1. Özgün Melike TOTUK GEDAR, MD Bahcesehir University (BAU), School of Medicine Assistant Professor of Ophthalmology Istanbul, Turkey www.melikegedar.com +90 5333367986 ozgunmelike.gedar@med.bau.edu.tr HOW CAN WE CONDUCT HUMAN STUDIES?

2. Clinical Study A clinical study involves research using human volunteers (also called participants) that is intended to add to medical knowledge. There are two main types of clinical studies: clinical trials (also called interventional studies) and observational studies

3. Potential treatments, however, must be studied in laboratory animals first to determine potential toxicity before they can be tried in people. Treatments having acceptable safety profiles and showing the most promise are then moved into clinical trials

4. Clinical Trials In a clinical trial, participants receive specific interventions according to the research plan or protocol created by the investigators. These interventions may be medical products, such as drugs or devices; procedures; or changes to participants' behavior, such as diet. Clinical trials may compare a new medical approach to a standard one that is already available, to a placebo that contains no active ingredients, or to no intervention. Some clinical trials compare interventions that are already available to each other.

5. Clinical Trials When a new product or approach is being studied, it is not usually known whether it will be helpful, harmful, or no different than available alternatives (including no intervention). The investigators try to determine the safety and efficacy of the intervention by measuring certain outcomes in the participants. For example, investigators may give a drug or treatment to participants who have high blood pressure to see whether their blood pressure decreases.

6. Clinical Trials Clinical trials used in drug development are sometimes described by phase. These phases are defined by the Food and Drug Administration (FDA).phases

7. PHASE Food and Drug Administration (FDA) descriptions of the clinical trial of a drug based on the study's characteristics, such as the objective and number of participants. There are five phases:descriptions Phase 0: Exploratory study involving very limited human exposure to the drug, with no therapeutic or diagnostic goals (for example, screening studies, microdose studies) Phase 1: Studies that are usually conducted with healthy volunteers and that emphasize safety. The goal is to find out what the drug's most frequent and serious adverse events are and, often, how the drug is metabolized and excreted.

8. PHASE Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition). For example, participants receiving the drug may be compared to similar participants receiving a different treatment, usually an inactive substance, called a placebo, or a different drug. Safety continues to be evaluated, and short-term adverse events are studied. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing. These including postmarket requirement and commitment studies that are required of or agreed to by the study sponsor. These studies gather additional information about a drug's safety, efficacy, or optimal use.

9. expanded access Some people who are not eligible to participate in a clinical trial may be able to get experimental drugs or devices outside of a clinical trial through expanded access Expanded access is a means by which manufacturers make investigational new drugs available, under certain circumstances, to treat a patient(s) with a serious disease or condition who cannot participate in a controlled clinical trial. For patients who cannot participate in a clinical trial of an investigational drug, but have a serious disease or condition that may benefit from treatment with the drug, FDA regulations enable manufacturers of such drugs to provide those patients access to the drug under certain situations, known as “expanded access.”

10. Observational Studies In an observational study, investigators assess health outcomes in groups of participants according to a research plan or protocol. Participants may receive interventions (which can include medical products such as drugs or devices) or procedures as part of their routine medical care, but participants are not assigned to specific interventions by the investigator (as in a clinical trial). For example, investigators may observe a group of older adults to learn more about the effects of different lifestyles on cardiac health.

11. Who Conducts Clinical Studies? Every clinical study is led by a principal investigator, who is often a medical doctor. Clinical studies also have a research team that may include doctors, nurses, social workers, and other health care professionals. Clinical studies can be sponsored, or funded, by pharmaceutical companies, academic medical centers, voluntary groups, and other organizations. Doctors, other health care providers, and other individuals can also sponsor clinical research

12. Where Are Clinical Studies Conducted? Clinical studies can take place in many locations, including hospitals, universities, doctors' offices, and community clinics. The location depends on who is conducting the study.

13. How Long Do Clinical Studies Last? The length of a clinical study varies, depending on what is being studied. Participants are told how long the study will last before they enroll.

14. Reasons for Conducting Clinical Studies In general, clinical studies are designed to add to medical knowledge related to the treatment, diagnosis, and prevention of diseases or conditions. Some common reasons for conducting clinical studies include: Evaluating one or more interventions (for example, drugs, medical devices, approaches to surgery or radiation therapy) for treating a disease, syndrome, or condition Finding ways to prevent the initial development or recurrence of a disease or condition. These can include medicines, vaccines, or lifestyle changes, among other approaches. Evaluating one or more interventions aimed at identifying or diagnosing a particular disease or condition Examining methods for identifying a condition or the risk factors for that condition Exploring and measuring ways to improve the comfort and quality of life through supportive care for people with a chronic illness

15. Participating in Clinical Studies A clinical study is conducted according to a research plan known as the protocol. The protocol is designed to answer specific research questions and safeguard the health of participants. It contains the following information: The reason for conducting the study Who may participate in the study (the eligibility criteria) The number of participants needed The schedule of tests, procedures, or drugs and their dosages The length of the study What information will be gathered about the participants

16. Who Can Participate in a Clinical Study? Clinical studies have standards outlining who can participate. These standards are called eligibility criteria and are listed in the protocol. Some research studies seek participants who have the illnesses or conditions that will be studied, other studies are looking for healthy participants, and some studies are limited to a predetermined group of people who are asked by researchers to enroll

17. Eligibility The factors that allow someone to participate in a clinical study are called inclusion criteria, and the factors that disqualify someone from participating are called exclusion criteria. They are based on characteristics such as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions.

18. How Are Participants Protected? Informed consent is a process used by researchers to provide potential and enrolled participants with information about a clinical study. This information helps people decide whether they want to enroll or continue to participate in the study. The informed consent process is intended to protect participants and should provide enough information for a person to understand the risks of, potential benefits of, and alternatives to the study. In addition to the informed consent document, the process may involve recruitment materials, verbal instructions, question-and- answer sessions, and activities to measure participant understanding. In general, a person must sign an informed consent document before joining a study to show that he or she was given information on the risks, potential benefits, and alternatives and that he or she understands it. Signing the document and providing consent is not a contract. Participants may withdraw from a study at any time, even if the study is not over.

19. Informed consent The goal of the informed consent process is to protect participants. It begins when a potential participant first asks for information about a study and continues throughout the study until the study ends. The researcher and potential participant have discussions that include answering the participant's questions about the research. All the important information about the study must also be given to the potential participant in a written document that is clear and easy to understand. The informed consent document is reviewed and approved by the human subjects review board before the document is given to potential participants. Generally, a person must sign an informed consent document to enroll in a clinical study.

20. What elements should be included in an informed consent? Purpose of the research Procedures involved in the research Alternatives to participation All foreseeable risks and discomforts to the subject. Note: that these include not only physical injury but also possible psychological, social, or economic harm, discomfort, or inconvenience. Benefits of the research to society and possibly to the individual human subject Length of time the subject is expected to participate Person to contact for answers to questions or in the event of a research-related injury or emergency Statement indicating that participation is voluntary and that refusal to participate will not result in any consequences or any loss of benefits that the subject is otherwise entitled to receive

21. What additional informed consent elements might be needed for certain projects? Certificate of Confidentiality (if any)/limitations of certification protection Payment for participation (if applicable) Risks to vulnerable subjects, e.g., embryo, fetus, pregnancy Circumstances for investigator “withdrawing” the subject Additional costs from participation Early withdrawal consequences Statement regarding how significant new findings will be communicated Number of subjects participating Probability of random assignment or placebo placement Additional information required by the IRB

22. Relationship to Usual Health Care Typically, participants continue to see their usual health care providers while enrolled in a clinical study. While most clinical studies provide participants with medical products or interventions related to the illness or condition being studied, they do not provide extended or complete health care. By having his or her usual health care provider work with the research team, a participant can make sure that the study protocol will not conflict with other medications or treatments that he or she receives.

23. Considerations for Participation Participating in a clinical study contributes to medical knowledge. The results of these studies can make a difference in the care of future patients by providing information about the benefits and risks of therapeutic, preventative, or diagnostic products or interventions

24. Considerations for Participation Clinical trials provide the basis for the development and marketing of new drugs, biological products, and medical devices. Sometimes, the safety and the effectiveness of the experimental approach or use may not be fully known at the time of the trial. Some trials may provide participants with the prospect of receiving direct medical benefits, while others do not. Most trials involve some risk of harm or injury to the participant, although it may not be greater than the risks related to routine medical care or disease progression

25. Considerations for Participation Many trials require participants to undergo additional procedures, tests, and assessments based on the study protocol. These requirements will be described in the informed consent document. A potential participant should also discuss these issues with members of the research team and with his or her usual health care provider

26. Institutional review boards An IRB is made up of doctors, researchers, and members of the community. Its role is to make sure that the study is ethical and that the rights and welfare of participants are protected. This includes making sure that research risks are minimized and are reasonable in relation to any potential benefits, among other responsibilities. The IRB also reviews the informed consent document.

27. Declaration of Helsinki The Declaration of Helsinki (DoH) is the WMA's best-known policy statement. The first version was adopted in 1964 and has been amended seven times since, most recently at the General Assembly in October 2013. The current (2013) version is the only official one; all previous versions have been replaced and should not be used or cited except for historical purposes.Declaration of Helsinki The new version is published on the website of the Journal of American Medical Association (JAMA). (available in pdf)Journal of American Medical Association (JAMA)pdf

28. ethics committee The Declaration of Helsinki requires that all medical research be submitted to and approved by an ethics committee. It states: 'The research protocol must be submitted for consideration, comment, guidance and approval to a research ethics committee before the study begins'

29. SUBMISSION OF APPLICATION The researcher should submit an application in a prescribed format along with the study protocol as prescribed by the ethic commitee The protocol should include the following : 1. The title with signature of Principal Investigator (PI) and Coinvestigators as attestation for conducting the study. 2. Clear research objectives and rationale for undertaking the investigation in human participants in the light of existing knowledge.

30. 3 Recent curriculum vitae of the Investigators indicating qualification and experience. 4. Participant recruitment procedures and brochures, if any. 5. Inclusion and exclusion criteria for entry of participants.

31. 6. Precise description of methodology of the proposed research, including sample size (with justification), type of study design (observational, experimental, pilot, randomized, blinded etc.), intended intervention, dosages of drugs, route of administration, duration of treatment and details of invasive procedures if any. 7.Plan to withdraw or withhold standard therapies in the course of research. 8.Plan for statistical analysis of the study.

32. 9.Procedure for seeking and obtaining informed consent with sample of patient information sheet and informed consent forms in Turkish 10. Safety of proposed intervention and any drug or vaccine to be tested, including results of relevant laboratory, animal and human research. 11. For research involving more than minimal risk, an account of management of such risk or injury.

33. 12. Proposed compensation and reimbursement of incidental expenses and management of research related and unrelated injury/ illness during and after research period. 13. An account of storage and maintenance of all data collected during the trial. 14. Plans for publication of results - positive or negative - while maintaining the privacy and confidentiality of the study participants.

34. 15. A statement on probable ethical issues and steps taken to tackle the same like justification for washout of standard drug, or the use of placebo control.. 16. All other relevant documents related to the study protocol like investigator's brochure for trial on drugs/ devices/ vaccines/ herbal remedies and statement of relevant regulatory clearances. 17.Agreement to comply with national and international Good Clinical Practices (GCP) protocols for clinical trials.

35. 18. Details of Funding agency/ Sponsors and fund allocation. 19. For international collaborative study details about foreign collaborators and documents for review of Health Ministry's Screening Committee(HMSC) or appropriate Committees under other agencies/ authority like Drug Controller General of India (DCGI) 20. For exchange of biological material in international collaborative study a MoU/ Material Transfer Agreement between the collaborating partners. 21.A statement on conflict-of-interest (COI), if any.