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Clinical Trail Prof. Dr. Saira Azhar PhD Pharmacy Practice  Introduction Clinical Research  Clinical research is the study of health and illness in people. There are two main types of clinical research: 1. Observational studies and 2. Clinical tri...

Clinical Trail Prof. Dr. Saira Azhar PhD Pharmacy Practice  Introduction Clinical Research  Clinical research is the study of health and illness in people. There are two main types of clinical research: 1. Observational studies and 2. Clinical trials. Observational studies:  Monitor people in normal settings.  Gather information from people and compare changes over time. For example, researchers may ask a group of older adults about their exercise habits and provide monthly memory tests for a year to learn how physical activity is associated with cognitive health.  Observational studies do not test a medical intervention, such as a drug or device, but may help identify new treatments or prevention strategies to test in clinical trials. 2 Clinical trial  A clinical trial is a systematic process intended to determine the safety and efficacy of a drug/device in treating/preventing/diagnosing a disease or a medical condition.  Clinical trial includes various phases that include phase 0 (micro-dosing studies), phase 1, phase 2, phase 3, and phase 4.  These trials are the primary way researchers determine if a new form of treatment or prevention, such as a new drug, diet, or medical device (for example, a pacemaker), is safe and effective in people.  A clinical trial is often designed to learn if a new treatment is more effective or has less harmful side effects than existing treatments. 3 Aims of clinical research include:  Testing ways to diagnose a disease early, sometimes before there are symptoms.  Finding approaches to prevent a health problem, including those who are healthy but at increased risk of developing a disease.  Improving quality of life for people with a life- threatening disease or chronic health problem.  Studying the role of caregivers or support groups 4 Clinical Trial of Drug Substances  Sets of tests are required to determine the safety and efficacy of pharmaceutical compounds, drugs, and treatments.  Research studies/programs are conducted to evaluate the drug to establish drug safety and efficacy. 5 Clinical Trial of Drug Substances  To discover or verify the clinical, pharmacological, or other pharmacodynamics effects of an investigational product  To identify any adverse reactions to an investigational product, (i.e. Phase I to Phase IV studies)  To study the absorption, distribution, metabolism and excretion of an investigational product to ascertain its safety and efficacy. 6 What is an Investigational Product?  Investigational products are experimental therapeutic goods with any type of active substance, including pharmaceutical, biological, herbal and homeopathic products, and medical devices.  It may be a registered drug or enlisted product, or a placebo.  Authorized products (registered/enlisted) may be used in accordance with the terms of the registration or enlistment as applicable, or  Used differently, e.g., at a higher dose, for a new indication or when packaged in a different container closure system. 7 Regulation of Clinical Trials in Pakistan.  The conduction of clinical trials in Pakistan is subjected to various regulatory control.  To ensure the safety of participants, and  To ensure that the experimental design of clinical study is appropriate to obtain valid data without exposing participants to unnecessary risks.  The Drug Regulatory Authority of Pakistan (DRAP) is mandated to regulate the clinical trials and to implement internationally recognized standards as adopted by the World Health Organization.  The Authority with the approval of Federal Government, has notified the Bio-study Rules, 2017 for regulation of the clinical trials activities in the country. 8  Clinical Studies Committee (CSC)  The CSC is responsible for assessing that rights, safety and well- being of trial participants are protected before the start of clinical trials, and the data generated will be reliable and strong.  This committee reviews the clinical studies protocols and monitors the compliance to Good Clinical Practices (GCP) for the conduction of clinical trials and can cause inspections of clinical trial sites.  In addition to CSC, Division of Pharmacy Services, Division of Quality Assurance & Lab Testing, and the National Bioethics Committee of Pakistan are also involved in regulatory oversight of various activities of clinical trials.  The decisions of CSC are available in the form of Minutes of Meetings on the website.  A list of Rejected applications for clinical trials is also uploaded regularly. 9 Authorization for Conduct of Clinical Trials  The application for approval of Clinical Trial Site(s) (CTS) should be from the Principal Investigator (PI) or Co-Principal Investigator (Co-PI) working at the applied site.  Whereas for Clinical Trials Sponsor or the Principal investigator of the study may apply to seek authorization to conduct a clinical trial in Pakistan.  Application for approval of Clinical trial site and conduct of clinical trials are required to be submitted to the Secretary, Clinical Studies Committee, Division of Pharmacy Services, DRAP. 10 Authorization for Conduct of Clinical Trials  DRAP has also published Guidelines to Conduct Clinical Research in Pakistan to assist applicants in making new applications for clinical trials on therapeutic goods, or any subsequent submissions and to explain the regulatory requirements to be fulfilled during the clinical trials.  This Guidance document also explains the procedure for submission, review, evaluation and approval of applications for the conduct of clinical trials.  In addition, application forms and checklists to fill out the requirements and documentation to be submitted by the applicants for clinical trials are also available on their website. 11  Ethical Approval of Clinical Trials  National Bioethics Committee (NBC) is a notified body on bioethics working under the Ministry of National Health Services, Regulation and Coordination.  NBC is mandated to uphold bioethical principles in all sectors of healthcare in the country.  All clinical trials are required to seek prior approval from the National Bioethical Committee under the Rules 9 of Bio-Study Rules, 2017.  The primary scope of information assessed by the NBC relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial,  NBC also assess the scientific basis and ethics of clinical trials, qualifications of researchers, and other relevant considerations to the corresponding ethical issues, laws, and regulations. 12  Drug Development Duration Time Frame Activities About 3 to 4 Years 1. Drug discoveries 2. Synthesis and selection of formulations. 3. Pre clinical Pharmacology and toxicology About 7 to 8 Years Clinical Development Onwards up to total 15 years 1. Data Processing 2. Regulatory submission 3. Product registration Marketing. 13 14 The stages of clinical trials for pharmaceutical products 15 Clinical trials around the world  According to the World Health Organization (WHO), a clinical trial is defined as ‘any research study that prospectively assigns human participants…to one or more health-related interventions to evaluate the effects on health outcomes’ these ‘interventions’ include drugs, as well as biological products, medical devices and surgical procedures among others. 16 Clinical trials around the world  Every drug that can be prescribed for patients around the world has been approved by authorities, such as the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and Australian Therapeutic Goods Administration (TGA), after completing all the required stages of clinical trials.  The process undertaken by pharmaceutical companies for drug candidates consists of a series of phases to ensure the product is safe and effective at treating the disease it is indicated for. 17 Stages of clinical trials  The stages of clinical trials start with pre-clinical studies and progress through Phase I, Phase II and Phase III.  Occasionally phase 0 studies are carried out before phase I and phase IV studies are undertaken after the drug has been approved and launched on the market. Pre-clinical studies  Before a drug candidate can begin the clinical trial process, it is tested by its manufacturer through pre-clinical studies for toxicity, otherwise known as its ability to cause serious harm, as well as pharmacokinetic information.  Dosing is also tested during the pre-clinical research period. This is done using both in vitro (on cell cultures) and in vivo (on animals) methods, as well as occasionally with the help of computer models. 18  Stages of clinical trials Phase 0  After exhibiting low toxicity and completing pre-clinical studies, some drugs go into the phase 0 stage of the clinical trial, while others skip this stage and progress directly to phase I.  Phase 0 is also commonly known as human micro-dose studies because it involves a very small group of participants, usually between ten and 15, who have been given a low, sub-therapeutic dose of the drug.  This low dose will not be able to treat the condition the drug is indicated for, instead, it allows companies to clarify that the drug behaves in humans in the same way as expected from the laboratory, pre-clinical research stage.  Some pharmaceutical companies also use this stage to decide which of their candidates has the best pharmacokinetic effect in humans and to visualize specific therapeutic targets. 19  Stages of clinical trials Phase I  Phase I trials are the first full human study the drug will be subject to and therefore they primarily focus on its safety and tolerability.  This stage involves a slightly larger number of participants than phase 0 studies, often between 20 and 100 subjects.  This stage of the clinical trial is often organized as a dose escalation study – where the first small group of participants receive a very low dose of the drug. If this is well tolerated, the dose is increased for the next cohort, and so on.  This helps the pharmaceutical company to more accurately calculate the best dose to continue testing in the next phase.  Phase I trials are usually conducted using healthy volunteers, however, patients with the indicated disease may be used if the mechanism of action of the drug suggests it may not be tolerated in healthy people. 20  Stages of clinical trials Phase II  If a drug is well tolerated in Phase I, it progresses to Phase II. In this stage, the number of patients is increased once more, with as many as several hundred participants being used to gauge the efficacy of the drug.  During this test period, researchers can also pinpoint related side effects and continue safety assessments from previous studies.  Phase II clinical studies also help to determine the best therapeutic doses for the next phase; sometimes this stage is designed to be divided into two parts so that dosing requirements can be specifically focused upon. 21  Stages of clinical trials Phase III  Phase III trials concentrate on discovering the efficacy of the drug and differ from phase I and phase II studies because they occur over a longer period, involve more patient participants and happen under conditions that reflect daily clinical life.  Participants in phase III trials are often randomized into two groups – with one taking the experimental drug candidate, and the other either taking a placebo or the standard treatment for the indicated disease.  This method allows pharmaceutical companies to evaluate if their drug contributes to the treatment of the indicated disease in practice.  It is common for phase III trials to be separated into two sub-stages – phase IIIA and phase IIIB.  Drug manufacturers often submit applications for regulatory approval after phase IIIA studies and, whilst waiting for approval, they undertake phase IIIB studies to obtain further safety data and further support their claims about the drug. 22 Stages of clinical trials Phase IV  Following approval from national regulatory authorities, some drugs continue in the clinical trial process and enter phase IV, which is also known as a post-marketing surveillance trial.  Phase IV studies allow drug companies to uncover more information about the side effects and safety of the drug.  It also provides an opportunity for researchers to learn the longer-term risks and benefits.  They are sometimes required by regulatory authorities or by investors into the drug. 23  Role of pharmacists in Clinical Research.  Pharmacists have paved their role as valuable partners in clinical research by providing a path for education about clinical trial participation and incorporating clinical trial referrals into their patient care services.  Pharmacists are providing the management of investigational products and medicines to participate in trial feasibility.  Once trials begin, they are responsible for supply ordering, handling, storage, dispensing, and accountability.  Pharmacists are key contributors to bringing new treatments and medications to patients and improving their quality of life.  Some use their experience and expertise as a pharmacist to expand their involvement in clinical research by becoming clinical research coordinators or principal investigators. 24 25