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Guideline for applications for authorisation of clinical trials of medicinal products in humansLast updated 19 March 2010 (updates concern section 7.1 and 9: Requirement for GMP documentation) Please see the Danish Medicines Agency’s guidelines from January 2004 for trials applied for prior to 1 May 2004. TABLE OF CONTENTS 1.LEGISLATION APPENDICES
1. LegislationPursuant to the terms of section 88 of the Danish Medicines Act (Appendix 1), an application must be submitted to the Danish Medicines Agency for authorisation to conduct clinical trials with medicinal products. Clinical trials with medicinal products must only be conducted when the Danish Medicines Agency has given an authorisation to this.Furthermore, trials of medicinal products on humans must be conducted in accordance with the Good Clinical Practice quality standards, see chapter 6. The obligation to apply for an authorisation under the Danish Medicines Act comprises all prospective trials in the clinical assessment of medicinal products (phases I-IV, including pilot studies).According to the Executive Order on clinical trials of medicinal products on humans (see Appendix 2), a clinical trial is defined as: Any investigation on human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal products and/or to identify any adverse reactions to one or more investigational medicinal products and/or to study the absorption, distribution, metabolism and excretion of one or more investigational medicinal products with the object of ascertaining their safety and/or efficacy. This includes clinical trials carried out at one or more sites, whether in one or more Member States. According to the Danish Medicines Act, the obligation to apply for an authorisation does not apply to non-interventional trials, which are defined in the Executive Order as: A study where the medicinal product or products are prescribed in the usual manner in accordance with the terms of the marketing authorisation. The prescription of the medicine is clearly separated from the decision to include the patient in the study. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data. Section 2 of the Danish Medicines Act establishes that medicinal products are products that is presented as a suitable product for the treatment or prevention of disease in human beings or animals, or may be used in or administered to human beings or animals in order to restore, change or modify physiological functions by having a pharmacological, immunological or metabolic effect or to make a medical diagnosis. The obligation to apply also applies to radiopharmaceuticals, herbal medicinal products as well as strong vitamin and mineral preparations For further information, please see Guidelines for marketing authorisation of vitamins and minerals etc. (hereunder Appendix 1) at http://www.dkma.dk/1024/visUKLSArtikel.asp?artikelID=2179. According to the Danish Medicines Act, the obligation to apply does not apply to trials in which a medicinal product is used solely to induce a known effect, which is also well-documented for the medicinal product in question (i.e. it is used as a tool), without an actual medicinal purpose and where no data concerning the pharmacodynamics or pharmacokinetics of the medicinal product are collated (e.g. studies with the purpose of clarifying physiological mechanisms). In pursuance of section 29 of the Danish Medicines Act, it is required that a compassionate use permit is obtained from the Danish Medicines Agency before any study is initiated, in cases where a medicinal product is only intended to be used as a tool and no marketing authorisation has been issued, or the medicinal product is not marketed. For further information concerning a possible obligation to apply, please call tel.: +45 4488 9595 or write to: Danish Medicines Agency e-mail: kf@dkma.dk 2. FeesFor more specific information about fees, please see the page Fees for clinical trials here at the Danish Medicines Agency's website. We charge fees for the authorisation of new applications for clinical trials as well as for notification of substantial protocol amendments of authorised trial protocols, which are to be authorised by the Danish Medicines Agency. The fee must be paid no later than one month after receipt of the invoice. It is up to the individual applicant to determine who should be the payee, whether this be the company/doctor (sponsor/investigator). The form containing the invoice details must be submitted together with applications for new trials or notifications of protocol amendments. See the form in the factbox to the right. When submitting protocol amendments for trial protocols not yet authorised, no further fees are to be paid to the Danish Medicines Agency. However, if material is submitted in the course of our processing of the application, it may, depending on the nature of the amendment, delay our reply to the application. A fee must only be paid for substantial protocol amendments that must be authorised by the Danish Medicines Agency, and if several amendments are submitted together, only one fee is to be paid. Please see our page on Amendments of clinical trials for further information on the types of protocol amendments for which a fee is charged. The executive order on application fees for the authorisation of clinical trials stipulates that the fee applies to all trials comprised by section 88 of the Danish Medicines Act, and the Danish Medicines Agency does not hold the statutory authority to grant any exemptions. 3. ApplicationPlease see chapter 4 with regard to the documents that must be submitted. Please see the guidelines for application for authorisation of a clinical trial, notification of substantial amendments and declaration of the end of the trial (CT1).These guidelines are available on http://eudract.emea.europa.eu//document.html under Guidance Documents. Before applying to the Danish Medicines Agency, the applicant must order a EudraCT number, which is an identification number for the clinical trial that applies throughout the EU. This number can be ordered via http://eudract.emea.europa.eu/. It is necessary to order a security code on the above link. This code can then be used for ordering a EudraCT number, but please note that the code is only valid for 24 hours. Both the security code and the EudraCT number are sent to the applicant by e-mail. A detailed description of the procedure is available at the above link.The email to which the EudraCT number is notified must be printed and enclosed in the application. The application must be filled in on a specific internet-based application form, please see Appendix 5 .The application form can be found at http://eudract.emea.europa.eu/ The application form must be filled in and edited via the internet (please see the guidelines “EudraCT User Manual” at http://eudract.emea.europa.eu//docs/05300000EN.pdf). The completed form must be printed out via the internet and signed by the sponsor/applicant.The form (please select Full data, see User Manual) must also be downloaded via the internet either onto a floppy disk or a CD-ROM and sent enclosed with the signed application form.This version of the form must also be downloaded to the applicant’s own computer. Guidelines for filling in the electronic form are available at the Danish Medicines Agency’s website www.laegemiddelstyrelsen.dk (http://www.laegemiddelstyrelsen.dk/db/filarkiv/4976/Usermanual.pdf ) and at the EudraCT link at http://eudract.emea.europa.eu/. Moreover, the information listed in this guideline must be enclosed in the application and submitted in a single copy (please see point 3). Please also see Appendix 10, which is a checklist listing what must be enclosed in an application. The sponsor is the applicant. Pursuant to the Danish Medicines Act, the sponsor is the person, company or institution which undertakes the responsibility for the initiation, management and possibly the financing of a clinical trial. The sponsor may delegate the task of applying for authorisation for a clinical trial. In such cases, a document that confirms this relation must be submitted. The sponsor or the sponsor’s legal representative must have a permanent address in an EU/EEA country, cf. the Danish Medicines Act section 88(7) (Appendix 1). In pursuance of section 88 of the Danish Medicines Act, clinical trials of medicinal products must not be initiated until the Danish Medicines Agency has granted authorisation to this. The intention is to ensure that no trials are initiated which the Danish Medicines Agency cannot accept for reasons pertaining to either ethics or patient safety. As a consequence of this, the Danish Medicines Agency requires detailed documentation on the risk/benefit ratio in order to make proper assessments. This applies to all trials and is particularly important for trials involving healthy volunteers, or for trials employing major invasive procedures, e.g. extra catheterisation in arteries and/or central veins. When describing the ethical considerations in relation to the clinical trial, it is thus not sufficient merely to claim adherence to the current Helsinki declaration! If a separate section on ethical considerations is prepared for the scientific ethical committee system, this can be submitted with advantage. According to the Danish Medicines Act section 88, the sponsor may amend the application once, in order to allow for a reasoned objection from the Danish Medicines Agency.If the application is not amended according to the objection, the application will be rejected.It is therefore recommended not to submit the application until the final protocol and all appendices are available. The Danish Medicines Agency has 60 calendar days to handle an application which is properly completed.The Danish Medicines Agency aims to give grounds for non-acceptance or grant authorisation within 30 working days.Please note that the time limit is not suspended when the Agency gives grounds for non-acceptance.It is therefore in the best interests of all parties that the sponsor’s reply to grounds for non-acceptance is submitted to the Danish Medicines Agency as quickly as possible. When processing applications for trials with medicinal products for gene therapy and somatic cell therapy as well as medicinal products containing genetically modified organisms, the 60-day deadline is extended by 30 calendar days. For these medicinal products, the deadline of 90 days may be extended by a further 90 days in cases where public boards or the like are consulted. In applications for trials of xenogeneic cell therapy there is no deadline for the Danish Medicines Agency’s decision. The sponsor must inform the manufacturer of the medicinal product or the manufacturer’s representative of the application at the same time as the application is submitted to the Danish Medicines Agency, cf. section 88 of the Danish Medicines Act. This allows the manufacturer to raise objections to the person responsible for the trial prior to its initiation. This information should account for the use of the medicinal product in such a manner that the manufacturer/the manufacturer’s representative gain a clear understanding of how the medicinal product will be employed in the trial. A copy of such information should be enclosed when an application is submitted for a clinical trial,. The application and floppy disk/CD-ROM containing the XML file should be sent to: Danish Medicines Agency Tel.: +45 4488 9595, extension 9123, Mondays to Thursdays between 8.30 a.m. and 4.00 p.m. and Fridays between 8.30 a.m. and 3.30 p.m. Fax: +45 4488 9195 3.1 Application for a multi-centre trial For trials concerning more than one site in Denmark, one full application must be submitted by the sponsor. Each other participating trial sites must be listed on the application form (Appendix 5 ). If the coordinating investigator or any other person responsible for the trial leaves the trial site, the Danish Medicines Agency must be informed as to whom is to replace them, and the sponsor must submit an amendment of the application to the Danish Medicines Agency. The form (see Appendix 6 ) can be downloaded as a Word file from http://eudract.emea.europa.eu/. 4. Contents of the applicationPlease see appendix 10. Here you may find a table of contents for the application. We recommend that this table of contents is followed as an aid for both the applicant and the Danish Medicines Agency, as it will enable us to complete the validation and check-in of the application more quickly. If any points of the table of contents are not relevant, please indicate this on the application. Please also see the guidelines for application for authorisation of clinical trials, amendments and the declaration of the end of a trial (CT 1), along with the guidelines for the EudraCT Database (CT 5). These guidelines are available at the following websites: The Commission's website http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev10.htm or the EudraCT website: http://eudract.emea.europa.eu/document.html. The application must include (only one copy of each appendix):
In addition
The scientific processing of the application will not be initiated until the application is complete. On receipt at the Danish Medicines Agency, the application will be checked in within a few days and if any shortcomings are found, the missing material will be requested. The Danish Medicines Agency’s evaluation of an application may take place at the same time as its evaluation in the research ethics committee system. Of consideration for the evaluation, it is important that the contents of the protocols, which form the basis for the evaluation in the two systems, are comparable. The Danish Medicines Agency will accept both English-language and Danish-language protocols, but only one protocol is to be submitted. It is up to the sponsor/applicant to decide which of the two languages they wish to use. 4.1 Scientific Ethical Committee According to the Act on a Scientific Ethical Committee System and the Processing of Biomedical Research Projects, a Biomedical Research Project must be authorised by a regional Scientific Ethical Committee..This also applies to projects covered by the Danish Medicines Act. In applications for trials with medicinal products on humans, the Danish Medicines Agency must make its decision known to the scientific ethical committee concerned, cf. the Danish Medicines Act section 88(6). Further information on applications to the scientific ethical committee system can be obtained by contacting the regional scientific ethical committees.If there is any doubt as to which regional scientific ethical committee the trial is to be notified to, the Danish National Committee for Biomedical Research Ethics may be contacted (tel. +45 7226 9370, cvk@sum.dk or www.cvk.sum.dk). 4.2. Danish Data Protection Agency According to the Danish Act on Processing of Personal Data, medicinal product trials must also be notified to the Danish Data Protection Agency.This may take place at the same time as the application to the Danish Medicines Agency. For further information on such notification, please contact the Danish Data Protection Agency (www.datatilsynet.dk or tel.: +45 3314 3844, 9.00 a.m. to 12 noon). 4.3. Danish Working Environment Authority (trial on gene therapy) Patient trials with products containing living genetically modified organisms are subject to the Danish Environment and Gene Technology Act, more specifically this Act’s rules on research.The rules are contained in the Danish Ministry of Labour’s Executive Order (No. 910 of 11 September 2008) on “gene technology and working environment”. One of the things this Executive Order covers is the requirement for notification of the classification of premises at which all or part of the trial is to take place, as well as notification of projects. The purpose of the notifications is to safeguard both the working environment and the external environment.The Danish Working Environment Authority will then grant authorisation of both the premises and the trial. A cooperative agreement has been entered into by the Danish Working Environment Authority and the Danish Environmental Protection Agency on the evaluation of certain notifications of the classification of premises and notification of research projects.This has led to the following practice: Notifications on the classification of premises for gene therapy and notification of projects concerning the use of living, genetically modified microorganisms for gene therapy are to be submitted to the Danish Working Environment Authority, which will then send a copy of notifications for consultation at the Danish Environmental Protection Agency. Medicinal product trials with gene therapy must be notified to the Danish Working Environment Authority, cf. above. This may take place at the same time as the application to the Danish Medicines Agency. For further details concerning notification, please contact the Danish Working Environment Authority (www.arbejdstilsynet.dk or tel. +45 3915 2000). 5. Trial protocolPlease see the “Bekendtgørelse om god klinisk praksis i forbindlese med kliniske forsøg med lægemidler på menensker, no 744 of 29 June 2006 (appendix 3). Generally, a trial protocol should comprise the points listed below.Some of the information may appear from separate appendices if local circumstances so require.Other parts of the points below may be described, for example, in the Investigator’s Brochure. A trial protocol must contain the following: 1. General information a. Protocol title, date and code (if applicable). All appendices and amendments must be numbered and dated. 2. Background information a. Product name(s) and a description of active substance(s). 3. Purpose A detailed description of the purpose of the trial. 4. Trial plan and trial design a. Clear indication of the primary and any secondary endpoints of the trial. 5. Selection of trial subjects and criteria for inclusion in and exclusion from the trial a. A description of the inclusion criteria. 6. Treatment of trial subjects a. A description of the treatment, including product name(s) of all products, dose, posology, frequency and treatment period(s), including follow-up periods. 7 Evaluation of effect a. Specification and justification of the effect parameters 8 Safety evaluation a. Specification and justification of safety parameters 9. Statistics a. Description of the statistical methods employed – including time(s) for scheduled interim analyses. 10 Direct access to source data/documents For all clinical trials, it must be ensured that the protocol or another written document specifically states that the investigator will allow direct access to source data/documents (including patient records) for monitoring, auditing and/or inspection by an ethical committee, the Danish Medicines Agency or other countries’ competent authorities respectively. 11. Quality control and quality assurance Confirmation that standard procedures for quality control and quality assurance will be complied with, cf. ICH GCP guidelines (see Glossary sections 1.46 and 1.47). 12 Ethical questions a. Specific ethical considerations in relation to the trial 13. Handling and archiving data Guidelines for handling, processing and archiving all of the collected data for each trial subject participating in the trial, plus other data relevant to the trial. 14. Financing and insurance Specification of the financing and insurance status of the trial. 15. Guidelines for publication Please see the current guidelines for researchers and scientific ethical committees. 16. Summary and appendices The trial protocol must contain a summary and relevant appendices (e.g. instructions for personnel, description of special methods of approach). 17. Literature references A list of the literature referred to in the protocol must be attached. Where relevant it must be clearly stated in the protocol, or in an amendment to this, that it is ensured that fertile women are not pregnant when included in the trial (negative pregnancy test at the inclusion) and that safe contraception is used. For some individuals or special populations, there may be arguments against using the above-mentioned methods. Examples include seriously ill, hospitalised patients or fertile children who are not sexually active. The investigator has the responsibility of determining whether any such populations exist. The reasons for a deviation, if any, must be recorded (in, for example, the CRF) and shall not be submitted to the Danish Medicines Agency, but must be stored for documentation in connection with any future inspection. 5.2. Non-compliance to the register A procedure for preauthorisations of non-compliance from the register (waivers) is in generel not accepted by the Danish Medicines Agency. 6. Good Clinical Practice (GCP)Clinical trials with medicinal products on humans must be conducted in accordance with good clinical practice (GCP) cf. the Danish Medicines Act section 88(2). Also view Executive order on good clinical practice on medicinal products - humans (no. 744 of 29 June 2006, appendix 3 §§ 3-6). Here it is evident, that there must be a monotoring and audit of the trials. The regulations on clinical trials are changed (latest 12 December 2005) so that the Act covers authority for implementation of parts of the European Parliament’s and the Council of Europe’s Directive 2001/20/EC of 4 April 2001 on the approximation of the Member State’s acts and administrative provisions on application of good clinical practice in trials of medicinal products for human use. The points which concern clinical trials in Act no. 382 enter into force on 1 May 2004. The Directive aims at harmonising legislation on clinical trials of medicinal products on humans within the EU. The Directive introduces the requirement that all phases of clinical medicinal product trials on humans must proceed according to GCP, which is an internationally recognised ethical and scientific quality standard.Thus, GCP comprises both the ethical and scientific aspects associated with clinical trials. Compliance with GCP standards for the protection of trial subjects’ rights, safety and welfare helps to ensure that it is ethically justifiable to let humans participate in medicinal product trials.At the same time, there is a requirement that the trial should be planned, conducted and reported in accordance with GCP, in order to ensure scientifically acceptable implementation.Study data must be well-documented and correct as to ensure reliable trial results, which can be used as documentation for the authorisation of a medicinal product and how it should be used in treatment of patients. Standards have also been introduced in other areas within development and handling of medicinal products. This development, which e.g. involves a toxicological assessment of a medicinal product’s constituents prior to any clinical trial, is encompassed by the Good Laboratory Practice (GLP) protocol. Likewise, there are standards for Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) respectively. GCP imposes demands on the parties of the trial (the sponsor and the investigator), the ethical committees and the competent authorities. A basic element of the GCP standard is that the sponsor, before an authorised trial is initiated, must construct a documented quality assurance system with standard operation procedures (SOPs) for the different phases of the trial and for data handling.During the trial, the sponsor must, as an element of quality control, ensure compliance with the established procedures and the competent authority may choose to carry out an inspection of the trial centre or other relevant centres.Once a trial is completed, quality control also encompasses analysis of data.All trial activities, control visits etc. must be documented by means of written reports. The Directive (2001/20/EC) is available at Pursuant to Directive 2001/83/EC, the information and documentation accompanying an application for marketing authorisation must be presented in accordance with a range of detailed rules.With regard to the execution of trials, all phases of the clinical development, including studies of bioavailability and bioequivalence, must be planned, conducted and reported in accordance with Good Clinical Practice. In a press release, the Committee for Proprietary Medicinal Products (CPMP) (now the Committee for Human Medicinal Products - CHMP), the EU “registration board”, has stressed that in handling marketing authorisation applications, emphasis will be placed on whether trials are carried out and reported according to the CHMP’s Note for guidance entitled Good Clinical Practice for Trials on Medicinal Products in the European Community III/3976/88-EN.In January 1997, this was replaced by the International Conference of Harmonisation (ICH) guidelines concerning GCP, entitled Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95).The guidance is available at: Under the Danish Medicines Act section 90, subsections 1, 2 and 3, the Danish Medicines Agency is entitled to inspect any trial it has authorised. An inspection of a clinical trial normally comprises inspections on the premises of both the sponsor and the investigator to establish whether the trial is carried out in accordance with national legislation, the GCP guidelines, the trial protocol and the sponsor’s quality assurance system, as well as to establish whether the data is correct and reliable. 7. DocumentationApplicants that have access to EudraVigilance must register the Investigational Medicinal Product (IMP) in the Medicinal Product Dictionary (MPD). Naturally, this only applies if the IMP is not already registered. Non-commercial sponsors are not expected to have access to EudraVigilance. For products for which a marketing authorisation is already issued or is being applied for, as well as for products for which documentation was submitted in connection with a previous application, reference to the previously submitted material is usually sufficient. For other products, documentation on the chemical, pharmaceutical, animal pharmacological, toxicological and human pharmacological properties must be attached along with information on existing clinical experience. The documentation must be submitted as a summary – in the form of an Investigational Medicinal Product Dossier (IMPD), (please see the guidelines for application for clinical trials, notification of amendments and declaration of the end of trial) and must be initiated with a summary of the contents. The guidelines can be found on http://eudract.emea.europa.eu/ under Documents. Where relevant, the Investigator’s Brochure may be referred to for information regarding toxicological, animal pharmacological and human pharmacological properties as well as existing clinical experience. If the Agency has previously assessed the documentation and amendments of e.g. the Investigator’s Brochure are subsequently submitted, any changes must be clearly indicated. The case handling proces will not start unless there is such a document. Information on changes to versions not submitted must likewise be indicated clearly. Revised versions should only be submitted for assessment if the changes are significant to ongoing trials or if it occurs in connection with an application for new trials.If necessary, the Danish Medicines Agency may order complete reports or any other supplementary information. Please see the guidelines for application for clinical trials, notification of amendments and declaration of the end of trial. http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-10/11_ca_14-2005.pdf Please also see the Danish executive order on GMP (available in the factbox to the right: 'Bekendtgørelse nr. 264 af 4. april 1997 om god fremstillingspraksis (GMP) og god distributionspraksis (GDP) for lægemidler'), Directive 2001/20/EC, article 13 and GMP Directive 2003/94/EC. The directives are available at: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/index.htm. For Directive 2001/20/EC, click 'Volume 1'; for the GMP Directive, click 'Volume 4'. In the case of direct import to Danish companies from third countries (non EU/EEA countries), please see the Danish GMP executive order referred to above. Please also see the form ”Documentation for good manufacturing practice (GMP) and the quality of investigational products in connection with the application for the conduct of clinical trials in Denmark” as well as the form ”Qualified Person declaration”. Please also see point 9. 7.2. Pharmaceutical chemical documentation Please see the guidelines for application for clinical trials, notification of amendments and declaration of the end of trial. For medicinal products on the market which, for trial technical (e.g. blinding) or other reasons, have the form, appearance or composition changed, information on the complete qualitative and quantitative composition must be submitted together with considerations on bioequivalence with enclosed results of relevant in vitro tests (for compressed medicinal products, e.g. in the form of dissolution tests) for both the marketed and the amended formulation. If this information has previously been submitted to the Danish Medicines Agency, it is sufficient to refer to it and, if possible, with an indication of the Danish Medicines Agency’s record number and/or EudraCT number. 8. LabellingLabelling must comply with the requirements of the current Annex 13 to the GMP directive. Link: Labelling must be in Danish, yet for products which are exclusively administered by hospital personnel English language marking may be accepted.However, Danish-language instructions must be available to the personnel. 9. Dispensing/SalePursuant to the explanatory notes to the Danish Medicines Act, No. 1180 of 12 December 2005, products may be dispensed or sold for use in clinical trials authorised by the Danish Medicines Agency. When the authorisation is granted, dispensing/sale may take place to:
Import and export (from third countries) as well as manufacture of medicinal products for clinical trials may only be undertaken by companies authorised pursuant to section 39 of the Danish Medicines Act. The authorisation must include manufacture of medicinal products for clinical trials. The import and export of such products thus require no further authorisation. Please also see the form ”Documentation for good manufacturing practice (GMP) and the quality of investigational products in connection with the application for the conduct of clinical trials in Denmark” for import or manufacturing activities in a third country as well as the form ”Qualified Person declaration”. The investigational medicinal products must not be dispensed to the investigator until the Danish Medicines Agency has authorised the trial. Dispensing to a pharmacy may take place before the trial is authorised, but the pharmacy must not supply the investigator with any investigational medicinal products until the authorisation is available. For further information, please see Directive 2003/94/EC, the GMP protocol and Annex 13. Test subjects must according to the GCP-amendmend must receive free testproducts. The sponsor provides the testproducts and possible orders to how to take the products. The sponsor must provide, but not necessarily pay for the testproducts. The Danish Medicines Agency can in special cases dispense form the rules on the delivery of free testproductsk, if testproducts free of charge will squander the purpose of the test. The dispensing of euphoriant substances/preparations for use in clinical trials is only allowed when the Danish Medicines Agency has issued an authorisation for this purpose, cf. section 4(5) of the Ministry of Health’s Executive Order on Euphoriants. Likewise, the receipt and possession of euphoriant substances by commercial companies requires an authorisation from the Danish Medicines Agency, cf. section 5 of the above-mentioned Executive Order. 10. Information for patients/trial subjectsRegulation on how to inform and obtain consent from patients/trial subjects participating in clinical trials are to be found in the Executive Order on information and consent on involving trial subjects in biomedical research projects. Among other things, this stipulates what information the written and verbal information must contain and how to obtain consent. Furthermore, guidelines for this can be found in the Guidance on information and consent when involving trial subjects in biomedical research projects and on application for and assessment of research projects in the Scientific Ethical Committee System (Vejledning om information og samtykke ved inddragelse af forsøgspersoner i biomedicinske forskningsprojekter og om ansøgning og bedømmelse af forskningsprojekter i det videnskabsetiske komitésystem). If necessary, please contact the Central Scientific Ethical Committee at cvk@sum.dk, website: www.cvk.sum.dk. As regards information about individual persons’ state of health, please note that monitoring, audit and inspection of clinical trials of medicinal products require access to patient records according to the GCP protocol.Information on individual persons’ state of health is comprised by the rules on confidentiality in the Act on patients’ legal status and the penal code. Hence, a hospital must not give third parties access to patient records. Third parties include monitors, auditors and inspectors. Individual patients can give their consent to company representatives and/or authority representatives having access to their records. However, pursuant to the Danish Patients' Rights Act, this consent expires no later than one year after it is given. Instead of consent, a power of attorney may be used. Under the Patients' Rights Act, patients have access to their own records. In pursuance of the Danish Public Administration Act, patients may allow another person, hereunder e.g. the monitor, to access their record on their behalf. Such an approval of access to records by another person must be by means of a power of attorney. A power of attorney – unlike consent – is not subject to a one-year time limit. The power of attorney should clearly appear exactly as a power of attorney, and it should be precisely formulated so as to avoid any doubt with regard to what it covers. The power of attorney should therefore be an independent document, from which it appears:
Moreover, the power of attorney should indicate that the Danish Medicines Agency is also granted access to the information. The written patient information must be enclosed with a view to ensuring that the above mentioned control can be conducted. The actual assessment of the patient information is carried out by the Scientific Ethical Committee System. 11. Initiation and implementation of the trialIn connection with parallel case handling by the Danish Medicines Agency and the Scientific Ethical Committee System, there may be cases where both systems produce grounds for non-acceptance to closely related problems. This must be regarded as the cost necessary to avoid the delay which a successive evaluation between the two systems would otherwise entail. The trial may be initiated when both the Danish Medicines Agency has granted an authorisation and the Scientific Ethical Committee System has approved the trial. Only when the authorisation from the Danish Medicines Agency is available, can the medicinal products for the trial can be dispensed to the party or parties responsible for the trial. Subsequent amendments/additions to the protocol and changes hereto must be sent in the same version to both the Danish Medicines Agency and the regional research ethics committee before implementation. Amendments to the protocol should be submitted in the same language as the protocol assessed during application. A fee must be paid, see section 2. The sponsor must apply for authorisation to make amendments, if the changes may affect:
or in case of any other amendments which might be regarded as significant. You can find further information on this in our message Amendments of clinical trials. For further information, please see the guidelines for applications for clinical trials, amendments and the declaration of the end of trials, http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-10/11_ca_14-2005.pdf, which contributes with examples of substantial amendments that requires an authorisation from the Danish Medicines Agency before the changes may be implemented. Furthermore, these guidelines contain an application form for authorisation for implementing amendments. The form can be downloaded as a Word file from the following link: http://eudract.emea.europa.eu/document.html via the link to Documents. The form must be filled in, printed and signed. 12. Adverse reactions/Adverse eventsThe sponsor must inform the Danish Medicines Agency immediately if suspected unexpected serious adverse reactions (SUSARs) occur during the trial, cf. the Danish Medicines Act section 89(2), no. 1. The definitions are as follows, cf. the Executive Order on clinical trials:
Please see the two guidelines on the subject:
Please also see Appendix 11: Overview of adverse reaction reporting. 12.1. Adverse reactions and adverse events occurring in trials in Denmark The trial protocol must state which adverse reactions and adverse events the investigator must report to the sponsor and when the reporting is to take place after the adverse reaction/adverse event is ascertained. It must also be stated how long the trial subjects are followed after they have stopped using the trial medication with regard to registering any late-occurring adverse reactions/adverse events. The following must be reported to the Danish Medicines Agency: Pursuant to the Danish Medicines Act, section 89(2), no. 1, the sponsor is under an obligation to inform the Danish Medicines Agency immediately if any suspected unexpected serious adverse reactions (SUSARs) occur during the trial. The sponsor must ensure that all relevant information about suspected unexpected serious adverse reactions, which are fatal or life-threatening, is recorded and reported to the Danish Medicines Agency as soon as possible and no later than 7 days after the sponsor is informed of such a suspected adverse reaction. No later than 8 days after the reporting, the sponsor must inform the Danish Medicines Agency of relevant follow-up information on the sponsor’s and the investigator’s follow-up action to the reporting. Any other suspected unexpected serious adverse reactions must be reported to the Danish Medicines Agency no later than 15 days from the time when the sponsor is informed about them. All reports must be accompanied by comments on possible consequences for the trial. With regard to blinded trials, please see point 5.1.8 of the guidelines on adverse reactions (CT 3). The report should be submitted electronically. Please see the guidelines for the SUSAR database (CT 4), link http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-10/22_cp_and_guidance_database_susars16_april_2004.pdf, Documents. You are required to register in the EudraVigilance system in order to be able to report electronically. Further details can be found at http://eudravigilance.emea.europa.eu/human/index.asp. Please also see the Executive Order on requirements for formulating adverse reaction reports and periodic safety updates etc. no. 262 of 19 April 2004 concerning the electronic reporting of adverse reactions (bekendtgørelse om krav til udformning af bivirkningsindberetninger og periodiske sikkerhedsopdateringer m.v.). It is available in Danish on www.retsinfo.dk. At the end of the trial, all adverse reactions and events must be reported to the Danish Medicines Agency in the final report. 12.2. Serious adverse reactions and serious adverse events occurring in trials abroad SUSARs occurring in other EU/EEA countries must be reported to the Danish Medicines Agency if the trials have the same protocol (EudraCT-number) as in Denmark. This only concerns trials applied for after 1 May 2004. Such adverse reaction reports must be submitted in a paper version. SUSARs from non-EU/EEA countries should not be reported to the Danish Medicines Agency. For further information, please see the guidelines for the SUSAR database (CT 4) and the guidelines on reporting adverse reactions arising from clinical trials (CT 3). SUSARs occurring in Danish trials should be reported electronically to the SUSAR database (EudraVigilance Clinical Trial Module). As non-commercial sponsors are not expected to have access to the SUSAR database, non-commercial sponsors can be reported on CIOMS forms, on which the EudraCT number and possibly the Danish Medicines Agency’s record number is indicated. A similar document can also be used. The CIOMS form can be found in Appendix 9 . SUSARs reported to the Danish Medicines Agency by commercial sponsors should be reported via the EudraVigilance Gateway. The Danish Medicines Agency’s ID concerning SUSARs is DKMAEUDRA. The form is of the same format as ICH E2B M2. However, there will be an interim arrangement until all commercial sponsors have been registered in the SUSAR database.Further details on electronic reporting: http://eudravigilance.emea.europa.eu/human/HowToRegister.asp. In order to report electronically, it is necessary to be able to report to EudraVigilance, be registered in the system and to have tested with EMEA (http://www.eudravigilance.emea.europa.eu/human/index.asp). Until all commercial sponsors are registered in the EudraVigilance system, the Danish Medicines Agency will accept SUSARs reported on CIOMS forms.Yet, the EudraCT number and possibly the Danish Medicines Agency’s record number must be entered on the form. The CIOMS form can be found in Appendix 9 . 12.4. Annual Safety Report and list of suspected serious adverse reactions Once a year throughout the duration of the clinical trial, the sponsor must provide the Danish Medicines Agency with a list of all suspected serious adverse reactions which have occurred during this period and a report on the trial subjects’ safety. The list and the report must be submitted to the competent authorities in the Member States on whose territory the clinical trial is being carried out. Please see the guidelines on reporting adverse reactions arisen in clinical trials (CT 3), item 5.2. 13. End of trial and trial reportNo more than 90 days after completion of trial, the sponsor must inform the Danish Medicines Agency that the trial has been completed (use Appendix 7 ) and as soon as possible and at the latest before one year after thereafter, the sponsor must submit the trial results to the Agency, cf. the Danish Medicines Act section 89(2), no. 4. In summarised form, this must comprise information about the number of patients treated, doses used, duration of medication and results obtained, as well as any adverse reactions observed. The Danish Medicines Agency will, if deemed necessary, request the complete report. 14. Other guidelinesSeveral EU guidelines exist on clinical trials in general as well as specific guidelines for certain therapeutic groups. More information on these can be found in “The Rules governing Medicinal Products in the European Community Vol. 3: Guidelines – medicinal products for human use”, which can be purchased from: J. H. Schultz Information A/S It is possible to find guidelines on the internet starting from the following address: Appendices
The Danish Medicines Act as amended on 12 December 2005 Executive Order on clinical trials of medicinal products on humans Bekendtgørelse om god klinisk praksis i forbindelse med kliniske forsøg med lægemidler på mennesker Executive Order on fees for application for authorisation of clinical trials
Go to: http://eudract.emea.europa.eu/document.html and click on: "Clinical trials application form". REQUEST FOR AUTHORISATION OF A CLINICAL TRIAL ON A MEDICINAL PRODUCT FOR HUMAN USE TO THE COMPETENT AUTHORITIES AND FOR THE OPINION OF THE ETHICS COMMITTEES IN THE COMMUNITY The form must be filled out via the Internet. Read the guideline above in section 3 where there is a link to guideline and form. Go to: http://eudract.emea.europa.eu/document.html and click on: "Notification of Amendment". REQUEST FOR AUTHORISATION OF A SUBSTANTIAL AMENDMENT TO A CLINICAL TRIAL ON A MEDICINAL PRODUCT FOR HUMAN USE TO THE COMPETENT AUTHORITIES AND FOR OPINION OF THE ETHICS COMMITTEES IN THE COMMUNITY. The form must be downloaded from the Internet. You can also read the guideline above in section 11.2. Go to: http://eudract.emea.europa.eu/document.html and click on: "Declaraton of the end of a clinical trial". The form must be downloaded from the Internet. You can also read the guideline above in section 11.2. List of guidelines Overview of the guidelines can be found on EU-Commissions Eudralex Volume 10, Clinical trials: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev10.htm CT 1: Application for authorisation of clinical trials, amendments and end of trial. Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial, as required by Article 9 (8) of Directive 2001/20/EC revision 1. CT 3: Reporting adverse reactions Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use, as required by Article 18 of Directive 2001/20/EC revision 1. CT 4: The SUSAR database Detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions (Eudravigilance – Clinical Trial Module), as required by Article 11, Article 17 and Article 18 of Directive 2001/20/EC revision 1. CT 5: The EudraCT database Detailed guidance on the European clinical trials database (EUDRACT Database), as required by Article 11 and Article 17 of Directive 2001/20/EC, These guidelines can also be found at: http://eudract.emea.europa.eu//document.html under Guidance Documents. Form for reporting suspected unexpected serious adverse reactions occurring in clinical trials Checklist for application for authorisation of a clinical trial Overview of adverse reaction reporting Reporting of adverse reactions from clinical trials of medicinal products applied for after 1 May 2004.
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Last updated - 09.09.2010
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