Download the Medicinal Products Act §24

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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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).
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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).
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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.
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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.
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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.
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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.