Ich guidelines e9 to e12

regulatory studies

1. Overview of ICH E9 –E12 guidelines ICH Guidelines Submitted to: Mrs. Azka Submitted by: Khushboo M. Pharm (DRA) 2 nd sem. A10651916010

2. E9 : Statistical Principles for Clinical Trials E10 : Choice of Control Group in Clinical Trials E11 : Clinical Trials in Pediatric population E12 : Clinical Evaluation by Therapeutic Category

3. E9- Statistical Principles for Clinical Trials A. INTRODUCTION : The efficacy and safety of medicinal products should be demonstrated by clinical trials which follow the guidance in 'Good Clinical Practice: Consolidated Guideline' (ICH E6) adopted by the ICH, 1 May 1996. This guidance is written primarily to attempt to harmonise the principles of statistical methodology applied to clinical trials for marketing applications submitted in Europe, Japan and the United States. Some topics related to statistical principles and methodology are also embedded within other ICH guidelines. The specific guidance that contains related text will be identified in various sections of this document.

4. SCOPE AND DIRECTION : The focus of this guidance is on statistical principles. Selected principles and procedures related to data management or clinical trial monitoring activities are covered in other ICH guidelines and are not addressed here. This guidance should be of interest to individuals from a broad range of scientific disciplines . The trial statistician should have a combination of education/training and experience sufficient to implement the principles articulated in this guidance. The principles outlined in this guidance are primarily relevant to clinical trials conducted in the later phases of development, many of which are confirmatory trials of efficacy. Many of the principles delineated in this guidance deal with minimizing bias (see Glossary) and maximizing precision.

5. ii. CONSIDERATIONS FOR OVERALL CLINICAL DEVELOPMENT : TRIAL CONTEXT Development plan: The broad aim of the process of clinical development of a new drug is to find out whether there is a dose range and schedule at which the drug can be shown to be simultaneously safe and effective, to the extent that the risk-benefit relationship is acceptable. 2) Confirmatory trial: A confirmatory trial is an adequately controlled trial in which the hypotheses are stated in advance and evaluated. As a rule, confirmatory trials are necessary to provide firm evidence of efficacy or safety .

6. 3)Exploratory trial: The rationale and design of confirmatory trials nearly always rests on earlier clinical work carried out in a series of exploratory studies. Like all clinical trials, these exploratory studies should have clear and precise objectives. In exploratory trials may sometimes require a more flexible approach to design so that changes can be made in response to accumulating results.

7. SCOPE OF TRIALS : 1) Population: In the earlier phases of drug development the choice of subjects for a clinical trial may be heavily influenced by the wish to maximize the chance of observing specific clinical effects of interest. 2) Primary and secondary variables: The primary variable should be the variable capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial. There should generally be only one primary variable. Secondary variables are either supportive measurements related to the primary objective or measurements of effects related to the secondary objectives. The number of secondary variables should be limited and should be related to the limited number of questions to be answered in the trial.

8. 3) Composite variables: If a single primary variable cannot be selected from multiple measurements associated with the primary objective, another useful strategy is to integrate or combine the multiple measurements into a single or 'composite' variable, using a pre-defined algorithm. 4) Global assessment variables: In some cases, 'global assessment' variables (see Glossary) are developed to measure the overall safety, overall efficacy, and/or overall usefulness of a treatment. Global assessment variables generally have a subjective component. Global assessment of usefulness integrates components of both benefit and risk and reflects the decision making process of the treating physician, who must weigh benefit and risk in making product use decisions.

9. 5) Multiple primary variables: It may sometimes be desirable to use more than one primary variable, each of which (or a subset of which) could be sufficient to cover the range of effects of the therapies. 6) Surrogate variables: When direct assessment of the clinical benefit to the subject through observing actual clinical efficacy is not practical, indirect criteria may be considered. 7) Categorized variables: Categorization of continuous or ordinal variables may sometimes be desirable. Categorizations are most useful when they have clear clinical relevance.

10. DESIGN TECHNIQUES TO AVOID BIAS: The most important design techniques for avoiding bias in clinical trials are blinding and randomization. Blinding: Blinding or masking is intended to limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial. The essential aim is to prevent identification of the treatments until all such opportunities for bias have passed. 2) Randomization: Randomization introduces a deliberate element of chance into the assignment of treatments to subjects in a clinical trial. During subsequent analysis of the trial data, it provides a sound statistical basis for the quantitative evaluation of the evidence relating to treatment effects.

11. iii. TRIAL DESIGN CONSIDERATION : Design Configurations: Parallel group design Crossover design Factorial design B. Multicentre trials: Multicentre trials are carried out for two main reasons. Firstly, a multicentre trial is an accepted way of evaluating a new medication more efficiently; under some circumstances, it may present the only practical means of accruing sufficient subjects to satisfy the trial objective within a reasonable time-frame. C. Types of comparison: Trials to show superiority Trials to show equivalence or non-inferiority Trials to show dose-response relationship

12. GROUP SEQUENTIAL DESIGNS: Group sequential designs are used to facilitate the conduct of interim analysis. SAMPLE SIZE: The number of subjects in a clinical trial should always be large enough to provide a reliable answer to the questions addressed.

13. iv. TRIAL CONDUCT CONSIDERATIONS: Trial monitoring and interim analysis Changes in inclusion and exclusion criteria Accrual rates Sample size adjustment Interim analysis and early stopping Role of independent data monitoring committee (IDMC)

14. v. DATA ANALYSIS CONSIDERATIONS: Prespecification of the analysis Analysis set: --Full analysis set --Per protocol set --Roles of different analysis set Missing values and outliers Data transformation Estimation, confidence intervals and hypothesis testing Adjustment of significance and confidence levels subgroups, interactions and covariates Integrity of data and computer software validity

15. vi. EVALUATION OF SAFETY AND TOLERABILITY: Scope evaluation Choice of variables and data collection Set of subjects to be evaluated and presentation of data Statistical evaluation Integrated summary

16. vii. REPORTING: Evaluation and reporting Summarizing the clinical database Efficacy data Safety data

17. E10- Choice of Control Group in Clinical Trials INTRODUCTION: The choice of control group is always a critical decision in designing a clinical trial. That choice affects the inferences that can be drawn from the trial, the ethical acceptability of the trial, the degree to which bias in conducting and analyzing the study can be minimized, the kind of endpoints that can be studied, the acceptability of the results by regulatory authorities, and many other features of the study, its conduct, and its interpretation.

18. B.PURPOSE OF GUIDELINE: The purpose of this guideline is to describe the general principles involved in choosing a control group for clinical trials intended to demonstrate the efficacy of a treatment and to discuss related trial design and conduct issues. The choice of the control group should be considered in the context of available standard therapies, the adequacy of the evidence to support the chosen design, and ethical considerations. The guideline then describes trials using each kind of control group in more detail and considers, for each: Its ability to minimize bias Ethical and practical issues associated with its use Its usefulness and the quality of inference in particular situations Modifications of study design or combinations with other controls that can resolve ethical, practical, or inferential concerns Its overall advantages and disadvantages

19. C.PURPOSE OF CONTROL GROUP: Control groups have one major purpose: to allow discrimination of patient outcomes caused by the test treatment from outcomes caused by other factors, such as the natural progression of the disease, observer or patient expectations, or other treatment. A concurrent control group is one chosen from the same population as the test group and treated in a defined way as part of the same trial that studies the test treatment, and over the same period of time. The test and control groups should be similar with regard to all baseline and on-treatment variables that could influence outcome, except for the study treatment. Failure to achieve this similarity can introduce a bias into the study. Bias here (and as used in ICH E9) means the systematic tendency of any aspects of the design, conduct, analysis, and interpretation of the results of clinical trials to make the estimate of a treatment effect deviate from its true value.

20. Randomization and blinding are the two techniques usually used to minimize the chance of such bias and to ensure that the test treatment and control groups are similar at the start of the study and are treated similarly in the course of the study (see ICH E9). RANDOMIZATION: Assurance that subject populations are similar in test and control groups is best attained by randomly dividing a single sample population into groups that receive the test or control treatments. Randomization avoids systematic differences between groups with respect to known or unknown baseline variables that could affect outcome. Randomization also provides a sound basis for statistical inference. BLINDING : The groups should not only be similar at baseline, but should be treated and observed similarly during the trial, except for receiving the test and control drug. Clinical trials are often double blinded.

21. Blinding is intended to minimize the potential biases resulting from differences in management, treatment, or assessment of patients, or interpretation of results that could arise as a result of subject or investigator knowledge of the assigned treatment. D.TYPES OF CONTROLS: Control groups in clinical trials can be classified on the basis of two critical attributes: the type of treatment used and the method of determining who will be in the The type of control treatment may be any of the following four: placebo, no treatment, different dose or regimen of the study treatment, or a different active treatment.

22. PLACEBO CONCURRENT CONTROL: In a placebo-controlled trial, subjects are randomly assigned to a test treatment or to an identical-appearing treatment that does not contain the test drug. Such trials are almost always double-blind. Placebo-controlled trials seek to show a difference between treatments when they are studying effectiveness, but may also seek to show lack of difference (of specified size) in evaluating a safety measurement. NO-TREATMENT CONCURRENT CONTROL: In a no treatment-controlled trial, subjects are randomly assigned to test treatment or to no (i.e., absence of) study treatment. The principal difference between this design and a placebo-controlled trial is that subjects and investigators are not blind to treatment assignment. DOSE-RESPONSE CONCURRENT CONTROL: In a randomized, fixed-dose, dose-response trial, subjects are randomized to one of several fixed-dose groups. Dose-response trials are usually double-blind. They may include a placebo (zero dose) and/or active control .

23. MULTIPLE CONTROL GROUPS: It is often possible and advantageous to use more than one kind of control in a single study, e.g., use of both an active control and placebo. Similarly, trials can use several doses of test drug and several doses of an active control, with or without placebo. E.PURPOSES OF CLINICAL TRIALS AND RELATED ISSUES: Purposes of clinical trials should be distinguished: assessment of the efficacy and/or safety of a treatment and assessment of the relative (comparative) efficacy, safety, risk/benefit relationship or utility of two treatments. Fairness of comparisons Dose Patient population Selection and timing of end points

24. E.ASSAY SENSTIVITY: Assay sensitivity is a property of a clinical trial defined as the ability to distinguish an effective treatment from a less effective or ineffective treatment. Assay sensitivity is important in any trial but has different implications for trials intended to show differences between treatments (superiority trials) and trials intended to show non-inferiority. If a trial intended to demonstrate efficacy by showing superiority of a test treatment to control lacks assay sensitivity, it will fail to show that the test treatment is superior and will fail to lead to a conclusion of efficacy.

25. E11 : CLINICAL TRIALS IN PEDIATRIC PATIENTS GENERAL PRINCIPLE: Pediatric patients should be given medicines that have been appropriately evaluated for their use. Obtaining knowledge of the effects of medicinal products in pediatric patients is an important goal.

26. ii . GUIDANCE ISSUES WHEN INITIATING A PEDIATRIC MEDICINAL PRODUCT DEVELOPMENT PROGRAM: Data on the appropriate use of medicinal products in the pediatric population should be generated unless the use of a specific medicinal product in pediatric patients is clearly inappropriate. The decision to proceed with a pediatric development program for a medicinal product, and the nature of that program, involve consideration of many factors The prevalence of the condition to be treated in the pediatric population The seriousness of the condition to be treated . The availability and suitability of alternative treatments for the condition in the pediatric population, including the efficacy and the adverse event profile of those treatments. Whether there are unique pediatric indications for the medicinal product The need for the development of pediatric-specific endpoints The age ranges of pediatric patients likely to be treated with the medicinal product. Unique pediatric (developmental) safety concerns with the medicinal product, including any nonclinical safety issues.

27. 2. PEDIATRIC FORMULATIONS: There is a need for pediatric formulations that permit accurate dosing and enhance patient compliance. For oral administration, different types of formulations, flavors and colors may be more acceptable in one region than another. Several formulations, such as liquids, suspensions, and chewable tablets, may be needed or desirable for pediatric patients of different age . 3.TIMING OF STUDIES: During clinical development, the timing of pediatric studies will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of alternative treatments. Medicinal Products for Diseases Predominantly or Exclusively Affecting Pediatric Patients Medicinal Products Intended to Treat Serious or Life-Threatening Diseases, Occurring in Both Adults and Pediatric Patients, for Which There Are Currently No or Limited Therapeutic Options. Medicinal Products Intended to Treat Other Diseases and Conditions

28. 4. TYPE OF STUDIES: The principles outlined in ICH E4, E5, E6, and E10 apply to pediatric studies. When a medicinal product is studied in pediatric patients in one region, the intrinsic and extrinsic factors that could impact on the extrapolation of data to other regions should be considered. Pharmacokinetics: Pharmacokinetic studies generally should be performed to support formulation development and determine pharmacokinetic parameters in different age groups to support dosing recommendations. Efficacy: The principles in study design, statistical considerations and choice of control groups detailed in ICH E6, E9, and E10 generally apply to pediatric efficacy studies. Safety: ICH guidances on E2 topics and ICH E6, which describe adverse event reporting, apply to pediatric studies. Post- marketing information: Normally the pediatric database is limited at the time of approval. Therefore, post-marketing surveillance is particularly important.

29. 5. AGE CLASSIFICATION OF PEDIATRIC PATIENTS: Any classification of the pediatric population into age categories is to some extent arbitrary, but a classification such as the one below provides a basis for thinking about study design in pediatric patients. Ages are defined in completed days, months, or years: Preterm newborn infants Term newborn infants (0 to 27 days) Infants and toddlers (28 days to 23 months) Children (2 to 11 years) Adolescents (12 to 16-18 years (dependent on region)) 6. ETHICAL ISSUES IN PEDIATRIC STUDIES: The purpose of this section is to provide a framework to ensure that pediatric studies are conducted ethically . Institutional review board /Independent Ethics committee (IRB/IEC) Recruitment Consent and assent Minimizing risk Minimizing distress

30. E12: CLINICAL EVALUATION BY THERAPUTIC CATEGORY 1.GENERAL PRINCIPLES FOR THE ASSESSMENT OF EFFICACY : The primary basis of assessment of efficacy of antihypertensive drugs is the effect of the drug on systolic and diastolic blood pressures. In the past the primary endpoint of most studies was diastolic blood pressure. 2.STUDY POPULATION: The patient population studied with a new antihypertensive should include a broad range of patients with essential hypertension. Most patients will be in the mild to moderate range.

31. 3.ASSESSMENT OF ANTIHYPERTENSIVE EFFECT: Studies to assess antihypertensive effect Pharmacodynamic studies Dose response relationship Comparison with standard therapy 4. ASSESSMENT OF SAFETY: ICH E1 suggests that a database of about 1500 patients (300-600 for 6 months, 100 for 1 year) is usually sufficient for chronically administered drugs, but as suggested in that guideline, this may be too small for the very long, very wide exposure in an asymptomatic population intended for antihypertensive drugs. 5.CO-ADMINISTRATION WITH OTHER ANTIHYPERTENSIVES: As antihypertensive treatments are often used in combination, it is important to study the efficacy and safety of the new drug in this situation. Information on combination use can be obtained in formal factorial studies and in combined use in the course of long- and short-term clinical studies.

32. 6.FIXED COMBINATION PRODUCTS: There are two approaches to the combination studies needed to obtain safety and efficacy data to support fixed combination products. It is essential to consult with regional regulatory authorities regarding the specific data needed to support the specific indications. Factorial study. Studies in Non-responders to each drug.

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