CT SOP version 2.0:

Changes from CT SOP version no 1.0.: Adapted to ICH GCP R3 and to the Safety SOPs. Added information about low.intervention. added possibility for sending IMP closer to the participant. Considerations about archiving "arbeidssedler" as part of the ISF. Added the manufacturer's need to maintain IMP samples.

Merging of LM SOP no. 2.07 and LM SOP 2.13. Adapted to the clinical trial regulation no 536/2014 including auxiliary medicinal products and low-intervention trials. Change of labelling requirements for authorised IMP/AxMPs.

The sponsor has overall responsibility for ensuring that this SOP is followed.

The sponsor may transfer any or all of the sponsor's trial-related duties and functions to a service provider such as a Contract Research Organisation (CRO), but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf. Transfer of duties shall be specified in a written agreement.

The coordinating investigator (CI) should ensure that the required information about IMPs and AxMPs is provided to competent authorities and ethics committees and that IMPs and AMPs are handled according to this SOP including:

• Ensuring that the IMP is included in the European database for medicinal product (XEVMPD).
• Ensuring that there is a written agreement with an approved manufacturer of IMPs if necessary for e.g blinding of the IMP.
• Ensuring that a plan for distribution of IMPs and any AxMP to all sites is in place.
• Ensuring that there are written procedures for storage and handling of IMPs and any auxiliary medicinal product at each site if necessary.

The principal investigator at each site is responsible for managing the IMPs and for keeping records of the use of the IMPs.

Requirements for Investigational and Auxiliary Medicinal Product Documentation 

Documentation requirements for IMPs include documentation of reference product (active comparator) and placebo, if applicable.

IMP documentation is required by the regulatory authorities, for the assessment of the trial and the overall safety of the products and must be presented when applying for approval of a drug trial to the competent authority (e.g. Norwegian Medicines Agency, DMP) and the Ethics Committee (e.g. Committees for Clinical Trials of Medicines and Medical Devices, REK KULMU).

The documentation shall provide investigators and other trial personnel with information including the Reference Safety Information (RSI) to facilitate their understanding of the rationale for, and their compliance with, key features of the protocol, such as:

• The dose, dose frequency/interval and methods of administration.
• Safety monitoring procedures.

The investigator's brochure (IB) if used, and other documents shall be marked with the version number and date.

When using AxMPs that are not authorised in the participating countries, the same requirements for safety and quality information as for IMPs are required.

The documentation which may be required for applications for competent authority and ethics approval for various investigational products is as follows:

Safety information

Summary of Product Characteristics (SmPC) (only competent authority)

For IMPs with marketing authorisation the approved Summary of Product Characteristics (SmPC, preparatomtale) can be used instead of investigator's brochure. The SmPC should be in Norwegian or in English.  

If the conditions of use in the clinical trial differ from those authorised, the SmPC shall be supplemented with a summary of relevant non-clinical and clinical data that support the use of the IMP in the clinical trial. This information should be included in the protocol.

For IMPs that are identified in the protocol by its active substance, the coordinating investigator should select one SmPC.

Investigator's Brochure (IB)

For IMPs without marketing authorisation the sponsor must provide an IB. The investigator's brochure is a compilation of physical, chemical and pharmaceutical properties and formulations, non-clinical and clinical data concerning the IMPs that are relevant to the study of the product(s) in human subjects. This includes data from animal studies, clinical trials, toxicity, pharmacokinetic and pharmacodynamic data, etc.

The IB shall contain a clearly identifiable section called the ‘Reference Safety Information’ (RSI). The RSI shall contain information on known adverse events and information on what adverse reactions are to be considered as expected adverse reactions, and on the frequency and nature of those adverse reactions. The IB shall also contain a summary of data and guidance to the investigator.

The use of Investigator's Brochure (IB)  will ensure that the requirements for the content of the IB given in ICH GCP appendix A are met. 

The information should be presented in a concise, simple, objective, balanced and non-promotional form.

In a non-commercial trial where a pharmaceutical company owns/manufactures the IMP, CI can ask the company for the IB. If the IMP is authorised, it is recommended to use the SmPC as RSI. 

Quality information

If a medicinal product is not authorised in the EEA, CI should ensure that the product is included in the European database for medicinal products (XEVMPD). Preferably, the CI should contact the company developing the product for relevant information about the IMP.

Investigational Medicinal Product Dossier (IMPD)

The IMPD gives information related to the quality of any IMP (including reference product and placebo), manufacture and control of the IMP, and data from non-clinical studies and from its clinical use.

For marketed IMPs, it is sufficient to refer to the SmPC.

If the IMP has marketing authorisation in another EU/EEA area or ICH country, or has previously been evaluated in connection with a clinical trial, a simplified IMPD can be submitted. For documentation requirements please refer to ANNEX I, Table 1 of Regulation (EU) No. 536 2014.

When requiring manufacturing of placebo and blinding of IMP, the manufacturer should provide the IMPD to the coordinating investigator. See Tilvirkning av legemidler. Other EU manufacturers may also be contracted.

If the IMP is not authorised, and does not have a marketing authorisation from a third country that is part of ICH, and is not manufactured in the EU the following documentation shall be submitted:

• A copy of the manufacturing authorisation, and
• Certification by the qualified person in the Union that the manufacturing complies with GMP at least equivalent to the GMP in the Union, unless there are specific arrangements provided for in mutual recognition agreements between the Union and third countries.

Documentation of Pharmaceutical, Chemical, Biological quality

For IMPs without marketing authorisation, documentation must be submitted to the competent authority with respect to chemical and pharmaceutical quality. The coordinating investigator should refer to the European Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (revision 2  – January 2022).

Non-clinical and Clinical evidence

For IMPs without marketing authorisation, relevant documentation will be sent appropriate to stage of development, dosage, duration of treatment and patient group. The documentation from non-clinical studies shall be in accordance with applicable European guidelines and ICH guidelines.

For marketed IMPs used outside the conditions of marketing authorisation, additional non-clinical and clinical data may be sent to Competent Authority if appropriate to permit assessment of the overall safety of the product(s). It is often sufficient to send the rationale for, or published articles that supports use outside the approved indications. The documentation can be in the protocol or other submitted document. For paediatric trials, it may be necessary to send additional non-clinical and clinical documentation.

The manufacturer should maintain sufficient quantities of the IMP(s) used in the trials to reconfirm specifications should this become necessary and maintain records of batch sample analyses and characteristics. The samples should be retained either until the analyses of the trial data are complete or as required by the applicable manufacturing requirement(s), whichever represents the longer retention period. 

Biological IMPs

Documentation shall be prepared in compliance with the Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials. 

Summary of requirements

The requirements are summarised in the following table.

Labeling

The following information shall appear on the outer packaging and on the immediate packaging of:

• Unauthorised IMPs and unauthorised AxMPs.
• Studies with blinded label on authorised IMP/AxMPs.

1. Information to identify contact persons or persons involved in the clinical trial.
2. Information to identify the clinical trial.
3. Information to identify the medicinal product.
4. Information related to the use of the medicinal product.

Details are described in Regulation for clinical trials 536/2014,  Annex VI.

The information which is to appear on the outer packaging and immediate packaging shall ensure subject safety and reliability and robustness of the data generated in the clinical trial, while taking into account the design of the clinical trial, whether the products are investigational or auxiliary medicinal product, and whether they are products with particular characteristics.

When using unauthorised IMPs or AxMPs, the manufacturer should ensure the labelling fulfils the requirements.

When using authorised IMPs and AxMPs in studies where there is no blinding of the label, there is in general no additional labelling requirements on the immediate and the outer packaging.

However, depending in the protocol, under specific circumstances to ensure the safety of the subject, especially vulnerable patients,  or the data quality, the following might be required on the immediate and the outer packaging.

1. Name of the main contact.
2. Clinical trial reference code allowing identification of the clinical trial site, investigator, sponsor and subject.
3. ’For clinical trial use only’ (Til klinisk utprøving) or similar wording.

Radiopharmaceuticals used as diagnostic investigational medicinal products or as diagnostic auxiliary medicinal products shall be labelled appropriately to ensure the safety of the subject and the reliability and robustness of data generated in the clinical trial. The usual labelling requirements described in Regulation for clinical trials 536/2014,  Annex VI do not apply.

Labelling should be in the local language. If the IMP is only handled by healthcare professionals, local language labelling may not be necessary. In Norway, Danish, Swedish or English is accepted.

Labelling of preparations reconstituted by pharmacies/sites (such as prefilled syringes and infusion bags) only needs to comply with the requirements of the regulations for ordering and release of drugs from the pharmacy. That is, there is no need for trial-specific labelling as long as administered by health care personnel. However, it is recommended to record trial-specific information, to ensure subject safety, and that trial documentation is complete. Pharmacists must be given information about which preparations are part of a clinical trial and which patients are receiving investigational medicinal product.

Preparation of Documentation

• Documentation of IMPs shall be prepared or obtained before an application for approval of the trial is sent to Competent Authority and Ethics Committee.
• The coordinating investigator should ensure that appropriate IMP documentation exists, as well as validate and update the documentation of the product(s) if required.
• If necessary, external expertise can be obtained from e.g. the pharmaceutical company/manufacturer and/or CRO, to the preparation of the necessary documentation of the product.
• If the IMP can be shipped to the participant’s location or supplied to/dispensed at a location closer to the participant (e.g. at a local pharmacy or a local healthcare centre), this should be specified in the protocol and the tick box for decentralised elements should be ticked in the cover letter of the application  to the competent authorities and ethics committees. 
• If the IMP(s) is/are authorised and used in accordance with the SmPC, considerations should be given as to whether the trial should be submitted to authorities as a low-intervention trial, see  Application Process and Approvals - SOP 1.9.a
• If the IMP(s) requests will be processed through an electronic system such as Cytodose, CMS or equivalent, the coordinating investigator should consider if the documentation from those systems (arbeidssedler) should be archived in the ISF or follow the archiving procedures of the pharmacy. If the pharmacy has little or no experience with the preparation of the IMP or similar IMPs, it is recommended to keep the documentation in the ISF. 

Supply

IMPs with marketing authorisation in countries other than Norway should be imported by the pharmacy or other approved importer. Pharmacies can import directly from the EEA. An approved drug wholesaler or other authorised institution (see Tilvirkning av legemidler) may import from countries outside the EEA. 

When using products that are manufactured specifically for a trial, there must be a written agreement with an approved manufacturer.

Randomisation, Blinding and Unblinding

When the IMP is blinded, systems should be in place to preserve the blinding for blinded personnel. The personnel that should be blinded are usually the site staff, the sponsor study team, monitors, data manager(s) and study statistician. An unblinded statistician or data manager should be allocated to the trial to provide the manufacturer with the randomisation list. The randomisation list should be stored out of reach from blinded personnel. 

Requests for IMP

Requests for IMP from pharmacies must be made by the investigator. This task cannot be delegated to nurses or other trial staff. Documentation of requests must be filed in the investigator’s site file and the sponsor’s TMF.

The requisition procedure and any required forms should be agreed before trial start-up. See IMP Requisition Form

Information for Trial Subjects

Information about the IMPs and possible adverse reactions should be included in the written information given to the trial subjects.

If the IMPs are to be taken home by the subject, information for handling of the IMP should be provided to the participants as approved by competent authorities.

Revision of documentation

Investigator's Brochure (IB)

Investigator's Brochure will be reviewed at least once a year, and updated earlier if new relevant information emerges.

The annual review shall be documented.

When updating investigator's brochure, the version number and date must be updated. It is advisable to write the previous issue number and date on the updated version.

Significant changes in the investigational product documentation/investigator's brochure will be sent to competent authorities for review.  A significant change is, for example:

• New toxicological or pharmacological data.
• New interpretation of toxicological.
• Pharmacological data of relevance for the investigator.
• Updated benefit/risk assessment or safety profile.

Updates that may change the initial risk-benefit assessment of the trial should be submitted to the competent authority.

Summary of product characteristics (SmPC)

It is recommended that the investigators have an electronic access to the SmPC ensuring thereby access to the newest SmPC. It is recommended that the SmPC is checked at least once a year, e.g. in connection with annual reporting, see  Safety reporting - SOP 1.4.b. Despite a possible change to the RSI, the RSI in effect at the start of the reporting period serves as RSI during the annual reporting period, so that the updated SmPC will be the RSI for the next reporting year.

Communication of information

The coordinating investigator will send the relevant written documentation of the investigational product to the principal investigators. The delivery and receipt of the documentation should be documented in the study files.

Filing

All documentation of the IMP is part of the essential documents and will be filed in investigator site file and trial master file. See Study Files – SOP 1.6.a

• Investigator's Brochure (IB) checklist - Template
• Investigator's Brochure (IB) - Template
• Tilvirkning av legemidler
• IMP Requisition Form - Template
• IMP Accountability Form with kit or ID-number - Template
• IMP Accountability Form Common Stock Unnumbered - Template
• IMP Accountability Form Different Manufacturers - Template
• IMP Reconciliation - Template
• IMP Destruction - Template