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Introduction to Clinical Research Phases
- 1. Introduction to Clinical Research - I By Benhur Pradeep Pradeep.ben84@gmail.com http://www.myclinicalresearchbook.blogspot.com/
- 2. Outline Definition of Clinical Research & Clinical Trial Importance of Research Different types of Clinical Trials Different Phases of Clinical Trials Players in Clinical Trials Overview of Clinical Trial Summary
- 3. Clinical Research Branch of Medical Science. Systematic, observational and experimental biomedical studies. Ultimate goal is to improve the Quality of Life (QoL).
- 4. Clinical Trial One form of Clinical research Systematic experimental Biomedical studies. To evaluate the effectiveness and safety of medications or medical devices or biologics etc.,.
- 5. Three important keywords Experimental Unit Treatment Evaluation
- 6. Importance of Research New techniques for screening and diagnosing a disease. New drugs to market. New methods for surgery. New approach for radiation therapy. New combination of standard treatments. New techniques, such as Gene therapy.
- 7. Types of Clinical Trials Based on researchers behave Observational study Interventional study Based on the purpose Prevention trials Screening trials Diagnostic trials Treatment trials Quality of Life Compassionate use trials
- 8. Phases of Clinical Trial
- 9. Phase 0 Also called Human Micro-dosing studies. Gathers preliminary data Pharmacodynamics and Pharmacokinetics. Gives no data on safety or efficacy. Small number of subjects (10-15).
- 10. Phase I First stage of testing in human subjects (20-100). Designed to assess the safety, tolerability, PK and PD of drug. Dose ranging β Dose escalation. Kinds of Phase I SAD MAD Food effect
- 11. Phase II Therapeutic Exploratory Trial. (20-300 Subjects). Efficacy in patients (primary objective) Safety issues (secondary objective) Optimum dose finding Phase II Phase IIA: Designed to assess dosing requirements Phases IIB: Designed to study efficacy
- 12. Phase III Therapeutic confirmatory trials. (300-3000 subjects). To establish efficacy of the drug against existing therapy in larger number of patients, method of usage etc.,. Subtypes Phase IIIA: to get sufficient and significant data. Phase IIIB: allows patients to continue the treatment, Label expansion, additional safety data.
- 13. Phase IV Post Marketing Studies (PMS). Involves safety surveillance. Determine behavior of drug in real life situations. Evaluate action of drug in a situation of missed dosage or over dosage.
- 14. Players in Clinical Trial Regulator Sponsor CRO Regulatory Personnel CRA Project Manager Medical Director Investigator/Sub-Investigator IRB CRA Subjects
- 15. Overview of Clinical Trial Study Design Notification to Regulatory Authority Statistical Review Final Report Design Study Documents Investigator Selection Data Management Follow up Visits End of Trial Ethics Committee Review Monitoring Patient Enrollment Approval Letter Investigator Meeting Site Initiation
- 16. What Happens During the Clinical Trial Depends on the kind of trial being conducted. Includes Doctors (Investigators), nurses, health care professionals etc., Monitors the participants carefully during the trial and stay in touch after the trial is completed. CT, successful when the protocol is carefully followed. Some trials involves interviews, questionnaires or surveys of interventional treatment.
- 17. Summary Clinical Research involves processes through which the testing article is tested for its effectiveness and safety for human use. Ensures complete safety of volunteers. Highly monitored and regulated.
Editor's Notes
- Clinical trials are research studies involving people. Clinical trials are the final step in a long research process that includes preliminary laboratory research and animal testing.Β Clinical trials try to answer specific scientific questions to find better ways to prevent, detect, or treat diseases, or to improve care for people with diseases.
- Let us start the session with the definition of CLINICAL RESEARCH.Clinical=relating to the observation and treatment of patients rather than laboratory.Research=The systematic investigation into and study of materials and sources in order to establish facts and reach new conclusions.So, Clinical Research isdefined as systematic observational and experimental biomedical studies performed in human subjects to test new drugs or combination of drugs or devices or biologics for its safety and therapeutic uses or new approaches to surgery or radiotherapy or procedures to improve the diagnosis of disease and the Quality life of the patient.
- Now let us see the What is Clinical Trial.Trial= A formal examination of evidence.Clinical Trial is defined as systematic experimental biomedical studies to evaluate the effectiveness and safety of medications or medical devices or biologics by monitoring their and their effects on person or group of people (Subjects).So,Clinical trials are one form of clinical research that involves a researcher or researchers who directly observe a person or people, and/or who collect data to answer a scientific or medical question about the safety or potential benefit of an intervention such as a medication, device, teaching concept, training method, or behavioural change.
- There are numerous definitions for clinical research/clinical trial.But in any definition we can find three important key words they are experimental unit, treatment, and evaluation of the treatment.Experimental Unit: 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 inferenced. For example, the intended population could be patients with certain diseases at certain stages or healthy human subjects. In practice, although a majority of clinical trials are usually conducted in patients to evaluatecertain test treatments, it is not uncommon that some clinical trials may involve healthy human subjects. For example, at very early phase trials of clinical development, initial investigation of a new pharmaceutical entity may only involve a small number of healthy subjects, say fewer than 30. Large primary prevention trials are often conducted with healthy human subjects with size in tens of thousand subjects.Treatment: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. For example, in the Physicianβs Health Study, one treatment arm is a combination of low-dose aspirin and beta carotene. Other examples include lumpectomy, 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 diagnostic enhancement; or a class III antiarrhythmic agent and an implanted cardioverter defibrillator as a combination of a drug and a medical device for treatment of patients with ventricular arrhythmia. As a result, a treatment is any intervention to be evaluated in human subjects regardless that it is a new intervention to be tested or serves as a referenced control group for comparison.Evaluation:Evaluation is assessment of efficacy and safety of an intervention such as adverse experiences, elevation of certain laboratory parameters, or change in findings of physical examination after administration of the treatment. Recently, 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.
- It is important to understand what clinical trials do to fight disease:Β·Β Β Β Β Β Β Β Β Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat disease.Β·Β Β Β Β Β Β Β Β Clinical trials contribute to knowledge and progress against disease. Many of todayβs most effective treatments are based on previous study results. Because of progress made through clinical trials, many people treated for various diseases are now living longer.Β·Β Β Β Β Β Β Β Β The more people that participate in clinical trials, the faster we can answer the critical research questions that will lead us to better treatment and prevention options for a range of diseases.
- One way of classifying clinical trials is by the way the researchers behave.In an observational study, the investigators observe the subjects and measure their outcomes. The researchers do not actively manage the study.In an interventional study, the investigators give the research subjects a particular medicine or other intervention. Usually, they compare the treated subjects to subjects who receive no treatment or standard treatment. Then the researchers measure how the subjects' health changes.Another way of classifying trials is by their purpose. 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, vitamins, vaccines, minerals, or lifestyle changes.Screening trials: test the best way to detect certain diseases or health conditions.Diagnostic trials: conducted to find better tests or procedures for diagnosing a particular disease or condition.Treatment trials: test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.Quality of life trials: explore ways to improve comfort and the quality of life for individuals with a chronic illness (a.k.a. Supportive Care trials).Compassionate use trials or expanded access: provide partially tested, unapproved therapeutics prior to a small number of patients that have no other realistic options. Usually, this involves a disease for which no effective therapy exists, or a patient that has already attempted and failed all other standard treatments and whose health is so poor that he does not qualify for participation in randomized clinical trials.
- Clinical trials take place in phases.Once laboratory studies (in test tubes and animals) show that a new approach has promise, a phase 1 trial can begin. A phase 1 trial is the first step in testing a new agent (drug or compound) in humans.Clinical trials involving new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate clinical trial. The drug-development process will normally proceed through all four phases over many years. 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.Pre-clinical studiesIt 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.
- Recent designation for exploratory, first-in-human trials. (US FDA)Also known as human micro dosing studies and are designed to speed up the development of promising drugs.Gathers preliminary data on Pharmacodynamics (what the drug does to the body) and Pharmacokinetics (what the body does to the drug).Gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect.
- Phase 1 trials are done to find out :Safe dosage rangeSide effectsHow the body copes with the drugUsually βsmall trials, recruiting 20-100 healthy volunteers or cancer patients(end stage)Patients are recruited very slowlyFirst few patients are given very small dose. If all goes well, then the next group will be given a higher dose and so onβ¦ untilβ¦ the best dose if found out. This is called DOSE ESCALATING STUDY.This phase includes trials designed to access thesaftey tolerability pharmacokineticspharmacodynamics of drughere are different kinds of Phase I trial:SAD Single Ascending Dose studies are those in which small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time. If they do not exhibit any adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the Maximum tolerated dose (MTD)). MAD Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics & pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level. Food effect A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study, with volunteers being given two identical doses of the drug while fasted, and after being fed.
- 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. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects.Phase II studies are sometimes divided into Phase IIA and Phase IIB.Phase IIA is specifically designed to assess dosing requirements (how much drug should be given).Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)).Some trials combine Phase I and Phase II, and test both efficacy and toxicity.Trial design Some Phase II trials are designed as case series, demonstrating a drug's safety and activity in a selected group of patients. Other Phase II trials are designed as randomized clinical trials, where some patients receive the drug/device and others receive placebo/standard treatment. Randomized Phase II trials have far fewer patients than randomized Phase III trials.
- Confirmatory Phase (Therapeutic confirmatory trial)βTrials are done to obtain sufficient evidence about efficacy and safetyConducted in larger number of patients.In comparison with standard drug/placebo.To establish efficacy of the drug against existing therapy in larger number of patientsTo establish the safety in relatively large number of patientsTo establish method usage in clinical practicesTo identify contraindications, warningsPhase IIIATo get the therapeutic and safety information about the drug on a lager number and diversified subjects.Generate sufficient and significant data to file NDAPhase IIIBAllows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchasePerforming 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
- Phase IVPhase IV trial is also known as Postmarketing 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). The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses
- Regulator/Regulatory Body/Regulatory Authority:Bodies having the power to regulate. βRegulatory authoritiesβ includes the authorities that review submitted clinical data and those that conduct inspections. These bodies are sometimes referred to as competent authorities. Sponsor: An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial. (ICH) According to 21 CFR 50.3, a corporation or agency whose employees conduct the investigation is considered a sponsor and the employees are considered investigators.CRO: (Contract Research Organization/Clinical Research Organization)An organization to which the sponsor may transfer or delegate some or all of the tasks ,duties and or obligations regarding a clinical study.Clinical research associate (CRA):Person employed by a sponsor, or by a contract research organization acting on a sponsorβs behalf, who monitors the progress of investigator sites participating in a clinical study. At some sites (primarily in academic settings), clinical research coordinators are called CRAs ormonitor.Investigator/Sub-Investigator:Investigator A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator.Sub-Investigator Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows).Clinical research coordinator (CRC):Person who handles most of the administrative responsibilities of a clinical trial, acts as liaison between investigative site and sponsor, and reviews all data and records before a monitorβs visit. Synonyms: trial coordinator, study coordinator, research coordinator, clinical coordinator, research nurse, protocol nurse.Institutional review board (IRB):An independent body constituted of medical, scientific, and non-scientific members, whose responsibility it is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.Subject/trial subject:An individual who participates in a clinical trial, either as recipient of the investigational product(s) or as a control.
- The clinical trial process depends on the kind of trial being conducted. The clinical trial team includes doctors and nurses as well other health care professionals. They check the health of the participant at the beginning of the trial, give specific instructions for participating in the trial, monitor the participant carefully during the trial, and stay in touch after the trial is completed. Some clinical trials involve more tests and doctor visits than the participant would normally have for an illness or condition. For all types of trials, the participant works with a research team. Clinical trial participation is most successful when the protocol is carefully followed, including frequent contact with the research staff. The protocol is a study plan on which all clinical trials are based. The plan is carefully designed to safeguard the health of the participants as well as answer specific research questions. A protocol describes what types of people may participate in the trial; the length of the study; and if applicable, the schedule of tests, procedures, medications, and dosages. Participants in an interventional (treatment) clinical trial are seen regularly by the research staff to monitor their health and to determine the safety and effectiveness of their treatment. Whereas, there are other types of research trials that involve interviews, questionnaires, or surveys instead of interventional treatment.
- Clinical research involves the processes by which a drug or medical device or treatment or surgery procedure or biologicals are developed and tested for its effectiveness and safety and at the same time ensuring the complete safety of volunteers participating in the research studies. These studies are closely monitored and regulated to determine that all the data collected is done in a methodical way and is accurate.
- Created by:Benhur Pradeep.Pradeep.ben84@gmail.comKeep visiting βhttp://www.myclinicalresearchbook.blogspot.comβ.