Legal aspect of clinical trials occupies the agenda of medical and pharmaceutical sector as of the cancellation action filed by the Turkish Medical Association ("TMA") in March 2009 against certain provisions of the Regulation Pertaining to Clinical Trials dated 2008 ("Regulation"). In course of time, legal grounds of the clinical trial legislation became subject to a profound debate.
The 10th Chamber of Council of State, who examined the action, ruled on stay of execution of some articles of the Regulation in November 2009 due to miscellaneous reasons, such as payment shall not be done to the volunteers as a result of their participation in clinical trials and they shall be informed and enlightened by a person who is independent from the research team; concurrent applications shall not be made to Ethical Committees and General Directorate of Pharmaceuticals and Pharmacy and it is not possible for the changes in protocols become effective unless such are approved; the impossibility of establishment of constant committees, namely Ethical Committees and Clinical Trials Consultative Committee by a regulation, such shall only be established by a law or under the authority of the High Council of Health. The Council of State, with this interlocutory stay of execution decision, prevented implementation of these provisions until a final decision is rendered on merits of the action and proceeded with the next examination stage in order to reach a final decision.
Upon this decision, the Ministry of Health ("MoH"), without waiting for finalization of the pending action, chose to constitute ethical committees within the scope of the High Council of Health by reflecting the above mentioned alterations to the Regulation on March 11, 2010. On the other hand, both the MoH and TMA filed a review request with the Plenary Session of the Chambers for Administrative Cases of the Council of State ("PSCAC") being the higher chamber of the 10th Chamber.
The review decision that was rendered by PSCAC in July 2010 initiated hot debates. With this decision, the decision of the 10th Chamber of Council of State is taken one step forward. It is underlined that the Regulation was directly related to right to life and immunity of physical integrity, which are among primary fundamental human rights, and the trials in scope of the Regulation constitute intervention to immunity of physical integrity, this basic human right could only be limited by law even in case of existence of subject's consent and it would be against the Constitution that a person be subject to scientific and medical experiments unless authorized by law. This decision gave rise to the interpretation that the Regulation became invalid from a legal aspect. Upon this decision, the MoH ceased accepting trial applications on October 1st, 2010 and this led to concerns with regard to the status of the ongoing trials.
Consequently, leading universities in clinical trials decided to take the required steps in order to continue clinical trials and constituted independent Ethical Committees within their scope by adopting the interpretation that universities are granted authority by the Higher Education Law to conduct scientific trials including clinical trials. And upon this development MoH announced that they continue accepting clinical trial applications.
In May 2011, the 10th Chamber of Council of State delivered its final judgment on the action. In this decision, contrary to PSCAC, it is accepted that the MoH has appropriate legal grounds to regulate clinical trials and the rules regarding clinical trials could be set forth under a legal text with the force of a regulation1. In April 2011 the TMA appealed the decision and appeal application is still under examination of the PSCAC. However, considering below summarized developments, the final decision is expected to be in direction of an approval of the decision of the 10th Chamber.
On the other hand, it is not ignored that the aforesaid developments have given rise to the necessity to enact a law in order to maintain an appropriate and legitimate background for the conduct of clinical trials and enactment procedures are initiated rapidly. By way of adding an article ("Law") to the Principal Law on Health Services no. 3359 on April 6, 2011 that appropriate legal ground was provided. This provision, which contents with drawing the general frame of clinical trials, leaves the details to be set forth by the MoH through issuing regulations.
Following the entry into force of the Law, the MoH acted quickly and issued a new clinical trial regulation ("the New Regulation") on August 19, 2011 which is based on the Law and the international treaties that Turkey is a party to, such as Helsinki Declaration.
Henceforward clinical trials in Turkey shall be conducted in compliance with below stated principles pursuant to the Law and the New Regulation:
- Even though such is not explicitly stated within the Regulation, it could be inferred from joint interpretation of the relevant articles that it is not possible to carry out clinical trials in private hospitals, and only universities, education and research hospitals and other governmental hospitals and health centres can be appointed as trial institutions.
- Either the pharmaceutical company that is to conduct the clinical trial (Sponsor) or the Contract Research Organization (CRO) that is assigned by this company shall be resident in Turkey.
- Clinical trials on human beings with medicinal products and combinations, even though registered or permitted, observational studies on medicinal products, observational studies on medical devices; clinical trials with all other ingredients or products which can be conducted in humans, including medical devices, advanced therapy products, traditional herbal medicinal products, cosmetic raw materials or products; bioavailability and bioequivalence studies, comparability studies for biosimilar products, studies to be conducted on industrial advanced medical products and non-industrial advanced medical products, studies on stem cell transplant on humans, studies on organ and tissue transplant, surgical studies, gene therapy studies, as well as the clinical trial sites and physical or legal persons conducting clinical trials are all subject to the New Regulation.
- The non-invasive clinical trials, else then the ones defined as observational studies, are left out of the scope of the Regulation and except from those, approval of the Ethical Committee is required for all of the above stated studies. However, due to some inconsistent wording in the New Regulation, definition of non-invasive still needs to be clarified.
- The Ethical Committees are grouped into three as "Pharmaceutical", "Non-Pharmaceutical" and "Bioavailability/Bioequivalence (BA/BE)" Clinical Trials Ethical Committees. 2
- Prior to the approval of the Ethical Committee; the issues such as objective of the trial; expected benefit, analysis of risks and damages; trial brochure; obtainment of consents of volunteers; insurance covering the researcher or sponsor and volunteer; research team; trial budget and places where the trial will be conducted shall be clarified.
- It is possible to inform and enlighten the volunteer by a member of the research team in course of obtaining the consent of the volunteer.
- During Ethical Committee approval phase, the Committee is permitted to request correction from the Sponsor or CRO only once and thus the approval procedure is aimed to be shortened.
- Upon approval of the Ethical Committee, it shall be applied to the relevant general directorate of the MoH in order to obtain trial permission after filling the forms and preparing the annexes published and required by the MoH.
- A pharmacist shall be assigned for storage, distribution, delivery, destruction of the trial product pursuant to the New Regulation; it is foreseen that the responsible pharmacist shall be notified during the course of the approval application before MoH.
- Following the approval of the MoH, the trial is expected to be conducted in line with the Law, New Regulation and the relevant guidelines.
Another recent development regarding clinical trials is the new Medical Device Regulation which is published in the Official Gazette and entered into force on June 7, 2011.
Article 15 of the Medical Device Regulation sets forth special provisions regarding medical device clinical trials while the Regulation Pertaining to Clinical Trials envisages general provisions for all types of clinical trials including medical device trials. The Medical Device Regulation can be deemed as an exact adoption of the EU Directive no. 93/42/EEC in general view.
Issuance of new rules for medical device clinical trials, while the Regulation Pertaining to Clinical Trials covering medical devices is still in force, give rise to questions regarding which set of rules has priority of implementation. Considering that there are huge legal gaps concerning clinical trials in the Medical Device Regulation such as details of the Ethical Committee approval procedure, the principles regarding the protection and insurance of trial subjects, the details of the ICF, the standards of the places where the trial will be conducted, the specifics of the trial approval of the MoH, the conduct of the trial, the responsibilities of the parties, the import of the trial product, adverse event reporting etc., the Regulation Pertaining to Clinical Trials still remains as an important and effective guide for the conduct of the medical device trials. Also, from a legal point of view, as the New Regulation Pertaning to Clinical Trials is published at a later date, it shall prevail over the rules set forth under the Medical Device Regulation as far as there is a contradiction between the same.
Since the medical device clinical trial related provisions are recent and unimplemented, changes in the latter are expected upon practice. However, at first glance, the below stated principles seem to be in force in order to conduct a medical device trial;
- The objective of a medical device clinical trial shall be to verify that under normal conditions of use, the performance of the devices conform to those referred to in Annex I of the Medical Device Regulation, and to determine any undesirable side-effects, under normal conditions of use, and to assess whether they constitute risks when weighed against the intended performance of the device.
- In case the clinical trial is conducted using a medical device bearing CE marking for the purpose that is referred to in the relevant conformity assessment procedure, only the provisions of Annex X of the Medical Device Regulation which are in line with the EU rules are applicable.
- Prior to applying to the MoH for approval, Ethical Committee approval shall be obtained in accordance with the new Regulation Pertaining to Clinical Trials.
- In accordance with Article 15 of the Medical Device Regulation, manufacturer or its authorized representative should prepare a declaration consisting of the data allowing identification of the device in question, a trial plan, investigator brochure, undertaking of insurance coverage for trial subjects, informed consent form, statement whether any substance included in Annex I/7.4 of the Medical Device Regulation or human blood derivatives is contained in the device, whether animal based tissues are used in the device, the opinion of the Ethical Committee concerned and details of the aspects covered by its opinion, the name of the medical practitioner or other authorized person and of the institution responsible for the trial, the place, starting date and scheduled duration for the trial, statement that the device in question conforms to the essential requirements apart from the aspects covered by the trial and that, with regard to these aspects, every precaution has been taken to protect the health and safety of the patient. It should be noted that the manufacturer declaration to be filed to the MoH consists of a broader and more detailed document when compared with the declaration envisaged in the EU Directive.
- Clinical trials must be performed on the basis of an appropriate trial plan reflecting the latest scientific and technical knowledge and defined in such a way to confirm or refute the manufacturer's claims for the device; these trials must include an adequate number of observations to guarantee the scientific validity of the conclusions.
- The procedures used to perform the trials must be appropriate to the device under examination and must be performed in circumstances similar to the normal conditions of use of the device. All the appropriate features, including those involving the safety and performance of the device, and its effect on patients must be examined.
- All adverse incidents must be fully recorded and notified to the MoH.
- The written report, signed by the medical practitioner or other authorized person responsible, must contain a critical evaluation of all the data collected during the clinical trial.
- According to Article 15, the MoH shall, if necessary, take the appropriate steps to ensure public health and public policy. In case the MoH refuses, ceases, suspends, demands significant alteration, it shall inform the European Union Commission. Similarly if the trial is terminated early due to security reasons, the EU Commission shall again be informed. In such way, different from other types of trials, medical device trials are maintained to be monitored in an international platform.
Given the latest developments, it could be stated that the problem related to the legal ground of clinical trials is almost solved. In our opinion, the problems that might arise during the implementation phase, especially related to medical device trials, can be solved by the MoH personnel, researchers and other related persons who are endowed with experience in the field.
However it should be borne in mind that there are still plenty of issues required to be solved by means of general principles of law. For instance, some issues remain unanswered within the scope of the clinical trial related legislation such as preparation of clinical trial protocol and trial reports; protection of clinical trial data; liability and limits of the sponsor, physician and research institution; the scope of damage and liability insurances. Consequently, it seems that all shareholders who take part in clinical trials need to put more effort to understand limits of their responsibilities and liabilities under the related legislation focused to protect human life.
1. The 10th Chamber of Council of State rejected demands of TMA except the volunteers being offered remuneration and being informed by the research team.
2. It is possible for the trials that are falling into responsibilty of "Pharmaceutical" and "Non-Pharmacological" Ethical Committees to be examined by only one Ethical Committee that is to be established as Clinical Rtrials Ethical Committee; however a seperate Ethical Committee shall certainly be established for BA/BE studies.