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Questions on clinical trials on human pharmaceuticals

Questions and answers from workshops for pharmacies held on April 8 and April 16 2010  


1) How should a pharmacy document training of its staff,  would acknowledgement of the protocol synopsis handover be sufficient?

Not only the protocol synopsis, but particularly information about the product and treatment (interactions, information on prohibited treatments, etc.) which should be provided by the sponsor should be available to the pharmacist, for the pharmacist to be able to provide the patient, if necessary, with valid information (e.g. on prohibited or permitted concomitant treatment). The pharmacy personnel should be trained (by the study monitor or by the investigator) for those activities which they conduct within the scope of the study; a record of the completed training should be made and the authorisations of the members of staff should be recorded in the site Delegation log (see study Delegation Log).

2) Is Investigator’s meeting considered to be sufficient for the training of a pharmacist as a study team member?

A pharmacist may attend the Investigator’s Meeting, yet not all information presented therein may be necessarily essential for him/her and, on the contrary, other information (concerning the medicinal product proper) may be of greater relevance to him/her. The scope of training should be established by the sponsor who is responsible for the study and its conduct.

3) Does the pharmacist have to attend all trainings?

No, not all information is necessary for him/her. The training shall be determined by the sponsor (e.g. different information is required for the investigator, for the nurse, laboratory technician, pharmacist, etc.).   

4) Is one pharmacist as a member of the study team sufficient?

No, it is not. It is necessary to have someone to substitute him/her in case he/she is not present (annual or sick leave).  

5) Is it always necessary to have a pharmacist as a member of the study team?

It is not obligatory, for example in situations when the investigational products are delivered to the pharmacy and in the pharmacy they are dispensed either on prescription to the patient or on request form issued by the site, it is not necessary to have a pharmacist in the study team.

6) How often is it necessary for the pharmacist to check the investigational products?

This varies from case to case, and also depends on the study duration – whether the study runs for 3 months with a single batch of the product or for several years with more than one batch….The conditions shall be determined by the study sponsor.

7) Which SPC is to be submitted in the case the product used is authorised in the Czech Republic, but it is delivered from a foreign country market?

For the purposes of authorisation of the clinical trial, it is necessary to submit to SÚKL the SPC of the country of origin of the medicinal product (in the original language) + its translation into the Czech or English language. In this case it is hence from the country from where the product is going to be imported.


8) Where a need to label a medicinal product for the purposes of a CT arises, is it possible to select a single arbitrary pharmacy?

The healthcare facility should be supplied by a pharmacy with adequate scope of operation. Inpatient healthcare facilities are supplied with medicinal products by the hospital pharmacy (a pharmacy with specialised workplaces), outpatient doctors' offices may be supplied with medicinal products by any pharmacy (a basic-type pharmacy).

Where products from the domestic market are to be used for the purposes of the clinical trial, it is possible to organise their additional labelling with a label “For clinical trial purposes” + the identification of the study, such as the EudraCT number or protocol number, in a single pharmacy, from where the products should be supplied to other sites. Where hospital sites are concerned, supplies should be made via the hospital pharmacies of these healthcare facilities.

9) Is it necessary to show the batch number on the outer packaging?

No, it is not, but in such a case it has to be possible to trace the batch number quickly by the code with the sponsor and it has to comply with the requirement set forth in item 26 of SÚKL guideline VYR-32, amendment 13, as amended (please note: where a centralised electronic randomised system is used for these purposes, it should be validated in compliance with the GMP principles).

10) Will SÚKL approve the stickers on the labelling of investigational medicinal products?

Yes, upon the submission of an application for clinical trial authorisation/notification, SÚKL will require also specimen packaging of the investigational products, i.e. it will check the product labelling.     

11) Does the relabelling of an IMP require the presence of 2 pharmacists (so called second check?)

Yes, in compliance with item 33 of the updated SÚKL guideline VYR-32, amendment 13, the other person in addition to the trained pharmacist should be another trained healthcare professional from the trial site.  

12) When investigational medicinal products (IMP) are supplied via a pharmacy, are all particulars of the request form stipulated by the legislation necessary?

The request form must contain all particulars stipulated by Decree No 54/2008 Coll., which are as follows: name of the provider = study site = healthcare workplace (such as a department or clinic), name of the prescribed (investigational) medicinal product, number of packages, stamp of the provider = department, outpatient office or clinic, issue date, name, surname and signature of the prescribing doctor. The request form should also contain the identification of the study/studies such as EudraCT number or protocol number, for which the medicinal product should be dispensed on the request form. 

13) Is it possible to label a product with two protocol numbers if it is intended for 2 studies, and then tick the CT for which it is to be used?

Yes, this is possible, if the final labelling is explicit. Moreover, the logging and accountability of the products should be carefully  considered and guaranteed if the products are to be used in 2 studies!  The two studies may both be running within the concerned site and then it is necessary to ensure traceability and, in particular, accountability for each study separately. The movements from the manufacturer through the distributor, pharmacy, site, trial subjects, and returns up to the disposal of the IMP have to be documented in a clear and straightforward manner.

14) In the pharmacy a topical medicinal product is refilled to injection syringes; taking into account the size, is it necessary to show all details required by the legislation on the packaging?

Yes, it is. Where the packaging is too small, it is possible to seal the syringe in a bag which will contain the necessary details.

Please note: Item 9 of SÚKL guideline VYR-32, amendment 13, mentions the Product specification file; the issue is whether this procedure is in compliance with the specification file – in this respect the opinion of the qualified person will be important! The packaging forms part of stability studies and in this situation it would be changed. Another aspect is the need to observe aseptic conditions where e.g. a sterile product is concerned.  


15) Under what preconditions is it possible to conduct the dilution of the antibody (classified by the ATC system as a cytostatic agent) directly in the healthcare facility (trial site)?

This exception applies only to monoclonal antibodies which are classified as cytostatic agents and only if the pharmaceutical documentation explicitly states that it is necessary to dilute the antibody directly before administration and the diluted antibody cannot be transported. A rationale for this procedure has to be provided and it has to be justifiable. It should apply to exceptional cases only.

16) If a pharmacy has been authorised for the preparation of cytostatic agents, does it have to have a standard operating procedure (SOP) for the transport of diluted cytostatic agents?

Yes, SÚKL authorisation includes a list of healthcare facilities to which it may supply diluted cytostatic agents and SOPs for the transport have to be drafted.  

17) When a pharmacist prepares a cytostatic agent within the scope of a CT, does he/she have to specify the dose on the packaging?

No, he/she must not do so. In the case of double-blind clinical trials the specification of this detail might cause unblinding. The administration of such cytostatic agent is governed by the protocol, instructions for use of the product within the concerned clinical trial. Labelling as per legislative requirements has to be observed - labels should be provided by the sponsor, products should be labelled with the code of the patient for whom they have been prepared. Labelling of products in a clinical trial differs from their use in regular practice. Nevertheless, retrospective traceability of products administered to the patient, incl. the administered quantities, has to be ensured. This has to form part of the IMP logging.


18) How is the issue of continuous temperature recording for non-thermally unstable products solved?

SÚKL guideline DIS-15 sets forth the rules governing the monitoring and control of temperature during the storage and transportation of pharmaceuticals and for conditions other than those in freezers and coolers it states – quote: “it is possible to record temperatures manually at least once a day at a time when the storage temperature is expected to be the least favourable.”

19) If a pharmaceutical has been exposed to a temperature beyond the specified temperature range, how should it be assessed whether degradation has occurred or not?

It is necessary for the sponsor to request stability data from the manufacturer and, on the basis of these data, assess whether such temperature fluctuation has been defined in the stability data and whether it is possible to state that the pharmaceutical has not been damaged by such fluctuation. 


20) Is the disposal of leftover medicinal products from studies indeed up to the sponsor?

Yes, it is. The sponsor is responsible for the conduct of the clinical trial, responsible for providing the investigational medicinal products, and therefore also for their disposal, be it the disposal of leftover investigational medicinal products or unused complete packs. Moreover, the sponsors shall maintain accurate documentation on everything they are obliged to evidence during an inspection or audit of the returns and disposal of investigational medicinal products.  

21) A question on the disposal of cytostatic agents – what procedure should be employed; it is not feasible for the pharmacy to keep leftover cytostatic agents from the isolator, is there another permissible procedure, such as double check during logging, etc.?

Yes, there is. With a view to the very nature of the product it is not possible to keep leftover cytostatic agents, it is necessary to dispose of them on an ongoing basis together with other leftover cytostatic agents. This is an exceptional situation when it is possible to ask the pharmacy to mediate the disposal; such disposal should then be reimbursed by the sponsor to the pharmacy. The records of disposal shall be then maintained in the pharmacy for the purposes of each clinical trial separately; double check during the disposal recording is sufficient.  


22) Where a non-IMP is used in a study, but it is used off-label, which way does it have to be distributed?

In such a case it is considered to be a non-authorised medicinal product and its distribution falls under the responsibility of the sponsor . Where an authorised medicinal product in the Czech Republic is concerned, and the product is to be taken from the Czech market, the sponsor may obtain it via a pharmacy which will then, on a request form, dispense it to the site or directly to the healthcare facility (IR, radiopharmaceuticals, and vaccines).

Where a medicinal product authorised in another EU Member State (not in the Czech Republic) is concerned, the sponsor shall import it in the same manner as the investigational medicinal product. As it will not be an investigational medicinal product, the labelling does not have to comply with the requirements governing the labelling of investigational medicinal products.  


23) In what cases does the standard treatment have to be reimbursed by the sponsor?

In those cases where a comparison of the standard treatment and the investigational product is concerned, including cases involving a combination of the standard treatment + the investigational medicinal product compared to the standard treatment alone (i.e. the standard treatment is the comparative treatment).


24) What does it mean that a centralised electronic system for IMP logging is validated?

Its functionality has to be properly documented and the protocol of functionality verification has to be drawn in writing.

You may refer to Annex 11 to EU GMP (Computerised systems) http://ec.europa.eu/health/files/eudralex/vol-4/annex11_01-2011_en.pdf . In general, the validation plan should include a list of all critical steps within the system. These steps should be, in an adequate manner, included in the validation measurements.

25) The word “viálka” has been used in the presentation, is this a slang expression or is it an officially used term?

The word “vialka” (viálka) is a slang expression adopted from the English and it stands for the Czech term “injekční lahvička” (vial). A vial is a small bottle containing the medicinal product, most often in the form of a solution (particularly a sealed sterile container from which the product is taken by an injection needle).

26) Is it better to use the word "blistr” (blister) for patient or the word “platíčko” (blister)?

Both are acceptable and both may be used.