April 13th 2013 SATURDAY the Official Gazette Issue: 28617

REGULATION

From the Turkish Drug and Medical Devices Institution:

REGULATION REGARDING MEDICAL RESEARCHES

PART ONE

Purpose, Scope, Reference and Definitions

Purpose

ARTICLE 1 – (1) The purpose of this Regulation is to regulate the procedures and principles for conducting scientific studies on people within the framework of good clinical practices, the European Union standards, the agreements that were made in relation to this subject and for the protection of the volunteers in question as well as the procedures and principles regarding the formation, duties and works of the Clinical Researches Advisory Committee and the ethical committees.

Scope

ARTICLE 2 – (1) This Regulation covers the clinical researches that are related to drug, medical product and herbal medical product researches to be conducted on humans including bioavailability and bioequivalence studies even if the relevant licenses were obtained and the clinical studies not related to drugs, the venues where these studies will be conducted and the legal or real persons to conducted these studies.

(2) Retrospective works are excluded from the scope of this Regulation.

Reference

MADDE 3 – (1) This Regulation was prepared based on the 10 th additional article of the Health Services Fundamental Law dated 7/5/1987 and numbered 3359 and the 27th and 40th articles of Decree Law Concerning the Organization and Duties of the Ministry of Health and Affiliated Institutions dated 11/10/2011 and numbered 663 and in parallel with the directives of the legislation of European Union regarding drugs, which are numbered 2001/20/EC and 2005/28/EC in terms of Good Clinical Practices.

Definitions

ARTICLE 4 - (1) The following terms used in this Regulation;

a) Adverse condition: It means desired and undesired conditions that may occur to the volunteers participating in the clinical research whether or not it has a causality relation with the treatment that was applied.

b) Adverse reaction: It means all the undesired and unintended responses given by the volunteer participating in the clinical research,

c) Researcher: It means the person participating in the clinical research under the supervision of the responsible researcher,

ç) Research brochure: It means the clinical and non-clinical documents regarding the product that is being researched or the practice in question,

d) Research protocol: It means the document defining the purposes, design and methodology of the clinical research and the statistical methods to be applied and the arrangements regarding the research,

e) Research product: It means the pharmaceutical form of the active substance or the placebo used as reference or tested during the clinical research,

f) Relative bioavailability: It means the bioavailability that is determined by being compared to the bioavailability obtained with a pharmaceutical that is given in the same or in a way which ensures the highest rate of bioavailability other than intravenous usage,

g) The Ministry: It means the Ministry of Health,

ğ) Unexpected and serious adverse reaction : It means all kinds of serious adverse reactions the quality, severity or result of which is inconsistent with its reference reliability information,

h) Informed volunteer consent form: It means the document documenting in writing the consent obtained by providing information regarding the research in a detailed and clear manner,

ı) Bioequivalence: It means the situation when two pharmaceutically equivalent patent medicines are similar to each other to the extent that their bioavailability and both their efficiency and safety are essentially same after they are administered at the same molar dose,

i) Bioavailability: It means the speed and degree of the active substance or its therapeutic molecular part in terms of being absorbed from the pharmaceutical form, passing to the systemic circulation and emerging in the site of action within the body or in the biological liquids reflecting it, generally in plasma,

j) Sever adverse condition or reaction: It means adverse condition or reaction that causes death, life threatening danger, hospitalization or extensions of stay in hospital, a permanent or significant injury or disability, a birth anomaly or defect,

k) Multicenter clinical research: It means the clinical research conducted in center in which more than one responsible researcher participates for this reason

l) Supervision: It means the activities of the Institution in terms of investigating the compliance to this Regulation and other relevant legislation by the venues where the clinical researches are made, the centers belonging to the contracted research institution, the documents and records of the research, the quality assurance regulations and all the institutions, committees and organizations including the relevant ethical committees,

m) Supporter: It means the person- institution or organization responsible for commencing, conducting or financing the clinical research,

n) Ethical committee: It means the independent committees, which will be formed and approved by the Institution for providing opinion regarding the methods and documents to be used while informing the volunteers, the consents to be taken from these people as well as other relevant issues regarding the research in order to protect the rights, safety and well-being of the volunteers,

o) Volunteer: It means the patient or healthy person to participate in the clinical research his or his legal representative's consent according to the provisions of the Regulation hereby and the relevant legislation,

ö) Observational drug research: It means the epidemiological studies during which the data regarding the drug that is spontaneously prescribed for the patients the treatment of whom are carried on according to the updated diagnoses and treatment guides of the Ministry in terms of indications, posology and administration ways of the drugs for which they obtained licenses in Turkey,

p) Drug or human medical product: It means natural, synthetic or biotechnological active substances or substance combination applied to the person in order to correct, regulate or change a physiological function or to

prevent, diagnose or treat a disease,

r) Non-pharmacological clinical research: It means a stem cell transfer research, tissue transfer research or organ transfer research or a new surgical method research to be conducted on humans other than the researches regarding drugs, biological or medical products, medical devices or cosmetic products,

s) Good clinical practices: It means the rules to be abode by the parties participating in the research which covers the regulations regarding the design, conduct , monitoring, budgeting, assessment and reporting of the research, protection of all the rights and physical integrity of the volunteer, providing the reliability of the research date and maintaining the confidentiality in order to ensure that the researches are conducted in international scientific and ethical standards,

ş) Limited person: It means the people subject to limitations defined in the Turkish Civil Code dated 22/11/2001 and numbered 4721,

t) Clinical research: It means the researches conducted on humans in order to reveal or confirm the clinical, pharmacological or other pharmacodynamical effects of one or more research products, to define the relevant adverse conditions or reactions, to determining absorption, distribution, metabolism and excretion and to study reliability and efficient aspects,

u) Clinical Researches Advisory Committee: It means the committee to be formed in order to provide opinion regarding the issues related to clinical researches

ü) Institution: It means the Turkish Institution of Drugs and Medical Devices,

v) Absolute bioavailability : It means the bioavailability rated for the bioavailability measured by giving the same molar amount of the drug in an intravenous manner,

y) Responsible researcher: It means the physician or the dentist who completed his residency or doctorate education in the research subject and the relevant area and who is responsible for conducting the research,

z) Contracted research institution: This means the independent institution to which the Supporter assigns all or part of its duties and powers related to the clinical search with a written contract and which works according to good clinical research practice principles,

.

PART TWO

General Principles of the Research, Obtaining Consent for the Research

General Principles of the Research

ARTICLE 5 – (1) The following conditions are sought for conducting researches over volunteers:

a) It is mandatory for the research to be conducted in a non-human test environment or over a sufficient number of experimental animals.

b) It is necessary for the scientific data obtained as a result of the experiments conducted on a non-human experiment environment or animals to oblige these to be conducted on humans in order to reach the desired objective.

c) Scientific benefits expected from the research and public interest cannot be considered more important than the health of the volunteers participating in the research or the possible risks that may emerge in terms of health care

and other personal rights.

d) No researches intended for disrupting the genetic structure of the germ cells of the volunteer is allowed to be conducted.

e) Decisions regarding the medical monitoring and treatment of the volunteer participating in the research belong to the physician or dentist with the vocational qualities that are required by such.

f) It is prohibited to apply methods that may cause pain to the volunteer in a way that does not comply with human dignity during the research.

g) The research is designed in a way that will minimize to the possible extent the pain, sickness, fear, any risk related to the sickness and development stage of the patient. It is necessary for the risk limit or discomfort degree to be defined especially and checked continuously.

h) It is necessary for the objective that is desired to be reached with the research to overweight the inconvenience that it brings to the person in question and the hazards it may cause to the health of this person.

i) It is necessary for the research to not to leave a predictable damaging and permanent effect on human health.

j) In the cases when it is considered by the ethical committee that the benefits to be obtained are more significant than the possible risk that may result from the research, provided that a duly informed consent form is obtained, the research may be started after getting the consent of the ethical committee and the Institution. The research can only be conducted if these conditions carry on to prevail.

k) Before a volunteer participates in the research, a responsible researcher from the research team or a physician or dentist researcher, who is competent in the subject of the research, informs the volunteer who will participate in the research or his legal representative adequately and in an understandable manner about the purpose and methodology of the research, expected benefits, predicted risks, difficulties, aspects that are inappropriate in terms of a person's health and personal qualities, conditions in which the research will be conducted and carried on and that he can withdraw whenever he wishes to do so.

l) Volunteer's consent, which will not be up to provision of any interest, is obtained completely based on his free will and his situation is documented with the Informed Volunteer Consent Form covering the provisions regarding information in (k) subclause.

j) At least one person is assigned from the research team for the volunteer to obtain information regarding his own health and the course of the research whenever he wants.

m) Volunteer can leave the research at his own will with or without justifications and he cannot be subjected to any loss from his then-current rights during the medical monitoring and treatment after that.

n) In accordance with the relevant legislation and with the purposes of securing the volunteers against damages that may result from the clinical research, it is necessary to make insurance for the volunteers to participate in the clinical researches other than Phase IV clinical researches and observational drug researches specified in (d) subclause of Article 10. However, this situation is determined according to the quality of the research in case of non-pharmacological researches.

o) Other than the insurance coverage, any kind of convincing or financial incentives cannot be presented for the volunteer or his legal representative for the volunteers to participate in the research or continue his participation. However, decrease in income resulting from the loss of working days with the participation of the volunteers in the research, is specified in the research budget and it is covered from this budget.

p) Identity information of the volunteer cannot be disclosed in the cases when the information to be obtained

as a result of the research is published.

Participation of children in the research

ARTICLE 6 – (1) In the cases when the research subject is directly related to children or is a clinical situation that can be examined only on children or it is mandatory for the data obtained as a result of the researches made on adults to be confirmed to be valid also on children, if the research does not have a predictable risk in terms of volunteers' health and there is a general medical opinion suggesting that the research will provide a direct benefit to the volunteers, it may be allowed to conduct researches on children within the framework of the points specified in Article 5 and the points specified below:

a) There should be a general medical opinion suggesting that there is no known risk of the product or practice to be researched on children.

b) If the child is able to express his consent, his consent, and if he is not able to do so his parents' consent or the consent of guardians , if he is under guardianship, is obtained in writing after they are all informed according to (k) subclause of the first clause of Article 5.

c) The child is excluded from the research in the cases when he rejects to participate in the research or wishes to leave the research at any stage of the research.

d) If the child is able to make an assessment and reach a conclusion about the information provided to him, all the information regarding the research is told to the child accordingly.

e) Ethical committee is informed by a physician, who specialized in children's health and diseases, about the clinical, ethical, psychological and social problems regarding the research whereas it is informed by a dentist, who did a doctorate or residency in dentistry, about the researches regarding dentistry and the protocol is assessed accordingly.

f) Ethical committee cannot approve this research without the affirmative opinion of a physician, who specialized in children's health and diseases, in cases of clinical researches to be made on children and without affirmative opinion of a dentist, who specialized in children's dentistry, in the cases of clinical researches regarding dentistry.

g) Any convincing or financial offer other than covering the mandatory costs that will result from children's participation in the research cannot be made in relation to the clinical researches to be made on the children.

Participation of pregnant women, puerperant women and breastfeeding women in the research

ARTICLE 7 – (1) In the cases when the subject of the research is directly related to pregnant, puerperant or breastfeeding women or it is about a clinical situation which occurs only with pregnant, puerperant or breastfeeding women, if the research does not pose a predictable risk for the health of the volunteer and the fetus or the baby and there is a general medical opinion suggesting that the research will provide a direct benefit to the volunteers, it can be allowed to conduct the research on pregnant, puerperant and breastfeeding women within the framework of the points specified in Article 5 and the points specified below:

a) There should be a general medical opinion suggesting that the product or practice to be researched does not pose any known risk for pregnant, puerperant and breastfeeding women and fetuses or babies.

b) Consent of pregnant, puerperant or breastfeeding women is obtained after they are informed according to (k) subclause of the first clause of Article 5.

c) Pregnant, puerperant or breastfeeding women are excluded from the research if they reject to participate or they want to leave the research at any stage.

d) Ethical committee is informed by a physician who specialized in the area of the research subject, in clinical, ethical, psychological and social problems related to the research and especially in terms of the health of the fetus or the baby and the protocol will be assessed accordingly.

e) No convincing incentive or financial offers other than covering the mandatory costs to result from the participation of regnant, puerperant or breastfeeding women in clinical researches can be presented.

Participation of limited people in the research

ARTICLE 8 – (1) In the cases when the research subject is a situation that is directly related to the limited people or a situation that can only be examined on them or when all the treatment options regarding the disease of the limited person is used, if there is a general medical opinion suggesting that the research may provide direct benefits to the limited people and it does not pose a predictable risk for such people, it may be allowed to conduct the research on the limited people within the framework of the points specified in article 5 and the points specified below:

a) There should be a general medical opinion suggesting that there is no known risk of the product or practice to be researched on limited people.

b) Written consent of the limited person, who is able to express his consent, and his guardian after they are informed according to (k) subclause of the first clause of Article 5.

c) If the limited person is able to reach an opinion by making an assessment regarding the information given to him, he will be excluded from the research when he rejects to participate in the research or to leave the research at any stage of the research.

d) Ethical committee is informed by a psychiatrist physician who specialized in the area of the research subject, in clinical, ethical, psychological and social problems related to the research and the protocol will be assessed accordingly.

e) Any convincing or financial offer other than covering the mandatory costs that will result from limited people's participation in the research cannot be made in relation to the clinical researches to be made on the limited people.

Participation of unconscious people and people in intensive care in the research

ARTICLE 9 – (1) In the cases when the research subject is a situation that is directly related to the unconscious people and people in intensive care or a situation that can only be examined on them or when all the treatment options regarding the disease of the people in intensive care or the unconscious people are used, if there is a general medical opinion suggesting that the research may provide direct benefits to the people in intensive care and unconscious people and it does not pose a predictable risk for such people, it may be allowed to conduct the research on the people in intensive care and unconscious people within the framework of the points specified in Article 5 and the points specified below:

a) There should be a general medical opinion suggesting that there is no known risk of the product or practice to be researched on people in intensive care or unconscious people.

b) Legal representatives, if any, or the relatives, if they do not have legal representatives, are informed according to (k) subclause of the first clause of the 5th article and their written consent is obtained.

c) If the people in intensive care and unconscious people become able to reach an opinion by making an assessment in the subject about which they were informed, they will excluded from the research if they reject to participate in the research and they want to leave the research at any stage.

d) Ethical committee is informed by a physician, who specialized in the area of the research subject, in

clinical, ethical, psychological and social problems related to the research and the protocol will be assessed accordingly.

e) No convincing incentive or financial offers other than covering the mandatory costs to result from the participation of unconscious people or people in intensive care in clinical researches can be presented.

(2) In the cases when the legal representative or relatives of the people in intensive care or unconscious people cannot be reached, if the provisions of the first article and the following conditions exist, under the supervision of a responsible researcher or a physician researcher, people in intensive care or unconscious people can be included to the research:

a) Ethical committee's previous assessment regarding if the suggested research protocol or other documents sufficiently cover the ethical provisions of the agreement or not,

b) In the cases of cardiac arrest, head trauma, central neural system infections, which develop suddenly, to which the physician must intervene promptly and regarding which all the current treatment options are used, a general medical opinion should exist suggesting that the research will directly benefit the people in intensive care and unconscious people.

PART THREE

Principles Regarding the Conduct of the Researches

Clinical Research Periods

ARTICLE 10 – (1) Clinical research periods are as it follows:

a) Phase I or 1st Period: This is the clinical research period in which the research product is tried by being applied to health volunteers in sufficient number, who are chosen according to the quality and nature of the research, or to sick volunteers in the cases when it is not possible to try the product on healthy volunteers, in order to determined pharmacokinetic qualities, toxicity and bodily functions of the research product in question. Phase I or 1st period clinical researches cannot be started if preclinical pharmacological, toxicological and similar researches of a newly developed research product was not by using experimental methods.

b) Phase II or 2nd Period: This is the clinical research period in which the research product is tried by being applied on a sufficient number of volunteering patients with the purpose of researching the clinical efficiency and safety of the therapeutic dose limits of the research product.

c) Phase III or 3rd Period: This is the clinical research period in which the research product, which passed Phase I and Phase II, is tried in terms of its efficiency, safety, possible new indications, different doses, new ways and methods of administer, new patient populations and new pharmaceutical manners by being applied on a sufficient number of patients chosen according to the qualities and nature of the research.

d) Phase IV or 4th Period: This is the clinical treatment period in which the clinical treatment is applied on many volunteering patients in order to thoroughly investigate or compare the products in question with other treatment products and methods in terms of confirmed indications, posology and implementation manners of products licensed in Turkey and the safety and efficient of the authorized products regarding the recommended uses.

Locations in which clinical researches will be done, the relevant standards and permit application

ARTICLE 11 – (1) Clinical researches can be conducted in places suitable for providing the safety of the people, n which researches will be conducted, and conducting the research in a healthy manner and which have personnel, equipments and laboratory facilities for the quality of the research, university health practice and research centers including Gülhane Military Medical Academy and military training-research hospitals, approved research and

development centers affiliated to universities and places designed in the training and research hospitals of the Ministry preferably for conducting clinical researches.

(2) Phase I clinical researches and bioavailability-bioequivalence are conducted in research and development centers and health institutions and organizations approved by the Institution and affiliated to the Ministry or universities which cover the standards determined for them and which are in conditions suitable for making a emergency response.

(3) Places in which clinical researches will be made have to have the following by taking basis the Good Clinical Research Practices Guide;

a) Sufficient number of personnel and equipment required by the qualities of the research,

b) Places and facilities required for the storage and distribution of the product according to the quality of the research product,

c) Facilities and equipment that can provide the appropriate carte for the volunteers including the care in the cases when emergency response is needed,

d) Facilities and equipment that may make the transfer of volunteers to a more advanced heath institution or organization when necessary,

e) Facilities and equipment that may retain the documents and information regarding the volunteers and the research after the research is completed.

Research application and permit

ARTICLE 12 – (1) Simultaneous applications can be made to the ethical committee and the Institution in order to obtain permits for the clinical researches within the scope of this Regulation.

(2) Research application file is prepared according to the application form and attachments on the web site of the Institution within the framework of the Good Clinical Practices Guide and other relevant guides.

(3) It is enough for a single ethical committee decision to exist for the multicenter clinical researches.

(4) Research application is made to the ethical committee and the Institution by the supporter to be formed of real or legal people or by the contracted research institution residing in Turkey to be assigned by the supporter. If the supporter does not have a representative residing in Turkey, the research application has to be made by means of the contracted research institution residing in Turkey.

(5) In the cases when the application is duly made, there is not deficiency in the documents and information that an appreciations needs to contain and the relevant ethical committee decision is presented, it is essential for the application to be examined by the Institution and finalized within thirty days.

(6) If the Institution made a negative decision for conducting the research, t notified the supporter about that with the relevant justification. Supporter can make another application by making changes about the issue specified by the Institution, provided that this re-application can only be made once, or it can appeal to the decision by stating the relevant justification. Investigation period is suspended during this process. In the cases hen the demanded changes are not fulfilled or an acceptable justification is not presented in relation to the subject, the Institution can reject the research.

(7) In the cases of non-pharmacological researches or the researches to be conducted by using products containing genetic modified organisms and cellular treatments or gene treatments, an additional period of thirty days

can be added to the period determined for the Institution's permit.

Starting and conducting clinical treatments

ARTICLE 13 – (1) Clinical treatments for which the Institution's permit is mandatory cannot be started without getting the permit from the Institution.

(2) Among the changes that occurred while conducting the research, the ones that are in nature of notifications and the ones requiring decisions and permits are determined by the Good Clinical Practices Guide. It is essential for the changes requiring decisions and permits to be examined to be finalized within fifteen days by the ethical committee and within thirty days by the Institution after the decisions of the committee is presented.

(3) Researches are conducted in the following manner:

a) The researches within the scope of this Regulation are conducted under the chairmanship of a responsible researcher and with a team appropriate for the quality of the research. Phase I clinical researches and bioavailability-bioequivalence works are conducted by a pharmacologist, who did his doctorate or residency, and a team within the sufficient experience and education in terms of good clinical practices.

b) Provided that the points specified in the second clause are reserved, in the cases when a new situation that may affect the safety of the relevant volunteers in relation to development of the research product or while conducting the research, the supporters, dentist, responsible researcher, physician or dentist researcher takes the necessary emergent safety measures to protect the volunteers against this hazard. Responsible researchers or supporter informs the Institution and the ethical committee about the new situation in question and the measures that were taken. Otherwise, the Institution will stop the research.

c) If the research could not be started on the date specified in the application file although it was permitted to be, the reasons for such situation will be notified to the Institution within ninety days.

d) Responsible researcher can include assistant researchers with suitable qualities provided that the necessary conditions and measures are provided in terms of patients' safety and this inclusion will be notified in the application form.

e) Provided that a written contract is made and the Institution is informed, supporter can assign a part of its duties to the contracted research institution according to the scientific principles and the good clinical practices. Assignment of duties to the contracted research institution does not eliminate the possible legal and penal responsibility regarding the duties of the supporter that were assigned. Supporter and the contracted research institution are responsible for the results of the procedures and the works subject to the contract.

Stopping or ending the clinical researches

ARTICLE 14 – (1) If the Institution determined that one of the conditions, which were existent when the permit was given during the conduct of the research, does not exist anymore, it will immediately stop the clinical research. In the cases when it is understood that these conditions are not fulfilled or when it is impossible to fulfill them within the specified period or when the health of the volunteer is in danger during this period, the research will be directly canceled.

(2) In the cases when there is no direct risks for the volunteers, opinion of the supporter or a responsible researcher regarding the issue is asked. In this case, supporter or the responsible researcher submits his opinion regarding the issue to the Institution within fifteen days.

(3) If the research is stopped by the supporter after it is started, together with the relevant justifications, the decision for stoppage is submitted to the Institution and the ethical committee within fifteen days by adding an information letter regarding the measures regarding the continuation of the treatment of the volunteers taken into the

research.

(4) Supporter notifies the Institution and the ethical committee about the fact that the research was stopped within ninety days after it ended.

(5) Decision regarding cancellation or stoppage of the clinical research is notified to the supporter or the responsible researcher with the relevant justification.

PART FOUR

Research Products

Responsibility of the supporter and the responsible researcher regarding the research product

ARTICLE 15 – (1) Supporter is responsible for the production of the research product and the storage of the product according to its qualities, its distribution and delivery to the research center and maintenance of these conditions in the research center, collection of the unused products from the research center and ensuring their return or duly disposal and keeping records regarding all these processes.

(2) The responsible researchers in each research center where the research is conducted are responsible for receiving the research products, maintaining them, distributing them according to written requests or research protocol, stock control, procedures to be conducted on the remaining part and keeping the relevant records. Responsible researcher assigns a pharmacist for conducting these procedures.

Production, import and labeling of the research products

ARTICLE 16 – (1) It is guaranteed that the research products are produced according to the rules specified in the Good Production Practices Guide.

(2) Relevant permits will be taken from the Institution regarding the production or import of the products to be used in the researches.

(3) Supporter, who will conduct the production or import of the research product, will fulfill the following conditions:

a) It is necessary to document in the application to be made to the Institution that each series of the research product that will be produced or imported to be in conditions appropriate for the good production practices at the very least and that its production and controls were conducted according to the product specifying indicated on the relevant file.

b) Samples belonging to each set of produced or imported products for conducting researches and the information and documents regarding them are kept at least for four years.

(4) Label on the outer packaging or the ready package (if it does not have any external packaging) of the research product is prepared in Turkish and according to the Good Production Practices Guide.

Withdrawal of research products

ARTICLE 17 – (1) In the cases when the research is stopped, all the products left with the responsible researcher or physician or dentist are withdrawn completely from the distribution places by the supporter and the situation is notified to the institution as a report within fifteen days with the relevant documents.

(2) Withdrawal of the research products, the procedures to be conducted regarding the withdrawn products and

the measures to be taken are specified in the report to be notified to the Institution in detail.

PART FIVE

Notification of the Adverse Conditions and Severe Adverse Reactions

Other Notifications, Supervision and Responsibility

Notification of adverse conditions

ARTICLE 18 – (1) Responsible researcher or a researcher to be assigned by the responsible researcher notifies the supporter immediately about all the adverse conditions other than the ones that were not required to be immediately reported which are specified in the protocol or the research brochure. A single code number is used for the volunteers participating in the works for emergency report and other reports following this.

(2) Adverse conditions or laboratory finding defined as critical for safety assessments are reported to the supporter within the time and according to manner specified in the protocol.

(3) Responsible researcher or a researcher to be assigned by he responsible researcher submits all kinds of additional information to the supporter, ethical committee and the Institution in case one of the volunteers participating in the research dies.

(4) Supporter keeps detailed reports of all the adverse conditions reported to it by the responsible researcher or the researcher. These records are submitted to the Institution and the ethical committee when it is requested.

Notification of sever adverse reactions

ARTICLE 19 – (1) Supporter notifies the ethical committee and the Institution about sever adverse reactions emerging during the research within seven days after obtaining such information at the latest. He delivers the monitoring reports including the additional information regarding such cases to the ethical committee and the Institution within eight days after obtaining them.

(2) All the other unexpected sever adverse reactions are notified by the supporter to the ethical committee and the Institution within ten days at the latest after the information is obtained.

(3) Supporter also informs all the researchers and the responsible researcher.

(4) Supporter submits the list of all the suspicious severe adverse reactions that were observed to the ethical committee and the Institution with the interim report form in the relevant guides to be published by the Institution in a way to include the information regarding the security of the volunteers at least once every year. The Institution may request reports when it deems necessary or in shortest periods of time in cases of short-term researches.

Other notifications

ARTICLE 20 – (1) Interim report and final report in the multicenter clinical researches are prepared in a way to include the results of all the centers participating in the research regarding the research and according to the forms published on the be site of the Institution.

(2) Among the assignments regarding the research, the ones that are notifications by nature and the ones requiring decisions and permits are determined by Good Clinical Practices Guide. However, if necessary the Institution can cancel the assignments, which are notifications by nature, together with their justifications.

(3) Supporter is responsible for regular delivery of the notifications to the Institution.

Research records, confidentiality and assignment

ARTICLE 21 – (1) All the records regarding the research is kept by the responsible research or researcher regularly and retained for at least four years after the research is completed in all the centers.

(2) In the cases when the research is assigned for any reason, this situation will be notified to the ethical committee and the Institution. The Institution will approve the assignment if it deems appropriate. In the cases when the researches are assigned, the new owner of data or documents is responsible for maintaining and archiving these.

(3) Archiving the information and documents regarding the research should be conducted according to the provisions of the relevant guides.

(4) Documents regarding the research should be kept confidential. These documents can only be given to the responsible people of the legally authorized people or authorities.

Audit

ARTICLE 22 – (1) The Institution audits the researches conducted in and outside the country, the places where such researches are conducted, the supporter and the contracted research institution, the places were researched products are produced and the laboratories in which the relevant analyses are made, the ethical committees in terms of compliance with the Regulation hereby and other relevant legislation by giving prior notification or without giving any notification at all.

(2) Auditors are chosen from among the doctors, pharmacists or people who had their undergraduate education in the appropriate department with the sufficient experience and degree of education in terms of good clinical practices.

(3) Good clinical practices auditors are responsible to maintain the confidentiality of the information they obtained during the audits.

Responsibility

ARTICLE 23 – (1) Costs of every kind of research products used in the research and equipments and materials for using such products, relevant examinations, investigations, analyses and treatments are covered by the supporter. Volunteers or social security institutions cannot be forced to pay such amounts.

(2) It is mandatory for the legal or real people who conducted the research to specify the financing of the research in their application files.

(3) Obtaining informed volunteer consent form from the volunteers participating in the research cannot eliminate the right of the volunteers to be compensated for the damages they are subjected as a result of the research.

Prohibitions

ARTICLE 24 – (1) It is prohibited of the researches within the scope of this Regulation to be conducted in contradiction with the Regulation hereby and the procedures and principles determined in other relevant legislation.

Administrative sanctions

ARTICLE 25 – (1) In the cases of breaches in terms of the provisions regarding the clinical researches, the relevant research or the part of it made in Turkey, if it is an international multicenter research, can be suspended or stopped by the Institution. In the cases when the reasons for such suspension are eliminated, this situation is notified to the Institution by the supporter and the research is carried on if deemed appropriate by the Institution.

(2) The Institution warns the ethical committee, which does not work according to the ethical principles or which does not fulfill the requirements of Ethical Committee Standard Working Method or which is determined to lack places, secretariat, archives and similar equipments that are mandatory in terms of conducting ethical committee works as a result of the audit . In the cases when the reason for the warning in question is not eliminate within the specified period, the approval that is given is canceled by the Institution according to the second clause of Article 26 and the membership of the ethical committee chairman is suspended for two years.

(3) Provisions of the Turkish Penal Code dated 26/9/2004 and numbered 5237 and the other relevant legislation are applied according to the quality of the acts of the people who acted and operated on the contrary to the provisions specified in this Regulation.

PART SIX

Structure, Duties, Operational Procedures and Principles of the Ethical Committees

Structure of the ethical committees

ARTICLE 26 – (1) Ethical committees are formed of at least seven and at most fifteen members from health occupational group , most of whom have had education at residency or doctorate level, in order to conducted scientific and ethical assessments regarding the methods and documents to be used while informing the volunteers, the consents to be taken from these volunteers as well as other issues regarding the research with the purpose of protecting the rights, safety and welfare of the volunteers.

(2) Ethical commits are formed with the approval and proposal of rectors in universities, of general secretary in Public Hospital Associations and of the dean in Gülhane Military Medical Academy and they start their activities as of the approval date.

(3) Ethical committees are formed as Clinician Researches Ethical Committees and Bioavailability, Bioequivalence Works Ethical Committees.

(4) Clinical Researches Ethical Committees are formed in order to assess researches other than bioavailability-bioequivalence in scientific and ethical terms.

(5) Bioavailability-Bioequivalence Studies Ethical Committee, is formed to assess bioavailability -bioequivalence studies in scientific and ethical terms.

(6) At least three of the ethical committee members are determined from the institution to which the ethical committee secretariat is affiliated.

(7) Member of an ethical committee cannot be the member of another ethical committee.

(8) Executives of the places, in which clinical research is made, cannot take place in ethical committees.

(9) After they are approved by the Institution, ethical committees conduct their correspondences with the Institution directly by using their own secretariat.

(10) Clinical Researches Ethical committees will include members who will have the following qualities at the very least:

a) Specialist physicians, preferably who have participated in international clinical researches, which were organized according to the good clinical practices rules, as researchers and preferably who are chosen from different specialties,

b) Pharmacists or medical doctors who did their doctorates or residency in pharmacology area,

c) A person or a health specialist who did his doctorate in biostatistics area or a medical doctor who did his doctorate in this area,

d) An engineer or specialist working in biomedical area or a biophysicist or a physiologist if such specialist or engineer could not be found,

e) Lawyer,

f) A person who does not work in health sector,

g) A person who did his doctorate or who got his residency in medicine ethics or deontology, if any,

h) A clinical pharmacist, if any.

(11) Bioavailability - Bioequivalence Works Ethical Committees will have members with the following qualities at the very least:

a) Specialist physicians, preferably who have participated in international clinical researches, which were organized according to the good clinical practices rules, as researchers,

b) Pharmacists or medical doctors who did their doctorates or residency in pharmacology area,

c) A person or a health specialist who did his doctorate in biostatistics area or a medical doctor who did his doctorate in this area,

d) A pharmacist, preferably who did his doctorate in pharmacokinetic or pharmaceutical technology area,

e) A pharmacist , chemist or chemistry engineer who did his doctorate in pharmaceutical chemistry or analytical chemistry,

f) Lawyer,

g) A person who does not work in health sector,

h) A person who did his doctorate or who got his residency in medicine ethics or deontology, if any,

Operational procedures and principles of ethical committees

ARTICLE 27 – (1) Operational procedures and principles of ethical committees are specified below.

a) Ethical committees are independent for assessing and making decisions regarding the clinical research applications in scientific and ethical terms.

b) Ethical committee members have to abide by the confidentiality principle regarding all kinds of information that they received.

c) Ethical committee members start their activities by signing a confidentiality document and letter of undertaking prepared by the Institution.

d) Ethical committee members, who are related to the examined research or who acts within the research, cannot participate in the discussion or voting of this research in the ethical committee and cannot sign relevant ethical

committee decisions.

e) Members of the ethical committee gather with the two third majority of the total number of members and make decisions with simple majority of the total number of members.

f) Ethical committee members work for two years and the members the terms of which have expired can be reelected.

g) Membership of a person who did not participate in three consecutive meetings without any excuse or who did not participate in five meetings in total will be canceled. A member is elected instead of members whose term ended or whose membership is canceled.

h) When necessary ethical committees obtain the written opinions of people in the relevant area or subspeciality and can invite such people to the meetings as consultants.

i) Working methods of the ethical committees are determined by the Institution and published on the website of the Institution. Ethical committees conduct their activities within the framework of these determined standards.

Duties and powers of the ethical committees

ARTICLE 28 – (1) Duties of the ethical committees are as it follows:

a) Clinical research applications made within the scope of this Regulation are assessed by the ethical committees formed according to Article 26.

b) No other ethical committees or separate committee or structure that will execute the ethical committee functions can be formed by other institutions or organizations with the purpose of assessing the subjects within the scope of this Regulation.

c) Ethical committees assess at least the following points while forming an opinion about the research application;

1) Analysis of the benefits, damages and risks expected from the research,

2) Whether or not the research is based on scientific data and new hypothesis,

3) Necessity of the research about being conducted firstly in a non-human experimental environment or on a sufficient number of animals in the cases of researches to be conducted on humans for the first time,

4) Whether or not the research and the scientific data obtained as a result of the experiments made in a non-human experiment or on animals reached the maturity level at which the research can be conducted on humans and the fact that it makes the research mandatory to be conducted on humans in terms of reaching the desired objective,

5) Research protocol,

6) Assessment of the content of the research brochure and whether or not it was duly arranged,

7) Written information submitted in relation to the research, the method followed with the purpose of obtaining the consent of the volunteers, the sufficiency of the justification regarding the researches to be conducted on limited people, children, pregnant women, puerperant women, unconscious people and people in intensive care,

8) Responsibility of the supporter or, researcher or the responsible researches in cases of injury or death including possible permanent health problems that may emerge as a result of the research,

9) Provision of compensation in cases of death or injury that can be associated with the research,

10) Regulations regarding the inclusion of volunteers in the research,

11) The suitability of the research team participating in the research based on the qualities of the research.

d) Ethical committee can monitor the approved applications during the research or in place.

e) Clinical Researches Ethical Committee submits its opinion to the applicant within fifteen days at the latest after the application was made whereas Bioavailability-Bioequivalence Works Ethical Committee submits its opinion within seven days at the latest after the application was made.

f) In the cases of non-pharmacological researches or the researches to be conducted by using products containing genetic modified organisms and cellular treatments or gene treatments, an additional period of thirty days can be added to the period of fifteen days determined for the ethical committee's permit.

g) In the cases when additional information or descriptions are needed during the examination process of the ethical committee, all the required demands are submitted to the applicant at once. Investigation process is suspended until required documents and information are provided to the ethical committee.

PART SEVEN

Structure, Operational Procedures and Principles of Clinical Researches Advisory Committee

Observational Drug Studies and Training

Structure of the Clinical Researches Advisory Committee

ARTICLE 29 – (1) Under the chairmanship of the Undersecretary of the Ministry of Health or a Deputy Undersecretary deemed appropriate by him, Clinical Researches Advisory Committee is formed of three people who were selected by the Institution and who did their residency or doctorate from surgical, internal diseases and basic sciences of medicine, one clinical psychologist and one theologist, 1st Legal Advisor of the Institution or a legal advisor to be assigned by the him.

Duties, operational procedures and principles of the Clinical Studies Advisory Committee

ARTICLE 30 – (1) Clinical Researches Advisory Committee, provides it opinion regarding the issues which were submitted to the Institution by the clinical researches or ethical committees in relation to the clinical researches and which requires its expert opinion.

(2) Operational procedures and principles of the Clinical Researches Advisory Committee are as it follows:

a) Clinical Researches Advisory Committee elects a vice chairman from among its members at the first meeting.

b) Term of the members elected to Clinical Researches Advisory Committee is two years and the members, whose terms ended, can be reelected.

c) Membership of people who did not participate in three consecutive meetings or people who did not participate in five meetings in total without any excuse is canceled. A member with same qualities of the member whose membership was canceled will be elected instead of this former member.

d) Clinical Researches Advisory Committee gathers with two third majority of the total number of its members

and makes decisions with simple majority of the total number of members.

e) When necessary, Clinical Researches Advisory Committee can get the opinion of the relevant experts or invite and listen to these experts.

f) Standard working method of the Clinician Researches Advisory Committee is prepared by the Institution.

g) Secretariat of the Clinical Researches Advisory Committee is managed by the Institution.

Observational drug studies

ARTICLE 31 – (1) Observational drug studies cannot be started without getting the relevant permits from the Institution and the ethical committee. Principles regarding such studies are determined with the guide to be prepared by the Institution.

Training

ARTICLE 32 – (1) The Institution can organize seminaries and courses in order to train qualified responsible researchers or researchers, health personnel and other kind of personnel working in this area to train such people in good clinical practices or can give its permission to the institution (s) desiring to organize such seminaries or courses according to the guide to be published by it.

Guide

ARTICLE 33 – (1) Instructive and explanatory guides are published by the Institution with the purpose of applying this Regulation.

PART EIGHT

Miscellaneous and Final Provisions

Situations for which there are no provisions

ARTICLE 34 – (1) In case of situations for which there are no provisions in this Regulation, Convention for the Protection of Human Rights and Human Dignity with Regarding to the application of Biology and Medicine, Medical Deontology Ordinance put into effect with the decision of the Council of Ministers dated 13/1/1960 and numbered 4/12578, provisions specified in the Regulation Regarding Patients' Right published in the Official Gazette numbered 23420 and dated 1/8/1998 in relation to the volunteers participating in the research and the provisions of other relevant legislation will be applied.

Repealed regulation

ARTICLE 35 – (1) Regulation Regarding Clinician Researches published in the Official Gazette dated 19/8/2011 and numbered 28030 was repealed.

Current ethical committees

PROVISIONAL ARTICLE 1 – (1) Ethical committees approved according to the Regulation Regarding Clinical Researches, which was published in the Official Gazette dated 19/8/2011 and numbered 28030, can carry on their duties at most for six more months after the publication of the Regulation hereby.

Coming into effect

ARTICLE 36 - (1) This Regulation will come into effect as of the date of its publication;

Execution

ARTICLE 37 – (1) Provisions of this Regulation will be executed by the Chairman of the Turkish Institution of Drugs and Medical Devices.