Clinical trial by chirag

Clinical Trials And Review & Approval Of Clinical Studies:

1 Clinical Trials And Review & Approval Of Clinical Studies Prepared by: Chirag J. Solanki M.Pharm (Q.A) Roll no 11 cs_apc_09@yahoo.in Guided by: Mrs. Hetal D. Solanki Assistant Professor Dept. of pharmacology Dharmaj Degree Pharmacy College

Definition :

Definition “Clinical trial is designed to test hypotheses and rigorously monitor and assess what happens, clinical trials can be seen as the application of the scientific method to understanding human or animal biology.” Synonyms for 'clinical trials' include clinical studies, research protocols and clinical research . 2

Introduction:

Introduction Clinical trials are conducted to allow safety and efficacy data to be collected for health interventions e.g., drugs, diagnostics, devices, therapy protocols. These trials can take place only after satisfactory information has been gathered on the quality of the non-clinical safety, and Health Authority/Ethics Committee approval is granted in the country where the trial is taking place. 3

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Depending on the type of product and the stage of its development, investigators enroll healthy volunteers and/or patients into small pilot studies initially, followed by larger scale studies in patients that often compare the new product with the currently prescribed treatment. As positive safety and efficacy data are gathered, the number of patients is typically increased. 4

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Clinical trials often involve patients with specific health conditions who then benefit from receiving otherwise unavailable treatments. More commonly, participants are healthy volunteers who receive financial incentives for their inconvenience. During dosing periods, study subjects typically remain on site at the unit for durations of anything from 1 to 30 nights, occasionally longer, although is not always required. 5

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During the clinical trial, the investigators: recruit patients with the predetermined characteristics, administer the treatment(s), and collect data on the patients' health for a defined time period. These data include measurements like vital signs, concentration of the study drug in the blood, and whether the patient's health improves or not . The researchers send the data to the trial sponsor who then analyzes the pooled data using statistical tests. 6

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Beginning in the 1980s, harmonization of clinical trial protocols was shown as feasible across countries of the European Union. At the same time, coordination between Europe, Japan and the United States led to a joint regulatory-industry initiative on international harmonization named after 1990 as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Currently, most clinical trial programs follow ICH guidelines, aimed at " ensuring that good quality, safe and effective medicines are developed and registered in the most efficient and cost-effective manner. 7

History:

History The concepts behind clinical trials, however, are ancient. The Book of Daniel verses 12 through 15, for instance, describes a planned experiment with both baseline and follow-up observations of two groups who either partook of, or did not partake of, "the King's meat" over a trial period of ten days. Persian physician and philosopher, Avicenna, gave such inquiries a more formal structure. In The Canon of Medicine in 1025 AD, he laid down rules for the experimental use and testing of drugs and wrote a precise guide for practical experimentation in the process of discovering and proving the effectiveness of medical drugs and substances 8

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Avicenna laid out the following rules and principles for testing the effectiveness of new drugs and medications: The drug must be free from any extraneous accidental quality. It must be used on a simple, not a composite, disease. 9

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The drug must be tested with two contrary types of diseases, because sometimes a drug cures one disease by its essential qualities and another by its accidental ones. The quality of the drug must correspond to the strength of the disease. For example, there are some drugs whose heat is less than the coldness of certain diseases, so that they would have no effect on them. 10

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The time of action must be observed, so that essence and accident are not confused. The effect of the drug must be seen to occur constantly or in many cases, for if this did not happen, it was an accidental effect. The experimentation must be done with the human body, for testing a drug on a lion or a horse might not prove anything about its effect on man.s 11

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Frederick Akbar Mahomed, 1884 who worked at Guy's Hospital in London, made substantial contributions to the process of clinical trials during his detailed clinical studies, where "he separated chronic nephritis with secondary hypertension from what we now term essential hypertension." He also founded "the Collective Investigation Record for the British Medical Association; this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials." 12

Types:

Types 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. 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. 13

Another way of classifying trials is by their purpose. The U.S. National Institutes of Health (NIH) organizes trials into five (5) different types :

Another way of classifying trials is by their purpose. The U.S. National Institutes of Health (NIH) organizes trials into five (5) different types 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. 14

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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. 15

Design:

Design A fundamental distinction in evidence-based medicine is between observational studies and randomized controlled trials. In observational studies , the investigators only observe associations (correlations) between the treatments experienced by participants and their health status or diseases. 16

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A randomized controlled trial is the study design that can provide the most compelling evidence that the study treatment causes the expected effect on human health. Currently, some Phase II and most Phase III drug trials are designed as randomized, double blind, and placebo-controlled. Randomized : Each study subject is randomly assigned to receive either the study treatment or a placebo. 17

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Blind : The subjects involved in the study do not know which study treatment they receive. If the study is double-blind , the researchers also do not know which treatment is being given to any given subject. If a physician knew which patient was getting the study treatment and which patient was getting the placebo, he/she might be tempted to give the study drug to a patient who could more easily benefit from it. 18

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In addition, a physician might give extra care to only the patients who receive the placebos to compensate for their ineffectiveness. Placebo-controlled : The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment. 19

Clinical study :

20 Clinical study Preclinical evaluation 4 phases of clinical study Phase 1 Phase 2 Phase 3 Phase 4

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Pre-clinical studies involve in vitro (test tube) and in vivo (animal or cell culture) 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. 21

Phase 0 :

Phase 0 Phase 0 trials are also known as human microdosing studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. Distinctive features of Phase 0 trials include the administration of single sub therapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacokinetics and pharmacodynamics. 22

Phase 1:

Phase 1 Phase I trials are the first stage of testing in human subjects. Normally, a small (20-100) group of healthy volunteers will be selected. This phase includes trials designed to assess the safety , tolerability, pharmacokinetics, and pharmacodynamics of a drug. 23

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Phase I trials most often include healthy volunteers. However, there are some circumstances when real patients are used, such as patients who have terminal cancer or HIV and lack other treatment options. Volunteers are paid an inconvenience fee for their time spent in the volunteer center(up to approx $6000 depending on length of participation.) 24

There are different kinds of Phase I trials: :

There are different kinds of Phase I trials: 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 25

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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 26

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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 on different occasions; one while fasted, and one after being fed. 27

Phase 2:

Phase 2 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. 28

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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)). 29

Phase 3 :

Phase 3 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. Most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. 30

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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. 31

Phase 4:

Phase 4 POST MARKETING STUDY PHASE The real clinical status and the nature and frequency of adverse reaction often becomes apparent only the drug is released for general use. It include additional information like drug’s use , benefits and optimal use. 32

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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 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. 33

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Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses. Recent examples involve cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx). 34

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Stages of Drug Development and Review :

36 Stages of Drug Development and Review Investigational New Drug Application (IND) Clinical Trials New Drug Application (NDA)

Investigational New Drug Application (IND) :

37 Investigational New Drug Application (IND) An investigational new drug application (IND) outlines what the sponsor of a new drug proposes for human testing in clinical trials. Sponsors-companies, research institutions, and other organizations that take responsibility for developing a drug must show the FDA results of preclinical testing they have done in laboratory animals and what are their propose to do for human testing.

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38 At this stage, the FDA decides whether it is reasonably safe for the company to move forward with testing the drug in humans.

Clinical Trials:

39 Clinical Trials Drug studies in humans can begin only after an IND is reviewed by the FDA and a local institutional review board (IRB). The board is a panel of scientists and non-scientists in hospitals and research institutions that oversees clinical research. IRBs approve the clinical trial protocols

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40 IRBs make sure the study is acceptable, that participants have given consent and are fully informed of their risks, and that researchers take appropriate steps to protect patients from harm.

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41 Phase 1 healthy volunteers. The goal is to determine what the drug's most frequent side effects are. Phase 2 studies begin if Phase 1 studies don't reveal unacceptable toxicity. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. Safety continues to be evaluated. Emphasis in Phase 1 is on safety, the emphasis in Phase 2 is on effectiveness

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42 At the end of Phase 2, the FDA and sponsors try to come to an agreement on how the large-scale studies in Phase 3 should be done. How often the FDA meets with a sponsor varies, but this is one of two most common meeting points prior to submission of a new drug application . The other most common time is pre-NDA--right before a new drug application is submitted.

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43 Phase 3 studies begin if evidence of effectiveness is shown in Phase 2 and conducted on larger population. Postmarket studies conducted after the FDA has approved a product for marketing. The FDA uses postmarket requirement and commitment studies to gather additional information about a product's safety, efficacy, or optimal use.

New Drug Application (NDA):

44 New Drug Application (NDA) This is the formal step a drug sponsor takes to ask that the FDA consider approving a new drug for marketing. An NDA includes all animal and human data and analysis of the data, as well as information about how the drug behaves in the body and how it is manufactured.

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45 When an NDA comes in, the FDA has 60 days to decide whether to file it so that it can be reviewed. The FDA can refuse to file an application that is incomplete. For example, some required studies may be missing.

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46 In accordance with the Prescription Drug User Fee Act (PDUFA), the FDA's Center for Drug Evaluation and Research (CDER) expects to review and act on at least 90 percent of NDAs for standard drugs no later than 10 months after the applications are received. The review goal is six months for priority drugs.

Reviewing Applications :

47 Reviewing Applications The official review time is the length of time it takes to review a new drug application and issue an action letter, an official statement informing a drug sponsor of the agency's decision. Once a new drug application is filed, an FDA review team--medical doctors, chemists, statisticians, microbiologists, pharmacologists, and other experts --evaluates whether the studies the sponsor submitted show that the drug is safe and effective for its proposed use.

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48 No drug is absolutely safe; all drugs have side effects. "Safe" in this sense means that the benefits of the drug appear to outweigh the risks. The review team analyzes study results and looks for possible issues with the application, such as weaknesses of the study design or analysis.

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49 Reviewers determine whether they agree with the sponsor's results and conclusions, or whether they need any additional information to make a decision. Each reviewer prepares a written evaluation containing conclusions and recommendations about the application. These evaluations are then considered by team leaders, division directors, and office directors, depending on the type of application.

Accelerated approval:

50 Accelerated approval Traditional approval requires that clinical benefit be shown before approval can be granted. Accelerated approval is given to some new drugs for serious and life-threatening illnesses that lack satisfactory treatments . This allows an NDA to be approved before measures of effectiveness that would usually be required for approval are available

Accelerated approval contd..:

51 Instead, less traditional measures called surrogate endpoints are used to evaluate effectiveness. These are laboratory findings or signs that may not be a direct measurement of how a patient feels, functions, or survives, but are considered likely to predict benefit. For example, a surrogate endpoint could be the lowering of HIV blood levels for short periods of time with anti-retroviral drugs Accelerated approval contd..

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52 Gleevec ( imatinib mesylate ) an oral treatment for patients with a life-threatening form of cancer called chronic myeloid leukemia (CML), received accelerated approval. Gleevec blocks enzymes that play a role in cancer growth. The approval was based on results of three large Phase 2 studies, which showed the drug could substantially reduce the level of cancerous cells in the bone marrow and blood.

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53 Most drugs to treat HIV have been approved under accelerated approval provisions, with the company required to continue its studies after the drug is on the market to confirm that its effects on virus levels are maintained and that it ultimately benefits the patient. Under accelerated approval rules, if studies don't confirm the initial results, the FDA can withdraw the approval

References :

54 References www.fda.gov http://google2.fda.gov/search?q=clinical+trial+guideline&x=0&y=0&client=FDAgov&lr=&proxysylesheet=FDAgov&output=xml_no_dtd&getfields=*&sort=date:D:L:d1&entqr=3&oe=UTF-8&ie=UTF-8&ud=1&site=FDAgov&btnG=Search http://en.wikipedia.org/wiki/Clinical_trial http://www.ich.org/cache/compo/276-254-1.html http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdfa www.cdsco.nic.in

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55 THANK U