Preclinical and Clinical Trial Requirements
Preclinical and Clinical Trial Requirements in Croatia – an overview. Prepared in association with Danijel Pribanić, a leading global law firm, this is an extract from The Pharma Legal Handbook: Croatia, available to purchase here for USD 99.
1. Are clinical trials required to be conducted locally as a condition (stated or implicit) for marketing approval?
Clinical trials are not required to be conducted locally as a condition for marketing approval.
2. How are clinical trials funded?
Clinical trials are usually funded by a sponsor. A sponsor of a clinical/non-interventional clinical trial is a private individual or business entity who takes responsibility for the initiation of a clinical/non-interventional clinical trial, the management of a clinical/non-interventional clinical trial and/or the financing of a clinical/noninterventional clinical trial.
A contract between the applicant and the legal entity in which the clinical trial is planned to be carried out has to establish:
- total cost of clinical trial,
- costs incurred by the applicant, including costs of medical and other services of a legal entity conducting clinical trials,
- the amount of compensation to legal persons, examinees and respondents,
- obligations of the applicant to bear the costs of all diagnostic procedures and examinations provided for in the test plan.
3. What are the requirements for preclinical and clinical trial protocols? Who must approve the protocols?
Clinical trials of medicinal products, including non-profit clinical trials, in Croatia may not commence without a favourable opinion of the Central Ethics Committee and the authorization of the Ministry of Health.
Protocol is a document that describes the objective(s), design, methodology, statistical considerations, and organisation of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents.
The contents of a trial protocol generally includes the following topics:
- general information;
- background information;
- trial objectives and purpose;
- trial design;
- selection and withdrawal of subjects;
- treatment of subjects;
- assessment of efficacy;
- assessment of safety;
- direct access to source data / documents;
- quality control and quality assurance;
- data handling and record keeping;
- financing and insurance;
- publication policy, and
4. What are the requirements for consent by participants in clinical trials?
Informed consent has to be written, signed by the subject, and dated, to take part in a clinical trial, taken freely further to duly received and appropriately documented information of its nature and significance, and implications and risks.
Where the person is not capable of giving consent, i.e. where a trial subject is unconscious, or suffering from severe mental impairment, or has no capacity to exercise her/his rights or where the person is under age, the consent is signed by his or her legal representative or guardian, after he had been made aware of the risks and the objectives of the trial. If the person concerned is illiterate or is unable to write, oral consent in the presence of at least one witness who is not a member of the investigating team may be given. Trial subjects may at any time withdraw their informed consent for the participation in the clinical trial. Prisoners or persons who might be coerced into giving consent to participate in a clinical trial, cannot be trial subjects by definition.
In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s) and should adhere to Good Clinical Practice and to the ethical principles that have their origin in the Helsinki Declaration. Prior to the beginning of the trial, the investigator should have the Committee’s written approval/favourable opinion of the written informed consent form and any other written information to be provided to subjects.
The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised written informed consent form, and written information should receive the Committee’s approval/favourable opinion in advance of use. The subject or the subject’s legally acceptable representative has to be informed in a timely manner if new information becomes available that may be relevant to the subject’s willingness to continue participation in the trial. The communication of this information has to be documented.
Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial.
None of the oral and written information concerning the trial, including the written informed consent form, should contain any language that causes the subject or the subject’s legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence.
The investigator, or a person designated by the investigator, should fully inform the subject or, if the subject is unable to provide informed consent, the subject’s legally acceptable representative, of all pertinent aspects of the trial including the written information and the approval/ favourable opinion by the Committee.
The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to the subject or the subject’s legally acceptable representative and the impartial witness, where applicable.
Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the subject or the subject’s legally acceptable representative sample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the trial should be answered to the satisfaction of the subject or the subject’s legally acceptable representative.
Prior to a subject’s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject’s legally acceptable representative, and by the person who conducted the informed consent discussion with the subject/legally acceptable representative.
If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. After the written informed consent form and any other written information to be provided to subjects, is read and explained to the subject or the subject’s legally acceptable representative, and after the subject or the subject’s legally acceptable representative has orally consented to the subject’s participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject’s legally acceptable representative, and that informed consent was freely given by the subject or the subject’s legally acceptable representative.
Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of the following:
- That the trial involves research;
- The purpose of the trial;
- The trial treatment(s) and the probability for random assignment to each treatment;
- The trial procedures to be followed, including all invasive procedures;
- The subject’s responsibilities;
- Those aspects of the trial that are experimental;
- The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant;
- The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this;
- The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks;
- The compensation and/or treatment available to the subject in the event of trial-related injury;
- The anticipated prorated payment, if any, to the subject for participating in the trial;
- The anticipated expenses, if any, to the subject for participating in the trial;
- That the subject’s participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled;
- That the monitor(s), the auditor(s), the Committee, and the regulatory authority(ies) will be granted direct access to the subject’s original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject’s legally acceptable representative is authorizing such access;
- That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the subject’s identity will remain confidential;
- That the subject or the subject’s legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject’s willingness to continue participation in the trial;
- The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom to contact in the event of trial-related injury;
- The foreseeable circumstances and/or reasons under which the subject’s participation in the trial may be terminated;
- The expected duration of the subject’s participation in the trial,
- The approximate number of subjects involved in the trial.
Prior to participation in the trial, the subject or the subject’s legally acceptable representative should receive a copy of the signed and dated written informed consent form and any other written information provided to the subjects. During a subject’s participation in the trial, the subject or the subject’s legally acceptable representative should receive a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to subjects.
When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject’s legally acceptable representative (e.g., minors, or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject’s understanding and, if capable, the subject should sign and personally date the written informed consent.
Non-therapeutic trial (i.e. a trial in which there is no anticipated direct clinical benefit to the subject), should be conducted in subjects who personally give consent and who sign and date the written informed consent form.
Exception, non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled:
- The objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally;
- The foreseeable risks to the subjects are low;
- The negative impact on the subject’s wellbeing is minimised and low;
- The trial is not prohibited by law, and
- The approval/favourable opinion of the Committee is expressly sought on the inclusion of such subjects, and the written approval/ favourable opinion covers this aspect. Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.
In emergency situations, when prior consent of the subject is not possible, the consent of the subject’s legally acceptable representative, if present, should be requested. When prior consent of the subject is not possible, and the subject’s legally acceptable representative is not available, enrolment of the subject should require measures described in the protocol and/or elsewhere, with the documented approval/favourable opinion by the Committee, to protect the rights, safety and wellbeing of the subject and to ensure compliance with applicable regulatory requirements. The subject or the subject’s legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate should be requested.
5. May participants in clinical trials be compensated?
The clinical trial sponsor has to pay compensations to the trial subjects and to the business entity with whom the sponsor has signed the clinical trial agreement.
The total costs of the clinical trial and expenses of the applicant include compensations to investigators and subjects and are determined by a contract.
6. How are participants in clinical trials protected and indemnified against any harm that arises as a result of participation in the trial?
Before the beginning of a clinical trial, clinical trial sponsors or their authorized representatives established in the European Union have to be insured against liability for injury, death, or treating of trial subjects, related to the clinical trial.
Sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.
The sponsor’s policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).
When trial subjects receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s).