Guideline for good clinical practice

INDEX
1.Introduction to Clinical Trials3
2.Clinical Trial Protocol5
3.International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use6 1.1.Introduction to GCP6
1.2.Sections of GCP Guidelines6
3.2.1.1Section 1- Glossary of various terms6
3.2.1.2Section 2- Principles of ICH-GCP7
3.2.1.3Section 3- Institutional Review Board/Independent Ethics Committee(IRB/IEC)8 3.2.1.4Responsibilities8
3.2.1.5Composition, Functions and Operations8
3.2.1.6Procedures8
3.2.1.7Records8
3.2.1.8Section 4- Investigator9
3.2.1.9Investigator’s Qualifications and Agreements9
3.2.1.10Adequate Resources9
3.2.1.11Medical Care of Trial Subjects9
3.2.1.12Communication with IRB/IEC9
3.2.1.13Compliance with Protocol9
3.2.1.14Investigational Product(s)10
3.2.1.15Randomization Procedures and Unblinding10
3.2.1.16Informed Consent of Trial Subjects10
3.2.1.17Records and Reports10
3.2.1.18 Progress Reports10
3.2.1.19 Safety Reporting11
3.2.1.20 Premature Termination or Suspension of a Trial11
3.2.1.21 Final Report(s) by Investigator11
3.2.1.22Section 5- Sponsor11
3.2.1.23Quality Assurance and Quality Control12
3.2.1.24Contract Research Organization (CRO)12
3.2.1.25Medical Expertise 12
3.2.1.26Trial Design 12
3.2.1.27Trial Management, Data Handling, and Record Keeping 12 3.2.1.28Investigator Selection 13
3.2.1.29Allocation of Responsibilities 13
3.2.1.30Compensation to Subjects and Investigators 13
3.2.1.31Financing 13
3.2.1.32 Notification/Submission to Regulatory Authority13
3.2.1.33 Confirmation of Review by IRB/IEC 13
3.2.1.34 Information on Investigational Product14
3.2.1.35 Manufacturing, Packaging, Labelling, and Coding Investigational Product14 3.2.1.36 Supplying and Handling Investigational Product(s) 14 3.2.1.37 Record Access 15
3.2.1.38 Safety Information 15
3.2.1.39 Adverse Drug Reaction Reporting 15
3.2.1.40 Monitoring 15
3.2.1.41Audit 16
3.2.1.42 Noncompliance17
3.2.1.43Premature Termination or Suspension of a Trial 17
3.2.1.44 Clinical Trial/Study Reports 17
3.2.1.45 Multicentre Trials 17
3.2.1.46Section 6- Clinical Trial Protocol and Protocol Amendment(s)18 3.2.1.47General Information19
3.2.1.48Background Information19
3.2.1.49Trial Objectives and Purpose 19
3.2.1.50Trial Design 19
3.2.1.51Selection and Withdrawal of Subjects 20
3.2.1.52Treatment of Subjects 20
3.2.1.53Assessment of Efficacy 21
3.2.1.54Assessment of Safety 21
3.2.1.55Statistics21
3.2.1.56Direct Access to Source Data/Documents21
3.2.1.57Quality Control and Quality Assurance 21
3.2.1.58Ethics 21
3.2.1.59 Data Handling and Record Keeping 22
3.2.1.60Financing and Insurance 22
3.2.1.61Publication Policy 22
3.2.1.62Supplements 22
3.2.1.63Section 7- Investigator’s Brochure22
3.2.1.64Introduction23
3.2.1.65General Considerations24
3.2.1.66Contents of the Investigator’s Brochure24
3.2.1.67Section 8- Essential Documents for the Conduct of a Clinical Trial25 3.2.1.68Introduction25
3.2.1.69Before the Clinical Phase of the Trial Commences26
3.2.1.70During the Clinical Conduct of the Trial27
3.2.1.71After Completion or Termination of the Trial29
4.References29

1. Introduction to Clinical Trials
Clinical trials are sets of tests in medical research and drug development that generate safety and efficacy data (or more specifically, information about adverse drug reactions and adverse effects of other treatments) for health interventions (e.g., drugs, diagnostics, devices, therapy protocols). They are conducted only after satisfactory information has been gathered on the quality of the nonclinical safety, and health authority/ethics committee approval is granted in the country where approval of the drug or device is sought. Previously, many emerging countries did not require local trials for product approvals. Now, though emerging countries still accept data from U.S./Europe, they also require some local trials. Depending on the type of product and the stage of its development, investigators initially enroll volunteers and/or patients into small pilot studies, and subsequently conduct larger scale studies in patients that often compare the new product with others already approved for the affliction of interest. As positive safety and efficacy data are gathered, the number of patients is typically increased. Clinical trials can vary in size, and can involve a single research entity in one country or many such entities in multiple countries. A full series of trials may incur sizable costs, and the burden of paying for all the necessary people and services is usually borne by the sponsor, which may be a governmental organization or a pharmaceutical, biotechnology or medical device company. When the diversity of required support roles exceeds the resources of the sponsor, a clinical trial is managed by an outsourced partner, such as a contract research organization or a clinical trials unit in the academic sector. Usually, one or more pilot experiments are conducted to gain insights for design of the
clinical trial to follow. In medical jargon, effectiveness is how well a treatment works in practice and efficacy is how well it works in a clinical trial. 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 patients are volunteers and they are not paid for participating in clinical trials. 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.

Some examples of what a clinical trial may be designed to do: Assess the safety and effectiveness of a new medication or device on a specific kind of patient (e.g., patients who have been diagnosed with Alzheimer’s disease) Assess the safety and effectiveness of a different dose of a medication than is commonly used (e.g., 10-mg dose instead of 5-mg dose) Assess the safety and effectiveness of an already marketed medication or device for a new indication, i.e. a disease for which the drug is not specifically approved Assess whether the new medication or device is more effective for the patient’s condition than the already used, standard medication or device (“the gold standard” or “standard therapy”) Compare the effectiveness in patients with a specific disease of two or more already approved or common interventions for that disease (e.g., device A vs. device B, therapy A vs. therapy B)

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 0, 1, 2, and 3, it will usually be approved by the national regulatory authority for use in the general population. Phase 0: Pharmacodynamics and Pharmacokinetics

Phase 1: Screening for safety
Phase 2: Establishing the efficacy of the drug, usually against a placebo
Phase 3: Final confirmation of safety and efficacy
Phase 4: Sentry studies during sales

Different clinical study designs are:-
Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo. 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. This ‘blinding’ is to prevent biases, since if a physician knew which patient was getting the study treatment and which patient was getting the placebo. Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment from the placebo effect. 2. Clinical Trial Protocol

A clinical trial protocol is a document used to gain confirmation of the trial design by a panel of experts and adherence by all study investigators, even if conducted in various countries. The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations, and organization of the planned trial. Details of the trial are also provided in other documents referenced in the protocol, such as an investigator’s brochure. The protocol contains a precise study plan for executing the clinical trial, not only to assure safety and health of the trial subjects, but also to provide an exact template for trial conduct by investigators at multiple locations (in a “multicenter” trial) to perform the study in exactly the same way. This harmonization allows data to be combined collectively as though all investigators (referred to as “sites”) were working closely together. The protocol also gives the study administrators (often a contract research organization), as well as the site team of physicians, nurses and clinic administrators, a common reference document for site responsibilities during the trial.

3. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline For Good Clinical Practice E6 (R1)

1.1. Introduction to GCP
Good Clinical Practice (GCP) is an international quality standard that is provided by International Conference on Harmonisation (ICH), an international body that defines standards, which governments can transpose into regulations for clinical trials involving human subjects. This guideline includes protection of human rights as a subject in clinical trial. It also provides assurance of the safety and efficacy of the newly developed compounds. Good Clinical Practice Guidelines include standards on how clinical trials should be conducted, define the roles and responsibilities of clinical trial sponsors, clinical research investigators, and monitors (Clinical Research Associates).

1.2. Sections of GCP Guidelines
3.2.1.1 Section 1- Glossary of various terms
Adverse drug reaction & Adverse Event
Case report form & Clinical Study Report
Coordinating Committee & Contract Research Organization
Independent Ethics Committee & Institutional Review Board
Investigator & Investigator’s Brochure
Monitoring & Monitoring report
Protocol & Protocol Amendment
Serious Adverse Event
Source data & Source documents
Sponsor & Sponsor investigator
Standard Operating Procedures
Vulnerable subjects

3.2.1.2 Section 2- Principles of ICH-GCP
1) Clinical Trials should be conducted in accordance with the ethical principles consistent with GCP and applicable regulatory requirements. 2) Before a trial is initiated, forseeable risks & inconveniences should be weighed against anticipated benefit for the trial subject & society. 3) The rights, safety, and well being of the trial subjects are the most important considerations & should prevail over interests of science and society. 4) The available nonclinical & clinical information on an investigational
product should be adequate support the proposed clinical trial. 5) Clinical trials should be scientifically sound, and described in a clear, detailed protocol. 6) Trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/ independent ethics committee (IEC) approval/favorable opinion. 7) The medical care and medical decisions for subjects should be the responsibility of a qualified physician. 8) Each individual involved in conducting a trial should be qualified by education, training & experience to perform his respective task. 9) Freely given informed consent should be obtained from every subject prior to clinical trial participation. 10) All clinical information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification. 11) The confidentiality of records that could identify patients should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirements 12) Investigational products should be manufactured, handled and stored in accordance with applicable GMP, and used in accordance with the protocol. 13) Systems with procedures that assure the quality of every aspect of the trial should be implemented.

3.2.1.3 Section 3- Institutional Review Board/Independent Ethics Committee(IRB/IEC) 3.2.1.4 Responsibilities
IRB safeguards the rights, safety & well being of all trial subjects. It obtains the following Documents: Protocol & their amendments, Patient Information sheet & consent form, subject recruitment procedures (e.g. advertisements), Investigator’s Brochure (IB), available safety information, information about payments and compensation available to subjects, the investigator’s current curriculum vitae and/or other documentation evidencing qualifications, and any other documents that the IRB/IEC may need to fulfill its responsibilities It conducts continuous review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year. 3.2.1.5 Composition, Functions and Operations

At least 5 members
At least one non scientific member
At least one independent member
IRB Maintains list of members and qualifications
Only independent members can vote
Quorum is to be maintained
3.2.1.6 Procedures
The IRB/IEC establishes document in writing and follows its procedures, which includes Composition
Meeting Scheduling & conduct
Specify that trial starts only after IRB review
Specify regarding changes in protocol
Specify prompt reporting of adverse events

3.2.1.7 Records
The IRB/IEC retains all relevant records (e.g., written procedures, membership lists, lists of occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for a period of at least 3 years after completion of the trial and makes them available upon request from the regulatory authority (ies). The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written procedures and membership lists. 3.2.1.8 Section 4- Investigator

3.2.1.9 Investigator’s Qualifications and Agreements
The investigator should be qualified (documented) by education, training & experience to assume responsibility for proper trial conduct. He/she should be familiar with the appropriate use of the investigational product, IB, and other information provided by sponsor. He/she should be aware of, & should comply with, GCP and the applicable regulatory requirements. The investigator permits monitoring, auditing and inspection. Delegation of duties is signed to appropriately qualified personnels.

3.2.1.10 Adequate Resources
The investigator should be able to demonstrate potential for recruitment. He/she should have sufficient time for trial conducts and completion. The investigator should have an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial
properly and safely. He/she should ensure training to the staff.

3.2.1.11 Medical Care of Trial Subjects
The qualified physician investigator/sub investigator for the trial takes the responsibility for all trial related medical decisions. The investigator makes sure that adequate medical care is given during and after trail participation to a subject. He/she makes the reasonable efforts ascertaining for premature withdrawal of subject from trial.

3.2.1.12 Communication with IRB/IEC
There is a written & dated approval for trial protocol, ICD, recruitment procedures etc prior to trial initiation. The investigator should provide latest copies of IB to IRB, and should also provide all relevant documents for review during trial.

3.2.1.13 Compliance with Protocol
Investigator should conduct trial in accordance with the protocol version agreed & documented by the sponsor, IRB and regulatory authority. And there are no changes allowed in the protocol except in case of immediate hazard to the patient; which should be submitted to all immediately.

3.2.1.14 Investigational Product(s)
Investigator is responsible for accountability at site and may be assigned to pharmacist/individual. The products are stored as specified by sponsor or regulatory authority and are used only in accordance with the protocol.

3.2.1.15 Randomization Procedures and Unblinding
The investigator should follow the trial’s randomization procedure and any premature unblinding is explained to the sponsor.

3.2.1.16 Informed Consent of Trial Subjects
The informed consent complies with regulatory requirement, GCP and ethical principles. There is a documented communication of revised ICD to IRB and patient. There is no influence or coercion to participate. The subject or their legal representative should be fully informed in their own language.
Use of non technical language should be done to explain details to the trial subjects. Ample time should be given for consent and opportunities for questions. There is an impartial witness for illiterate patients. Subjects receive a copy of the signed and dated ICD/ amendment.

3.2.1.17 Records and Reports
Investigator should ensure accuracy, completeness, legibility and timeliness of data to sponsor in CRF. Any correction in CRF should be signed and dated. Investigator maintains the trial related documents. The financial aspect of the trial is documented in an agreement between the sponsor and the investigator/institution. Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution makes available for direct access all requested trial-related records. The progress report is send to IRB.

3.2.1.18 Progress Reports
The investigator submits a written summary of the trial status to the IRB/IEC annually, or more frequently, if requested by the IRB/IEC. The investigator provides written reports to the sponsor, the IRB/IEC and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or increasing the risk to subjects.

3.2.1.19 Safety Reporting
All the serious adverse events (SAEs) are reported immediately to sponsor, and timely as required to IRB/regulatory agency. Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations are reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol. For reported deaths, the investigator supplies the sponsor and the IRB/IEC with any additional requested information (e.g., autopsy reports and terminal medical reports).

3.2.1.20 Premature Termination or Suspension of a Trial
If the trial is prematurely terminated or suspended for any reason, Investigator: Informs the subjects
Assures therapy and follow up
Informs regulatory authorities
Informs sponsor/IRB with explanation

3.2.1.21 Final Report(s) by Investigator
Upon completion, the investigator informs institution, IRB, and regulatory authorities with a summary of the trial’s outcome.

3.2.1.22 Section 5- Sponsor
An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial can be called as a Sponsor.

3.2.1.23 Quality Assurance and Quality Control
The sponsors implement & maintain QA and QC systems with written SOPs to ensure GCP compliance. The sponsors secure agreements from all sites for monitoring, auditing, and inspections sectors. They also look over QC of data handling and payment agreements.

3.2.1.24 Contract Research Organization (CRO)
CRO can be a person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor’s trial related duties and functions. Sponsor may transfer all or some duties to CRO. Ultimate responsibility for quality lies with the sponsor.

3.2.1.25 Medical Expertise
The sponsor designates appropriately qualified medical personnel who will be readily available to advise on trial related medical questions or problems. If necessary, outside consultant(s) may be appointed for this purpose.

3.2.1.26 Trial Design
The sponsor utilizes qualified individuals (e.g. biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports.

3.2.1.27 Trial Management, Data Handling, and Record Keeping The sponsor utilizes appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports. The sponsor can establish an independent data-monitoring committee (IDMC) to assess the progress of a clinical trial if required. If data are transformed during processing, it is possible to compare the original data and observations with the processed data. The sponsor retains all sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) of the country(ies) where the product is approved, and/or where the sponsor intends to apply for approval(s). If the sponsor discontinues the clinical development of an investigational product, the sponsor notifies all the trial investigators/institutions and all the regulatory authorities. Any transfer of ownership of the data is reported to the appropriate authority(ies), as required by the applicable regulatory requirement(s).

3.2.1.28 Investigator Selection
The sponsor selects the investigator(s)/institution(s). Each investigator should be qualified by training and experience and should have adequate resources to properly conduct the trial for which the investigator is selected. Before entering an agreement with an investigator/institution to conduct a trial, the sponsor provides the investigator(s)/institution(s) with the protocol and an up-to-date Investigator’s Brochure, and gives sufficient time for the investigator/institution to review the protocol and the information provided. The sponsor and the investigator/institution sign the protocol, or an alternative document, to confirm this agreement.

3.2.1.29 Allocation of Responsibilities
Prior to initiating a trial, the sponsor defines establishes, and allocates all trial-related duties and functions.

3.2.1.30 Compensation to Subjects and Investigators
The sponsor provides insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the
trial, except for claims that arise from malpractice and/or negligence. When trial subjects receive compensation, the method and manner of compensation complies with applicable regulatory requirement(s).

3.2.1.31 Financing
The financial aspects of the trial are documented in an agreement between the sponsor and the investigator/institution.

3.2.1.32 Notification/Submission to Regulatory Authority
Before initiating the clinical trial(s), the sponsor submits any required application(s) to the appropriate authority for review, acceptance, and/or permission to begin the trials. Any notification/submission is dated and contains sufficient information to identify the protocol.

3.2.1.33 Confirmation of Review by IRB/IEC
The sponsor obtains from the investigator/institution:
(a) The name and address of the investigator’s/institution’s IRB/IEC. (b) A statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations. (c) Documented IRB/IEC approval/favorable opinion.

3.2.1.34 Information on Investigational Product
When planning trials, the sponsor ensures that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied. The sponsor updates the Investigator’s Brochure as significant new information becomes available.

3.2.1.35 Manufacturing, Packaging, Labelling, and Coding Investigational Product The sponsor ensures that the investigational product is characterized as appropriate to the stage of development of the product, is manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding, if applicable. The sponsor determines acceptable storage temperatures, storage conditions (e.g. protection from light), storage times, reconstitution fluids and procedures,
and devices for product infusion, if any for the investigational product. The sponsor informs all involved parties (e.g. monitors, investigators, pharmacists, storage managers) of these determinations.

3.2.1.36 Supplying and Handling Investigational Product(s) The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s). The sponsor should:
(a) Ensure timely delivery of investigational product(s) to the investigator(s). (b) Maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product. (c) Maintain a system for retrieving investigational products and documenting this retrieval (e.g. for deficient product recall, reclaim after trial completion, expired product reclaim). (d) Maintain a system for the disposition of unused investigational product(s) and for the documentation of this disposition. (e) Take steps to ensure that the investigational product(s) are stable over the period of use. (f) Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics.

3.2.1.37 Record Access
The sponsor ensures that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory inspection. The sponsor verifies that each subject has consented, in writing, to direct access to his/her original medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection.

3.2.1.38 Safety Information
The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).

3.2.1.39 Adverse Drug Reaction Reporting
The sponsor sends a report to all concerned investigator(s)/institutions(s),
to the IRB(s)/IEC(s), where required, and to the regulatory authority of all adverse drug reactions (ADRs) that are both serious and unexpected. Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.

3.2.1.40 Monitoring
A. Purpose
The purposes of trial monitoring are to verify that:
The rights and well-being of human subjects are protected.
The reported trial data are accurate, complete, and verifiable from source documents. The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s). B. Selection and Qualifications of Monitors

Monitors are appointed by the sponsor.
Monitors are appropriately trained, and have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented. Monitors are thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s). C. Extent and Nature of Monitoring

The sponsor ensures that the trials are adequately monitored. The sponsor determines the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring are based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. D. Monitor’s Responsibilities

The monitor(s) in accordance with the sponsor’s requirements ensures that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site. E. Monitoring Procedures

The monitor(s) follows the sponsor’s established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial. F. Monitoring Report
The monitor submits a written report to the sponsor after each trial-site visit or trial-related communication. Reports include the date, site, name of the monitor, and name of the investigator or other individual(s) contacted. The review and follow-up of the monitoring report with the sponsor is documented by the sponsor’s designated representative.

3.2.1.41 Audit
If or when sponsors perform audits, as part of implementing quality assurance, they consider: A. Purpose
The purpose of a sponsor’s audit, which is independent of and separate from routine monitoring or quality control functions, is to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.

B. Selection and Qualification of Auditors
The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits. The sponsor ensures that the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications are documented. C. Auditing Procedures

The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the sponsor’s written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports. The observations and findings of the auditor are documented. When required by applicable law or regulation, the sponsor provides an audit certificate.

3.2.1.42 Noncompliance
Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirements by an investigator/institution, or by members of the sponsor’s staff leads to prompt action by the sponsor to secure compliance. If the monitoring and/or auditing identify a serious and/or persistent
noncompliance on the part of an investigator/institution, the sponsor then terminates the investigator’s/institution’s participation in the trial.

3.2.1.43 Premature Termination or Suspension of a Trial
If a trial is prematurely terminated or suspended, the sponsor then informs the investigators/institutions, and the regulatory authorities of the termination or suspension and the reason(s) for the termination or suspension. The IRB/IEC is also informed.

3.2.1.44 Clinical Trial/Study Reports
Whether the trial is completed or prematurely terminated, the sponsor ensures that the clinical trial reports are prepared and provided to the regulatory agencies as required by the applicable regulatory requirement(s).

3.2.1.45 Multicentre Trials
For multicentre trials, the sponsor ensures that:
All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies), and given approval/favorable opinion by the IRB/IEC. The CRFs are designed to capture the required data at all multicentre trial sites. For those investigators who are collecting additional data, supplemental CRFs should also be provided those are designed to capture the additional data. The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial. All investigators are given instructions on following the protocol, on complying with a uniform set of standards for the assessment of clinical and laboratory findings, and on completing the CRFs. Communication between investigators is facilitated.

3.2.1.46 Section 6- Clinical Trial Protocol and Protocol Amendment(s) The contents of a trial protocol are generally included in the following topics. However, site specific information may be provided on separate protocol page(s), or addressed in a separate agreement, and some of the information listed below may be contained in other protocol referenced documents, such as an Investigator’s Brochure.

3.2.1.47 General Information
It mainly includes:-
Protocol Title, identifying number & date. Any amendments should also bear the Amendment number. Contact names and addresses of sponsor, monitor and sponsor’s medical expert. Name and title of Authorized signatory

Contact information of the investigator(s)
Contact information of Institution(s), Laboratories and other associated departments.

3.2.1.48 Background Information
It consists of:-
Name & description of Investigational product
Summary of non clinical & clinical studies
Summary of risks & benefits
Description of route of administration, dosage
Statement of GCP compliance

3.2.1.49 Trial Objectives and Purpose
A detailed description of the objectives and the purpose of the trial are to be set.

3.2.1.50 Trial Design
A description of the trial design includes:
A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial. A description of the type/design of trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stages. A description of the measures taken to minimize/avoid bias, including randomization and blinding. A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labelling of the investigational product(s). The expected duration of subject participation, and a description of the sequence and duration of all trial periods,
including follow-up, if any. A description of the “stopping rules” or “discontinuation criteria” for individual subjects, parts of trial and entire trial. Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any. Maintenance of trial treatment randomization codes and procedures for breaking codes. The identification of any data to be recorded directly on the CRFs (i.e. no prior written or electronic record of data), and to be considered to be source data.

3.2.1.51 Selection and Withdrawal of Subjects
Subject inclusion criteria (age, gender, ethnic groups, prognostic factors, diagnostic criteria). Subject exclusion criteria.
Subject withdrawal criteria (i.e. terminating investigational product treatment/trial treatment) and procedures specifying: When and how to withdraw subjects from the trial/ investigational product treatment. The type and timing of the data to be collected for withdrawn subjects. Whether and how subjects are to be replaced.

The follow-up for subjects withdrawn from investigational product treatment/trial treatment.

3.2.1.52 Treatment of Subjects
Protocols are set for the treatment(s) to be administered, including the name of all the products, the doses, the dosing schedules, the route/modes of administration, and the treatment period, including the follow-up periods for subjects for each investigational product treatment/trial treatment group/arm of the trial. Medications/treatments permitted and not permitted before and/or during the trial. 3.2.1.53 Assessment of Efficacy

Protocols specifying the efficacy parameters are made which also includes methods and timing for assessing, recording, and analysing of efficacy parameters.

3.2.1.54 Assessment of Safety
Protocols specifying the safety parameters are made which also includes the
methods and timing for assessing, recording, and analysing safety parameters. Procedures for eliciting reports for recording and reporting adverse event and intercurrent illnesses are added too. Protocols for the type and duration of the follow-up of subjects after adverse events are also made.

3.2.1.55 Statistics
Protocols giving the description of statistical methods employed are mentioned, including timing of any planned interim analysis. Details of enrollment plan are also given. The level of significance is used. Protocol should be included in the final report if any deviations from the original statistical plan are made. The selection of subjects is included in final analysis.

3.2.1.56 Direct Access to Source Data/Documents
The sponsor ensures that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data/documents.

3.2.1.57 Quality Control and Quality Assurance
It includes the steps & procedures for monitoring study, instructions are mentioned for protocol deviations. Duties & responsibilities are allocated within the research teams. Protocols for quality control of methods & evaluation procedures are followed.

3.2.1.58 Ethics
Description of how patients/volunteers would be informed about the ethical considerations relating to the trial.

3.2.1.59 Data Handling and Record Keeping
These protocols include the procedures for handling & processing records of effects and adverse events. Handling of Products like safe handling and storage measures, system to be followed for labelling and labeling specifications.

3.2.1.60 Financing and Insurance
It includes budget, financial aspects, and source of economic support, subject payments, reimbursement to team members and insurance details of study subjects.

3.2.1.61 Publication Policy
Publication policy, if not addressed in a separate agreement. 3.2.1.62 Supplements
Since the protocol and the clinical trial/study report are closely related, further relevant information can be found in the ICH Guideline for Structure and Content of Clinical Study Reports.

3.2.1.63 Section 7- Investigator’s Brochure
3.2.1.64 Introduction
The Investigator’s Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures. The IB also provides insight to support the clinical management of the study subjects during the course of the clinical trial. The information should be presented in a concise, simple, objective, balanced, and non-promotional form that enables a clinician, or potential investigator, to understand it and make his/her own unbiased risk-benefit assessment of the appropriateness of the proposed trial. For this reason, a medically qualified person should generally participate in the editing of an IB, but the contents of the IB should be approved by the disciplines that generated the described data. This guideline delineates the minimum information that should be included in an IB and provides suggestions for its layout. It is expected that the type and extent of information available will vary with the stage of development of the investigational product. If the investigational product is marketed and its pharmacology is widely
understood by medical practitioners, an extensive IB may not be necessary If a marketed product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared. The IB should be reviewed at least annually and revised as necessary in compliance with a sponsor’s written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available to the investigator(s) and the investigators are responsible for providing the up-to-date IB to the responsible IRBs/IECs. In the case of an investigator sponsored trial, the sponsor-investigator should determine whether a brochure is available from the commercial manufacturer. If the investigational product is provided by the sponsor-investigator, then he or she should provide the necessary information to the trial personnel. In cases where preparation of a formal IB is impractical, the sponsor-investigator should provide, as a substitute, an expanded background information section in the trial protocol that contains the minimum current information described in this guideline.

3.2.1.65 General Considerations
The IB includes:
Title Page
This provides the sponsor’s name, the identity of each investigational product (i.e., research number, chemical or approved generic name, and trade name(s) where legally permissible and desired by the sponsor), and the release date. Confidentiality Statement

The sponsor may wish to include a statement instructing the investigator/recipients to treat the IB as a confidential document for the sole information and use of the investigator’s team and the IRB/IEC.

TITLE PAGE (Example)

SPONSOR’S NAME

Product:
Research Number:
Name(s): Chemical, Generic (if approved)
Trade Name(s) (if legally permissible and desired by the sponsor)

INVESTIGATOR’S BROCHURE

Edition Number:
Release Date:

Replaces Previous Edition Number:
Date:

3.2.1.66 Contents of the Investigator’s Brochure
The aim of this section is to provide the investigator with a clear understanding of the possible risks and adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical trial. This understanding is based on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information on the investigational product(s). Guidance is also provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that are based on previous human experience and on the pharmacology of the investigational product.

TABLE OF CONTENTS OF INVESTIGATOR’S BROCHURE (Example)

– Confidentiality Statement (optional)……………………………………………………………… – Signature Page (optional)………………………………………………………………………………. 1 Table of Contents ………………………………………………………………………………………….. 2 Summary ……………………………………………………………………………………………………… 3 Introduction …………………………………………………………………..
………………………………. 4 Physical, Chemical, and Pharmaceutical Properties and Formulation …………………. 5 Nonclinical Studies ………………………………………………………………………………………… 5.1 Nonclinical Pharmacology ………………………………………………………………………………. 5.2 Pharmacokinetics and Product Metabolism in Animals …………………………………….. 5.3 Toxicology ……………………………………………………………………………………………………… 6 Effects in Humans ………………………………………………………………………………………….. 6.1 Pharmacokinetics and Product Metabolism in Humans …………………………………….. 6.2 Safety and Efficacy …………………………………………………………………………………………. 6.3 Marketing Experience …………………………………………………………………………………….. 7 Summary of Data and Guidance for the Investigator …………………………………………

NB: References on 1. Publications
2. Reports

These references should be found at the end of each chapter Appendices (if any)

3.2.1.67 Section 8- Essential Documents for the Conduct of a Clinical Trial 3.2.1.68 Introduction
Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements. Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites in a timely
manner can greatly assist in the successful management of a trial by the investigator, sponsor and monitor. These documents are also the ones which are usually audited by the sponsor’s independent audit function and inspected by the regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected. The minimum list of essential documents which has been developed follows. The various documents are grouped in three sections according to the stage of the trial during which they will normally be generated: 1) before the clinical phase of the trial commences, 2) during the clinical conduct of the trial, and 3) after completion or termination of the trial. A description is given of the purpose of each document, and whether it should be filed in either the investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided the individual elements are readily identifiable.

3.2.1.69 Before the Clinical Phase of the Trial Commences
During this planning stage the following documents are generated and should be on file before the trial formally starts:- 1) Investigators Brochure
2) Signed protocols, amendments (if any) and sample Case Report Form(CRF) 3) Information given to the trial subject
Informed Consent Form (including all applicable translation) Any other written information
Advertisements for subject recruitment (if used)
4) Financial aspects of the trial
5) Insurance statement(where required)
6) Signed agreement between involved parties

7) Dated, documented approval/favourable opinion of institutional review board (IRB) /independent ethics committee (IEC) of the following: protocol and any amendments
CRF (if applicable)
informed consent form(s)
any other written information to be provided to the subject(s) advertisement for subject recruitment (if used)
subject compensation (if any)
any other documents given approval/ favourable opinion
8) Institutional review board/independent ethics committee composition 9) Regulatory authority(ies) authorisation/approval/notification of protocol(where required) 10) Curriculum vitae and/or other relevant documents evidencing qualifications of investigator(s) and sub-investigator(s) 11) Normal value(s)/range(s) for medical/ laboratory/technical procedure(s) and/or test(s) included in the protocol 12) Medical/laboratory/technical procedures /tests

certification or
accreditation or
established quality control and/or external quality assessment or other validation (where required)
13) Sample of label(s) attached to investigational product container(s) 14) Instructions for handling of investigational product(s) and trial-related materials (if not included in protocol or investigator’s brochure) 15) Shipping records for investigational product(s) and trial-related materials 16) Certificate(s) of analysis of investigational product(s) shipped 17) Decoding procedures for blinded trials

18) Master randomisation list
19) Pre-trial monitoring report
20) Trial initiation monitoring report

3.2.1.70 During the Clinical Conduct of the Trial
In addition to having on file the above documents, the following are also added to the files during the trial as evidence that all new relevant information is documented as it becomes available:- 1) Investigator’s brochure updates

2) Any revision to:
protocol/amendment(s) and CRF
informed consent form
any other written information provided to subjects
advertisement for subject recruitment(if used)
3) Dated, documented approval/favourable opinion of institutional review board (IRB) /independent ethics committee (IEC) of the following: protocol amendment(s)
revision(s) of:
informed consent form
any other written information to be provided to the subject
advertisement for subject recruitment (if used)
any other documents given approval/favourable opinion
continuing review of trial (where required)
4) Regulatory authority(ies) authorisations/approvals/notifications where required for protocol amendment(s) and other documents 5) Curriculum vitae for new investigator(s) and/or sub-investigator(s) 6) Updates to normal value(s)/range(s) for medical/ laboratory/ technical procedure(s)/test(s) included in the protocol 7) Updates of medical/laboratory/ technical procedures/tests certification or

accreditation or
established quality control and/or external quality assessment or other validation (where required)
8) Documentation of investigational product(s) and trial-related materials shipment 9) Certificate(s) of analysis for new batches of investigational products 10) Monitoring visit reports
11) Relevant communications other than site visits
12) Signed informed consent forms
13) Source documents
14) Signed, dated and completed case report forms (CRF)
15) Documentation of CRF corrections
16) Notification by originating investigator to sponsor of serious adverse events and related reports 17) Notification by sponsor and/or investigator, where applicable, to regulatory authority(ies) and IRB(s)/IEC(s) of unexpected serious adverse drug reactions and of other safety information 18) Notification by sponsor to investigators of safety information 19) Interim or annual reports to IRB/IEC and authority(ies)

20) Subject screening log