The State Institute for Drug Control hereby informs about the requirements for documentation to be submitted for clinical trials on medicinal products containing genetically modified organisms (GMO) intended for the treatment of COVID-19, submitted at the time of the COVID-19 pandemics.
In terms of pharmaceutical, preclinical, and other documentation, the requirements set forth by guideline KLH-20 are still applicable. For clinical trials (CT) on medicinal products intended for the treatment or prevention of COVID-19, submitted at the time of the COVID19 pandemics, however, some other requirements shall apply, as stipulated below.
GMO-containing medicinal products
Generally, authorisation of CTs on GMO-containing medicinal products require approval by the Ministry of Environment (MoE) as referred to under Act No 78/2004 Coll., on the Use of Genetically Modified Organisms and Genetic Products, as amended. On the basis of Regulation (EU) 2020/1043, however, such approval is not required for CTs on medicinal products with GMOs intended for the treatment or prevention of the COVID-19 disease. The authorisation to handle GMOs is not required for hospitals, laboratories and other sites where the CTs or sample analyses are to be conducted. With a view to the aforementioned, the application for the CT should be submitted only to SÚKL and to the ethics committees.
The purpose of the aforementioned EU regulation is to accelerate the conduct of CTs on medicinal products containing or consisting of GMOs intended for the treatment or prevention of COVID-19, i.e., in particular, to accelerate the testing of anti-COVID-19 vaccines. The applicability of the Regulation is restricted to the period of the COVID-19 pandemics (as declared and terminated by the WHO). Pursuant to this Regulation, for the duration of the pandemics, prior environmental risk assessment or authorisations required by regulations governing GMOs (Act No 78/2004 Coll.) shall not be required for CTs on the aforementioned medicinal products. Clinical trials shall be hence authorised only on the basis of regulations governing medicinal products (by SÚKL and by ethics committees).
At the same time, however, please be notified that regulations governing the use of GMOs do apply to the manufacture of recombinant medicinal products and associated laboratory analyses of GMO-containing medicinal products, i.e. also to medicinal products intended for the treatment and prevention of COVID-19, even during the pandemics. This is essential information for those medicinal products that do not contain GMOs, yet GMOs are used in their manufacture.
Although, pursuant to Regulation EU 2020/1043, MoE's approval is not necessary for the CTs, the sponsor shall be responsible for the handling of GMO-containing medicinal products. The sponsor should implement adequate measures to minimise the negative impact upon the environment that may be expected with a view to the available knowledge as a result of the intended or unintended release of the investigational medicinal product into the environment, and inform of such measures within the scope of the application for CT authorisation submitted to SÚKL. An impact upon the environment may be, for instance, the consequences of recombination of the GMO contained in the medicinal product with a naturally occurring microorganism or the transfer of the GMO to animals.
In case of applications for authorisation of a clinical trial on a GMO-containing medicinal product intended for the treatment or prevention of COVID-19 at the time of the pandemics, SÚKL will require, along with the documentation referred to under guideline KLH-20, an overview of measures to minimise the negative impact upon the environment. Along with the application dossier as referred to under guideline KLH-20, the following shall be submitted:
1) A detailed description of handling and storage conditions for the medicinal product containing GMOs, including treatment/preparation of the medicinal product for application (so called “Study Specific IMP Manual / Pharmacy manual”);
2) Rules of operation / manual for sites and persons coming into contact with the medicinal product (e.g. surface disinfection, handling of dressings, protective aids for healthcare professionals, etc.);
3) Waste management (used injection syringes, infusion bags, medicinal product packaging, gloves, etc.);
4) A drafted emergency plan for sites where the CT on the GMO-containing medicinal product is to be conducted. The emergency plan must contain instructions on the course of action to be taken when handling medicinal products containing GMOs (e.g. how to proceed when the packaging of the medicinal product breaks, first aid upon staining, etc.).
MoE and SÚKL
Act No 78/2004 Coll. contains a general provision under Section 3(3): "In the use of genetically modified organisms and genetic products, any person shall be obliged to protect human and animal health, the environment and biological diversity in accordance with the precautionary principle."
SÚKL and the MoE closely cooperate in the sphere of risk assessment for GMO-containing medicinal products. On the basis of an informal agreement, when assessing applications for CTs on anti-COVID-19 medicinal products, SÚKL shall consult the environmental risks with the MoE.
SÚKL does not assess trial sites. The documentation, however, should specify, how sites are to handle GMOs (including decontamination procedures, e.g. when a packaging of a vaccine breaks) and to manage waste (for more details, please refer above).
Deliveries of vaccines to sites
Vaccines or medicinal products with GMOs intended for the treatment or prevention of COVID-19 may be delivered directly to the trial sites. It is necessary to safeguard the conditions of storage and handling of the vaccines in question in accordance with the manufacturer's instructions; this information should form part of the application for CT authorisation. Sites must receive the “Study Specific IMP Manual / Pharmacy manual” for the handling of the product.
For more information, please refer here.
How will SÚKL consider stability data in case of CTs on medicinal products for the treatment of COVID-19?
In case of an emergency situation (COVID-19 pandemics), SÚKL will proceed analogously to other European medicines agencies. In case of an emergency situation, the stability of the medicinal product may be approved on the basis of stability data that will not be of the complete scope as generally required pursuant to document EMA/CHMP/BWP/534898/2008. The situation will be always assessed individually, with regard to the specific submitted data. Generally, however, it may be said that the following philosophy may be acceptable in the documentation and subsequent approval of stability:
- Shelf-life above the scope of the documented stability data obtained under the conditions intended for long-term storage of the medicinal product may be approved.
- Stability models in case of missing stability data obtained under conditions intended for long-term storage of the medicinal product may be accepted.
- Relevant data from abbreviated stability studies may be used for the support of shelf-life longer than that supported by the stability data obtained under conditions intended for long-term storage of the medicinal product. The use of predictive stability models derived from prior knowledge of structurally similar molecules, if available, and ongoing continuation of stability studies under conditions intended for long-term storage of the medicinal product shall be also acceptable.
- Relevant data from stress stability studies may be used to evidence degradation routes.
- It is possible to avail of extrapolation of data from various medicinal product presentations, unless associated with substantial changes to the manufacturing process of the medicinal product (e.g. glass vial x prefilled injection syringe).
Nevertheless, the applicant must always submit the stability plan which shall be compliant with the requirements set forth by ICH Q5C, stability testing must have been initiated, and any OOS or negative trends appearing in the course of stability testing shall be forthwith communicated to the national authority.
In compliance with the effective legislation, labels on primary and secondary packaging must be in the Czech language; this refers specifically to EU guidance Eudralex Volume 4, Annex 13, its Czech version being guideline VYR-32, Amendment 13, version 1. Nevertheless, in this specific case that concerns a study on an anti-COVID-19 vaccine, which will be always administered by a doctor, English labels may be also acceptable.
The expiry date must be always specified (on the basis of adequate stability studies); in this case, however, it does not have to be shown on the label, but it must be specified in the electronic batch traceability system or in the documentation provided by the study sponsor, as healthcare staff must check the medicinal product expiry prior to its administration.
Addition on 12 November 2020
The particulars of emergency response plan submission are set forth by Act No 78/2004 Coll. (Section 20(3))
3) Persons referred to in paragraph 2 (the applicant prior to starting the use of the GMO and the person notifying contained use of second risk class) shall submit the emergency response plan prior to commencement of the use of genetically modified organisms, and in the cases referred to in paragraph 2 letters c) and d) (person authorised for contained use of GMO of second and higher class and person authorised to place the GMO in the environment every five years or upon change to facts that could impact measures in case of an emergency) also to the concerned municipalities in whose cadastre areas genetically modified organisms are used, to the fire brigade covering the given area and the concerned Regional Authority and on request also to the persons that may be directly affected by an accident. For the purposes of this paragraph, a concerned municipality in terms of the place of use shall not be a municipality through whose territory the genetically modified organism is only transferred without any interruption.
Marketing Authorisation Section, Department of Clinical Trials on Medicinal Products
Prague, 07 October 2020, updated 12 November 2020