Accredited Member of the Association of Clinical Research Professionals, USA Tips on clinical trials Maha Al-Farhan B.Sc, M.Phil., M.B.A., D.I.C

In this session Essential clinical trials documents and materials Essential clinical trials documents and materials Definition of the protocol Definition of the protocol How to write a clinical study protocol How to write a clinical study protocol Ethical Considerations: The declaration of Helsinki Ethical Considerations: The declaration of Helsinki Informed consent Informed consent Case record forms. Case record forms. Current Compliance Concerns (FDA) Current Compliance Concerns (FDA)

Basic Documents and materials of clinical trials Clinical Trial Protocol Clinical Trial Protocol Informed Consent form Informed Consent form Trial Case Record Forms (CRF) Trial Case Record Forms (CRF) Investigational Product Investigational Product Study Materials Study Materials

Definition Of the Protocol (according to ICH Good Clinical Practice Guideline) A document that describes the objective(s), design, methodology, statistical considerations, and organisation of the trial. A document that describes the objective(s), design, methodology, statistical considerations, and organisation of the trial. Usually, the protocol also gives the background and rational for the trial. Usually, the protocol also gives the background and rational for the trial.

How to write a protocol How detailed should a protocol be: How detailed should a protocol be: –This is a matter of judgement –Rule of thumb: Include the right amount of detail necessary for the reader of each section to be able to understand exactly what is required to conduct the study.

Start by mapping out a study schedule Visit 1 Baseline (day 0) Visit 2 Randomization(day10) Visit 3 (day 20) Follow-upVisit (after end of treatment) Informed Consent X Inclusion/ Exclusion X Medical History X Primary diagnosis X Clinical assessment XXXX RandomisationX Adverse Events XXX Assessment of relapse X

Objectives and end-points Get the primary objective right Get the primary objective right The primary objective will dictate the primary end-point. The primary objective will dictate the primary end-point. Primary end point measurement will be used to calculate sample size. Primary end point measurement will be used to calculate sample size.

Get the primary objective right Could be either efficacy or safety Could be either efficacy or safety Well defined Well defined Well founded Well founded

Defined measurement or assessment. Defined measurement or assessment. Implies a time point of clinical interest. Implies a time point of clinical interest. If possible, end-points need to be objective measurements rather than subjective outcomes If possible, end-points need to be objective measurements rather than subjective outcomes The primary end-point.

Primary end point measurement will be used to calculate sample size. Statisticians should be consulted. Statisticians should be consulted. Many different ways of calculation depending on whether: Many different ways of calculation depending on whether: –Trial is designed to show superiority against placebo or another treatment. –Trial is designed to show equivalence or non- inferiority against standard treatment Allowance for subjects drop out. Allowance for subjects drop out.

Choice of study design Two main types: Two main types: –Non-Comparative: usually used to assess a treatment’s safety and tolerability. –Comparative design used when comparing treatments: Cross-overParallel-group

Choice of comparative study design Cross-over Parallel group VariabilityMinimal Variability must be taken into account Number of subjects needed SmallerLarger Wash out period between treatments Must be adequate to ensure baseline status No need Disease characteristic Ethically, must be stable during wash out period. No restrictions Primary end-point Subjective No restriction

Bias Selection/ Allocation bias Selection/ Allocation bias Observer bias Observer bias Randomisation Blinding How to avoid it

Subject Selection criteria Define the population to be studied. Define the population to be studied. Inclusion criteria/Exclusion criteria should reflect the wider population of patients. Inclusion criteria/Exclusion criteria should reflect the wider population of patients. Balance the scientific integrity and final application of the treatment in question. Balance the scientific integrity and final application of the treatment in question.

Methodology/ assessments Details of this section ensure that: all observations are performed in a standard manner. all observations are performed in a standard manner. Sample collection procedure and laboratory tests are performed in a standard manner Sample collection procedure and laboratory tests are performed in a standard manner

Ethical considerations: General issues Has every possible precaution been taken to ensure the safety of the subject? Has every possible precaution been taken to ensure the safety of the subject? Are the assessments really necessary, especially those that involve some risk to the subject (e.g. invasive measurements)? Are the assessments really necessary, especially those that involve some risk to the subject (e.g. invasive measurements)? Is the comparator (especially if it is placebo) ethical to use or is the subject being deprived of current proven effective treatment? Is the comparator (especially if it is placebo) ethical to use or is the subject being deprived of current proven effective treatment?

Ethical Considerations: The Declaration of Helsinki It is a statement of clinical principles to provide guidance to physicians and other participants in medical research involving human subjects. It is a statement of clinical principles to provide guidance to physicians and other participants in medical research involving human subjects. It confirm the role of the physician above that of the investigator It confirm the role of the physician above that of the investigator It is a set of principles defining the standards that should apply to biomedical research worldwide. It is a set of principles defining the standards that should apply to biomedical research worldwide.

Ethical Considerations: Informed consent. Often come in two parts: Often come in two parts: –Written information describing the clinical trial –A form which the subject signs to document that he/she has given consent to take part in the study Closely reviewed by ethics committees. Closely reviewed by ethics committees. Consent is valid when freely given. Consent is valid when freely given.

Should include up to date information Should include up to date information That the trial involves research. That the trial involves research. The purpose of the trial (experimental aspects). The purpose of the trial (experimental aspects). Trial treatments and probability for random assignment to each treatment. Trial treatments and probability for random assignment to each treatment. Trial procedures to be followed and Subject’s responsibilities. Trial procedures to be followed and Subject’s responsibilities. Risks, inconveniences, and benefits to the subject. Risks, inconveniences, and benefits to the subject. Ethical Considerations: Informed consent content.

Compensation and/or treatment available to subject in the event of trial-related injury. Compensation and/or treatment available to subject in the event of trial-related injury. That subject’s participation is voluntary and that he/she may refuse to participate or withdraw from the trial at any time. That subject’s participation is voluntary and that he/she may refuse to participate or withdraw from the trial at any time. Monitor(s), Auditor(s), Ethics committee, and regulatory authority(ies) will be granted access to subjects medical records. Monitor(s), Auditor(s), Ethics committee, and regulatory authority(ies) will be granted access to subjects medical records. Confidentiality of subject’s records. Confidentiality of subject’s records. Expected duration of the trial. Expected duration of the trial. Approximate number of trial subjects Approximate number of trial subjects Ethical Considerations: Informed consent content.

Alternative treatments available. Alternative treatments available. Subject’s should not be unduly influenced to participate Subject’s should not be unduly influenced to participate Subjects should be fully informed of all pertinent aspects of the study. Subjects should be fully informed of all pertinent aspects of the study. Written information should be as non-technical as possible. Written information should be as non-technical as possible. Ethical Considerations: Informed consent process.

Subjects must be given ample time to ask questions. Subjects must be given ample time to ask questions. Should be signed and personally dated by the subject (or his/her legally acceptable representative) and by the person who conducted the informed consent discussion. Should be signed and personally dated by the subject (or his/her legally acceptable representative) and by the person who conducted the informed consent discussion.

Case Record Forms Document used to record data on which: Reporting of the clinical trial Reporting of the clinical trial Analysis Analysis Will be based

Purpose of the information collected in the CRF: –To answer the hypothesis formulated in the study protocol –To provide relevant safety data relating to the study drug. Case Record Forms

The CRF should: The CRF should: –Request the precise information required by the protocol. –Request Only the information required by the protocol –Request the information in a way that completion is simple, relatively quick, and as unambiguous as possible, and that all assessment are straight forward to complete –Presents information clearly to enable the investigator to review the subjects continuing eligibility Case Record Forms Design

Summary Study Protocol Study Protocol Scientific consideration Scientific consideration Practical Considerations Practical Considerations Ethical Issues Ethical Issues Collection of Data (Case Record Forms) Collection of Data (Case Record Forms)

GCP COMPLIANCE : Emerging Issues in Worldwide Clinical Trials David A. Lepay, M.D., Ph.D. Director, Division of Scientific Investigations, CDER June 29, 1999

Current Compliance Concerns Most commonly observed deficiencies Most commonly observed deficiencies –Failure to follow the protocol Violation of inclusion/exclusion criteria Violation of inclusion/exclusion criteria Failure to perform required tests Failure to perform required tests –Failure to maintain adequate and accurate records absence of supporting source documents absence of supporting source documents inaccurate or incomplete source documents inaccurate or incomplete source documents

Clinical Investigator Deficiency Categories Protocol Consent Form Records Drug Accountability Adverse Events

–Personally conduct or supervise the investigation* –Ensure that all associates, colleagues, and employees assisting in study conduct are informed about their obligations* –Conduct the study in accordance with the protocol –Comply with all requirements regarding obligations of clinical investigators* –Inform subjects drugs are being used for investigational purposes and ensure informed consent and IRB requirements are met –Report Adverse Events to the sponsor *Delegation high risk YOU ARE AN INVESTIGATOR FULLY COMMITTED TO: