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DANISH GUIDELINE ON NOTIFICATION OF CLINICAL TRIALS OF MEDICINAL PRODUCTS IN HUMANS January 2004 Replaces guideline dated July 2003 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 Changes in the new edition The fee for the notification of clinical trials (DKK 6,590) and for amendments (DKK 1,500) has been changed as of 1 January 2004. The telephone number of the the Central Scientific Ethical Committee has been changed (Tel. + 45 33 95 56 26) Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 TABLE OF CONTENTS 1. LEGAL BACKGROUND ................................................................................................................................ 1 2. FEE ..................................................................................................................................................................... 2 3. NOTIFICATION .............................................................................................................................................. 3 3.1 NOTIFICATION FROM THE MANUFACTURER ................................................................................................... 4 3.2 CO-NOTIFICATION IN MULTICENTRE TRIALS .................................................................................................. 5 3.3 PARALLEL IMPORT AND NOTIFICATION.......................................................................................................... 5 4. CONTENTS OF THE NOTIFICATION ........................................................................................................ 7 4.1 ETHICS COMMITTEE ...................................................................................................................................... 7 4.2 DATA SURVEILLANCE AUTHORITY ............................................................................................................... 8 5. THE TRIAL PROTOCOL ............................................................................................................................... 8 5.1 GENERAL INFORMATION ............................................................................................................................... 8 5.2 BACKGROUND INFORMATION ........................................................................................................................ 9 5.3 PURPOSE ....................................................................................................................................................... 9 5.4 TRIAL PLAN AND DESIGN ............................................................................................................................... 9 5.5 SELECTION OF TRIAL VOLUNTEERS AND CRITERIA FOR INCLUSION/EXCLUSION .......................................... 10 5.6 TREATMENT OF TRIAL VOLUNTEERS............................................................................................................ 11 5.7 EVALUATION OF EFFICACY .......................................................................................................................... 11 5.8 EVALUATION OF SAFETY ............................................................................................................................. 11 5.9 STATISTICS .................................................................................................................................................. 12 5.10 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................................................................................ 12 5.11 QUALITY CONTROL AND QUALITY ASSURANCE ......................................................................................... 13 5.12 ETHICAL QUESTIONS ................................................................................................................................. 13 5.13 HANDLING AND STORING OF DATA ............................................................................................................ 13 5.14 FINANCING AND INSURANCE ..................................................................................................................... 13 5.15 GUIDELINE FOR PUBLICATION ................................................................................................................... 13 5.16 SUMMARY AND ANNEXES .......................................................................................................................... 13 5.17 LITERATURE REFERENCES ......................................................................................................................... 14 6. GCP (GOOD CLINICAL PRACTICE) ........................................................................................................ 14 6.1 INSPECTION ................................................................................................................................................. 15 7. DOCUMENTATION ...................................................................................................................................... 15 7.1 MANUFACTURER ......................................................................................................................................... 15 7.1.1 Information on the manufacturer of reference products marketed and purchased in the EU/EEA, USA or Japan. ...................................................................................................................................................... 16 7.1.2 Information on the manufacturer of reference products not marketed in the EU/EEA, USA or Japan. ..................................................................................................................................................................... 16 7.2 PHARMACEUTICAL-CHEMICAL DOCUMENTATION........................................................................................ 16 8. LABELLING ................................................................................................................................................... 17 9. DISPENSING/SALE ....................................................................................................................................... 19 10. INFORMATION TO PATIENTS/VOLUNTEERS ................................................................................... 20 11. INITIATION AND IMPLEMENTATION OF THE TRIAL ................................................................... 21 11.1 PERMIT ...................................................................................................................................................... 21 11.2 CHANGES .................................................................................................................................................. 21 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 12. ADVERSE DRUG REACTIONS/ADVERSE EVENTS ........................................................................... 22 12.1 ADVERSE DRUG REACTION ....................................................................................................................... 22 12.2 ADVERSE EVENT ....................................................................................................................................... 22 12.3 SERIOUS ADVERSE DRUG REACTION OR SERIOUS ADVERSE EVENT ......................................................... 22 12.4 ADVERSE DRUG REACTIONS AND ADVERSE EVENTS DURING TRIALS IN DENMARK ................................. 23 12.5 SERIOUS ADVERSE DRUG REACTIONS AND SERIOUS ADVERSE EVENTS DURING TRIALS ABROAD ............ 23 12.6 NOTIFICATION FORM ................................................................................................................................. 24 13. REPORT ........................................................................................................................................................ 24 14. OTHER GUIDELINES ................................................................................................................................ 24 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 LIST OF APPENDICES Appendix 1: Extracts from the Medicinal Products Act as amended as at 28 July 1995. Appendix 2: Executive Order on Fees in connection with Applications for Approval of Clinical Trials. Appendix 3: Notification to the Danish Medicines Agency on a clinical trial in humans, according to the Medicinal Products Act, section 24 (4 pages). Appendix 4: Notification to the Danish Medicines Agency of a clinical trial, where a complete notification has been submitted by the co-ordinating investigator. Appendix 5: Commission directive of 19 July 1991 concerning the changes of the annex to Council directive 75/318/EEC on approximation of member states’ laws on standards and protocols concerning analytical, toxicologicalpharmacological and clinical studies of medicinal products. Directive 91/507/EEC. Appendix 6: Extract from the executive order on Good Manufacturing (GMP) and Good Distribution (GDP) Practice for Medicinal products. Appendix 7: Form to be used in connection with cataloguing active substances in pharmaceutical specialities (“cataloguing form”). Appendix 8: Adverse drug reactions and adverse events notification form for clinical trials. Appendix 9: Reporting of adverse events and adverse drug reactions in clinical trials on medical products in Denmark. Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 1. LEGAL BACKGROUND Pursuant to § 24 of the Medicinal Products Act (Appendix 1), clinical trials of medicinal products must be notified to the Danish Medicines Agency. The guideline employs preferentially the words ‘study’ or ‘trial’ rather than ‘test’. The duty of notification according to the Medicinal Products Act comprises all prospective trials concerning clinical evaluation of medicinal products (including pilot trials) with the aim of systematically providing or verifying knowledge on the clinical effect and/or adverse events of medicinal products (pharmacodynamics) as well as studies of the fate of medicinal products in the human body (pharmacokinetics). Thus, the duty of notification includes all phases of the clinical evaluation of medicinal products regardless whether or not the medicinal product under study has been granted a marketing authorisation. The Medicinal Products Act applies to products that are intended to be administered to human beings or animals to prevent, diagnose, alleviate, treat or cure disease, symptoms of disease and pain, or to modify body functions (medicinal products). The provisions of the Act also apply to contraceptives. The duty of notification pursuant to the Medicinal Products Act does not apply to trials in which a medicinal product is used solely to induce a known and well-documented effect of the medicinal product (used as a tool) without an actual medicinal purpose and where consequently no data concerning the pharmacodynamics or pharmacokinetics of the medicinal product are compiled (i.e. studies to elicit physiological mechanisms). Questions concerning the duty of notification may be directed to the Clinical trials, Inspection and enforcement division, the Danish Medicines Agency, by telephone or in writing. An authorisation for dispensing pursuant to § 25, section 2 of the Medicinal Products Act must be obtained when a marketing authorisation has not been issued for the medicinal product or the medicinal product has not been marketed. 1 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 The duty of notification also applies to radioactive medicinal products, herbal medicines as well as strong vitamin and mineral products. Clinical trials with medicinal products may not be initiated before the Danish Medicines Agency has issued a permit. The permit is issued on the basis of the Danish Medicines Agency’s assessment and the recommendation from the scientific ethical committee system. 2. Fee The Minister of Health has authorised the Danish Medicines Agency to collect a fee of DKK 6,590 per trial to cover in part the Danish Medicines Agency’s expenses in connection with the handling of applications for authorisation of and control with clinical trials of medicinal products. The Ministry of Health has issued a regulation on fees (Appendix 2) in December 2003. The fee applies to all trials comprised by the duty of notification. The Danish Medicines Agency has no authority to grant dispensation. Payment shall be sent to the Danish Medicines account in Jyske bank: Registration no. 8109 Account no. 100835-9 Reference: “Clinical Trial” and protocol no./protocol code, protocol title and the name of the payer. The professional assessment will not be initiated until the application is completed and the Danish Medicines Agency has registered the payment of the above-mentioned fee. 2 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 The applicants may decide the payer: Company/physician (sponsor/investigator). On submission of protocol additions/amendments to approved protocols a fee on DKK 1,500 must be paid, see Executive Order on Fees in connection with Applications for Approval of Clinical Trials 3. NOTIFICATION The notification shall be submitted on the prescribed form (Appendix 3). The form may be obtained from: Danish Medicines Agency Clinical trials, Inspection and enforcement division Axel Heides Gade 1 2300 Copenhagen S Denmark Telephone: +45 44 88 95 95, ext. 251/256, between 8.30 a.m. and 4 p.m. Fax: +45 44 88 95 99. One copy of the notification and the information specified in this guideline shall be submitted to the above address. It is possible to download the notification form using Word 97 from the Danish Medicines Agency’s homepage at www.laegemiddelstyrelsen.dk; Under § 24 of the Medicinal Products Act, it is stated that clinical trials of medicinal products may not be initiated until the Danish Medicines Agency has granted permission. The intention is that no trial should be initiated that the Danish Medicines Agency cannot accept for reasons of ethics or patient safety. In order to enable the Danish Medicines Agency to make its decision, detailed documentation on risk/benefit ratio is required. This applies to all trials and is particularly important for trials including healthy volunteers, or for trials employing major invasive procedures, e.g. the placement of extra catheters in arteries and/or central veins. 3 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 In describing the ethical considerations in relation to the clinical trial, it is not sufficient merely to claim adherence to the current Helsinki declaration! If a separate section on ethical considerations is prepared for the ethics committee, this can be submitted. Notification should not be submitted until the final version of the protocol is available. The submission of preliminary protocols causes double administrative evaluation and results in unnecessary delays in the decision making process. 3.1 Notification from the manufacturer The physician or dentist in charge of the trial (the responsible investigator) must submit the notification. The manufacturer of the medicinal product or the manufacturer’s Danish representative must also submit notification, provided: 1) “The trial concerns a medicinal product, which has not been issued a marketing authorisation.” 2) “The trial concerns a medicinal product, which has been issued a marketing authorisation to be investigated concerning a non-approved indication.” 3) “The trial is conducted in co-operation with the manufacturer of the medicinal product or the manufacturer’s representative.” This request is based on the manufacturer’s particularly extensive knowledge of the properties of the medicinal product. This enables the manufacturer to supply valuable information concerning the planning of the trial. The Danish Medicines Agency may, however, in special situations allow omission of a notification from the manufacturer of the medicinal product or the manufacturer’s representative. Such exemptions may be granted by the Danish Medicines Agency in circumstances where the requirement would prevent the execution of a scientifically motivated trial with proper patient safety. It is underlined that an attempt must have been made to obtain a notification. 4 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 The responsible investigator shall inform the manufacturer of the medicinal product or the manufacturer’s representative of the notification at the same time the notification is submitted to the Danish Medicines Agency, even when a joint notification is not required pursuant to § 24, section 6 of the Medicinal Products Act. This allows the manufacturer to raise any objections with the responsible investigator prior to the initiation of the trial. In this information the use of the medicinal product should be described in such a way that the manufacturer or the manufacturer’s representative obtains a clear understanding of how the medicinal product will be employed in the trial. When submitting a notification for a clinical trial, a copy of the information should be submitted. Companies or persons submitting a notification must have a representative with legal residence in Denmark pursuant to the Medicinal Products Act, § 24, section 3 (Appendix 1), provided their own legal residence is in a country which has not ratified or adopted the EEA-Agreement. 3.2 Co-notification in multicentre trials The co-ordinator for trials including more than one study centre (multicentre studies) shall submit a complete notification. A special co-notification form (Appendix 4) must be submitted from each of the participating study centres, preferably together with the co-ordinator’s notification. A co-notification must be submitted to the Danish Medicines Agency from the physician responsible for continued trial, should the responsible investigator leave the study centre. 3.3 Parallel import and notification Only the originating company will possess the detailed knowledge of the medicinal product, which justifies the demand for notification in situations where it is wished to conduct a clinical trial with a parallel imported product. The Danish representative will not possess information concerning the parallel imported product and the parallel importer usually has a less than profound knowledge of the medicinal product. It is therefore a requirement that notification is submitted by the originating company in trials concerning parallel imported medicinal products investigated concerning a non-approved indication. 5 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 This applies to the initial notification as well as to any later change to a parallel imported product. A change may under no circumstances take place before the Danish Medicines Agency has received information on the change accompanied by the new notification from the originating company. In cases where the notification from the Danish representative is solely founded on collaboration, this collaboration is considered terminated when a change to the parallel imported product takes place unless the originating company wishes to participate with a notification. It is a requirement that the responsible investigator informs the originating company concomitant with the exchange, as stipulated in § 24, section 6 of the Medicinal Products Act, provided the product is investigated concerning an approved indication and a notification from the producer is not required. Furthermore, the exchange must not take place until the Danish Medicines Agency has been informed. 6 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 4. Contents of the notification - Notification form (Appendix 3) - Any joint notification form (Appendix 4) - Trial protocol - Patient information incl. power of attorney declaration - Copy of information to the manufacturer, if necessary according to the Medicinal Products Act § 24, section 6, see also section 3 of this guideline - Documentation if necessary in accordance with section 7 - Information on the nature and quantity of the ingredients (Appendix 7) - If necessary, a copy of receipt of payment of fee - If necessary, a separate section on ethical considerations, see also section 3 The scientific assessment will not be initiated until the Danish Medicines Agency has received the fee and the notification is complete. On arrival at the Danish Medicines Agency the notification is checked and any missing items requested. The notification will be returned in the event that the missing items are not submitted within 14 days. The processing of the notification by the Danish Medicines Agency may take place concomitantly with the deliberations by the scientific ethical committee system, provided the notification is forwarded to the two authorities at the same time. It is important that the protocols to be assessed by the two authorities are of the same wording. The Danish Medicines Agency accepts protocols in English or in Danish but only one protocol should be submitted. The applicant(s) is (are) free to choose between the two languages. If an English protocol is submitted to the Danish Medicines Agency, the Ethics Committee must receive a Danish version of the same protocol. 4.1 Ethics Committee The regional scientific ethical committees shall, pursuant to the Act on a scientific ethical committee system and the handling of biomedical research projects, submit a recommendation on the scientific ethical evaluation to the Danish Medicines Agency. 7 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 Further information concerning the notification to the scientific ethical committee system may be obtained from the regional scientific ethical committees or The Central Scientific Ethical Committee (Tel. +45 33 95 56 26). 4.2 Data Surveillance Authority Trials of medicinal products must pursuant to the laws on data registers be notified to the Data Surveillance Authority. This may also be done in parallel to (concomitant with) the notification to the Danish Medicines Agency. Further information may be obtained from the Data Surveillance Authority (http://www.datatilsynet.dk/ or Tel: +45 33 14 38 44). 5. THE TRIAL PROTOCOL Refer to “Note for Guidance on Good Clinical Practice” (CPMP/ICH/135/95). A trial protocol shall ordinarily include the parts listed below. Some of the information may be submitted as separate annexes when justified by local conditions. Other parts of the requested information may be described in e.g. the Investigator’s Brochure. 5.1 General information a. Title of the protocol, date and any protocol code. All annexes and any amendments shall be numbered and dated. b. Name and address of the sponsor and any CRO (e.g. monitoring). c. Name and title of the person(s), who are authorised to sign the protocol and protocol amendment(s) for the sponsor. d. Name, title, address and telephone number of sponsor’s medical/dental advisors for the trial. 8 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 e. Name and title of the trial responsible investigator and address and telephone number of the research centre in question. For multicentre trials the name and title of the trial responsible investigator at all centres and of the co-ordinating investigator as well as the address and telephone number of all trial centres must be stated. f. Name and address of laboratories and other hospital departments, technical departments and/or institutions involved in the trial. g. A statement that the trial is performed in accordance with the protocol and current laws or requirements from the authorities, and a statement on whether the trial is conducted according to the GCP guideline. h. Description of the time plan including the dates for the initiation of the trial, trial period and termination. 5.2 Background information a. Name of the medicinal product(s) and description of the active components. b. Summary of relevant non-clinical and clinical studies. c. Summary of known and potential risks and possible advantages for the trial volunteers. d. Description and justification of the dose, posology, dosing frequency and treatment period. e. Description of the trial population. f. Reference to literature and data, which are relevant, and constitutes a background (foundation) for the trial. 5.3 Purpose A detailed description of the purpose of the trial. 5.4 Trial plan and design a. Unambiguous statement of the trial’s primary and any secondary endpoints. 9 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 b. A description of the trial type/design (e.g. double blind, placebo controlled, parallel group comparison) - possibly illustrated by a flow chart. c. Description of measures to reduce or eliminate bias, including: - Randomisation: description of the randomisation method including procedure and practical arrangement - Blinding: description of blinding (single blind, double blind, double dummy etc.), and practical procedures to assure blinding. d. Description of the trial treatment, dose, posology, frequency, packaging and labelling of the trial medication incl. placebo and reference preparation (see section 7.2 for further information on requirements to the documentation for the products employed and section 8 concerning requirements for the labelling). e. Description of the expected duration of each trial volunteer’s participation in the trial and description of trial periods (e.g. washout and follow-up) and their duration. f. Description of the rules for terminating the trial or stop the treatment of individual trial volunteers and/or parts of the trial. g. Procedures for accounting for the trial medication, incl. placebo and reference preparations. h. Information on where the randomisation code will be stored and rules and procedures for breaking the code. i. Statement of which data will be considered source data and will be registered directly in the CRF (Case Report Forms) - e.g. not previously written or electronically registered data. 5.5 Selection of trial volunteers and criteria for inclusion/exclusion a. Description of inclusion criteria1 including age limits, sex and ethnic group. b. Description of exclusion criteria. c. Description of criteria and procedures for leaving the trial (i.e. discontinuation of the trial medication/termination of participation in the study) stating: 1 The Danish Medicines Agency normally find the pill and IUD safe for prevention of contraception during clinical trials. 10 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 - When and how trial volunteers shall discontinue the trial medication/leave the trial. - Which data that should be collected from trial volunteers in whom the trial medication is discontinued or from trial volunteers having left the trial, and when such data shall be collected. - Whether and how discontinued trial volunteers will be replaced by new trial volunteers. - Follow-up procedures for trial volunteers who have discontinued the trial medication/have left the trial, including dropouts. 5.6 Treatment of trial volunteers a. Description of the treatment incl. the product names of all medicinal products, dose, posology, frequency and treatment period(s), including follow-up periods. b. Rules for additional treatment/medication before and/or during the trial (incl. “rescue medicine”). c. Procedures to further and control a careful observance of the treatment (surveillance of compliance). d. Statement of any following treatment for the trial volunteers when they leave/terminate the trial. 5.7 Evaluation of efficacy a. Specification and justification of efficacy parameters. b. Methods and time points for measurement, registration and analysis of efficacy parameters. 5.8 Evaluation of safety a. Specification and justification of the safety parameters. b. Methods and time points for measurement, registration and analysis of safety parameters. 11 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 c. Procedures for registration and reporting of events/adverse events (see the guideline page 18-19 concerning events/adverse events), including for how long this registration shall continue after the trial volunteer has discontinued the trial medication. Furthermore procedures for how these single reports are reported at the end of the trial Final report. d. Procedures to avoid and treat complications. e. Statement of how and for how long the trial volunteer shall be followed in case of events/adverse events. 5.9 Statistics a. A description of the statistical methods to be employed, incl. the time points for planned interim analyses. b. Justification for the number of patients chosen - including considerations/calculations of the statistical power and clinical relevance of the trial. The number of trial volunteers to be included at each trial centre must be stated for multicentre trials. c. The level of significance to be employed. d. Criteria for the termination of the trial. e. Procedures for registering missing data, unused data and false data. False data may be interpolated data and are not necessarily dishonest. f. Procedures for reporting deviations from the original statistical plan. g. Statement of which trial volunteer’s data that will be used in the statistical analysis (e.g. all randomised trial volunteers, all trial volunteers receiving medication, all eligible trial volunteers and all the trial volunteers it is possible to evaluate). 5.10 Direct access to source data/documents For all clinical trials it should be ensured that it is specifically stated in the protocol or other written document that investigator allows direct access to source data/documents (including patient charts) for monitoring, auditing and inspection from an ethics committee and the Danish Medicines Agency. This further presupposes that the trial volunteers are informed and that these give their informed consent to this (see section 10). 12 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 5.11 Quality control and quality assurance Confirmation that standard procedures for quality control and quality assurance is followed according to ICH GCP guideline, Glossary sections 1.46 and 1.47. 5.12 Ethical questions a. Actual ethical considerations in relation to the trial. b. Description of how the trial volunteers (patients, healthy persons and patients in whom the treatment of their disease is not the aim of the trial) will be informed and how their consent will be obtained (see section 10). c. Possible reasons for not obtaining informed consent from the trial volunteer himself/herself. 5.13 Handling and storing of data Guidelines for handling, processing and storing all collected data for each volunteer participating in the study as well as other trial relevant data. 5.14 Financing and insurance Specification of the trial’s financing and insurance. 5.15 Guideline for publication Refer to Recommendation no. 8 from the scientific-ethical committee system. 5.16 Summary and annexes The trial protocol shall include a summary and relevant annexes (e.g. instructions to the personnel, description of particular procedures). 13 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 5.17 Literature references A list of the literature referred to in the protocol must be included. 6. GCP (Good Clinical Practice) The Commission’s directive 91/507/EEC of 19 July 1991 (Appendix 5) came into power on 1 January 1992. The information and documentation accompanying an application for a marketing authorisation shall be presented according to a specified set of rules described in this directive. Concerning the conduct of trials, it is stated that all phases of the clinical development including studies on bioavailability and bioequivalence shall be planned, carried out and reported according to 'Good Clinical Practice'. The Committee for Proprietary Medicinal Products (CPMP), the EU authorisation committee, has in a press release stressed that great importance will be attached to the trials being conducted and reported according to CPMP's Note for Guidance entitled Good Clinical Practice for Trials on Medicinal Products in the European Community III/3976/88-EN. Note for Guidance on Good Clinical Practice (CPMP/ICH2/135/95) came into power in January 1997. This will replace the above-mentioned EEC guideline. The purpose of this ICH GCP guideline is to contribute to a unified standard for trials of medicinal products in the EU, Japan and the US in order to facilitate the reciprocal acceptance of clinical data by the authorities in these regions. Therefore, the Danish Medicines Agency requests information on whether a clinical trial is envisioned being conducted according to the GCP guideline enclosed with the notification on the trial. It is not presently a legal requirement in Denmark that trials of medicinal products must comply with the GCP guideline. However, great importance will be attached to the GCP guideline being complied with when the results of the trial are envisioned as a part of the documentation accompanying an application for a marketing authorisation. 2 ICH = International Conference on Harmonisation. 14 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 6.1 Inspection Pursuant to the Medicinal Products Act, the Danish Medicines Agency may inspect the approved trials. In trials where it is stated in the notification that the GCP guideline will be complied with, an inspection will usually consist of an inspection with the sponsor and an inspection with the investigator to ascertain that the trial has been conducted in accordance with the trial protocol and the sponsor’s quality assurance system and that the data are correct and reliable. 7. DOCUMENTATION Reference to previously submitted documentation will usually be sufficient for medicinal products issued a marketing authorisation, medicinal products for which an application for a marketing authorisation has been submitted and medicinal products for which documentation has been submitted in connection with a previous notification. For other medicinal products documentation must be enclosed concerning the chemical, pharmaceutical, animal pharmacological, toxicological and human pharmacological properties of the product as well as information on the existing clinical experience. The documentation shall be submitted as a summary - e.g. as an 'Investigator's Brochure, CTX CTA or the like'. Any changes in the e.g. Investigator’s Brochure shall be clearly marked when a new brochure is submitted following a previous assessment of the documentation. If necessary the Danish Medicines Agency may request the reports in full or other supplementary information. 7.1 Manufacturer Concerning products that do not hold a marketing authorisation in Denmark, all manufacturers involved in the manufacture of the medicinal products should be mentioned on the notification form. Regarding products marketed and purchased in Denmark, it is sufficient to mention the holder of the marketing authorisation together with information on where blinding and labelling is made. 15 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 By manufacture is meant all processes that lead to the finished product, e.g. preparation, mixing, decanting, filling, packaging, labelling and release. In Denmark it is required, under Act no 264 of 4 April 1997, § 1 (Appendix 6) and EUdirective 91/356/EEC, that products for clinical trials are manufactured and distributed according to Good Manufacturing Practice (GMP) and Good Distribution Practice (GCP) 7.1.1 Information on the manufacturer of reference products marketed and purchased in the EU/EEA, USA or Japan. Information on the manufacturer is not required. However, details must be submitted where blinding and labelling of the reference product for the clinical trial are conducted. 7.1.2 Information on the manufacturer of reference products not marketed in the EU/EEA, USA or Japan. Documentation concerning all manufacturers involved in the production of the product must be submitted (see section 7.1 for definition of manufacturers). 7.2 Pharmaceutical-chemical documentation Information concerning the qualitative and quantitative composition shall be submitted for dosage forms and/or strengths, which have not been granted a marketing authorisation in Denmark, and for placebo preparations. This information can be given on a catalogue form (Appendix 7) or appear in the Investigators Brochure. Specifications for raw materials shall be given with reference to a pharmacopoeial monograph (Ph. Eur., BP, USP, JP etc.). The specification states requirements for e.g. purity of raw materials, content of impurities and analytical tests. When a pharmacopoeial monograph is not available, a reference to foodstuff specifications is acceptable. Internal specifications are only acceptable provided none of the above mentioned specifications are in existence. In this case, the internal specifications must be submitted with the notification. 16 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 In the case of reference products marketed and purchased in the EU/EEA, USA or Japan, a patient information leaflet from the concerned country may be submitted instead of a catalogue form. The patient package leaflet must state information on the qualitative contents of the product as well as the approved indication and dosing in the concerned country. Changes in the trial related to the form, appearance or composition of medicinal products that are granted a marketing authorisation must be notified accompanied by information on the complete quantitative and qualitative composition. Considerations concerning the bioequivalence must be submitted accompanied by results of relevant in vitro tests (e.g. a dissolution test for compressed medicinal products) for both the marketed and the altered formulation. Information on the production method shall be submitted for medicinal products produced by biotechnology methods and medicinal products produced from biological material, which have not been granted a marketing authorisation. The information must include documentation on the purification concerning the removal/inactivation of virus, DNA and other biological/chemical impurities originating from the production. The information shall be presented according to the relevant EU guidelines. It is sufficient to refer to previously submitted information provided this has been submitted previously to the Danish Medicines Agency. The Danish Medical Agency’s journal number should be quoted if possible. 8. LABELLING Labelling must be in Danish3 and contain the following: 1. ‘For clinical trial’ (‘Til klinisk forsøg’). 2. Drug formulation according to Danish Drug Standards (DLS). 3 For preparations administered solely by hospital personnel, English labelling is accepted. 17 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 3. Code designation. Packages for use in open clinical trials may be identified by the name of the medicinal product or the drug instead of a code designation. The strength must also be stated in these cases. 4. Pack size. The contents must be stated as g, ml and - for predosed drugs - number. 5. Batch number or other designation allowing an unequivocal identification of the amount of medicinal products to be produced in one batch for clinical trial. Thus, it shall be possible to withdraw all the faulty items should a fault be confirmed or suspected in the product at a later date. The numbering of batches must ensure any blinding. 6. Sponsor’s name and place of business. The Danish representative may be listed as a supplement (cf. Medicinal Products Act, section 14 (1) and (2)). 7. Expiry date must be stated as 'use before..' ('Anvendes inden..' or 'Anvendes før..'). Expiry date may also be stated as ‘retest date’. Other information on limited shelf life may be stated as necessary when relevant. 8. Storage conditions when this is considered necessary. 9. Dosage. 10. The name of the responsible investigator. 11. The necessary warnings and instructions shall accompany preparations dispensed to patients, cf. regulation on labelling of and package inserts for medicinal products. 12. Small drug containers, e.g. ampoules, must at least be marked with the name or code designation of the preparation and the amount when complete labelling is not possible. Likewise each single unit of single packaged predosed medicinal products must be supplied with identifying labelling. 18 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 9. DISPENSING/SALE Medicinal products may, pursuant to the Medicinal Products Act, § 25, section 1, be dispensed or sold for use in clinical trials, which have been approved by the Danish Medicines Agency. Following the granting of the approval, the medicinal product may be dispensed/sold to: - The physician or dentist responsible for the trial - Pharmacist or hospital pharmacist supplying the responsible investigator for the trial Import, export and the manufacturing of medicinal products for clinical trials must only be undertaken by companies in possession of permits according to § 8 of the Medicinal Products Act. Thus, no further permission is necessary for the import or export of these products. However, the investigator must not be supplied until the Danish Medicines Agency has approved the trial. Dispensing to a pharmacy may take place prior to the approval of the trial, but the pharmacy must not dispense the medicinal products to the investigator until the approval has been issued. The dispensing of narcotic drugs/products for use in clinical trials is only permitted when the Danish Medicines Agency has issued a permit, cf. § 4, section 5 of the Ministry of Health’s regulation on narcotic drugs. Moreover, the receipt and possession of narcotic drugs by commercial companies requires a permit from the Danish Medicines Agency, cf. § 5 of the above-mentioned regulation. 19 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 10. INFORMATION TO PATIENTS/VOLUNTEERS Rules on information of and consent from patients/trial volunteers participating in clinical trials are found in the National Board of Health’s circular on information and consent etc. 'The duty of physicians and the right of patients'. It specifies e.g. which information the written and oral information shall include and how the consent shall be obtained. The written patient information incl. the power of attorney declaration should be submitted with the notification of a clinical trial to the Danish Medicines Agency. This is to allow the agency to assure that permission to third party access to the patient chart is given. In all trials, the trial volunteer must give his or her permission to third party access to the patient chart in relation to data verification during monitoring, auditing and inspection. It is in the Danish Medicines Agency’s opinion essential that this power of attorney declaration clearly states, -That it is a power of attorney declaration, which potentially requires the preparation of a separate declaration. - What the power of attorney is intended for, e.g. as a direct reference to § 20 of the Act on patients legal status, No. 482 of 1998. - To whom the power of attorney declaration is issued - For which period of time the power of attorney declaration is valid and - What the power of attorney declaration comprises, i.e. a specification of the hospital chart. 20 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 11. INITIATION AND IMPLEMENTATION OF THE TRIAL Because of the parallel evaluation by the Danish Medicines Agency and the scientific ethical committee system, a situation may arise where both authorities request additional information on closely related aspects before a permit can be issued. This must be regarded as the necessary price to pay to avoid the delay caused by a successive evaluation by the two systems. The regional scientific ethical committee submits it’s recommendation to the Danish Medicines Agency and forwards concomitantly a copy to the responsible investigator. 11.1 Permit The trial may be initiated when the Danish Medicines Agency has issued a permit. The necessary medicinal products for the trial may not be dispensed to the responsible investigator(s) before the permit is issued. 11.2 Changes Changes of the protocol or later additions to the protocol must be submitted to the Danish Medicines Agency and the regional scientific ethical committees in the same version before the changes or additions are implemented. Additions and changes to the protocol should be submitted in the same language as the protocol assessed at the notification. Examples of changes that shall be notified to the Danish Medicines Agency are changes in - dosage - treatment period - number of patients/trial volunteers - trial design - inclusion and exclusion criteria - efficacy parameters and sampling schedules 21 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 - product (original/parallel import (for the latter also the country of origin)) Furthermore, considerations on the possible influence of the changes on the final result of the trial must be submitted if patients have been entered into the trial before the implementation of the changes. The protocol number and the date for the latest accepted trial protocol shall be stated. A precise specification of the suggested changes should be submitted. The responsible investigator shall sign the changes. The changes may not be implemented until the Danish Medicines Agency has issued a permit. Major changes may necessitate submission of a new notification. The termination of the study ahead of schedule and the reason for this termination shall be communicated to the two authorities. 12. ADVERSE DRUG REACTIONS/ADVERSE EVENTS 12.1 Adverse Drug Reactions All noxious and unintended responses to a medicinal product related to any dose. 12.2 Adverse Events Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. 12.3 Serious Adverse Drug Reactions or Serious Adverse Events Any untoward medical occurrence that at any dose: - results in death, - is life-threatening, - requires inpatient hospitalisation or prolongation of existing hospitalisation, 22 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 - results in persistent or significant disability/incapacity, or - is a congenital anomaly/birth defect. 12.4 Adverse Drug Reactions and Adverse Events during trials in Denmark The trial protocol shall state which adverse drug reactions and adverse events the investigator shall report to the sponsor and when the reporting shall take place after the adverse drug reaction/ adverse event is ascertained. It shall also be stated for how long the trial volunteers are followed after they have finished the trial medication in order to register any late occurring adverse drug reactions/adverse events. The following shall be notified to the Danish Medicines Agency. The responsible investigator shall pursuant to the Medicinal Products Act § 24, section 7 inform the Danish Medicines Agency immediately in the event of serious adverse drug reactions and/or serious adverse events unless the Danish Medicines Agency has stipulated otherwise in its accept of the trial. However, serious adverse events judged by the investigator not to have causal relationship to the trial subjects’ participation in the trial, are not included in this reporting. Each notification shall be accompanied by comments on any possible consequences for the trial. All adverse drug reactions and adverse events (including the serious) shall at the end of the trial be reported in the final report to the Danish Medicines Agency. 12.5 Serious Adverse Drug Reactions and Serious Adverse Events during trials abroad Serious adverse drug reactions and serious adverse events noted abroad in relation to trials of medicinal products also under investigation in Denmark shall not be notified to the Danish Medicines Agency as single reports. Should such serious adverse drug reactions/adverse events noted abroad result in changes in a protocol for current trials in Denmark, then they shall be notified as single reports and any consequences immediately implemented as an amendment to the protocol. These adverse reactions or events shall subsequently be incorporated in the Investigator’s Brochure. The occurrence of serious drug reactions in safety studies abroad with products that are granted a marketing authorisation in Denmark, shall be notified according to the particular /specific 23 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 pharmacovigilance rules as single reports on a specific form for side effect notifications from the industry. These notifications are in principle independent of the notification rules for clinical trials in Denmark, cf. Notice to Applicants. 12.6 Notification form Adverse drug reactions and adverse events during trials in Denmark must be notified on the Danish Medicines Agency’s notification form for clinical trials, cf. Appendix 8. Notification on a CIOMS form is also acceptable. Appendix 9 lists the adverse events and adverse drug reactions to be notified in relation to trials in Denmark. 13. REPORT The responsible investigator shall submit information on the results of the trial following its completion to the Danish Medicines Agency according to § 24, section 8of the Medicinal Products Act. The report shall summarise information on the number of treated patients, doses employed, length of treatment, the results obtained and the side effects observed. The Danish Medicines Agency will request the complete report if this is deemed necessary. 14. OTHER GUIDELINES In addition, several EU guidelines are in existence concerning clinical trials of various groups of medicinal products etc. Further information may be found in The Rules governing Medicinal Products in the European Community vol. III. Guidelines on the quality, safety and efficacy of medicinal products for human use. This may be purchased from: 24 Danish guideline on notification of clinical trials of medicinal products in humans, January 2004 J. H. Schultz Information A/S EU Publications Herstedvang 12 DK-2620 Albertslund The ICH GCP guideline may be obtained from: The European Commission Østergade 61 Postboks 144 DK-1004 Copenhagen K It is possible to find guidelines on the Internet starting from the following address: http://www.eudra.org/document.htm. Guidelines may be downloaded using Adobe Acrobat Reader. The Adobe programme itself may be downloaded from the following address: http://www.adobe.com 25 Appendix 1 Extract from the Medicinal Products Act as amended pr. 28. July 1995 permission to perform the trial, in special cases, decides otherwise, or 2) serious events, unless the Danish Medicines Agency, in special cases, decides otherwise. Part 5 Clinical Trials. Distribution of medicinal products for special purposes 24. (1) Clinical trials of medicinal products must be notified to The Danish Medicines Agency by the physician, dentist or veterinarian responsible for the trial (investigator). The manufacturer of the medicinal product or his representative must also notify The Danish Medicines Agency provided, 1) the trial concerns a medicinal product without a marketing authorization. 2) the trial concerns a medicinal product with a marketing authorization intending to investigate a non-approved indication, or 3) the trial is conducted in co-operation with the manufacturer of the medicinal product or his representative. (2) The Danish Medicines Agency may, in special cases, permit that notification from the manufacturer or his representative (co-investigator) is omitted. (3) Investigators and co-investigators of clinical trials who are not established in a state, which have ratified or acceded to the EEAagreement must have a representative in this country. (4) Clinical trials of medicinal products must not be initiated until The Danish Medicines Agency has given its permission. (5) The Danish Medicines Agency may make its permission conditional and may at any stage order that the trial be stopped or changed. (6) The investigator must inform the manufacturer of the medicinal product or his representative of the notification concurrent with its submission to The Danish Medicines Agency. Following the completion of the trial the investigator must, on request from the manufacturer of the medicinal product or his representative, inform this party of the result of the trial. (7) The investigator must immediately notify the Danish Medicines Agency where the trial reveals: 1) serious adverse reactions, unless the Danish Medicines Agency in connection with its (8) At the completion of the trial the investigator must submit the results of the trial to the Danish Medicines Agency. (9) The Danish Medicines Agency may lay down regulations on the required information in and the handling of notifications on clinical trials. (10) The Minister for Health may authorise The Danish Medicines Agency to collect a fee, entirely or partially covering The Danish Medicines Agency’s costs incurred by examining applications for permission to perform clinical trials and inspection of such trials and for the granting of authorizations to undertakings to perform toxicological and pharmacological trials according to Section 8 (1). (11) The Danish Medicines Agency may inspect anyone performing or having performed clinical trials of medicinal products. On presentation of appropriate identification and without a court order the representatives of the Danish Medicines Agency have access to undertakings, hospitals, practices or similar. The Danish Medicines Agency has access to patients journals or similar provided that the patient or person in connection with participation in the trial, in writing, has been informed about the Danish Medicines Agency's access to journals. Appendix 2 Executive Order on Fees in connection with Applications for Approval of Clinical Trials (EO No. 1101 of 12 December 2003) The following provisions are laid down pursuant to Section 24 (10) of the Medicinal Products Act: 1. In partial payment of the costs of the Danish Medicines Agency in connection with the administration of applications for approval and supervision of clinical trials, the applicant shall pay a fee of DKK 6,590 for each application for approval of a clinical trial. (2) In partial payment of the costs of the Danish Medicines Agency in connection with the administration of applications for amendments in a by the Danish Medicines Agency approved trialprotocol, the applicant shall pay a fee of DKK 1.500. (3) If an application concerning (2) includes several changes to the trial protocol only one fee shall bee paid. 2. The fee referred to in Section 1 of this Executive Order shall be paid to the Danish Medicines Agency simultaneously with the submission of the application for approval of a clinical trial to the Danish Medicines Agency. 3. This Executive Order shall enter into force on 1 January 2004. (2) The Executive Order no. 1132 of 13 December 2003 on Fees in connection with applications for approval of clinical trials is abolished. Appendix 3 For use by the Danish Medicines Agency Date received: Journal number 2612 – Notification to the Danish Medicines Agency on a clinical trail in humans, according to the Medicinal Products Act §24 PROTOCOL (final version must be enclosed) Title: Any code number: RESPONSIBLE INVESTIGATOR Physician Dentist Name/Address: Tel.: MEDICINAL PRODUCT(S) TO BE INVESTIGATED Brand name(s) and any code designation Dosage form and strength (tablets, injectables, etc.) Active ingredient(s) Manufacturers involved in the manufacture of the medicinal product; hereby is understood all processes which leads to the finished product, e.g. preparation, mixing, decantation, filling, packaging, labelling and release. Please state the company name, address, country and process (activity) Cf. the Danish Medicines Agency's guidelines on notification of clinical trials, section 7.1. Extension: 1 2 The product holds a marketing authorisation in Denmark in this dosage form and strength? If no: Has a marketing authorisation been applied for concerning this dosage form and strength? no no yes* D.sp.nr. yes* D.sp.nr. no no Has the medicinal product been granted a marketing authorisation in other dosage forms and/or strengths? no Has a marketing authorisation been applied for concerning other dosage forms and/or strengths? no Has the active ingredient previously been used in clinical trials in Denmark? ------------------------------------------Catalogue form no yes yes yes Appl.no. yes Appl.no. no D.sp.nr. yes D.sp.nr. no Appl.no. yes Appl.no. no yes ------------------------------------------enclosed yes ------------------------------------------enclosed previously submitted if known, journal no.: previously submitted if known, journal no.: PLACEBO is not included is included as a comparative product other (wash-out or double dummy) Catalogue form enclosed previously submitted journal no., if known: THE TRIAL Phase: Phase I Phase II Phase III Phase IV Pharmacokinetic etc. for marketed medicinal products Trial of a marketed medicinal product concerning a new indication combination of phase I and II combination of phase II and III other: * Design: placebo controlled other control group no control group cross-over randomisation open single-blind double-blind double dummy other: If the medicinal product is investigated concerning the registered indication without co-notification from the manufacturer of the medicinal product, it is a requirement that the responsible investigator informs the manufacturer of the medicinal product or the manufacturer's representative concomitant with the notification to the Danish Medicines Agency (a copy shall not be submitted to the Danish Medicines Agency) according to the Medicinal products Act, § 24, section 6. LOCATION OF THE TRIAL hospital general practice specialist practice company university other If different from the responsible investigator’s address Address: MULTICENTER no yes Danish International total no. centre: total no. centre in Denmark: no. of patients in Denmark: Co-ordinating investigator (name and address): Co-notification from the other centres must be enclosed (should be submitted together including a listing of the centres). Co-notification forms can be found on the Internet (www.dkma.dk) or copied from the Danish Medicines Agency's guideline on notification of clinical trials (Appendix 4). TRIAL PERIOD Scheduled start: Scheduled termination: Submitted to the scientific-ethical committee in: INFORMEd CONSENT To be obtained from the trial participant parents/legal guardian This written information to patients is usually not required, however cf. the Danish Medicines Agency’s guideline on notification of clinical trials GCP (Good Clinical Practices), cf. CPMP’s Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) No Yes sponsor’s name: (company name, organisation) Trial being monitored by: (company name, organisation) THE NOTIFICATION IS: Signed by the responsible investigating physician/dentist Signed by the producer/representative (medicinal product 1) Signed by the producer/representative (medicinal product 2) AND ENCLOSED: Trial protocol Proof that payment has been made Investigator’s Brochure, CTX or the like (by revision please enclose a list showing the changes compared to earlier versions) Patient information incl. power of attorney declaration Copy of information to manufacturer according to the Medicinal Products Ac 24 (6) Other: SIGNATURE (company 1) Name (signature): SIGNATURE (company 2) Name (signature): Name of company/Address: Name of company/Address: Tel.: Date: Tel.: Date: SIGNATURE (responsible investigating physician/dentist) ................................................................................. Date: The completed form should be signed and submitted to: The Danish Medicines Agency, Clinical trials, Inspection and enforcement division, Axel Heides Gade 1, 2300 Copenhagen S, Denmark Tel. no.: +45 4488 9595 Monday-Thursday 8.30-16, Friday 8.30-15.30. Fax: +45 4488 9599. Download the notification form from: www.dkma.dk; Medicinal Products, Clinical Trials, Guideline Appendix 4 NOTIFICATION TO THE DANISH MEDICINES AGENCY OF A CLINICAL TRIAL, WHERE A COMPLETE NOTIFICATION HAS BEEN SUBMITTED BY THE COORDINATING INVESTIGATOR The Danish Medicines Agency’s journal no.: 2612(if known) MEDICINAL PRODUCT(S) INCLUDED IN THE TRIAL: (Name and any code designation in the trial) PROTOCOL Title: Code no.: COORDINATING INVESTIGATOR (trial co-ordinator): Code no.: (Name and address): LOCATION OF TRIAL (participating centre) and address: hospital general practice specialist practice company (stamp) university other The undersigned hereby notifies his/her participation in the above-mentioned clinical trial. I accept that the Danish Medicines Agency takes contact with the trial co-ordinator in all matters concerning the trial. The permit, conditions, time limits and other orders from the Danish Medicines Agency as well as additional information concerning the trial will be given to the trial co-ordinator only. SIGNATURE (Responsible investigating physician/dentist): Date: (stamp) The completed form should be signed and submitted to: The Danish Medicines Agency, Clinical trials, Inspection and enforcement division, Axel Heides Gade 1, 2300 Copenhagen S, Denmark Tel. no.: +45 4488 9595 Monday-Thursday 8.30-16, Friday 8.30-15.30. Fax: +45 4488 9599. Download the notification form from: www.dkma.dk; Medicinal Products, Clinical Trials, Guideline Appendix 5 Commission directive of 19 July 1991 (91/507/EEC) concerning the changes of the annex to Council directive 75/318/EEC on approximation of member states’ laws on standards and protocols concerning analytical, toxicological-pharmacological and clinical studies of medicinal products. This document is not electronically available but can be requested at: Danish Medicines Agency Clinical trials, Inspection and enforcement division Axel Heides Gade 1 DK-2300 Copenhagen S Denmark Appendix 6 Extract form the executive order on Good manufacturing (GMP) and Good Distribution (GDP) Practice for medicinal products (EO No. 264 of 4 April 1997). Part 1 Scope of the Executive Order 1. (1) This Executive Order encompasses medicinal products, including proprietary medicinal products, blood and blood components, radioactive medicinal products, gases for medicinal use, readymade non-proprietary veterinary medicinal products, extempore preparations and investigational medicinal products. (2) This Executive Order lays down provisions for the manufacture of medicinal products, including manufacture intended for export, and for import, wholesale and retail distribution, including stock holding of medicinal products. Appendix 7 CLINICAL TRIALS Form to be used in connection with cataloguing active substances in pharmaceutical specialities Name of the medicinal product: 2) Dosage form/strength (only one dosage form/strength in each form): 3) Name of substance* 4) Quantity * 5) Specification* 6) Letter of iden tification * * Please see next page Date: Signature: The completed form should be signed and submitted to: The Danish Medicines Agency, Clinical trials, Inspection and enforcement division, Axel Heides Gade 1, 2300 Copenhagen S, Denmark Tel. no.: +45 4488 9595 Monday-Thursday 8.30-16, Friday 8.30-15.30. Fax: +45 4488 9599. Download the notification form from: www.dkma.dk; Medicinal Products, Clinical Trials, Guideline Additional information to the following spaces: Re 3) Name of substance, i.e. the real active substance (not any declared active substance). (Ex.: Tetracyclini hydrochloridum and not Tetracyclinum (as chloride)). The names of the active substances are those stated in the “Danske Lægemiddelstandarder” (DLS) (Danish drug standards). If no name is given in the DLS, use the name in the INN, NFN, BAN or USAN. If no names are provided there either, use the trade name or the chemical name. For colouring matters, state also Colour Index numbers according to the work Colour Index, 3rd edition, 1971. Re 4) State the quantitative composition of the preparation in mg or g exclusive of any surplus of effective substances. If a surplus of effective substances is added, state this in per cent in brackets after the statement of quantity. State the quantities per unit (ml, g, tablet, etc.) with as few digits as possible, and indicate the unit used at the top of the space. If a quantity cannot be given exactly, add the word “approximate” in front of the statement of quantity. Re 5) Specification of identity and purity of all active substances. If it is not possible to make a reference to a pharmacopoeia or the like (e.g. EUR, NORD, BP, USP, DLS), then refer to an appendix accompanying the form or to an appendix contained in the material sent in. Re 6) After each substance, state a letter for the identification of the type of substance. Use the following letters: A: Effective substances F: Colouring matters K: Preservatives X: Aroma and flavour additives C: Other inactive substances Page 2 of 2 Appendix 8 Adverse drug reactions and adverse events notification form for clinical trials. This notification form is for the use of the investigator only and therefore only available in Danish. Appendix 9 Reporting of adverse events and adverse drug reactions in clinical trials on medicinal products in Denmark Observed in Denmark Events+ and drug reactions++ Serious events* and serious drug reactions* Observed in another country Must appear from the final report Must appear from updatings of the to the Danish Medicines Agency basis documentation when new on the results of the trial. trials are notified. Must immediately be reported on a specific form by the responsible investigator. Serious adverse events judged by the investigator not to have causal relationship to the trial subjects’ participation in the trial are not included in this reporting. Comments on consequences for the trial must be enclosed. When the company/investigator considers serious drug reactions and whether serious events will have consequences for ongoing trials in Denmark, these have to be reported to the Danish Medicines Agency immediately and a protocol amendment has to be forwarded. + Event: Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product an which does not necessarily have a causal relationship with this treatment ++ * Drug reaction: All noxious and unintended responses to a medicinal product related to any dose Serious event and serious drug reaction: Any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.