3) VARIOUS PHASES) NICAL T Clinical research is done in four phases (1, I, III, and IV), each designed to address different questions. The knowledge gained from onc phasc is assessed before progressing to the next phase. However, research in a particular phase may continue after the drug has progressed to further stages of development. Based upon data gathered from the pre-clinical (animal testing) trials, the sponsor has some estimation of: + The drug's therapeutic effect and dose levels. + Toxicity profile and dose levels. This information is used in the design of Phase I trials. Phase I Clinical Trials: + The first question in drug research is to find out the safety of drug in humans. Phase 1 studies, sometimes called "first in man", starts to answer this question by testing the investigational product in healthy volunteers. «Ifthe drug has a potential for toxic adverse events, it may be given only to subjects with the targeted condition to reduce risks to healthy subjects (i.e, anticancer drugs are never tested in healthy volunteers). «The main purpose of the initial Phase. I studies is to establish a safe dosage range. These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain carly evidence on effectiveness. «During Phase I, sufficient information about the drug's pharmacokinetics (ADME) and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase II studies. + These are generally conducted on 20-80 healthy human volunteers and typically last 3-6 months. Initially, a single small dose is administered to cach volunteer in a hospital-type setting, so that the Scanned with CamScannerEffects of the drug can be closely monitored. In Phase I studies, regulatory bodies (i.e., FDA) can impose a clinical hold (i.c., prohibit the study from proceeding or stop a trial that has started) for reasons of safety, or because ofa sponsor's failurc to accurately disclose the risk of study to investigators, Phase II Clinical Trials: Phase I clinical trial gives valuable information about any adverse reactions and the fate of the drug in the healthy human body, these parameters may be different in patients suffering from the disease which the drug under test is designed to treat. For example, some antibiotics (like benzyl-penicillin) only penetrate into the cerebro-spinal fluid (CSF) if the meninges (the membranes covering the brain and spinal chord) are inflamed whereas penetration is poor in healthy individuals. Phase II clinical trials are conducted on patients. The main question asked by Phase II studies is: "What is the most effective dosage range and is the drug safe within that range?" Phase 1] studies enroll small numbers of subjects, typically 100 to 300 and the trial may last from six months to two years. Subjects have the disease or condition being studied. The primary aims of Phase II cli ical. trials are to establish clinical efficacy, determine the incidence of adverse reactions, define the optimum therapeutic dosage and provide detailed pharmacokinetic and pharmacological data to substantiate the adequate trial of the drug. Phase IIT Clinical Trials: Phase III studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained in Phase II, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug. Phase !II clinical trials may involve several hundred to several thousand patients and lasts 1-5 years. The aims of this phase are to verify the drug's effectiveness and any adverse reactions in a large group of patients over a longer period of exposure, to cstublish safety Scanned with CamScannerand efficacy of drug. Phase Il studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the package insert. Very often Phase III trials involve different patient sub-groups such as children, the elderly and perhaps those with impairments in liver or kidney function. + Inboth Phase II and III, regulatory bodies can impose a clinical hold if study is unsafe (as in Phase 1), or if the protocol is clearly deficient in mecting its stated objectives, Great care is taken to ensure that this determination is not madc in isolation, but reflects current scientific knowledge. regulatory agency experience with the design of clinical trials, and experience with the class of drugs under investigation. Once the phase III, clinical trial has been completed satisfactorily, the drug company is in a position to apply the marketing application to the regulatory authoritics to market the drug. 1 I — [ Sponsor | Steering Data Monitorin aye Committee "| Committee (DMC) ib . Reports/Queries Contact — 3 Research D Data Organization Management —— Management . (CRo) Center Center Data (CRFsyQueries Clinical Study Site Investigators Figure 4 : Trtal Organization New Drug Application (NDA) Following the completion of all three phases of clinical trial, the company analyzes all of the data and files an NDA to FDA, if the data successfully demonstrate safety and effectiveness. The NDA must contain all of the scientific information that the company has gathered. NDA’s typically run 100,000 pages or more. By law, FDA is allowed six months to review an NDA. In almost all cases, the period between the first submission of an NDA and final FDA approval ———— Scanned with CamScannerexceeds that limit, the average NDA review time for new molecular entities approved in 1992 was 29.9 months. Phase IV Clinical Trials (Post-Marketing Surveillance) + Sometimes adverse drug reactions only come to light after the drug has been in the market for a while and has been used by very large numbers of patients. «+ Phase IV Clinical Trials (sometimes referred to as Post-Marketing Surveillance) identifies such problems. Withdrawal of a drug from the market is not an uncommon occurrence- ‘one such case is in 1960's Thalidomide tragedy. Abbreviated New Drug Application (ANDA) « An Abbreviated New Drug Application (ANDA) is submitted to regulatory bodies to obtain the approval to market a generic drug product. It contains data which when, provided for the review and once approved, an applicant may manufacture and market the generic drug product as a low cost alternative. «© Generic drug applications are termed "abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness, Instead, generic applicants must scientifically demonstrate that their product is biocquivalent to innovator. Generic drug application reviewers focus on bioequivalence data, chemistry and microbiology data, plant inspection, and drug labeling information, List of Essential Clinical Trial Documents 1. Protocol . Informed Consent Document(ICD) Investigator’s Brochure(IB) . Case Report Form/Clinical Report Form(CRE) . Source Data/Document(SD) . Regulatory Approval . ERB/IRB/EC/EC Approval Se ANANALN . Advertisement —_—__— oo :.—OO] 0 Scanned with CamScanner9. Financial Agreement 10. Insurance Statement 11.Curriculum Vitae(CV) 12. Laboratory Reference Range 13.Monitoring Report 14. Investigational Product Accountability Log 15.Certificate(s) of Analysis(COA) 16.SAE Report Form 17. Correspondence 18. Queries 19. Clinical Study Report(CSR) Scanned with CamScanner