MEDLINE INDIA - GOOD CLINICAL PRACTICE GUIDELINES

The Sponsor is responsible for selecting the Investigator(s) / Institutions taking into account the appropriateness and availability of the study site and facilities. The Sponsor must assure itself of the Investigator’s qualifications and availability for the entire duration of the Study. If organisation of a co-ordinating committee and / or selection of co-ordinating investigators are to be utilised in multi-centric studies their organisation and / or selection are Sponsor’s responsibilities.

Before entering an agreement with an Investigator(s) / Institution(s) to conduct a Study, the Sponsor should provide the Investigator(s) / Institution(s) with the Protocol and an up-to-date Investigator’s Brochure. Sponsor should provide sufficient time to review the Protocol and the information provided in the Investigator’s Brochure.

3.1.2. Contract

The Sponsor should enter into a formal and legal agreement / contract with the Investigator(s) / Institution(s) on the following terms:

a. To conduct the Study in compliance with GCP, the applicable regulatory requirements and the Protocol agreed to by the Sponsor and given approval / favourable opinion by the Ethics Committee

b. To comply with the procedures for data recording, and reporting

c. To permit monitoring, auditing and inspection

d. To retain the study related essential documents until the Sponsor informs the Investigator(s) / Institution(s) in writing that these documents are no longer needed

The agreement should define the relationship between the investigator and the sponsor in matters such as financial support, fees, honorarium, payments in kind etc.

The Sponsor should establish detailed Standard Operating Procedures (SOP’s). The Sponsor and the Investigator(s) should sign a copy of the Protocol and the SOPs or an alternative document to confirm their agreement.

3.1.4. Allocation of duties and responsibilities:

Prior to initiating a Study the Sponsor should define and allocate all Study related duties and responsibilities to the respective identified person(s) / organisation(s).

3.1.5. Study management, data handling and record keeping:

The Sponsor is responsible for securing agreement with all involved parties on the allocation of Protocol related and other responsibilities like:

a. Access to all Study related sites, source data / documents and reports for the purpose of inspection, monitoring and auditing by the authorised parties and inspection by national and foreign regulatory authorities

c. Breaking of the Code

d. Statistical analysis

e. Preparation of the Study Report

f. Preparation and submission of materials to the Ethics Committee, Regulatory Authorities and any other review bodies

g. Reporting the ADRs, AEs to the Ethics Committee

h. Quality Assurance and Quality Control systems with written SOPs to ensure that the Study is conducted and data are generated, documented (recorded), and reported – in compliance with the Protocol, GCP and the applicable regulatory requirement(s)

It shall be the responsibility of sponsor to make arrangements for safe and secure custody of all study related documents and material for a period of three years after the completion of the study or submission of the data to the regulatory authority(ies) whichever is later.

The Sponsor may consider establishing an Independent Data Monitoring Committee (IDMC) to assess the progress of the Study. This includes the safety data and the critical efficacy endpoints at various intervals, and to recommend to the Sponsor whether to continue, modify, or stop a Study. The IDMC should have written operating procedures and should maintain written records of all its meetings.

3.1.6. Compensation for Participation

Subjects may be paid compensation for participation in accordance with the guidelines listed in 2.4.5.

3.1.7. Confirmation of review by the Ethics Committee

The Sponsor shall obtain from the Investigator(s) and / or the Institutions

a. The particulars about the members of the Investigator’s / Institution’s Ethics Committee including their names, addresses, qualifications and experience

b. An undertaking that the Ethics Committee is organised and operates according to the GCP and the applicable laws and regulations

c. Documented approval / favourable opinion of the Ethics Committee before the initiation of the Study

d. A copy of the recommendations in case the Ethics Committee conditions its approval upon change(s) in any aspect of the Study such as modification(s) of the Protocol, written Informed Consent Form, any other written information and / or other procedures

e. Ethics Committee’s documents relating to re-evaluations / re-approvals with favourable opinion, and of any withdrawals or suspensions of approval / favourable opinion

3.1.8. Information on Investigational Products

As a prerequisite to planning of a Study, the Sponsor is responsible for providing the Investigator(s) with an Investigator’s Brochure. The Brochure must contain the available chemical, pharmaceutical, toxicological, pharmacological and clinical data including the available data from previous and ongoing clinical studies regarding the Investigational Product and, where appropriate, the Comparator Product. This information should be accurate and adequate to justify the nature, scale and the duration of the Study. In addition, the Sponsor must bring any relevant new information arising during the period of Study to the attention of the Investigator(s) as well as the Ethics Committee.

3.1.9. Supply, storage and handling of Pharmaceutical Products

The Sponsor is responsible for supplying the Investigational Product’s, including Comparator(s) and Placebo if applicable. The Products should be manufactured in accordance with the principles of GMPs and they should be suitably packaged in the manner that will protect the product from deterioration and safeguard blinding procedures (if applicable) and should be affixed with appropriate investigational labelling.

The Sponsor should determine the Investigational Product’s acceptable storage conditions, reconstitution procedures and devices for product infusions if any, and communicate them in writing to all involved parties, besides stating them on the Product labels where ever possible.

In case any significant formulation changes are made in the Investigational Product during the course of the Study - the results of any additional studies of the new formulation (e.g. stability, bioavailability, dissolution rate) should be provided to the involved parties to enable them to determine their effects on the pharmacokinetic profile of the Product prior to the use in the Study.

The Sponsor should not supply an Investigator / Institution with the Product until the Sponsor obtains all required documentation (e.g. approval / favourable opinion from Ethics Committee and Regulatory Authorities).

The Sponsor should document procedures and lay down responsibilities for

a. adequate and safe receipt, handling, storage, dispensing of the Product

b. retrieval of unused Product from the Subjects and

c. return of unused Product to the Sponsor (or its alternative disposal procedure).

Sponsor should maintain records for retrieval of Product (e.g. retrieval after study completion, expired product retrieval etc.).

Sponsor should also maintain records of the quantities of Investigational Product with proper batch numbers. The Sponsor should ensure that the Investigator is able to establish a system within his / her Institution for proper management of the Products as per the procedures.

The Sponsor should maintain sufficient samples from each batch and keep the record of their analyses and characteristics for reference, so that if necessary an independent laboratory may be able to recheck the same.

3.1.10. Safety Information:

Sponsor is responsible for the ongoing safety evaluation of the Product. The Sponsor should promptly notify all concerned of findings that could adversely affect the safety of the Subjects, impact the conduct of the Study or alter the Ethics Committee’s approval / favourable opinion to continue the Study. The Sponsor, together with Investigator(s), should take appropriate measures necessary to safeguard the study subjects.

3.1.11. Adverse Drug Reaction Reporting:

The Sponsor should provide ADR / AE reporting forms to the Investigator(s) / Institution(s). The Sponsor should expedite the reporting to all concerned (including the Ethics Committee and the regulatory authorities) of all serious and/or unexpected adverse drug reactions.

3.1.12. Study Reports:

The Sponsor should ensure the preparation and appropriate approval(s) of a comprehensive final clinical study report suitable for regulatory and / or marketing purposes, whether or not the study has been completed. All reports prepared should meet the standards of the GCP guidelines for Format and Content of Clinical Study Reports. The sponsor should also submit any safety updates and / or periodic reports as prescribed by the regulatory authorities.

3.1.13. Monitoring

Although an extensively written guidance can assure appropriate conduct of the study, the sponsor should ensure that the studies are adequately monitored. The determination of the extent and the nature of monitoring should be based on considerations such as objective, purpose, design, complexity, blinding, size and endpoints of the study. The sponsor must appoint adequately trained monitors or CRO to supervise an ongoing study.

3.1.14. Audit:

Sponsor should perform an audit as a part of QA system. This audit should be conducted with the purpose of being independent and separate from routine monitoring or quality control functions. Audit should evaluate the study conduct and compliance with the protocol, SOPs, GCPs and applicable regulatory requirements. For the purpose of carrying out the audit – the sponsor may appoint individuals qualified by training and experience to conduct audits. The Auditors should be independent of the parties involved in the study and their qualifications should be documented.

The Sponsor should ensure that the auditing is conducted in accordance with the Sponsor’s SOPs on what to audit, how to audit, the frequency of audit and the form & content of audit reports. Auditors should document their observations which should be archived by the Sponsors and made available to the Regulatory Authorities when called for.

Sponsor should initiate prompt action in case it is discovered that any party involved has not entirely complied with the GCP, SOPs, Protocol and / or any applicable regulatory requirements. If monitoring / auditing identifies serious and / or persistent non-compliance - the Sponsor should terminate the defaulting party’s participation in the study and promptly notify to the regulatory authority.

3.1.15. Multicentre Studies

Since multicentre studies are conducted simultaneously by several investigators at different institutions following the same protocol, the sponsor should make special administrative arrangements for their conduct. These administrative arrangements should provide adequate assurance that the study will be planned and conducted according to GCPs.

The various tasks that may need special consideration include responsibility for commencement and overall performance of the study, supervision of the data, monitoring of the ADRs / AEs and various other policy matters. The functions, responsibilities and mandate of any special committee(s) set up or person(s) should be described in the study protocol, along with the procedure for their nomination.

A co-ordinating committee may be set up or a co-ordinator appointed with responsibility for the control of practical performance and progress of the study and maintaining contact with the regulatory authorities and the ethics committee(s).

Ideally, the studies should begin and end simultaneously at all institutions.

The sponsor should make arrangements to facilitate the communication between investigators at various sites. All investigators and other specialists should be given the training to follow the same protocol and systems. The sponsor should obtain written acceptance of the protocol and its annexes from each of the investigator and institution involved.

The CRFs should be so designed as to record the required data at all multicentre sites. For those investigators who are collecting additional data, supplemental CRFs should be provided to record the additional data.

Before initiation of multi-centre studies the sponsor should carefully define and document the following:

a. ethics committee(s), and the number of ethics committees to be consulted

b. role and responsibilities of the co-ordinating investigators

c. role and responsibilities of the CRO

d. randomisation procedure

e. standardisation and validation of methods of evaluation and analyses of laboratory and diagnostic data at various centres

f. structure and function of a centralised data management set-up

3.1.16. Premature Termination or Suspension of a Study

In case the sponsor chooses to or is required to terminate prematurely or suspend the study, then the sponsor should notify the investigator(s), institution(s), the ethics committee and the regulatory authorities accordingly. The notification should document the reason(s) for the termination or suspension by the sponsor or by the investigator / institution.

3.1.17. Role of Foreign Sponsor

If the sponsor is a foreign company, organisation or person(s) – it shall appoint a local representative or CRO to fulfil the appropriate local responsibilities as governed by the national regulations. The Sponsor may transfer any or all of the Sponsor’s study related duties and functions to a CRO but the ultimate responsibility for the quality and the integrity of the Study Data shall always reside with the Sponsor. Any Study related duty, function or responsibility transferred to and assumed by a local representative or a CRO should be specified in writing. Any Study related duties, functions or responsibilities not specifically transferred to and assumed by a CRO or a local representative shall be deemed to have been retained by the Sponsor. The sponsor should utilise the services of qualified individuals e.g. bio-statisticians, clinical pharmacologists, and physicians, as appropriate, throughout all stages of the study process, from designing the protocol and CRFs and planning the analyses to analysing and preparing interim and final clinical study reports.

3.2. The Monitor:

The monitor is the principal communication link between the sponsor and the investigator and is appointed by the sponsor.

3.2.1. Qualifications

The monitor should have adequate medical, pharmaceutical and / or scientific qualifications and clinical trial experience. Monitor should be fully aware of all the aspects of the product under investigation and the protocol (including its annexes and amendments).

3.2.2. Responsibility

The main responsibility of the monitor is to oversee the progress of the study and to ensure that the study conduct and data handling comply with the protocol, GCPs and applicable ethical and regulatory requirements.

(a) The Monitor should verify that the investigator(s) have the adequate qualifications, expertise and the resources to carry out the study. Monitor should also confirm that the investigator(s) shall be available throughout the study period.

(b) Monitor should ascertain that the institutional facilities like laboratories, equipment, staff, storage space etc. are adequate for safe and proper conduct of the study and that they will remain available throughout the study.

1. the investigational product(s) are sufficiently available throughout the study and is stored properly

2. the investigational product(s) are supplied only to subjects who are eligible to receive it and at the specified dose(s) and time(s)

3. the subjects are provided with the necessary instructions on proper handling of the product(s)

4. the receipt, use, return and disposal of the product(s) at the site are controlled and documented as prescribed

5. the investigator receives the current Investigator’s Brochure and all supplies needed to conduct the study as per the protocol

6. the investigator follows the protocol

7. the investigator maintains the essential documents

8. all parties involved are adequately informed about various aspects of the study and follow the GCP guidelines and the prescribed SOPs

9. verifying that each party is performing the specified function in accordance with the protocol and / or in accordance with the agreement between the sponsor and the party concerned

10. verifying that none of the parties delegate any assigned function to unauthorised individuals

(d) The monitor should promptly inform the sponsor and the ethics committee in case any unwarranted deviation from the protocol or any transgression of the principles embodied in GCP is noted.

(e) The monitor should follow a pre-determined written set of SOPs. A written record should be kept of the monitor’s visits, phone calls and correspondence with the investigators and any other involved parties.

(f) The monitor should assess the institution(s) prior to the study to ensure that the premises and facilities are adequate and that an adequate number of subjects is likely to be available during the study.

(g) The monitor should observe and report the subject recruitment rate to the sponsor.

(h) The monitor should visit the investigator before, during and after the study to make assessments of the protocol compliance and data handling in accordance with the predetermined SOPs.

(i) The monitor should ensure that all staff assisting the investigator in the study have been adequately informed about and will comply with the protocol, SOPs and other details of the study.

(j) The monitor should assist the investigator in reporting the data and results of the study to the sponsor, e.g. by providing guidance on correct procedures for CRF completion and by providing data verification.

(k) The monitor shall be responsible for ensuring that all CRFs are correctly filled out in accordance with original observations, are legible, complete, and dated. The monitor should specifically verify that

1. the data required by the protocol are reported accurately on the CRFs and are consistent with the source documents

2. any dose and / or therapy modifications are well documented for each of the study subjects

3. adverse events, concomitant medications and inter-current illnesses are promptly reported on the CRFs in accordance with the protocol and the SOPs

4. visits that the subjects fail to make, tests that are not conducted and examinations that are not performed are clearly reported as such on the CRFs

5. all withdrawals and drop-outs of enrolled subjects from the study are reported and explained on the CRFs

(l) Any deviations, errors or omissions should be promptly clarified with the investigator, corrected and explained on the CRF. Monitor should also take appropriate actions designed to prevent recurrence of detected deviations. Monitor should ensure that investigator certifies the accuracy of CRF by signing it at the places provided for the purpose. All procedures for ensuring accuracy of CRFs must be maintained throughout the course of the study.

(m) The monitor should submit a written report to the sponsor after each site visit and after all telephone calls, letters and other correspondence with the investigator. Monitor’s report should include the date, name of site, names of the monitor and the individuals contacted, a summary of what the monitor reviewed, findings, deviations & deficiencies observed, and any actions taken / proposed to secure compliance. The review and follow-up of the monitoring report with the sponsor should be documented by the sponsor’s designated representative.

(n) The monitor should confirm that the prescribed procedures for storage, handling, dispensing and return of investigational product are being followed and their compliance is being documented in a form as in the SOPs.

3.3. Investigator

3.3.1. Qualifications

The investigator should be qualified by education, training and experience to assume responsibility for the proper conduct of the study and should have qualifications prescribed by the Medical Council of India (MCI). The investigator should provide a copy of the curriculum vitae and / or other relevant documents requested by the sponsor, the ethics committee, the CRO or the regulatory authorities. He / she should clearly understand the time and other resource demands the study is likely to make and ensure they can be made available throughout the duration of the study. The investigator should also ensure that other studies do not divert essential subjects or facilities away from the study at hand.

The investigator should be thoroughly familiar with the safety, efficacy and appropriate use of the investigational product as described in the protocol, investigator’s brochure and other information sources provided by the sponsor from time to time.

The investigator should be aware of and comply with GCPs, SOPs and the applicable regulatory requirements.

3.3.2. Medical care of the study subjects

A qualified Medical Practitioner (or a Dentist, when appropriate) who is an Investigator or a Co-Investigator for the study should be responsible for all study related medical decisions. Investigator has to ensure that adequate medical care is provided to a subject for any adverse events including clinically significant laboratory values related to the study. Investigator should inform the subject when medical care is needed for inter-current illness(es) of which the investigator becomes aware. Investigator should also inform the subject’s other attending physician(s) about the subject’s participation in the study if the subject has another attending physician(s) and if the subject agrees to such other physician(s). Subsequent to the completion of the study or dropping out of the subject(s) the investigator should ensure that medical care and relevant follow-up procedures are maintained as needed by the medical condition of the subject and the study and the interventions made.

Although a subject is not obliged to give reason(s) for withdrawing prematurely from a study, the investigator should make a reasonable effort to ascertain the reason(s) while fully respecting the subject’s rights.

3.3.3. Monitoring and Auditing of Records

The investigator / institution shall allow monitoring and auditing of the records, procedures and facilities, by the sponsor, the ethics committee, CRO or their authorised representative(s) or by the appropriate regulatory authority. The investigator should maintain a list of appropriately qualified person(s) to whom the investigator has delegated study-related duties.

Investigator should ensure that all persons involved in the study are adequately informed about the protocol, SOPs, the investigational product(s) and their study related duties and functions.

3.3.4. Communication with Ethics Committee

Before initiating a study the investigator / institution must ensure that the proposed study has been reviewed and accepted in writing by the relevant ethics committee(s) for the protocol, written informed consent form, subject recruitment procedures (e.g. advertisements) and any written / verbal information to be provided to the subjects.

The investigator should promptly report to the ethics committee, the monitor and the sponsor:

1. deviations from or changes of, the protocol to eliminate immediate hazards to the subjects

2. changes that increase the risk to subject(s) and / or affecting significantly the conduct of the study

3. all adverse drug reactions and adverse events that are serious and / or unexpected

4. new information that may adversely affect safety of the subjects or the conduct of the study

5. for reported deaths the investigator should supply any additional information e.g. autopsy reports and terminal medical reports.

3.3.5. Compliance with the protocol

The investigator / institution must agree and sign the protocol and / or another legally acceptable document with the sponsor, mentioning the agreement with the protocol, and confirm in writing that he / she has read and understood the protocol, GCPs and SOPs and will work as stipulated in them.

The investigator may implement a deviation from, or change of protocol to eliminate an immediate hazard(s) to study subjects without prior ethics committee approval / favourable opinion. The implemented deviation or change, the reasons for it and if appropriate the proposed protocol amendment(s) should be submitted by the investigator to the ethics committee (for review and approval / favourable opinion), to the sponsor (for agreement) and if required to the regulatory authority(ies).

The investigator or person designated by him/her should document and explain any deviation from the approved protocol. The Investigator should follow the study randomisation procedure, if any, and should ensure that the randomisation code is broken only in accordance with the Protocol. If the study is blinded, the Investigator should promptly document and explain to the Sponsor any premature un-blinding e.g. accidental un-blinding, un-blinding due to serious adverse event) of the Investigational Product(s).

3.3.6. Investigational Product(s)

Investigator has the primary responsibility for investigational product(s) accountability at the study site(s). Investigator should maintain records of the product’s delivery to the study site, the inventory at the site, the use by each subject, and the return to the sponsor or the alternative disposal of the unused product(s). These records should include dates, quantities, batch / serial numbers, expiry dates if applicable, and the unique code number assigned to the investigational product packs and study subjects. Investigator should maintain records that describe that the subjects were provided the dosage specified by the protocol and reconcile all investigational products received from the sponsor. Investigator should ensure that the product(s) are stored under specified conditions and are used only in accordance with the approved protocol.

The investigator should assign some or all of his / her duties for investigational product’s accountability at the study site(s) to his subordinate who is under the supervision of the investigator / institution. The investigator or subordinate should explain the correct use of the product(s) to each subject and should check at intervals appropriate for the study that each subject is following the instructions properly. The person who carries them out should document such periodic checks.

3.3.7. Selection and recruitment of study subjects:

The investigator is responsible for ensuring the unbiased selection of an adequate number of suitable subjects according to the protocol. It may be necessary to secure the co-operation of other physicians in order to obtain a sufficient number of subjects. In order to assess the probability of an adequate recruitment rate for subjects for the study it may be useful to determine prospectively or review retrospectively the availability of the subjects. Investigator should check whether the subject(s) so identified could be included in the study according to the protocol. The investigator should keep a confidential list of names of all Study Subjects allocated to each study. This list facilitates the investigator / institution to reveal identity of the subject(s) in case of need and also serve as a proof of Subject’s existence. The investigator / institution shall also maintain a Subjects’ screening log to document identification of Subjects who enter pre-study screening. A Subject’s enrolment log shall also be maintained to document chronological enrolment of Subjects in a particular Study.

The Investigator is responsible for giving adequate information to subjects about the trial in accordance with the GCP. The nature of the investigational product and the stage of development and the complexity of the study should be considered in determining the nature and extent of the information that should be provided.

Obligations of investigators regarding informed consent: The investigator has the duty to -

1. Communicate to prospective subjects all the information necessary for informed consent. There should not be any restriction on subject's right to ask any questions related to the study as any restriction on this undermines the validity of informed consent.

2. Exclude the possibility of unjustified deception, undue influence and intimidation. Deception of the subject is not permissible However, sometimes information can be withheld till the completion of study, if such information would jeopardize the validity of research.

3. Seek consent only after the prospective subject is adequately informed. Investigator should not give any unjustifiable subject's decision to participate in the study.

4. As a general rule obtain from each prospective subject a signed form as an evidence of informed consent (written informed consent) preferably witnessed by a person not related to the trial, and in case of incompetence to do so, a legal guardian or other duly authorised representative.

5. Renew the informed consent of each subject, if there are material changes in the conditions or procedures of the research or new information becomes available during the ongoing trial.

6. Not use intimidation in any form which invalidates informed consent. The investigator must assure prospective subjects that their decision to participate or not will not affect the patient-clinician relationship or any other benefits to which they are entitled.

As part of the information provided to the Subject, the Investigator should supply subjects with, and encourage them to carry with them, information about their participation in the trial and information about contact persons who can assist in an emergency situation.

3.3.8. Records/Reports

The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports. Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained.

Any change or correction to the CRF should be dated, signed and explained (if necessary) and should not obscure the original entry (i.e. an audit trail should be maintained); this applies to both written and electronic changes or corrections.

Sponsor should provide guidelines to investigators and / or the investigator’s designated representatives on making such corrections and should have written procedures to assure that changes in CRFs are documented and endorsed by the Investigator. The Investigator should retain records of the changes and corrections.

Progress Reports

The investigator should submit the written summaries of the study status at the periodicity specified in the protocol to the person(s) / organisation(s) to whom the investigator is reporting. All reportings made by the investigator should identify the subjects by unique code numbers assigned to the study subjects rather than by the subjects’ name(s), personal identification number(s) and / or addresses.

Termination and final report:

In case the investigator and sponsor agree to prematurely terminate or suspend the study for any reason, the investigator / institution should promptly inform the study Subjects, the Ethics Committee as well as the Regulatory Authorities. The investigators should also ensure appropriate therapy and follow-up for the subjects.

However, if the investigator or the sponsor or the ethics committee decide to terminate or suspend the study without prior agreement of all parties concerned then the party initiating the suspension / termination should promptly inform all the concerned parties about such suspension / termination and suspension along with a detailed written explanation for such termination / suspension.

The Investigator should maintain documents as specified in the essential documents’ list and take measures to prevent accidental or premature destruction.

The study can be closed only when the Investigator (or the Monitor or CRO – if this responsibility has been delegated to them) has reviewed both Investigator / Institution and Sponsor files and confirm that all necessary documents are in the appropriate files.

The completion of the study should be informed by the investigator to the institution, the sponsor and the ethics committee. The investigator should sign and forward the data (CRFs, results and interpretations, analyses and reports, of the study from his / her centre to the sponsor and the ethics committee. Collaborative investigators and those responsible for the analyses (including statistical analyses) and the interpretation of the results must also sign the relevant portions of the study report. Investigator should submit his signed and dated final report to the institution, the ethics committee and the sponsor verifying the responsibility for the validity of data.

In case of a multi-centre study – the signature of the co-ordinating investigator may suffice if agreed in the protocol.

In case the investigator is the sponsor then he / she assumes the responsibilities of both the functionaries.

The investigator should familiarise himself / herself with the various other responsibilities assigned to him/her under the protocol and ensure that they are carried out as expected.

Responsibilities