Clinical Trials - An Introduction

CLINICAL TRIALS,[object Object],INTRODUCTORY CONCEPTS,[object Object],1,[object Object]

TOPICS TO BE DISCUSSED,[object Object],Clinical Trials – Definitions, Importance of trials ,[object Object],Role of Clinical trials in Clinical Product Development ,[object Object],Different types of Clinical trials and their phases,[object Object],Important Regulations and Guidelines – ICH & GCP,[object Object],Design of a Clinical Trial,[object Object],Randomization and Blinding,[object Object],Data Management in clinical trials – Standards (CDISC, SDTM),[object Object],Overview of Analysis of Clinical Trials,[object Object],2,[object Object]

CLINICAL TRIALS,[object Object],DEFINITIONS AND IMPORTANCE ,[object Object],3,[object Object]

WHAT EXACTLY ARE CLINICAL TRIALS?,[object Object],Clinical trials are scientific investigations that examine and evaluate safety and efficacy of different therapies in human subjects. There are various definitions available as different individuals have tried to which try to capture the essence of clinical trials at different times, e.g.,[object Object],Meinert (1986) indicates that a clinical trial is a research activity that involves administration of a test treatment to some experimental unit in order to evaluate the treatment.,[object Object],Piantadosi (1997) simply defined a clinical trial as an experimental testing of medical treatment on human subject.,[object Object],The Code of Federal Regulations (CFR)* defines a clinical trial as the clinical investigation of a drug that is administered or dispensed to, or used involving one or more human subjects (21 CFR 312.3)*. ,[object Object],Three important key words in these definitions of clinical trials are experimental unit, treatment, and evaluation of the treatment.,[object Object],4,[object Object]

THE THREE IMPORTANT KEY WORDS,[object Object],Experimental Unit,[object Object],An experimental unit is usually referred to as a subject from a targeted population under study. Therefore the experimental unit is usually used to specify the intended study population to which the results of the study are inferred. For example, the intended population could be patients with certain diseases at certain stages or healthy human subjects.,[object Object],Treatment,[object Object],In clinical trials a treatment can be a placebo or any combinations of a new pharmaceutical identity (e.g., a compound or drug), a new diet, a surgical procedure, a diagnostic test, a medial device, a health education program, or no treatment. Other examples include surgical excision, radiotherapy, and chemotherapy as a combination of surgical procedure and drug therapy for breast cancer; magnetic resonance imaging (MRI) with a contrast imaging agent as a combination of diagnostic test and a drug for enhancement of the efficacy of a diagnostic test.,[object Object],Evaluation,[object Object],In addition to the traditional evaluation of effectiveness and safety of a test treatment, clinical trials are also designed to assess quality of life, pharmacogenomics, and pharmacoeconomics such as cost-minimization, cost-effectiveness, and cost-benefit analyses to human subjects associated with the treatment under study. It is therefore recommended that clinical trials should not only evaluate the effectiveness and safety of the treatment but also assess quality of life, impact of genetic factors, pharmacoeconomics, and outcomes research associated with the treatment.,[object Object],5,[object Object]

21 CFR (CODE OF FEDERAL REGULATIONS),[object Object], The Code of Federal Regulations (CFR) is the codification of the general and permanent rules and regulations (sometimes called administrative law) published in the Federal Register by the executive departments and agencies of the Federal Government of the United States.,[object Object], Title 21 is the portion of the Code of Federal Regulations that governs food and drugs within the United States for the Food and Drug Administration (FDA). It is divided into 3 chapters:,[object Object],[object Object],Important sections in relation to Clinical Trials are:,[object Object],[object Object]

54 Financial Disclosure by Clinical Investigators

56 Institutional Review Boards that oversee clinical trials

58 Good Laboratory Practices (GLP) for nonclinical studies

312 Investigational New Drug Application

Chapter 2 - Drug Enforcement Administration, Department of Justice

Chapter 3 - Office of National Drug Control Policy 6,[object Object]

SPONSORS FOR CLINICAL TRIALS IN THE U.S.,[object Object],Pharmaceutical and Biotechnology companies – which must prove the safety and effectiveness of their medicines before they can be marketed ,[object Object],National Institutes of Health (NIH) – whichare funded by the US Government. The National Cancer Institute (NCI), which is a part of the NIH, sponsors a good portion of the thousands of cancer clinical trials going on at any point of time.,[object Object],Other government agencies, including parts of the Department of Veterans Affairs and the Department of Defence, also sponsor cancer clinical trials.,[object Object],University Medical Schools and Hospitals, or any other medical research centers.,[object Object],Some non-profit organizations and even individual or group of physicians also sometimes sponsor clinical trials.,[object Object],7,[object Object]

SIGNIFICANT HISTORICAL EVENTS FOR CLINICAL TRIALS,[object Object],8,[object Object]

THE BIGGER LANDSCAPE,[object Object],ROLE IN CLINICAL PRODUCT DEVELOPMENT,[object Object],9,[object Object]

CLINICAL PRODUCT DEVELOPMENT - PHASES,[object Object],PRECLINICAL RESEARCH,[object Object],CLINICAL,[object Object], RESEARCH,[object Object],NDA ,[object Object],REVIEW,[object Object],RATIONAL DRUG DESIGN,[object Object],PHASE 1,[object Object],PHASE 2,[object Object],SYNTHESIS & PURIFICATION,[object Object],PHASE 3,[object Object],ANIMAL,[object Object],TESTING,[object Object],ACCELERATED DEVELOPMENT/REVIEW,[object Object],TREATMENT IND,[object Object],SHORT TERM,[object Object],PARALLEL TRACK,[object Object],LONG TERM,[object Object],INSTITUTIONAL REVIEW BOARDS,[object Object],LAUNCH,[object Object],NDA SUBMITTED,[object Object],SPONSOR DEFENCE,[object Object],IND SUBMITTED,[object Object],SPONSOR/FDA MEETINGS ,[object Object],REVIEW DECISION,[object Object],ADVISORY COMMITTEES ,[object Object],10,[object Object]

IMPORTANT TERMS,[object Object],INVESTIGATIONAL NEW DRUG (IND): A new drug, antibiotic drug, or biological drug that is used in a clinical investigation. It also includes a biological product used in vitro for diagnostic purposes.,[object Object],INSTITUTIONAL REVIEW BOARD (IRB): 1. A committee of physicians, statisticians, researchers, community advocates, and others that ensures that a clinical trial is ethical and that the rights of study participants are protected. All clinical trials in the U.S. must be approved by an IRB before they begin. 2. Every institution that conducts or supports biomedical or behavioral research involving human participants must, by federal regulation, have an IRB that initially approves and periodically reviews the research in order to protect the rights of human participants. It is similar to the Independent Ethics Committee (IEC) outside the United States.,[object Object],NEW DRUG APPLICATION (NDA): An application submitted by the manufacturer of a drug to the FDA - after clinical trials have been completed - for a license to market the drug for a specified indication.,[object Object],TREATMENT IND: IND stands for Investigational New Drug application, which is part of the process to get approval from the FDA for marketing a new prescription drug in the U.S. It makes promising new drugs available to desperately ill participants as early in the drug development process as possible. Treatment INDs are made available to participants before general marketing begins, typically during Phase III studies. To be considered for a treatment IND a participant cannot be eligible to be in the definitive clinical trial.,[object Object],11,[object Object]

RATIONAL DRUG DESIGN,[object Object],Drugs work by interacting with target molecules (receptors) in our bodies and altering their activities in a way that is beneficial to our health. In some cases, the effect of a drug is to stimulate the activity of its target (an agonist) while in other cases the drug blocks the activity of its target (an antagonist).,[object Object],Throughout most of the history of medical science, new drugs have been discovered though a process of trial-and-error or simply through sheer luck. As the demand for new and more effective drugs has increased, a new method of drug development called Rational Drug Design has begun to replace the old methods. In rational drug design, biologically active compounds are specifically designed or chosen to work with a particular drug target. Rational drug design often involves the use of molecular design software, which researchers use to create three-dimensional models of drugs and their biological targets. For this reason, the process is also known as computer-aided drug design.,[object Object],There are two major types of drug design. The first is referred to as ligand-based drug design and the second, structure-based drug design.,[object Object],Ligand based - Ligand-based drug design (or indirect drug design) relies on knowledge of other molecules that bind to the biological target of interest. These other molecules may be used to derive a pharmacophore model which defines the minimum necessary structural characteristics a molecule must possess in order to bind to the target. ,[object Object],Structure based - Structure-based drug design (or direct drug design) relies on knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography or NMR spectroscopy.,[object Object],12,[object Object]

EXAMPLE OF AN ANTICANCER DRUG IN ACTION,[object Object],Mechanism of Action - Imatinib mesylate (Gleevec) in Chronic Myeloid Leukemia,[object Object],13,[object Object]

STRATEGIES OF STRUCTURE-BASED DRUG DESIGN,[object Object],STRATEGY A STRATEGY B,[object Object],NO,[object Object],NO YES,[object Object],YES YES NO,[object Object],PHARMACOPHORE** IDENTIFICATION,[object Object],ACTIVE SITE IDENTIFICATION,[object Object],PHARMACOPHORE MODIFICATION,[object Object],LIGAND FRAGMENTS GROWING,[object Object],COMPLETE GROWING,[object Object],FIT FOR RECEPTOR,[object Object],FIT FOR RECEPTOR,[object Object],CHANGE FRAGMENT,[object Object],POTENTIAL DRUG,[object Object],POTENTIAL DRUG,[object Object],**A pharmacophore was first defined by Paul Ehrlich in 1909 as "a molecular framework that carries (phoros) the essential features responsible for a drug’s (=pharmacon's) biological activity" (Ehrlich. Dtsch. Chem. Ges. 1909, 42: p.17),[object Object],14,[object Object]

CLASSIFICATION,[object Object],DIFFERENT TYPES AND PHASES,[object Object],15,[object Object]

DIFFERENT TYPES OF CLINICAL TRIALS,[object Object],[object Object]

Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vaccines, vitamins, minerals, or lifestyle changes.

Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition. Diagnostic trials usually include people who have signs or symptoms of the disease or condition being studied.

Screening (Early detection) trials test the best way to detect certain diseases or health conditions.

Quality of Life trials (or Supportive Care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness.16,[object Object]

DIFFERENT PHASES OF CLINICAL TRIALS,[object Object],Clinical trials involving new drugs are commonly classified into four phases (I, II, III and IV). Each phase of the drug approval process is treated as a separate clinical trial. If the drug successfully passes through Phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV are 'post-approval' studies. Before pharmaceutical companies start clinical trials on a drug, they conduct extensive pre-clinical studies.,[object Object],THE PHASES:,[object Object],PRE-CLINICAL - It involves in vitro (test tube or cell culture) and in vivo (animal) experiments using wide-ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an investigational new drug (IND).,[object Object],PHASE I TRIALS: Initial studies to determine the metabolism and pharmacologic actions of drugs in humans, the side effects associated with increasing doses, and to gain early evidence of effectiveness; may include healthy participants and/or patients. ,[object Object],PHASE II TRIALS: Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks. ,[object Object],PHASE III TRIALS: Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labelling. ,[object Object],PHASE IV TRIALS: Post-marketing studies to delineate additional information including the drug's risks, benefits, and optimal use. ,[object Object],17,[object Object]

PRE-CLINICAL TRIALS,[object Object],As described earlier, a preclinical trial involves in vitro (test tube or cell culture) and in vivo (animal) experiments using wide-ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic information.,[object Object],Steps involved in designing a Pre-Clinical Trial/Study: ,[object Object],Identifying a Drug Target: Alldrugstarget specific points in biochemical pathways. Almost all illnesses except infectious diseases are caused by problems associated with specific biochemical pathways. Identifying the appropriate target step in the biochemical pathway is critical and can determine the chances of success of the prospective drug molecule.,[object Object],Developing a Bioassay: A bioassay is a “live” system that is devised to measure the effects of a drug. It varies from a cell or tissue culture system to organs or even a whole living being. For example, a zebra fish embryo can be used to observe the effects of drugs on bone density, blood vessel growth, among other systems. ,[object Object],Screening the drug in the Bioassay: This is a screening test done with the bioassay to determine the safety and effectiveness of the molecule. The drug must clear this step.,[object Object],Establishing effective and toxic doses: This step involves establishing the safe and toxic dose ranges. Future studies take cues from here about the dose ranges to be tested in humans.,[object Object],Filing for an approval as an IND (Investigational New Drug): After all these steps are cleared the drug is fit for an application to the FDA as an IND.,[object Object],18,[object Object]

PHASE 1 CLINICAL TRIALS,[object Object],Phase 1 Clinical Trials are the earliest trials in the life of a new drug or treatment. They are usually small trials, recruiting anything up to about 30 patients (mainly healthy volunteers), although often a lot less. These trials are often conducted in an inpatient clinic, where the subject can be observed by full-time staff. The subject who receives the drug is usually observed until several half-lives of the drug have passed.,[object Object],These trials are designed to obtain the following information:,[object Object],Safety – Determine the most significant adverse events in human subjects.,[object Object],Tolerability – The safe dose range is determined by dose escalations and corresponding serial lab tests.,[object Object],Pharmacokinetics – How the drug molecule is absorbed in the body and its metabolites are distributed and eliminated from the body,[object Object],Pharmacodynamics – The effects of the drug on the body, i.e. how the effects of the drug vary with the plasma concentration.,[object Object],Types of Phase 1 trials:,[object Object],SAD – Single Ascending Dose,[object Object],MAD – Multiple Ascending Dose,[object Object],Food Effect – Effects of food substances on the absorption of the drug,[object Object],19,[object Object]

PHASE 2 CLINICAL TRIALS,[object Object],Phase 2 Clinical Trials (typically Therapeutic Exploratory) are controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks. ,[object Object],Once the initial safety of the study drug has been confirmed in Phase I trials, Phase II trials are performed on larger groups (20-300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. Studies in Phase II are typically conducted in a group of patients who are selected by relatively narrow criteria, leading to a relatively homogeneous population and are closely monitored. ,[object Object],An important goal for this phase is to determine the dose(s) and regimen for Phase III trials. Early studies in this phase often utilise dose escalation designs to give an early estimate of dose response and later studies may confirm the dose response relationship for the indication in question by using recognised parallel dose-response designs. Confirmatory dose response studies may be conducted in Phase II or left for Phase III. Doses used in Phase II are usually but not always less than the highest doses used in Phase I.,[object Object],Additional objectives of clinical trials conducted in Phase II may include evaluation of potential study endpoints, therapeutic regimens (including concomitant medications) and target populations (e.g. mild versus severe disease) for further study in Phase II or III. These objectives may be served by exploratory analyses, examining subsets of data and by including multiple endpoints in trials. ,[object Object],Types: Phase II studies are sometimes divided into Phase IIA and Phase IIB.,[object Object],Phase IIA is specifically designed to assess dosing requirements (how much drug should be given).,[object Object],Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s),[object Object],20,[object Object]

PHASE 3 CLINICAL TRIALS,[object Object],Phase III Clinical Trials usually are considered to begin with the initiation of studies in which the primary objective is to demonstrate, or confirm therapeutic benefit. These trials are, therefore, most typically of Therapeutic Confirmatory type.,[object Object],Studies in Phase III are designed to confirm the preliminary evidence accumulated in Phase II that a drug is safe and effective for use in the intended indication and recipient population. These studies are intended to provide an adequate basis for marketing approval. ,[object Object],Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions.,[object Object],It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies in this phase are by some companies categorised as "Phase IIIB studies.“,[object Object],Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities in different countries. They will review the submission, and, it is hoped, give the sponsor approval to market the drug.,[object Object],21,[object Object]

PHASE 4 CLINICAL TRIALS,[object Object],A Phase IV Clinical trial is also known as Post Marketing Surveillance Trial. Phase IV trials involve the safety surveillance (Pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials).,[object Object],Phase IV begins after drug approval and these studies are also known as Therapeutic use studies. Therapeutic use studies go beyond the prior demonstration of the drug’s safety, efficacy and dose definition. They are studies that were not considered necessary for approval but are often important for optimising the drug's use. ,[object Object],The main rationale behind conducting Phase IV trials is :,[object Object],In prior clinical trials, up to Phase 3, patients are selected and limited in number,[object Object],Conditions of use in trials differ from those in clinical practice,[object Object],Duration of trials is limited,[object Object],Information about rare but serious adverse reactions, chronic toxicity, use in special groups (such as children, the elderly or pregnant women) or drug interactions is often not available.,[object Object],22,[object Object]

CORRELATION BETWEEN DEVELOPMENT PHASES AND TYPES OF STUDY,[object Object],PROGRESS,[object Object],TIME,[object Object],FREQUENTLY DONE,[object Object],SOMETIMES DONE,[object Object],23,[object Object]

IMPORTANT GUIDELINES,[object Object],ICH AND GCP,[object Object],24,[object Object]

IMPORTANT GUIDELINES – ICH ,[object Object],ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use) is a unique undertaking that brings together the drug regulatory authorities and the pharmaceutical industry of Europe, Japan and the United States.,[object Object],Regulatory harmonisation offers many direct benefits to both regulatory authorities and the pharmaceutical industry with beneficial impact for the protection of public health. Key benefits include: ,[object Object],Preventing duplication of clinical trials in humans and minimising the use of animal testing without compromising safety and effectiveness; ,[object Object],Streamlining the regulatory assessment process for new drug applications; ,[object Object],Reducing the development times and resources for drug development.,[object Object],This regulatory harmonization is achieved by developing guidelines. These guidelines are divided into four categories as follows:,[object Object],Q – Quality Guidelines: Defining relevant thresholds for impurities testing and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP) risk management.,[object Object],S – Safety Guidelines: ICH has produced a comprehensive set of safety guidelines to uncover potential risks like carcinogenicity, genotoxicity and reproductive toxicity.,[object Object],E – Efficacy Guidelines: The work carried out by ICH under the Efficacy heading is concerned with the design, conduct, safety and reporting of clinical trials.,[object Object],M – Multidisciplinary Guidelines: Those are the cross-cutting topics which do not fit uniquely into one of the Quality, Safety and Efficacy categories. It includes the ICH medical terminology (MedDRA) and the Common Technical Document (CTD) ,[object Object],25,[object Object]

EFFICACY GUIDELINES,[object Object],Clinical Safety E1 – E2F,[object Object],Clinical Study Reports E3,[object Object],Dose-Response Studies E4,[object Object],Ethnic Factors E5,[object Object],Good Clinical Practice E6,[object Object],Clinical Trials E7 – E11,[object Object],Guidelines for Clinical Evaluation by Therapeutic Category E12,[object Object],Clinical Evaluation E14,[object Object],Pharmacogenomics E15 – E16,[object Object],Joint Safety/Efficacy Topic M3,[object Object],26,[object Object]

PRINCIPLES OF GCP (GOOD CLINICAL PRACTICE),[object Object],Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).,[object Object],Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.,[object Object],The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.,[object Object],The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.,[object Object],Clinical trials should be scientifically sound, and described in a clear, detailed protocol.,[object Object],A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favourable opinion. ,[object Object],The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.,[object Object],27,[object Object]

PRINCIPLES OF GCP (CONTD.),[object Object],Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).,[object Object],Freely given informed consent should be obtained from every subject prior to clinical trial participation.,[object Object],All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.,[object Object],The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).,[object Object],Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.,[object Object],Systems with procedures that assure the quality of every aspect of the trial should be implemented.,[object Object],28,[object Object]

DESIGN OF STUDIES,[object Object],BASIC CONSIDERATIONS,[object Object],29,[object Object]

DESIGN – BASIC CONSIDERATIONS,[object Object],The basic considerations that need to be kept in mind while designing a trial are as follows:,[object Object],Objective of the Trial: The medical questions that need to be answered should be clearly formulated so that necessary resources such as the number of subjects, study duration, study endpoints for evaluation of the study drug, facility/equipment, and clinical personnel can be determined in order to provide an accurate and reliable statistical/clinical inference for addressing these questions. The objectives may be more than one and may be segregated into primary and secondary as demonstrated by the example of Lung Cancer trial below: ,[object Object],Primary Objectives - This is a randomized, parallel-group trial to demonstrate that the one-year survival of the patients with pre-treated advanced (Stage IIIB/IV) non-small-cell lung cancer (NSCLC) receiving the oral investigational drug is not inferior to those receiving intravenous (IV) docetaxel. ,[object Object],Secondary Objectives - Secondary objectives of the trial are to evaluate overall survival, time to progression, response rate, time to response, improvement in quality of life, and qualitative and quantitative toxicities.,[object Object],Target population and patient selection: In clinical trials a set of eligibility criteria is usually developed to define the target patient population from which qualified (or eligible) patients can be recruited to enrol the studies. Typically a set of eligibility criteria consists of a set of inclusion criteria and a set of exclusion criteria. The set of inclusion criteria is used to roughly outline the target patient population, while the set of exclusion criteria is used to fine-tune the target patient population by removing the expected sources of variability. To be eligible for the intended study, patients must meet all the inclusion criteria. The next slide shows an example of the eligibility criteria required for a trial involving an anti-infective agent. ,[object Object],30,[object Object]

ELIGIBILITY CRITERIA FOR ANTI-INFECTIVE AGENTS,[object Object],A. Inclusion Criteria,[object Object],1. Hospitalized patients aged 18 years or older.,[object Object],2. An oral temperature greater than 38.5°C once or greater than 38°C on two or more occasions during a 12-hour period.,[object Object],3. Fewer than 500 absolute neutrophils (polymorphonuclear and segmented) per mm3, or patients presenting with between 500 and 1000 absolute neutrophils per mm3, whose counts are anticipated to fall below 500 per mm3 within 48 hours because of antecedent therapy.,[object Object],B. Exclusion Criteria,[object Object],1. History of hypersensitivity to a cephalosporin or penicillin.,[object Object],2. Pregnant or breast-feeding.,[object Object],3. Requiring other systemic antibacterial drugs concomitantly except for intravenous vancomycin.,[object Object],4. Creatinine clearance 15 mL/min or requiring hemodialysis or peritoneal dialysis.,[object Object],5. History of positive antibody test for HIV.,[object Object],6. A severe underlying disease such as meningitis, osteomyelitis, or endocarditis.,[object Object],7. Patients undergoing bone marrow transplantation or stem cell harvesting and infusion.,[object Object],8. Any other condition that in the opinion of the investigator(s) would make the patient unsuitable for enrollment.,[object Object],31,[object Object]

DESIGN – BASIC CONSIDERATIONS (contd.) ,[object Object],SELECTION OF CONTROLS: In clinical trials, bias and variability can occur in many ways depending on the experimental conditions. These bias and variability will have an impact on the accuracy and reliability of statistical and clinical inference of the trials. Uncontrolled (or non-comparative) studies are rarely of value in clinical research, since definitive efficacy data are unobtainable and data on adverse events can be difficult to interpret.,[object Object], FDA requires that adequate well-controlled clinical trials be conducted to provide an unbiased and valid evaluation of the effectiveness and safety of study medicines. The purpose of a well-controlled study is not only to eliminate bias but also to minimize the variability, and consequently to improve the accuracy and reliability of the statistical and clinical inference of the study.,[object Object],STATISTICAL CONSIDERATIONS: At the planning stage some statistical considerations regarding the manner in which the data will be tabulated and analyzed at the end of the study should be carefully considered. These considerations include the primary and secondary response variables, the criteria for efficacy and safety assessment, sample size estimation, possible interim analysis and data monitoring, and statistical and clinical inference. ,[object Object],OTHER CONSIDERATIONS: In addition to these considerations, some other issues are dependent on individual trials e.g. treatment duration, patient compliance, missing value, and drop outs. ,[object Object],32,[object Object]

DIFFERENT DESIGNS OF TRIALS,[object Object],Parallel Group Design: A parallel group design is a complete randomized design in which each patient receives one and only one treatment in a random fashion. Basically there are two types of parallel group design for comparative clinical trials, namely, group comparison (or parallel-group) designs and matched pairs parallel designs. The simplest group comparison parallel group design is the two-group parallel design which compares two treatments (e.g., a treatment group vs. a control group). Each treatment group usually, but not necessarily, contains approximately the same number of patients. ,[object Object],Run-in Periods,[object Object], Before patients enter a clinical trial, a run-in (or lead-in) period of placebo, no active treatment, dietary control, or active maintenance therapy (e.g., diuretic and/or digoxin in heart failure studies) is usually employed prior to randomization. The inclusion of a run-in period prior to the active treatment has the following advantages:,[object Object],1. It acts as a washout period to remove eﬀects of previous therapy.,[object Object],2. It can be used to obtain baseline data and to evaluate if patient fulﬁls study entry criteria.,[object Object],3. It can be used as a training period for patients, investigators, and their staff.,[object Object],4. It helps in identifying placebo responders.,[object Object],5. It provides useful information regarding patient compliance.,[object Object],6. It can be used to estimate and compare the magnitude of possible placebo effects between groups.,[object Object],33,[object Object],TEST,[object Object],RANDOMIZATION,[object Object],RUN IN,[object Object],PATIENTS,[object Object],CONTROL A,[object Object],CONTROL B,[object Object]

DIFFERENT DESIGNS OF TRIALS - CONTD,[object Object],Crossover Design: In the crossover design, each subject is randomised to a sequence of two or more treatments, and hence acts as his own control for treatment comparisons. This simple manoeuvre is attractive primarily because it reduces the number of subjects and usually the number of assessments needed to achieve a specific power, sometimes to a marked extent. In the simplest 2×2 crossover design each subject receives each of two treatments in randomised order in two successive treatment periods, often separated by a washout period. The most common extension of this entails comparing n(>2) treatments in n periods, each subject receiving all n treatments. Numerous variations exist, such as designs in which each subject receives a subset of n(>2) treatments, or ones in which treatments are repeated within a subject. ,[object Object],I II,[object Object],STANDARD TWO-SEQUENCE, TWO-PERIOD CROSSOVER DESIGN,[object Object],34,[object Object],PERIOD,[object Object],TEST,[object Object],CONTROL,[object Object],SEQUENCE A,[object Object],RANDOMIZATION,[object Object],WASHOUT,[object Object],PATIENTS,[object Object],CONTROL,[object Object],TEST,[object Object],SEQUENCE B,[object Object]

DIFFERENT DESIGNS OF TRIALS - CONTD,[object Object],TITRATION DESIGNS,[object Object],For phase I safety and tolerance studies, Rodda et al. (1988) classify traditional designs as follows:,[object Object],1. Rising single-dose design.,[object Object],2. Rising single-dose crossover design.,[object Object],3. Alternative-panel rising single-dose design.,[object Object],4. Alternative-panel rising single-dose crossover design.,[object Object],5. Parallel-panel rising multiple-dose design.,[object Object],6. Alternative-panel rising multiple-dose design. ,[object Object],FACTORIAL DESIGNS: ,[object Object],In a factorial design two or more treatments are evaluated simultaneously through the use of varying combinations of the treatments. The simplest example is the 2×2 factorial design in which subjects are randomly allocated to one of the four possible combinations of two treatments, A and B say. These are: A alone; B alone; both A and B; neither A nor B. In many cases this design is used for the specific purpose of examining the interaction of A and B. The statistical test of interaction may lack power to detect an interaction if the sample size was calculated based on the test for main effects. This consideration is important when this design is used for examining the joint effects of A and B, in particular, if the treatments are likely to be used together.,[object Object],35,[object Object]

RANDOMIZATION ANDBLINDING,[object Object],36,[object Object]

RANDOMIZATION,[object Object],Randomization is a process in which the study subjects, after assessment of eligibility and recruitment, but before the intervention to be studied begins, are randomly allocated to receive one or other of the alternative treatments under study. ,[object Object],Some ethical considerations may arise as some subjects receive the treatment under study while the remaining receive the standard treatment or the placebo. But it is to be noted that before the study data is analyzed, no one knows whether the treatment under investigation is more effective than the standard treatment or less effective compared to the placebo, as the case may be for the individual trial under consideration.,[object Object],The benefits of randomization are as follows:,[object Object],It eliminates selection bias .,[object Object],It eliminates confounding by adjusting for co-variates.,[object Object],It facilitates blinding of the identity of treatments from investigators, participants, and assessors.,[object Object],It permits the use of probability theory to express the likelihood that any difference in outcome between treatment groups merely indicates chance.,[object Object],Different randomization procedures are there like simple randomization, restricted randomization and adaptive randomization. ,[object Object],37,[object Object]

CONSORT 2010 FLOW DIAGRAM,[object Object],38,[object Object],Assessment for eligibility,[object Object],Enrollment,[object Object],Excluded,[object Object],Randomization,[object Object],Allocation,[object Object],TEST,[object Object],CONTROL,[object Object],Allocated to Intervention,[object Object],Allocated to Intervention,[object Object],Did not receive,[object Object],Did not receive,[object Object],Received Intervention,[object Object],Received Intervention,[object Object],Follow-Up,[object Object],Lost to Follow up,[object Object],Lost to Follow up,[object Object],Followed Up,[object Object],Followed Up,[object Object],Not Analyzed,[object Object],Not Analyzed,[object Object],Analysis,[object Object],Analyzed,[object Object],Analyzed,[object Object],CONSORT - Consolidated Standards of Reporting Trials,[object Object]

BLINDING / MASKING,[object Object],Blinding is defined as an experimental condition in which various groups of the individuals involved with the trial are withheld from the knowledge of the treatments assigned to patients and corresponding relevant information. The blinding is also known as masking by some research organizations such as NIH.,[object Object],The purpose of blinding is to eliminate bias in subjective judgment due to knowledge of the treatment. Although the concept of randomization is to prevent bias from a statistically sound assessment of the study drug, it does not guarantee that there will be no bias caused by subjective judgment in reporting, evaluation, data processing, and statistical analysis due to the knowledge of the identity of the treatments.Since this subjective and judgmental bias is directly or indirectly related to treatment, it can seriously distort statistical inference on the treatment effect. it is therefore imperative to eliminate such bias by blocking the identity of treatments. ,[object Object],Blinding in clinical trials can be classified into four types: open label, single blind, double blind, and triple blind. ,[object Object],An open-label study is a clinical trial in which no blinding is employed.,[object Object],A single-blind trial is a trial in which only the patient is unaware of his or her treatment assignment.,[object Object],A double-blind trial is a trial in which neither the patients nor the investigator (study centre) are aware of patient’s treatment assignment. ,[object Object],In addition to the patient’s treatment assignment, the blindness also applies to concealment of the overall results of the trial.,[object Object],A triple-blind study with respect to blindness can provide the highest degree for the validity of a controlled clinical trial.,[object Object],39,[object Object]

DATA MANAGEMENT,[object Object],ESSENTIALS,[object Object],40,[object Object]

CLINICAL DATA MANAGEMENT - OVERVIEW,[object Object],CDM (Clinical Data Management) is an integral part of the clinical trial process, which ensures the validity, quality, and integrity of data collected from trial subjects to a database system. CDM delivers a clean and high-quality database for statistical analysis and consequently enables clinical scientists to draw conclusions regarding the effectiveness, safety, and clinical benefit / risk of the drug product under investigation. ,[object Object],The CDM process includes:,[object Object],Case Report Form (CRF) development,[object Object],Database development and validation,[object Object],Data entry, query, and correction,[object Object],Data quality assurance,[object Object],Data lock, archive, and transfer.,[object Object],The CDM process may encounter the following obstacles during the trial:,[object Object],CDM process may fails to collect useful information for addressing the scientific/clinical questions that the clinical trial intends to answer,[object Object],CDM process may collect information that is irrelevant to the study objectives of the clinical trials,[object Object],The quality of the collected data may be poor with missing values and/or inconsistencies across case report forms and/or study sites,[object Object],To overcome these obstacles, the implementation of good data management practice (GDMP) is necessary. GDMP is a set of standards/procedures for assurance of the validity, quality, and integrity of clinical data collected from trial subjects to a database system. GDMP takes guidance from the ICH-GCP and 21 CFR regulations.,[object Object],41,[object Object]

Clinical Trials - An Introduction

Clinical Trials - An Introduction

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