Your research file must include a number of basic documents before you submit it for a primary review to an accredited MREC or CCMO. These are listed below. Some of the documents only have to be submitted when applicable. This is indicated at the end of the list (when applicable).

Here you can find a pdf-file with an overview of and explanatory notes on the complete research file.

If an accredited MREC carries out the review then it is possible that additional documents may be required which are not listed in the standard research file. Enquiries can be made to the accredited MREC concerned.

Submit the documents preferably in the indicated order. When a hard copy of the research file is required, separate the documents by using the separating pages. This makes it possible for the reviewing committee to carry out a quick and efficient check of whether or not the file is complete. The review starts at the moment the submitted research file is complete.

In the case of research with a medicinal product additional documents are required: these are indicated in the standard research file with the symbol

The research file of a research with a medicinal product which is submitted to the reviewing committee must also be submitted to the competent authority (CCMO or Ministry of Health, Welfare and Sport). For more information see Extra review competent authority research with a medicinal product. The competent authority requires you submit the file digitally. See Digital or hard copy for more information on the requirements for digital submission.

In the list of documents of the standard research file are documents required for primary submission and documents to be submitted to the reviewing committee and the competent authority (if applicable) after a positive decision and/or no grounds for non-acceptance.

The Medical Research Involving Human Subjects Act (WMO) and the Regulation scientific research with medicinal products form the basis for the standard research file.

A. Correspondence

A1: Cover letter to reviewing committee and the competent authority

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The cover letter must clearly state to which MREC and/or competent authority the research file is submitted and which documents the submission contains (including version numbers and/or dates). In addition we recommend to describe the status of the study (number of included patients, completed phases/cohorts) when submitting multicenter studies in which the Netherlands does not participate in all phases of the study and to indicate which group(s) of study subjects (adults/children, patients/healthy volunteers) will be included in the Netherlands. The cover letter must be signed by the submitting party. If the submitting party is the project leader/coordinating investigator/head of department, it is recommended that the cover letter be co-signed by one of these persons.

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A2: Authorisation from the sponsor (if the submitting party is not the sponsor)

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If the submitting party is not the sponsor, an authorisation stating that the submitting party is authorised to submit the research file on behalf of the sponsor must be submitted.

Section 13d of the WMO also applies to research with medicinal products, which states that the party organising the research (the sponsor) or his/her legal representative must hold offices within the European Union. A legal representative is a natural person or legal person who is able to carry out tasks on behalf of the sponsor with regards to the research. The legal representative can be an organisation or investigator who is responsible for carrying out the study in the Netherlands on behalf of the sponsor. The tasks and responsibilities of the legal representative must be described in detail in a contract.

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A3: Confirmation of receipt EudraCT number

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The EudraCT number is a unique number linked to a research file for registration in the European database for research with medicinal products (EudraCT database). A EudraCT number can be obtained by filling in the request form on the website of the EMA.

The following information must be filled in to obtain a EudraCT number:

  • contact details for the submitting party and his/her organisation (name, address, place of residence)
  • the research protocol number for the party organising the research/sponsor
  • the e-mail address the EudraCT number must be sent to
  • the country where the research is being carried out

The EudraCT number is sent to the e-mail address entered during the application procedure. The assigned EudraCT number must be submitted by e-mail to the reviewing MREC and the competent authority.

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B. Forms

B1: ABR form and summary (online, signed and dated)

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The ABR form is the general assessment and registration form. The ABR form must be completed online in ToetsingOnline.

After the form has been completed and submitted it must be printed. The signed hard copy version must be submitted to the reviewing MREC. The competent authority must receive the ABR form digitally (as pdf). The digital version does not have to be signed.
- Example ABR form april 2014 with explanatory notes (for studies submitted before 15 December 2015)

- Example ABR form december 2015 with explanatory notes

 

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B2: Local addendum to ABR form (at the accredited reviewing research ethics committee’s request)

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Some MRECs have an addendum to the ABR form in which additional questions are asked. Ask the MREC to where the research is being submitted whether they require an addendum to be filled in.

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B3: EudraCT Application Form: (online, signed and dated)

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The EudraCT Application Form (Clinical Trial Application Form) may be filled in via the website of the European Clinical Trials Database. You will need the assigned EudraCT number for this. Once the EudraCT Application Form has been completed, the data must be saved as an xml file and as a PDF file to your own computer.

A signed hard copy version of the EudraCT Application Form must be submitted to the reviewing MREC. The pdf is for the competent authority. This version does not have to be signed. You then send the xml file via ToetsingOnline (question B1a of the ABR form) for registration in the EudraCT database and it therefore does not need to be submitted with the research file.

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B4: Gene therapy/GMO form (if applicable)

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Only applicable to gene therapy/GMO research. The application form ‘Review of clinical research with gene therapy’ is available from the gene therapy office (Loket Gentherapie).

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B5: EudraCT Notification of Amendment Form   

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In the event of substantial amendments, a signed and dated EudraCT Notification of Amendment Form must be submitted to the reviewing committee. The competent authority must receive the notification of amendment digitally (pdf).

This latter version does not need to be signed. Correct answering of question E1 of the form is essential for processing the amendment by the competent authority in ToetsingOnline. The form is available for downloading from Eudralex under ‘Chapter I’. If the substantial amendment also involves a change to the EudraCT Application Form (B3) and the ABR form (B1), these must also be altered and submitted to the reviewing committee. The competent authority only has to receive the notification of amendment form and the the new Application form (if changed) (pdf + online), but not the revised ABR form.

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B6: CCMO end of trial form

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All WMO research brings with it a number of obligations required by the positive decision obtained. This includes reporting the end of the research to the reviewing committee.

If the research is terminated prematurely, a reason must be given. The CCMO form end of trial may be used for this purpose. In the case of international research it is required you also give the international end of trial date if this differs from the end of trial date in the Netherlands. For research with a medicinal product it is required you use the EudraCT form End of Trial (see B7).

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B7: EudraCT End of trial form

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Following (premature) termination of a research trial, the EudraCT End of Trial Form must be completed and submitted to the reviewing committee and digitally (pdf) to the competent authority.

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C. Protocol and amendments

C1: Research protocol

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A research protocol template is available for downloading from the CCMO website along with the explanatory notes.

Guidance document for notification procedure SAEs to MRECs (Dutch)

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C2: Protocol amendments, in chronological order

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Protocol amendments must clearly outline the changes, the reasons for changes and which passages in the original research protocol have been changed. It is advised to send a version with track changes and a version with the changes already accepted in the text. A detailed overview of the changes is also acceptable.

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D. Product information

D1: Investigator’s Brochure

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An Investigator’s Brochure is a summary of clinical and preclinical data regarding a/the research product(s) relevant for the evaluation of the research product(s) in research subjects. Chapter 7 of the ICH-GCP guideline describes the requirements for an Investigator’s Brochure.

Evaluation
The IB must be evaluated at least annually and revised where needed. More frequent revision may be required depending on the developmental stage and availability of new information. Relevant new information may be of such importance, however, that it must be submitted to the WMO reviewing committee and the competent authority before it is integrated into a revised IB, as required by GCP rules. Therefore, the IB may not be older than 1 year, unless annual evaluation has shown revision was not required. It must also be clear that the IB was evaluated less than one year ago.

SUSARs
Additionally, all relevant information regarding the safety of the product that has not yet been included in the IB must be submitted. At this time, this information is limited to a line- listing of the SUSARs that have occurred. This line listing must be accompanied by a review by the sponsor which clearly indicates whether this information has any consequences for the safety of the research subjects. If each SUSAR has been evaluated individually by the sponsor, a declaration must be given in the cover letter indicating whether these SUSARs have any consequences for the human subjects participating in the study in question.

Authorised products
An extensive Investigator’s Brochure is not always required for authorised products for which the pharmacological aspects are known to the doctor/investigators. An SPC (summary of product characteristics) may suffice, as long as it contains all information relevant to the investigator. This exception does not apply to authorised products used in a research setting for uses other than the authorised use or with another route of administration.

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D2: IMPD (or SPC if applicable), incl. list of relevant research with the medicinal product being researched

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An Investigational Medicinal Product Dossier (IMPD) contains data on the quality, production and control of the medicinal product being researched.

This information concerns the active product, placebo and reference product (if applicable). It also contains a summary of data from all clinical and non-clinical research. The Investigator’s Brochure may be referred to for the latter. An example of an IMPD and explanatory notes are available on this website.

Requirements
The requirements of the IMPD are mentioned in paragraph 2.7 of the CT-1 directive ‘Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial’. See also the template Investigational Medicinal Product Dossier (IMPD) and the accompanying explanatory notes.

If a product is authorised and will be used in the licensed form, an SPC (summary of product characteristics) will suffice, if it is available. SPC texts for many medicinal products (summary product characteristics, IB-1 text) may be found on the Medicines Evaluation Board website. The website also has a link to a template for an SPC.

It is important that the research file for the reviewing MREC contains sufficient information on the medicinal product being used in the research so that it can reach an informed decision on the safety and vailidity of the research. Table 1 states the minimum information on the medicinal product which you must submit for review.

D2. IMPD cellular medicinal product for advanced therapies

The template IMPD can also be used for medicinal products used for advanced therapies. The field has also developed a manual for an Investigational Medicinal Product Dossier (IMPD) for cellular therapeutics, as part of the National Programme for Cancer Prevention.

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D2. IMDD (if applicable)

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The Investigational Medical Device Dossier (IMDD) specifies the content of the documentation for medical devices without CE-marking in clinical trials submitted to a medical ethics research committee (MREC) for review.

The quality managing aspects of the clinical research and the design and execution of the study do not form part of the IMDD. These aspects must be described in the plan for the clinical research. See the model IMDD and the explanatory notes IMDD.

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D3: Example labels in Dutch

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An example label for the medicinal product being researched must be submitted for review. The label must meet the requirements set in annex 13 of the Good Manufacturing Practice Guideline (2003/94/EG).

Information on the label

The following information (in Dutch) must be listed on the label, unless there are good reasons not to do so:

  1. Name, address and telephone number of the sponsor, CRO or investigator (these are contact details which are important when information on the product, the research or deblinding is required in the event of an emergency). Address and telephone number can be omitted if the research subject has been given a patient card or similar which already states this information and the research subject has been given the instruction to always have this card with them.
  2. Pharmaceutical formulation (tablets, capsules, etc.), the dosage form, the number of dosage units (in open label research: name and dosage of the product).
  3. The batch and/or code number (for tracing contents and packaging activities).
  4. A research reference code, allowing identification of research, centre, investigator and sponsor (unless listed elsewhere).
  5. A research subject/treatment number and if required, a visit number.
  6. The investigator’s name (if not listed under points 1 or 4).
  7. Instructions regarding use (can be achieved via referral to included information or the instruction to use the research product as instructed by the doctor).
  8. Solely destined for clinical research (or similar text).
  9. Storing conditions.
  10. Storage life (use-by date, expiration date or re-test date); to be referred to as month/year with clear instructions.
  11. Keep out of reach of children (unless the research medication is not taken home).

Exceptions

  • a. Research medicinal products in an inner packaging together with an outer packaging, designed to remain attached. The outer packaging lists all the information (points 1 -11) and the inner packaging only lists: 1 (the name only), 2, 3, 4, 5.
  • b. Research medicinal products in an inner packaging too small to list all information (e.g. vials). All information must then be listed on the outer packaging and the inner packaging must only list: 1 (the name only), 2 (the dosage form only (exception: oral fixed dosage forms), name and dosage of the product in open label research), 3, 4, 5.
  • c. Research medicinal products not requiring any unique manufacturing methods or packaging, and which are authorised and with research subjects who exhibit the same characteristics as the patients for which the medicinal product is authorised. In this case, the following must be added to the original label (the original text must, of course, still be legible): 1 (the name only).

The use of symbols and pictograms is permitted.

Relabeling
In the event of re-labeling due to the expiration date being changed, an additional label must be affixed to the packaging listing the new expiration date and the batch number in accordance with the EU Guidelines to Good Manufacturing Practice for medicinal products for human and veterinary use, Annex 13.

The original information, particularly the batch number and/or the production code, must remain as visible as possible.

General example medicinal product label for the research

Name of pharmaceutical company (Name of research product)
30 tablets, 500 mg each, oral
Batch code XXX
Protocol number
Centre XXX
Patient number XXX
Use according to doctor’s instructions
Only for use in clinical research
Store at room temperature (max 30° C)
Do not use after mm/yyyy
Keep out of reach of children

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D4: Applicable statements/licenses

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Information on medicinal products without marketing authorization can be found on the website of the Dutch Health and Youth Care Inspectorate. Here you can find information on the production, import, release and storage of research medication.

Production and import of research medication

An application for a licence for the manufacture or import can be submitted to the Farmatec Unit (in Dutch) of the Central Information Point for Professions in Healthcare (CIBG). The license application is compulsory for those who prepare, let prepare or import medicinal products. Import is the obtaining of medicinal products from outside the EER, the European Economic Area: The EU member states plus Norway, Iceland and Lichtenstein.

A manufacturing licence is also required for the preparation of medicinal products in the Netherlands. This applies to production, packaging and labeling of products. A manufacturing license gives the carrier the right to produce and export self-prepared and imported medicinal products.

Hospital pharmacies may only prepare research medicinal products if they have a valid licence. Preparation does not cover the following:

  • preparing the product for administration;
  • relabeling in accordance with a set randomization list. For example, if a hospital pharmacist receives batches of a placebo and and active product, prepares these for a research subject (for example, measuring the product according to body weight) and blinds the relabeling (by addition of a label with a code);
  • relabeling due to extension of an expiration date on the product. This must be done in accordance with a written standard procedure including a quality control by a second competent person.

Release of research medication
A batch of a research medication may only be released by a Qualified Person (QP) given in the manufacturing license. The requirements which must be met by a QP are given in chapter 2 of the Medicine Law Regulation. (in Dutch)

Storage of research medication
Only hospital pharmacists and holders of a trading license may store medicinal products for use in research. If a Clinical Research Organisation (CRO) stores research medication in another manner than intended, then it is required to have a trading license. Research medicinal products may not be directly delivered by the trading licensee to the investigator or the patient. This falls under the responsibility of the hospital pharmacist.

Other licenses
Information regarding licences for research with genetically modified organisms is available from the Gene Therapy Office website. For studies with substances subject to the Opium Act, a grant exemption (in Dutch) is needed. This can be applied for at Farmatec.

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D5: Hospital pharmacist product details (if applicable)

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These are documents from the hospital pharmacist regarding execution of the medicinal product research, such as the prescription request forms, issuing of study medication, technical information required for preparation, whether the pharmacist prepares the medication himself, etc.

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D6: Additional product details (if applicable)  

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For gene therapy, the nucleotide sequence of the vector must be submitted for review. Other additional product details may include additional product information relevant to the review of your research protocol.

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E. Information for the research subjects

E1/E2: Research subject/representative information leaflet including the consent form(s)

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You can compile the subject information leaflet using the Template Subject Information (including Subject Consent Forms) (in Dutch). This template includes  the CCMO-template insurance text research subject information for studies reviewed after 1-7-2015 (in Dutch). For studies reviewed before 1-7-2015, you can use the CCMO-template insurance text research subject information (review before 1-7-2015) (in Dutch).

The Template Subject Information is a product of the DCRF-working group Study subjects. It is supported by the CCMO, NVMETC, NFU, STZ, Association Innovative Medicines, Acron and the department research professionals of the V&VN. Patient organizations also participated in the development of the Template.

The use of this Template will help investigators to write in a clear and concise manner and prevents that investigators will overlook essential parts of the information when writing the leaflet.

The template has also been translated in English.

Early 2018 a user-friendly web based version will be available for use: a practical and easy to use tool that will support investigators step by step when writing the information leaflet.

When needed, you can use the checklist research subject information (Dutch). There may also be additional instructional documents. Ask the MREC to where the research is being submitted for review for further information. You are advised to provide the research subjects and patients and/or their parents or representatives with the General brochure for research subjects (also available in Dutch). This brochure can also be ordered free of charge via brochures@minvws.nl.

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E3: Any advertising texts or other promotional materials

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All written information presented to (potential) participants in the medical research must be submitted to the MREC for review. This includes text to be published on a website concerning the possibility of participation in medical research, provided the text is related to specifically mentioned studies.

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E4: Other informational materials (if applicable)

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For example: general brochures regarding participation in medical research, IVF treatment, etc.

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E5. Newsletters or letters with study results (after approval of the study)

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All written information presented to participants in the study after the study has commenced, other than changes of documents mentioned under E1 through E4 above. This information must also be submitted to the reviewing MREC.

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F Questionnaires, patient diaries, patient cards, etc (if applicable)

F1. Questionnaires

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All questionnaires that must be completed by research participants must be drafted in Dutch and submitted for review. An exception is an English questionnaire usually used in the Netherlands and which has been validated.

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F2. Patient diary

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Diaries that must be kept by research subjects must be drafted in Dutch and submitted for review.

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F3. Patient card

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A patient card is a card that research subjects carry with them, listing the research they are participating in along with contact details for the sponsor and/or investigator in order to alert them in the event of an emergency. Such a card is commonly used in clinical medicinal product research.

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F4. Other

G. Insurance information

G1: Insurance certificate for WMO research with human subject insurance or written request for exemption from insurance obligation

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People participating in research covered by the Medical Research Involving Human Subjects Act (WMO) must be insured against any potential damages incurred as a result of participating in the research. The insurance must comply with specific regulations stated in the Compulsory Insurance Decree in Medical Research Involving Suman Subjects (dd 1-7-2015). Exemption from this insurance obligation is possible under certain conditions. In this case, a request must be included in the submitted application. Even if exemption from the WMO insurance obligation is granted, the liability insurance must still be covered.

If the research is carried out by an ministerial appointed institution, service or governmental organization, such as those which fall under the Ministry of Health, Welfare and Sport, or the Ministry of Defence, then a WMO human subject insurance or a liability insurance is not needed (section 7, sub 10 WMO).

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G1. Declaration of human subject insurance

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As of the 1st of July 2015 the new Insurance Decree (in Dutch) will come into force. This Decree makes it mandatory that the sponsor ensures that any potential damages for all participating human subjects of a research are covered. The Declaration of human subject insurance serves the purpose of clarifying how the sponsor has arranged this insurance.

The new Insurance Decree does not apply to research issued a positive decision by an accredited MREC or the CCMO before the 1st of July 2015, irregardless of any amendments to the research reviewed after this date. The old Insurance Decree applies to those studies.

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G2: Proof of coverage of investigator or sponsor

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The new WMO, which came into force on the 1st of July 2012, outlines rules regarding the liability of the sponsor or the executing party in medical research in section 7, paragraphs 8 through 11. These rules apply to all the research projects covered by the WMO.

This means that, in addition to WMO research subject insurance (G1), there must be a guarantee that the sponsor or the executing party is capable of fulfilling the responsibilities resulting from liability. This guarantee can emerge from a liability insurance of the sponsor or the executing party. The WMO does not state specific requirements to the liability insurance. In general, a common liability insurance policy is sufficient. The insurance must cover the whole research. There is a possibility for the sponsor or executing party liability not to be covered by insurance, but instead for them to guarantee the fulfilment of responsibilities in another manner. Bank guarantees, a blocked third-party account or another form of financial security may be used. This means that a sufficiently solvent sponsor or executing party, for whom there are sufficient guarantees that he can fulfil his obligations, is not required to have insurance or other financial security. This is also the case if the research is conducted by an institution, service or company that is appointed by the Dutch government - for example those under the authorization of the Dutch Ministry of Health, Welfare and Sport or the Ministry of Defence – when there is no obligation for a liability insurance (art. 7 sub 10 WMO).

Multicentre research

An insurance certificate for a hospital covers persons employed by that hospital. A copy of a professional liability insurance certificate will suffice for research with general practitioners. On the Research declaration you can fill in the name of the company that is responsible for proof of insurance coverage under ‘Liability insurance’. If your own centre is responsible then you can choose the option ‘our centre’. You then do not have to submit a certificate of the liability insurance. Also see: multicentre research.

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H. CVs

H1: CV(s) Independent expert (doctor(s) or other independent expert(s)

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A recent CV for each independent doctor or other independent expert must be submitted for review.

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H2: CV Coordinating investigator

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A coordinating investigator is an investigator who bears the responsibility for the coordination of investigators operating in the various centres participating in multicentre research. Not all multicentre research will have a coordinating investigator. There is no requirement to appoint one.

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I. Information per participating centre in the Netherlands

I1: List of participating centres and coordinating investigators

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An overview list of all potential participating centres must be submitted. This list must include contact details and the name of the coordinating investigator per centre.

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I2: Research Declaration(s) from the head of the department/healthcare group manager (or equivalent) per centre (for external review/multicentre research)

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The Research Declaration Form is a Declaration of the feasibility of a medical research in a (research) centre in the Netherlands.

The Head of Department, the healthcare group manager or a person in a similar position compiles the research declaration. This can be done with the aid of the research declaration form. More information can be found in the CCMO External Review Directive (RET 2012) (in Dutch)  the research declaration forms part of this, and at multicentre research.

As of the 1st of July 2015 the new RET 2012 (in Dutch) will come into force. As a result of the changes the information on the human subjects insurance on the research declaration will no longer apply. This new research declaration applies to initial submissions for research files submitted after the 1st of July 2015.

The changes to the RET 2012 are a result of the new Insurance Decree (in Dutch) that will come into force on the 1st of July 2015. This Decree makes it mandatory that the sponsor ensures that any potential damages for all participating human subjects in the Netherlands of a research are covered by a single insurance policy. Under the old Insurance Decree it was possible for each participating centre to take out human subjects insurance separately.

The new RET 2012 is not applicable to requests for a further decision on a research protocol which has been issued with a positive decision by the reviewing committee before the 1st of July 2015. The (old) CCMO External Review Directive 2012 and the accompanying (old) research declaration form from before the 1st of July 2015 (the moment the new directive comes into forces) applies to those researches.

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I3: CV Principal investigator per centre

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A recent CV of the principal investigator per participating centre must be submitted for review.

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I4: Other information per participating centre

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Other information per participating centre, if applicable and necessary for the review of the research file, should be submitted for review.

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J. Additional information regarding
financial compensation

J1: Additional information regarding financial compensation for research subjects

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This is only applicable when the information in the ABR form is not sufficient.

There are no detailed instructions regarding the amount of compensation for research subjects for participating in a clinical trial. The CCMO has various models which have been described in field literature and has gone over the possible criteria and discussed this with the accredited MRECs. The CCMO finally came to a consensus together with the accredited MRECs. This is described in the CCMO statement on financial compensation for research subjects and investigators.

The most important elements for the review of a proposed financial compensation for the research subjects are:

  • any expenses made are always reimbursed;
  • financial compensation is based on invested time, on the basis of the minimum wage and the burden of the research;
  • a higher financial compensation is not ruled out, as long as there is sufficient reason for doing so;
  • the compensation is not based on the risks;
  • the type of research (therapeutic or non-therapeutic) and the phase of research can be used for determing the amount of the financial compensation deemed acceptable for/appointed to the patients.

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J2: Additional information financial compensation for investigators and participating centres

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Only applicable if the information in the ABR form is not sufficient. This could include, for example, the financial paragraph in the contract between sponsor, investigator and research institution.

There are no detailed instructions regarding the amount of the compensation for investigators and centres participating in a clinical trial. The CCMO has various models which have been described in field literature and has gone over the possible criteria and discussed this with the accredited MRECs. The CCMO finally came to a consensus together with the accredited MRECs. This is described in the CCMO statement on financial compensation for research subjects and investigators. The CCMO uses the statement as a starting point for the review of proposed financial compensation. The statement is guiding for the accredited MRECs.

The most important elements used in the review of a proposed financial compensation for investigators or centres are:

  • any expenses are always reimbursed;
  • the financial compensation is based on time invested and the going hourly rate for the professional group;
  • any extra financial compensation is not desirable;
  • personal gain is not acceptable;
  • gain for the centre or research institution is acceptable within reasonable limits;
  • agreements on financial compensation between the sponsor, executing party and participating centre must be laid down in a contract. This contract can be provided upon request during the review of the research protocol.

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K. Other relevant document

K1: Copy of review by other institutions

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Examples include reviews by subsidy providers or the institution’s scientific committee. Recommendations made by a regulatory authority such as the FDA, EMA or MEB also fall under this category of document.

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K2: Overview list of authorised international intuitions that the protocol has been submitted to, along with a copy of reviews by foreign MRECs/ECs or competent authorities (including VHP)

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If the research is also being carried out in other countries of the European Union, an overview of competent authorities to which the protocol has been submitted must be included. Additionally, a copy of the decision made by foreign MRECs and/or competent authorities must be included, if available.

If a research has been reviewed in the Voluntary Harmonisation Procedure (VHP) the correspondence (all the questions by the participating member states and the response of the applicant) and the VHP decision must also be submitted.

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K3: Signed clinical trial agreement between the party organising the research (sponsor) or the funder and the investigator and/or institution

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When reviewing the clinical trial agreement an accredited medical research ethics committee (MREC) and the CCMO will follow the Revised CCMO Directive on the Assessment of Clinical Trial Agreements. The directive is applicable to research that falls under the scope of the WMO and when there is a written agreement between the parties involved in the financing, set up and execution of the research.

A signed copy of the clinical trial agreement between the party organising the research (sponsor) and the investigator and/or institution must be available for the reviewing committee before approval can be given. The reviewing committee decides whether a signed copy should already be included with the primary submission of the research file or whether this can be submitted later. In the latter case, an unsigned copy should be included in the research file for primary submission. In the case of multicentre research, a positive decision from the reviewing committee can follow if at least one signed clinical trial agreement is reviewed and approved. The clinical trial agreements of the other participating centres can be submitted as an amendment together with the Research Declarations.

If there is no clinical trial agreement, this must be mentioned in the cover letter. Without such a mention, the research file will be considered incomplete as long as the clinical trial agreement is missing.

The review of the clinical trial agreement is limited to the following two aspects, on the basis of the CCMO directive on the the assessment of clinical trial agreements:

  • The provisions with regards to premature termination of the scientific research or the agreement;
  • The provisions with regards to the publication of the study results of the scientific research.

Please note that similar provisions in the research protocol will also be reviewed.

You can use the model clinical trial agreement written by a collaboration of parties united in the Dutch Clinical Research Foundation (DCRF). These parties include the Samenwerkende Topklinische opleidingsZiekenhuizen (STZ) and the Netherlands Federation of University Medical Centres (NFU).

The CCMO considers the clauses regarding premature termination of the study and regarding publication in this model to be in line with the CCMO Directive on the Assessment of Clinical Trial Agreements.

Multicentre research

In the case of multicentre research, if clinical trial agreemenst have been reached, at least one clinical trial agreement is required for the review of the research file. This is the reference clinical trial agreement. A written statement by the sponsor is sufficient for the other Dutch centres. This must mention that the clinical trial agreements for the other centres are similar to the reference clinical trial agreement with regards to the two aspects reviewed by the accredited MREC or the CCMO, in accordance with the CCMO Directive on the Assessment of Clinical Trial Agreements. If such a statement is not included, then the signed clinical trial agreements must be submitted for all the participating centres.

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K4: Scientific publications

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Scientific publications on previous and/or comparable researches associated with the research being submitted. These publications are to be provided by the party submitting the research file for review.

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K5. Data Safety Monitoring Board (composition, charter)

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A safety committee can be established to monitor the safety of the participants during the study. This can also be useful or appropriate for studies other than with medicinal products.

The EMA guideline on Data Monitoring Committees (EMA/CHMP/EWP/5872/03) covers information on when a safety committee is needed and provides information on the establishment of a DSMB and their working procedures.

If a safety committee is to be established for a study, the composition and charter of this committee needs to be submitted and approved by the reviewing MREC. The MREC can ask for establishment of a DSMB when deemed appropriate. The DAMOCLES Study Group published a template for a DSMB charter (Lancet 2005;365:711- 722).

An unsigned copy of the charter can be submitted as part of the primary submission. However, a signed version must be made available to the reviewing committee before approval can be given. Any previous advice of the safety committee or advice given during the review process of the MREC can be included under section K5 of the research file (advice given during the study falls under section L5 of the file: ‘Advice Data Safety Monitoring Board’).

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K6: Other relevant documentation

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Examples of other relevant documents include the letter to general practitioners/treating medical consultants or recommendations by a radiation committee.

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L. Safety information (after approval of the study)

L1: SUSARs

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SUSAR is the abbreviation of Suspected Unexpected Serious Adverse Reaction.

Criteria

If an adverse reaction arises during a study in the patient/subject, then this is deemed to be a SUSAR if the following three criteria are met:

1. The event must be serious, that is to say, the event (regardless of the dose):

  • is fatal, and/or
  • threatens the life of the subject, and/or
  • makes hospital admission or an extension of the admission necessary, and/or
  • causes persistent or significant invalidity or work disability, and/or
  • manifests itself in a congenital abnormality or malformation.
  • could, according to the person that carries out the research, have developed to a serious undesired medical event, but was however prevented due to premature interference.

2. There must be a certain degree of probability that the event is a harmful and undesirable reaction to the medicinal product under investigation, regardless of the administered dose (in other words, there is an adverse reaction).

3. The adverse reaction must be unexpected, that is to say, the nature and severity of the adverse reaction are not in agreement with the product information as recorded in:

  • for an authorised medicine: the SPC text (Summary of Product Characteristics; in the Netherlands this is the IB1 text). In the case of an international multicentre research with an authorised product, the sponsor may choose an SPC. If there is, in comparison to the authorisation, a different dosage form, indication, patient group or dose, then the summary of the product information must be supplemented with the relevant information for the concerned study.
  • for a non-authorised medicine: the Investigator’s Brochure.

When to send (accelerated) reports and to which authority/authorities?

SUSARs must be reported to the reviewing committee (accredited MREC or CCMO), to the competent authority (CCMO or Ministry of Health, Welfare and Sport), the Medicines Evaluation Board (MEB) and the accredited institutions in other involved member states. The reviewing committee only receives accelerated reports, i.e. within the legally defined term of 7 or 15 days, for the following SUSARs:

  • SUSARs that have arisen in the study that was reviewed by the review committee;
  • SUSARs that have arisen in other studies of the same sponsor and with the same medicinal product and that could have consequences for the safety of the subjects involved in the study reviewed by the review committee.

None of the remaining SUSARs need to undergo accelerated reporting to the reviewing committee. These are included in an overview line listing that must be submitted to the reviewing committee once every six months. This line listing provides an overview of all SUSARs of the research medicinal product.

The competent authority and the MEB must receive accelerated reports of all SUSARs. SUSARs that have already been reported to the EMA Eudravigilance database do not need to be reported again to the competent authority and the MEB, as both have direct access to the Eudravigilance database. A sponsor can request a waiver for this at the MEB 

Reporting in ToetsingOnline

For studies with an NL-number (all studies submitted after 1st of March 2006) all SUSARs have to be reported through the webportal ToetsingOnline. When submitted via ToetsingOnline, the SUSAR will automatically be forwarded to all organisations involved in SUSAR reporting in the Netherlands: the reviewing committee (MREC or CCMO), the competent authority (CCMO or Ministry of Health, Welfare and Sport) and the Medicine Evaluation Board (CBG-MEB).

Reporting outwith of ToetsingOnline

If you report your SUSAR outwith of ToetsingOnline you can use one of the following templates. A SUSAR report form is available on this website. Other examples can be found on the websites of CIOMS, the Council for International Organizations of Medical Sciences, and Medwatch, the Safety Information and Adverse Event Reporting Program of the U.S. Food and Drug Administration

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L2: Periodic SUSAR line listings

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Once every six months, a line listing of SUSARs must be submitted to the reviewing committee (accredited MREC or CCMO). This line listing provides an overview of all SUSARs for the study medicinal product that have occurred since that last update of the Investigator’s Brochure or the SPC text.

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L3: Development Safety Update Report

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The sponsor is required to ensure that each year a Development Safety Update Report (DSUR) on the medicinal product is submitted to the reviewing committee (MREC or CCMO) and the competent authority (CCMO or Ministry of Health, Welfare and Sport).

The DSUR contains at least:

  • a list of all suspected (expected and unexpected) serious adverse reactions, along with an aggregate summary table of all reported serious adverse reactions, arranged by organ system, per study;
  • a report concerning the safety of the subjects, consisting of a complete safety analysis and an evaluation of the balance between the efficacy and the harmfulness of the medicine under investigation.

Details on the safety report are available in the ICH Guideline E2F – Development Safety Update Report (DSUR). A DSUR may be combined with the progress report. In that case the (international) fixed date for the DSUR may be leading.

Safety reports must be submitted from the date of submission of the research file until the study has ended in the Netherlands. The end of the study is generally the last visit of the last patient, unless otherwise defined in the research protocol.

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L4: SAEs

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SAE is short for Serious Adverse Event. An SAE is an undesired medical event involving a patient or test subject, which is not necessarily associated with the treatment, that:

  • is fatal, and/or
  • threatens the life of the subject, and/or
  • makes hospital admission or an extension of the admission necessary, and/or
  • causes persistent or significant invalidity or work disability, and/or
  • manifests itself in a congenital abnormality or malformation.
  • could, according to the person that carries out the research, have developed to a serious undesired medical event, but was however prevented due to premature interference.

Like SUSARs, SAEs can be reported through ToetsingOnline. In principle all individual SAEs must be reported. However, it can be indicated in the research protocol that certain SAEs will not be reported immediately, but instead will be sent periodically as an SAE overview to the reviewing committee. This approach does however require prior approval from the reviewing committee.

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L5. Advice Data Safety Monitoring Board

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Results of interim safety analyses by a safety committee and the advices of this committee concerning the continuation of the study, including the accompanying letter of the sponsor. In general the DSMB advice will only be sent to the sponsor of the study. Only when the sponsor decides not to fully follow the advice of the DSMB, must the sponsor send the advice to the MREC. In the accompanying letter the sponsor has to substantiate why (part of) the advice will not be followed. In specific situations, when the MREC feels reasons for this, the sponsor can be asked to send all DSMB advices to the MREC.

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L6: Other relevant safety information

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Examples of other relevant safety information are: results of toxicity studies in animals, results of temporary safety analyses by a safety committee, scientific publications revealing new safety information, etc.

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M. Progress report and study results

M1: Progress reports/interim reports

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The sponsor must inform the reviewing committee (MREC or CCMO) at least once a year on the progress of the ongoing research.

Is your research proposal reviewed by the CCMO? Then you are required to submit a progress report one year after the issuing of the decision, and every year thereafter. You can make use of the template progress report. Is your research not reviewed by the CCMO? Please ask the committee in question on their policy with regards to progress reporting.

A progress report contains at least:

  • the number of included subjects (including subjects that left the study prematurely);
  • an estimate of the extent to which research objectives are being met;
  • the adverse events and other notifications that may be important to review the progress of the study.

In the case of research with a medicinal product, the progress report may be combined with a Development Safety Update Report (DSUR). In that case the (international) fixed date for the DSUR may be leading.

 

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M2: Summary of research results/scientific publications

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Once the research is completed, a summary of the results and/or any scientific publications must be submitted to the reviewing committee. For more information on this subject, please see: CCMO statement on publication policy.

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M3: Clinical trial report

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A final report must be submitted to the reviewing committee and the competent authority within one year of the end of the study (worldwide). For a sample report, see Annex 1 of the ICH E3 Guideline on the Contents and Structure of Clinical Trial Reports (CPMP/137/95.

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