and packaged at different sites under the supervision of different QPs, the recommendations listed in Annex 16 8 to the GMP Guide should be followed as applicable. Where permitted, in accordance with local regulations, packaging or labelling is carried out at the investigator site by, or under the supervision of a clinical trials pharmacist, or other health care professional as allowed in those regulations, the QP is not required to certify the activity in question. The sponsor is nevertheless responsible for ensuring that the activity is adequately documented and carried out in accordance with the principles of GMP and should seek the advice of the QP in this regard Shipping Shipping of IMPs should be conducted according to instructions given by or on behalf of the sponsor in the shipping order. IMPs should remain under the control of the manufacturer until after completion of a two-step release procedure: certification by the QP; and release following fulfilment of the requirements of Article 9 (Commencement of a clinical trial) of Directive 2001/20/EC 3. The CI, on WWORTH-SOP04TrialSuppliesLabellingV Page 12 of 34 Not guaranteed if printed

13 behalf of the sponsor, should ensure that these are consistent with the details actually considered by the QP. Both releases should be recorded and retained in the relevant trial files held by or on behalf of the sponsor. De-coding arrangements should be available to the appropriate responsible personnel before IMPs are shipped to the investigator site/s. A detailed record of the shipments made by the manufacturer or importer should be maintained. It should particularly mention to whom the shipment is addressed and delivered. Transfers of IMPs from one trial site to another should remain the exception. Such transfers should be covered by trial specific procedures. The product history while outside of the control of the manufacturer, through for example, trial monitoring reports and records of storage conditions at the original trial site, should be reviewed as part of the assessment of the product s suitability for transfer and the advice of the QP should be sought. The product should be returned to the manufacturer or another authorised manufacturer for re-labelling, if necessary, and certification by a QP. Records should be retained and full traceability ensured Storage Pharmacies must have facilities that allow for IMPs to be stored separately from normal pharmacy stock in an area with restricted access. The instructions of storage should be supplied with the IMP. This should include any information about the temperature range or light conditions. It is the responsibility of the investigator to ensure that the supplies are managed and used correctly at their site. If there is a temperature requirement the trial supplies should be monitored to ensure that storage conditions meet these requirements and a temperature log should be maintained. If the drugs needs to be kept in a refrigerator there should be a temperature-recording device to monitor changes in temperature and it should ideally be alarmed. Accuracy and safety checks should be made on the equipment. Regular maintenance and recalibration of temperature monitoring equipment is essential; and is the responsibility of the LCTP Recalls Procedures for retrieving IMPs and documenting this retrieval should be agreed by the sponsor, in collaboration with the manufacturer or importer where different. The investigator and monitor need to understand their obligations under the retrieval procedure. The CI, as delegated by the sponsor, should ensure that the supplier of any comparator or other medication to be used in a CT has a system for WWORTH-SOP04TrialSuppliesLabellingV Page 13 of 34 Not guaranteed if printed

14 communicating to the trial team the need to recall any product supplied Returns of IMP IMPs should be returned on agreed conditions defined by the sponsor, specified in approved written procedures as agreed and approved by protocol. Returned IMPs should be clearly identified and stored in an appropriately controlled, dedicated area. Inventory records of the returned IMPs should be kept Destruction of IMP The Sponsor is responsible for the destruction of unused and/or returned IMPs. IMPs should not be destroyed without prior written authorisation by the CI, PI or other delegated representative of the Sponsor. The quantities of product delivered, used and recovered should be recorded, reconciled and verified by the CI or other delegated person on behalf of the sponsor for each trial site and each trial period. Destruction of unused IMPs should be carried out for a given trial site or a given trial period only after any discrepancies have been investigated and satisfactorily explained and the reconciliation has been accepted. Recording of destruction operations should be carried out in such a manner that all operations may be accounted for. The records should be kept by the Sponsor or delegated person. When destruction of IMPs takes place (even when a manufacturer does not require returns) a dated certificate of, or receipt for destruction, should be provided to the sponsor or sponsor s delegated representative (usually the CI). These documents should clearly identify, or allow traceability to, the batches and/or patient numbers involved and the actual quantities destroyed. 6.4 Trial Supplies Trial supplies should be discussed in the early stages of protocol design. The importance and time needed to set up the trial supplies should not be underestimated. The clinical trial supplies are the supplies provided to the investigator to conduct the study. This includes drugs, devices, meters, laboratory kits and other special equipment. The provision of clinical supplies is highly regulated and it is important to ensure compliance with GCP requirements. Trial supplies should be considered during the protocol development phase and sufficient resources should be requested to cover the cost of all trial supplies (see WWORTH SOP13 Protocol Development). The Department of WWORTH-SOP04TrialSuppliesLabellingV Page 14 of 34 Not guaranteed if printed

15 Health/MRC Clinical Trials Toolkit 7 trial supplies flow charts can help determine trial supplies requirements. Non-IMP related supplies purchased by a trial rather than the NHS should be ordered in accordance to the University s usual purchasing procedures, e.g. VAT exemption etc. In pragmatic trials, where the drug is already used in practice, it can be supplied from hospital stock but the processes of accountability and labelling should still be followed as per protocol and as directed by the CI in consultation with the CCTP as part of the TMG Trial supplies considerations and the treatment protocol Taken from: 7. There are different arrangements for trial supplies depending on the trial protocol, and the MA status of the product involved. Where a trial is to take place in an NHS hospital, early discussion with the LCTP is advised so that plans can be put in place early. By allowing time during the initiation phase for the LCTP to be satisfied with the local arrangements, delay to trial commencement can be avoided. The treatment protocols should be available at the pharmacy involved in providing the trial supplies to the patient, and to hospital staff who would be administering the investigational product to the trial participant, (the treatment protocols would include any particular procedures or precautions to be adopted where the IMP is to be administered to the patient by a health professional.) In many cases IMPs are solid dose forms of medicines which are selfadministered by the patients participating in a trial. This is the starting point in the general description that follows. Where other forms of IMPs are required this would affect the details of matters such as the facilities and authorisation for manufacture of that form, storage requirements, instructions for administration, etc. Also there may be other legal restrictions on some medicines (e.g. controls under the Misuse of Drugs Act). Such matters will depend upon the particulars of the trial itself, and will need to be addressed in planning the arrangements about IMP supply IMP considerations in different types of trial Different considerations apply to the handling of three different types of clinical trial: WWORTH-SOP04TrialSuppliesLabellingV Page 15 of 34 Not guaranteed if printed

16 a. trials of existing marketed medicines used according to their licensed indications b. trials involving medicines used outside their marketing authorisations or which otherwise require assembly c. other trials of new products or presentations of existing products which require manufacture. The first group does not normally involve a new manufacturing process. However, the repackaging of these products is considered to be an assembly activity. All manufacturing (it should be noted that dissolving or dispersing a product in, or diluting it or mixing it with, some other substance used as a vehicle for the purposes of administering it, is not manufacturing) and assembly activities will need to be conducted in a unit which has an IMP MA with a named QP. However, Regulation 37 (The Medicines (Clinical Trials) Regulations 2004 (SI 2004/1031) 5 provides an exception from the requirement to hold an IMP MA for the assembly of an IMP in a hospital of a health centre by a doctor or a pharmacist or a person acting under the supervision of a pharmacist this is considered below under repackaging Trials of EU marketed medicines used in accordance with their MA These trials are common amongst publicly funded trial (e.g. comparative studies, trials of different treatment combinations of medicines). Medicines marketed in the EU and certain other countries under the EEA arrangements with a MA from a regulatory body are required to be made to GMP standards, so the quality standards are met. Supplies to study participants can take place under normal prescription and dispensing arrangements. For trials in NHS hospitals, suitable arrangements should be made with the LCTP concerned. It may be possible for dispensary labelling machines to be pre-programmed. Supply could be made from medicines held as normal pharmacy stock. However: In cases where there are documented differences in bioavailability, the trial protocol should state which products are to be used. If a trial involves products that are not normally used in the host WWORTH-SOP04TrialSuppliesLabellingV Page 16 of 34 Not guaranteed if printed

17 hospital, special supplies obtained for the purpose will need to be separately controlled. Some manufacturers may agree to supply specific medicines free or at a reduced rate for trial use. This may involve centralised ordering through one pharmacy, and the hospitals would need to comply with appropriate conditions agreed with the manufacturer. The Department of Health has published separate guidance on commercial sponsorship which covers such arrangements. (Agreement by a commercial manufacturer to contribute medicines free to a collaborative trial does not necessarily imply that the manufacturer is the sponsor for that trial. It is for separate agreement whether the manufacturer would be willing to take on any sponsorship responsibilities. For example, a company might consider joining a collaboration, which is allocating sponsor responsibilities in accordance with Regulation 3(2)(b), and take on sponsorship responsibilities for pharmacovigilance where the trial involves a product that it owns. In that case, it would not take on the other responsibilities it would normally have when it is the single sponsor for a commercial trial leading to a marketing authorisation.) Repackaging can be undertaken in a hospital or health centre by a pharmacist or a person acting under his/her control or a doctor, for use within that institution. Supply can be made to other hospitals or health centres which are trial sites involved in the trial of that product (under provisions of Regulation 37 of the UK Regulations 5 ). This would reduce the extent of variation (and hence potential for misunderstanding) in such products within a single trial. Although batch sign off by a QP is not required for products repackaged under these exemption provisions, it would be good practice for a quality control pharmacist to be invited to comment on proposed arrangements. It may be able to arrange this as part of a normal NHS independent quality control audit on facilities taking place at regular intervals. Assembling pre-labelled supplies can help with the arrangements to supply to individual patients in the trial. It would be normal practice for a pharmacy department to maintain records of goods received. There would also normally be some record of supply such as through endorsement on the prescribing physician s prescription card, which would be retained with the patient s notes. There is advantage in agreement between the local investigator and pharmacy department for a trial specific direction or prescription form, which, where retained in the pharmacy after dispensing, can help with record keeping. Although good practice suggests that records be made of the batch number of the medication supplied in case of a product recall for a faulty batch (this information could indicate that the fault may affect the results of the trial) it is unlikely to be presently practical to undertake such recording. WWORTH-SOP04TrialSuppliesLabellingV Page 17 of 34 Not guaranteed if printed

18 Where the trial takes place in primary care the arrangements would most likely be different from trials in hospitals, unless a trial was undertaken in a single locality with local coordination and cooperation with the health professionals who may interact with the patient as trial participant. In the normal NHS prescribing and dispensing arrangements, patients cannot be directed to a specific pharmacy to receive their medication. Thus it is likely that the dispenser may not be aware of the patient s involvement in a trial, and so the dispensed medicine would be labelled in conformity with the normal requirements, rather than those for a clinical trial. The UK Regulations (Regulation 46, labelling) address this situation by permitting the use of the normal dispensing label for use in trials which have the characteristics specified in the second paragraph of Article 14 3 of the Clinical Trials Directive. Thus trials which fall outside these characteristics need to be supplied with the fuller clinical trials labelling as per paragraph 26 of Annex 13 1 (see Section 6.5 Labelling). It may be possible to arrange to supply the clinical trial medicines from the surgery that the patient attends, where there are a limited number of practices involved. Dispensing would then take place under the supervision of the doctor, by a responsible person who has received appropriate training. Pre-labelled supplies prepared by an assembly unit can help to facilitate this Trials involving medicines used outside their MA or which otherwise require assembly: IMP assembly and manufacturing in a unit with IMP MA Assembly will be necessary in circumstances such as the following: Where the trial involves an EU marketed medicine to be used with participant patients who do not have the same characteristics as those covered by the licensed indication for the marketed medicine; or Where there is to be blinding of the local clinical staff or other investigators to an active medicine, e.g. in comparative trials. The marketing company may be willing to provide supplies in the first example. In this case the label on the assembled product would need to comply with paragraph 26 of Annex A sample label would need to be provided to WWORTH-SOP04TrialSuppliesLabellingV Page 18 of 34 Not guaranteed if printed

19 the MHRA as part of the application for clinical trial authorisation. The choice of packaging material and description of the finished product may need discussion with the pharmacist in charge of the assembly unit Other trials of new products or presentations of existing products which require manufacture New products or presentations of existing products will require manufacturing. (This would include placebos and disguising active products by reprocessing them for blinding purposes.) All medicinal products for use by humans are required to be manufactured to Good Manufacturing Practice standards and released by a Qualified Person. GMP principles have been established for marketed products for many years, and they are now set out for both marketed products and IMPs in the in European Commission Directive 2003/94/EC 4. This also points to guidance in Annex From 1 May 2004, IMP manufacture is required to be undertaken by manufacturers with an IMP manufacturing authorisation covering the appropriate activities. The IMP manufacturing authorisation will specify the physical types of medicines that can be manufactured (eg capsules, liquids, sterile injections) and name the QP concerned (separate manufacturing authorisations are not needed for every trial). An importer of an IMP from a third country outside the EU is required to hold a manufacturing authorisation that authorises the importation of IMPs. The importer is expected to name a QP who conducts similar activities to a QP for full manufacture. The application requirements and standard provisions for IMP MAs are set out in Schedules to the Medicines for Human Use (Clinical Trials) Regulations The MHRA have published some guidance on the qualifications for QPs (including those who would be included on IMP MAs under the Grandfather provisions of the Directive). Possible manufacturers Where commercially manufactured products require a matching placebo form, the most appropriate source would be the original manufacturer, if that organisation is willing to provide such a supply; however while the company would have a manufacturer s licence for the original product, they would still need an IMP MA to prepare such placebos. It is known that many NHS hospital manufacturing units are planning to apply for IMP MA, but the overall range of products is not yet clear. There may be capacity constraints. There is extant advice (under provisions WWORTH-SOP04TrialSuppliesLabellingV Page 19 of 34 Not guaranteed if printed

20 relating to income generation) on the basis for NHS bodies to charge for manufacturing or assembly. Commercial contract manufacturers may also plan to operate in this market, and the contract research organisations who offer a manufacturing service to their clients are likely to continue to do so. It is not known how many university based units there are (e.g. undertaking manufacturing for phase I/early phase II trials), although those presently without pharmaceutical support may be able to call on hospital based manufacturing pharmacists and QPs to assist them in applying for IMP MAs. Agreements for the supply of manufactured products are likely to take the form of contracts which specify to some degree of detail what is to be supplied. It may be that more than one organisation will be involved, e.g. one to prepare a specialised product and supply in quantity to another body which then undertakes filling, packaging, labelling and other finishing operations. In some cases there may need to be preliminary formulation and stability studies to satisfy the MHRA for clinical trial authorisation. This all points to the need particularly to consider the IMP specification early on where it is likely that new products or presentations are concerned. Manufacturing processes can involve a sequence of different contractors, e.g. one for manufacturing the bulk forms, another for capsule filling, a third for packaging and labelling. Each contractor would require its own appropriate manufacturing authorisation and QP for that part of the work. The final QP will need to carefully consider the composite process for GMP and compliance with the IMP description in the request for clinical trial authorisation. QPs are required to certify in a register (or equivalent document) that each production batch satisfies the requirements set out in Article 13 3 of the Clinical Trials Directive. Once products are released by the IMP manufacturer s QP, the supplies would normally be transported to a designated store for the trial. Control and distribution of such supplies for a large trial may present logistical difficulties which will need to be considered as part of overall trial management. Circumstances requiring particular considerations Normal considerations of health and safety (including during transport), temperature, security or other forms of storage, and record keeping will apply to trial supplies as to other medicines. However new products or presentations may introduce new hazards, for which a risk assessment should be undertaken. This should include processes for disposal of WWORTH-SOP04TrialSuppliesLabellingV Page 20 of 34 Not guaranteed if printed

21 unused products at the end of a trial. Ingredients for manufacturing, for which there are no existing pharmacopoeial or other appropriate standards, will require QP consideration as to their quality. There are also requirements which relate to transmissible spongiform encephalopathy and medicinal products, published by the MHRA. The QP will also need to decide whether products manufactured and marketed outside of the EU have been prepared according to GMP standards as part of the process for importing such products under IMP manufacturing authorisations covering importation. 6.5 Labelling This section explains labelling requirements for IMPS used in CTs which come under the requirements of Directive 2001/20/EC 3 and the Medicines for Human Use Regulations which implement the Directive. Please see 7 for more detail. In the UK, where a clinical trial involves a marketed medicine used within its marketing authorisation, the product can be labelled in accordance with the requirements for a dispensed medicine. The relevant aspects and make up of such labels are shown below. Guidance on the requirements of IMPs in other situations is given in Annex 13 1 of the EU s good manufacturing practices documentation. This is shown below. A sample or description of the labelling to appear on each IMP when supplied to the patient in the trial will be provided as part of the request for the CTA from the MHRA. The style examples provided in this note may be able to help in this regard. There may be other items with pharmacological effects used in a trial, but which are not IMPs. These should be labelled in accordance with good practice for the type of product concerned Adapted provisions for labelling IMPs used within MA Article 14 (second paragraph) of the Directive 3 points to adapted provisions for labelling IMPS intended for CTs with the following characteristics: WWORTH-SOP04TrialSuppliesLabellingV Page 21 of 34 Not guaranteed if printed

22 the planning of the trial does not require particular manufacturing or packaging processes; the trial is conducted with medicinal products with, in the MS concerned by the study, a MA, manufactured or imported in accordance with the provisions of Directive 2001/83/EC the patients participating in the trial have the same characteristics as those covered by the indication specified in the above mentioned authorisation. In this situation, labelling according to normal dispensing labelling requirements is allowed. In addition, the cautionary label Keep out of the reach of children is a legal requirement on all UK dispensed medicines. Thus, the normal dispensing label required would take the form of the exemplar overleaf (although the quantity of dosage forms (tablets, capsules etc) is generally also added for dispensed medication, and the patient study ID number should also be added). Product name, form and strength Directions [as specified by the prescriber] Patient name Date of dispensing Name + address of hospital/primary care supplier Keep out of the reach of children [Any additional cautionary label (as recommended by the British National Formulary)] However for consistency with other countries (e.g. to allow for single sourcing of supplies) sponsors of commercial trials may wish their products be labelled following the guidance in Annex 13 1 for this type of trial. This is set out in paragraph 32 of Annex 13 1, and requires that the following particulars be added to the original container (but not obscure the original labelling): i. name of sponsor, contract research organisation or investigator; ii. trial reference code allowing identification of the trial site, WWORTH-SOP04TrialSuppliesLabellingV Page 22 of 34 Not guaranteed if printed

23 investigator and trial subject. The original labelling on a marketed product would contain information on the product, usage and storage conditions, batch number etc. If this alternative is followed in a publicly-funded trial, it would be appropriate to add to the original pack s existing label: i. the name of the investigator; ii. iii. a code, eg the EudraCT number for the trial, the name and address of the pharmacy etc supplying direct to the patient to indicate the trial site; and code for the trial subject in practice publicly-funded trials would normally include the patient s name on the supply, so the code would be additional. It would be normal good practice to add the date of the supply. The labelling of the original EU marketed product would have to follow other legal requirements. The additional label would look similar to a dispensing label (see below). Labelling in this manner (in association with the product s existing labelling) would therefore be consistent with UK Regulation Trial [EudraCT number] Investigator: Dr XXXXXXXXXX Patient name and identification code Date of supply Name + address of hospital etc supplier Marketed products to be used outside of its licensed indications in a clinical trial This section relates to trials which go beyond the boundary of the circumstances set out second paragraph of Article 14 of the Clinical Trials Directive 3, but still use marketed products, which would already be made to GMP standards. Such products would need to be labelled in compliance with UK Regulation 46 5 which specifies labelling in accordance with Article 15 of the GMP Directive 2003/94/EC 4. Article 15 of the GMP Directive 4 states: Labelling. In the case of an investigational medicinal product, labelling shall be such as to ensure protection of the subject and traceability, to enable identification of the WWORTH-SOP04TrialSuppliesLabellingV Page 23 of 34 Not guaranteed if printed