all about clinical trials_katalyst hls

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All about Clinical Trial

12-25-2016Katalyst Healthcares & Life Sciences

2Sources of Safety Information

Clinical trial data for the indication Nonclinical data (CMC, in vitro, animals) Clinical Pharmacology studies Clinical trial safety data for other indications Postmarketing experience Medical literature Safety profile of other drugs in the same class


3Nonclinical information

Chemical structure/Drug classo Class toxicitiesIn vitro toxicity evaluationo Genotoxicityo Cardiac repolarizationPharmacology-Toxicology studies in animalso Organ specific toxicitieso Carcinogenicityo Teratogenicity


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CT: It is an experimental epidemiological method. It is an interventional study on individuals, usually on patients.A research study in human volunteers to answer a specific health question (U.S National Library of Medicine).PHASES OF CLINICAL TRIALS: Phase -I trials (20-30 patients/subjects)Phase -II trials (100-300 patient/subjects)Phase -III trials (1000-3000 patients/subjects)Phase -IV trials (wide populations, race..)


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Phase-I: Initial safety trials on a new medicine. An attempt is made to establish the dose range tolerated by volunteers for single and for multiple doses. Phase I trials are sometimes conducted in severely ill patients (e.g., in the field of cancer) or in less ill patients when pharmacokinetic issues are addressed (e.g. metabolism of a new antiepileptic medicine in stable epileptic patients whose microsomal liver enzymes have been induced by other antiepileptic medicines). Pharmacokinetic trials are usually considered Phase I trials regardless of when they are conducted during a medicine's development.


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Phase-IIa: Pilot clinical trials to evaluate efficacy ( and safety) in selected populations of patients with the disease or condition to be treated, diagnosed, or prevented.Objectives may focus on dose-response, type of patient, frequency of dosing, or numerous other characteristics of safety and efficacy. Phase-IIb: Well controlled trials to evaluate efficacy (and safety) in patients with the disease or condition to be treated, diagnosed, or prevented. These clinical trials.Usually represent the most rigorous demonstration of a medicine's efficacy. Sometimes referred to as pivotal trials.


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Phase-IIIa: Trials conducted after efficacy of the medicine is demonstrated, but prior to regulatory submission of a New Drug Application (NDA) or other dossier. These clinical trials are conducted in patient populations for which the medicine is eventually intended. Phase-IIIa clinical trials generate additional data on both safety and efficacy in relatively large numbers of patients in both controlled and uncontrolled trials. Clinical trials are also conducted in special groups of patients (e.g., renal failure patients) , or under special conditions dictated by the nature of the medicine and disease. These trials often provide much of the information needed for the package insert and labeling of the medicine.


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Phase-IIIb: Clinical trials conducted after regulatory submission of an NDA or other dossier, but prior to the medicine's approval and launch. These trials may supplement earlier trials, complete earlier trials, or may be directed toward new types of trials (e.g., quality of life, marketing) or Phase IV evaluations. This is the period between submission and approval of a regulatory dossier for marketing authorization.


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Phase-IV: Studies or trials conducted after a medicine is marketed to provide additional details about the medicine's efficacy or safety profile. Different formulations, dosages, durations of treatment, medicine interactions, and other medicine comparisons may be evaluated. New age groups, races, and other types of patients can be studied. Detection and definition of previously unknown or inadequately quantified adverse reactions and related risk factors are an important aspect of many Phase IV studies. If a marketed medicine is to be evaluated for another (i.e., new) indication, then those clinical trials are considered Phase II clinical trials.Post-marketing surveillance (PMS) is frequently used to describe those clinical studies in Phase IV (i.e., the period following marketing) that are primarily observational or non-experimental in nature.


10DESIGN OF CLINICAL TRIAL

Selecting the reference population

Selecting the experimental population (Exclude Non-participants)

Selecting the study population (Participants)

Random allocation into

Intervention group Comparison group

Apply intervention No intervention

Assessment of outcomes


11PROTOCOL (STUDY PLAN)

Study plan is carefully designed to safeguard the health of the participants and to answer the specific research question.

It describes what types of people can participate, the schedule of tests, procedures, medications, dosages The length of study.

It has to be explained in detail , to all the participants, particularly regarding benefits and risks. It should be submitted to the ethical committee for prior approval before commencing the study.


12Endpoint Definition

“Results, condition or events associated with individual study patients that are used to assess study treatments”

For marketing approval, there must be substantial evidence (consisting of adequate and well-controlled investigations) of something that matters.

The primary endpoint(s) of confirmatory Phase 3 trials should represent (directly or through a surrogate) something that matters to a patient.

There is a pathway for approval based on something that probably matters (an incompletely validated surrogate), but this comes with certain commitments. (“Subpart H”, “accelerated approval”).

Patient reported outcome (PRO) instruments and composite endpoints may be used to establish a benefit that matters.


13INFORMED CONSENT

Informed consent document will be obtained from the participants in the study population after explaining them fully aboutThe purpose,Duration,Required procedures,Expectations,Risks and benefits,Adverse effects of the trial if any,Participants’ rightsIt is a continuous process throughout the study of learning of key facts by participants about a clinical trial.It also explains the rights of the participant including reimbursement.It is not a contract and the participant can withdraw from the trial at any time.


14Blocking

This is done ,when the study population is heterogeneous consisting of men, women, patients with different levels of severity of illness and suspected to give results of varying frequency.

This is done before random allocation.

Sub –groups are stratified and blocked to make the trial more accurate.

Participants are randomly allocated from these various blocks or groups so that the trial’s internal validity will be increased.


15Random Allocation/Randomization

The participants in the study population are randomly allocated into two groups (Arms) using Random Number tables to avoid selection and confounding biases.Allocation bias is minimized This elimination of allocation bias will greatly enhance the validity of the trial.Types:Simple RandomizationBlock RandomizationStratified RandomizationUnequal Randomization


16Blinding

The investigator, the participant and sometimes even the evaluator are all kept unaware (blinded) of the outcomes of the trial and secrecy is maintained to improve the validity.Blinding or Masking is done to eliminate Investigator bias Evaluation bias Hawthorne effect

SINGLE BLINDING means the process wherein only the participant is unaware about what he is receiving.DOUBLE BLINDING means is where both the participant and the investigator are unaware about of the intervention. This eliminates observer bias to a large extent.TRIPLE BLINDING is a trial where even the evaluator is also not aware of the process.


17Unblinding

Only blinded studies require unblinding,Reporting Group user receives single case unblinding information by: IVRS/IWRS Envelope Directly from sponsor

The user unblinds and enters the patient treatment information in the caseWhen complete, the case is locked and routed to Distribution & Submission User needs special rights to view and/or print unblinded report form - Important!


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In order to unblind a case, the case should be unlocked! Always remember all the cases associated with the patient

needs to be unblinded. The study drug to be chosen from drop down menu

(products tab). For completed studies, the “End of Study” utility can be

used to unblind all the cases associated with the study in bulk instead of unblinding each case individually one by one


19Observational and interventional study

There are many study designs to choose from within two broad categories of observational and interventional studies. Each design has its own strengths and weaknesses, and the need to understand these limitations is necessary to arrive at correct study conclusions.

Interventional studies are often prospective and are specifically tailored to evaluate direct impacts of treatment or preventive measures on disease. Each study design has specific outcome measures that rely on the type and quality of data utilized. Additionally, each study design has potential limitations that are more severe and need to be addressed in the design phase of the study.

20Observational / Non-interventional Studies (NIS):

Observational study designs, also called epidemiologic study designs, are often retrospective and are used to assess potential causation in exposure-outcome relationships and therefore influence preventive methods.

Types: Ecological designs, cross sectional, case-control, case-crossover, retrospective and prospective cohorts. An important subset of observational studies is diagnostic study designs, which evaluate the accuracy of diagnostic procedures and tests as compared to other diagnostic measures. These include diagnostic accuracy designs, diagnostic cohort designs, and diagnostic randomized controlled trials.


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Observational or Non-Interventional Studies investigate various aspects of drug use, including efficacy and safety, under real-life conditions. NIS are defined by methodological approach, and not scientific objectives.

From an EU regulation perspective, a study qualifies as non-interventional and does not fall under the scope of the clinical trials directive 2001/20/EC, provided the following requirements are cumulatively fulfilled:

Medicinal product is prescribed in the usual manner in accordance with the terms of the marketing authorization

Assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol, but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study

No additional diagnostic or monitoring procedures are applied to the patients, and epidemiological methods are used for the analysis of collected data. Of note, interviews, questionnaires, and collection of blood samples may be performed as part of normal clinical practice

For non-interventional studies in Europe, there is little to no homogeneity from one country to another in terms of regulation, documents to be submitted, submission timelines, or processes. In addition, the regulatory bodies involved


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Washout period. A period in a clinical study during which subjects receive no treatment for the indication under study and the effects of a previous treatment are eliminated (or assumed to be eliminated).Essential documents in clinical trial:1. Investigator's Brochure.2. Clinical Study Protocol.3. Subject Information and Informed Consent Form.4. Clinical Study Reports.5. Case Report Form (CRF)


23KEY Differences between Ct and pm reporting


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Clinical trialsClinical Trial Directive 2001/20/ECClinical trials - Regulation EU No 536/2014 (effective from May 2016)

Post- MarketingDirective 2010/84/EURegulation (EU) No 1235/2010The above legislation amended existing pharmacovigilance laws contained in Directive 2001/83/EC and Regulation (EC) No. 726/2004


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