UNIT IV

UNIT IV

History and purpose of GCP development of ICH GCP   

History of GCP

Early 1960s : Widespread concern about the safety and control of investigational drugs and the clinical research process developed among member of the medical profession, the scientific

community, regulatory authorities, and general public.

WHO WHO’s s “Guidelines for Good Clinical Practice (GCP) for trials on pharmaceutical products products”1995.

• The GCP guideline is Topic E6 ICH, 1997

• International Standard Organization (ISO), “Clinical investigation of medical devices for human subjects, Part I (General requirements) and Part 2 (Clinical investigation plans) (2001)

• Pan American Health Organization (PAHO). Pan American Network on Drug Regulatory Harmonization (PANDRH). “GCP: Document of the Americas Americas” (2005)

History of ICH--GCP

•Need for safe and efficient products for various health problemshealth problems

•Drug development is expensive and time consumingDrug consuming

•Need for efficient quality systemsNeed systems••Global drug marketGlobal market

•Existence of national laws and regulations for drug developmentdevelopment.

Goal

• To provide a unified standard to facilitate the mutual acceptance of clinical data by the

regulatory authorities

• Remove redundancy /duplication in development and review process.

Process

• Developed guidelines applicable for

• Drugs

• Biologics

• Medical devices

• Approved by ICH members

• Adopted by National Regulatory Authorities

Good Clinical Practice (GCP)

An international ethical and scientific quality standard for designing, conducting, recording, and

reporting trials that involve the participation of human subjects Public assurance that the rights, safety, and well well- being of trial subjects are protected

• Consistent with the Declaration of Helsinki

• Results in credible data

Who are responsible for GCP

The responsibility for GCP is shared by all of the parties involved, including including:

– sponsors

– investigators and site staff

– contract research organizations ( CROs CROs)

– ethics committees

– regulatory authorities

– research subjects.

WHO Principles of GCP

Principle 1 : Ethical Conduct

Research involving humans should be scientifically sound and conducted in accordance with basic ethical principles, which have their origin in the Declaration of Helsinki. Three basic ethical principles of equal importance, namely respect for persons, beneficence, and justice justice, permeate all other GCP principles.

Principle 2 Research Described in a Protocol Research involving humans should be scientifically justified and described in a clear, detailed protocol.

Principle 3: Risk Identification :

Before research involving humans is initiated,

foreseeable risks and discomforts and any

anticipated benefit (s) for the individual

research subject and society should be

identified. Research of investigational products

or procedures should be supported by

adequate non non-clinical and, when applicable,

clinical information.

Principle 4: Benefit Benefit-Risk Assessment

Research involving humans should be initiated only if the anticipated benefit(s s) for the ) individual research subject and society clearly outweigh the risks. Although the benefit of the results of the trial to science and society should be taken into account, the most important considerations are those related to the rights, safety, and well well-being of the research subjects.

Principle 5 : Review by IEC/IRB

Research involving humans should receive independent ethics committee/institutional review board (IEC/IRB) approval/ favourable opinion prior to initiation

Principle 6 : Protocol Compliance

Research involving humans should be conducted in compliance with the approved

protocol.

Principle 7 : Informed Consent

Freely given informed consent should be obtained from every subject prior to research participation in accordance with national culture (s) and requirements. When a subject is not capable of giving informed consent, the permission of a legally authorized representative should be obtained in accordance with applicable law.

Principle 8 : Continuing Review/Ongoing

Benefit Benefit-Risk Assessment Research involving humans should be continued only if the benefit benefit-risk profile remains favorable.      

Principle 9 : Investigator Qualifications

Qualified and duly licensed medical personnel (i.e. physician or, when appropriate, dentist) should be responsible for the medical care of research subjects, and for any medical decision (s) made on their behalf.         

Principle 10: Staff Qualifications

Each individual involved in conducting a trial should be qualified by education, training,

and experience to perform his or her respective task (s) and currently licensed to

do so, where required.

Principle 11 : Records

All clinical trial information should be recorded, handled, and stored in a way that

allows its accurate reporting, interpretation, and verification.

Principle 12 : Confidentiality/Privacy

The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement (s)

Principle 13 : Good Manufacturing Practice

Investigational products should be manufactured, handled, and stored in accordance with applicable Good Manufacturing Practice (GMP) and should be used in accordance with the approved protocol.

Principle 14: Quality Systems

Systems with procedures that assure the quality of every aspect of the trial should be implemented.

                                  

GCP Design Standards

• Written protocol

• Investigator brochure

• Scientific soundness

• Feasibility

• Adequate resources

• Randomization / blinding

GCP Conduct Standards

• IRB & Regulatory approval

• Compliance with protocol

• Informed consent

• Confidentiality of data

• Medical management of adverse events

• Product accountability

• Qualification & training

GCP Recording Standards

• CRF completion

• Data handling

• Security maintenance

• Audit requirements

• Product accountability

• Management of study files/essential

Documents

GCP Reporting Standards

• Adverse events

• Interim reviews

• Progress reports

• Final reports

• Monitoring / audit reports

To ••SponsorsSponsors••IRB/IECIRB/IEC••Regulatory authoritiesRegulatory authorities

• Other investigators

(ref : http://www.jirb.org.tw/DB/File/Download/970127 03_History%20and %20 Principles% 20of%20 Good%20Clinical%20PracticeTaipei_Christine%20Maure.pdf)

Roles and responsibilities in clinical research according to ICH GCP

Roles and Responsibilities of Clinical Research Coordinator (CRC)

Categories: Clinical Research, Ethics in Clinical Research  |  Tags: CRC job profile, Role of Clinical Research Coordinator (CRC), Role of CRC, Roles and Responsibilities of a CRC

A clinical research coordinator (CRC) is responsible for conducting clinical trials at clinical trial sites according to the protocol, ICH-GCP and other regulatory requirements. The role of a study coordinator in clinical trials is very important. Every clinical trial site may have one or more study coordinators depending on the workload at the trial site. Clinical trials at site level can be roughly divided into 3 stages. Let us discuss about the role of the study coordinator in these three stages. The three stages are:

1) Before the start of the clinical trial

2) During the conduct of the clinical trial

3) After close out of the clinical trial

1) Before the start of the Clinical Trial:

During this stage the study coordinator has to collect and complete feasibility questionnaires received form different CRO’s and Sponsor’s. CRC’s also have to collect required information from the principal investigator, and send it back to the respective people who contacted the site regarding the study. Sponsors select sites based on the responses filled in the feasibility questionnaire and conduct Pre-site selection visits to confirm the sites participating in the study.

The sponsors or CRO’s after selecting clinical trial sites conduct Investigator meetings, which have to be attended by the study coordinator along with the principal or co-investigator. Investigator meetings are conducted either at national level or international level. Before start of the trial CRC’s are usually busy with submitting all study documents to the ethics committee.

Documents to be submitted to the ethics committee normally include the study protocol, investigator brochure and informed consent forms (vernacular languages at site) with translation certificates. If any amendments are available those also need to be submitted to the ethics committee. In addition to these documents, investigator’s CV with MRC, FDA-1572, Financial disclosure forms, Insurance statement, subject diaries if applicable, clinical trial agreement, indemnification letter, protocol signature page and different study logs, eCRF or CRF entry guidelines, blank CRF’s etc also need to be submitted.

In all these processes a clinical study coordinator plays a vital role. After obtaining approval from the ethics committee the clinical trial can be initiated at the site level.

2) During the conduct of clinical trial:

By the time a clinical trial is initiated at a site the CRC must have a good understanding of the study protocol and must know well about inclusion and exclusion criteria. During the screening time, the study coordinator has to obtain informed consent from the subject in if delegated to do so by the Principal Investigator. Study coordinators have to collect subjects previous medical records and according to study protocol he/she has to conduct subjects scheduled visits. Before randomization visit of the subject the CRC must check inclusion and exclusion criteria thoroughly, and only then eligible subjects must be enrolled into the study.

After completion of all visit procedures coordinators have to enter data in case report forms (CRF). CRF’s are two types, one is paper CRF and another one is eCRF. eCRF’s are usually of 5 types namely , Phase forward – Inform, oracle clinical remote data capture, medi data rave, novartis EDC (or) Pasco and Data track. All the visit details like demographics, vital signs, subject past medical history, any SAE or AE details have to be entered in these online data collection tools based on source documentation available. During monitoring, sponsor representatives (CRA’s) cross verify both the source documents & the data filled by the CRC in the case report forms. During the monitoring visit the CRA’s also verify EC notifications and Investigator Site Files (ISF). To keep all these documents up to date is the responsibility of the clinical study coordinator. Study coordinator also has to maintain site SOP’s, EC sops and EC members list.

Whenever study subjects come for next schedule visit, study drug accountability has to be calculated by the CRC. Along with that subject diaries have to be reviewed if applicable. IVRS (Interactive voice response system) and IWRS (Interactive web response system) to record the subject visit have to be performed as per the study requirement. IVRS reports have to be maintained in the ISF’s. IP (Investigational product) is the major part in clinical trial and study coordinators have to store the same in proper condition and maintain required temperature logs.

In case of any adverse events (AE’s) or serious adverse events (SAE’s) that occurred at the trial site, coordinators have to collect all applicable details such as start date, stop date, severity (Mild, Moderate or Severe), concomitant medications consumed by the subject and the route of administration. Also information related to any dechallenge and rechallenge, therapy provided to the subject during the SAE, recovery details and whether it is related to study drug or not have to be collected. Study Coordinators have to notify SAE’s to the Ethics committee within 7 working days and details of SAE have to sent to the sponsor within 24 hours.

Throughout the clinical trial the study coordinators have to check all Central lab reports as well as local lab reports and take PI signatures on them to document that the PI reviewed the lab reports. CRC is also responsible for telephonic reminders to the subjects regarding the visits. If the CRC is involved in data entry then it is the study coordinators responsibility to resolve all queries within 48 hours or as per timeline specified by the sponsor. Queries are of three types i.e. 1) system generated queries 2) data management generated queries and 3) CRA generated queries.

3) After Close out of clinical trial:

Before a clinical trial is closed at the site, study coordinators have to check all documents and all the documents have to be updated. On the day of close out CRA will verify all documents. After verification of all documents by the CRA, CRC will assist in archiving the documents at site. Site has to maintain all study related records for 15 to 20 years.

As you can see a CRC plays a vital role in managing a clinical trial at the site level and acts as a link between the sponsor, EC and the Investigator Site.

(Ref: http://www.jli.edu.in/blog/roles-and-responsibilities-of-clinical-research-coordinator-crc/)

Sponser

5. SPONSOR

5.1 Quality Assurance and Quality Control

5.1.1 The sponsor is responsible for implementing and maintaining quality  assurance and quality control systems with written SOPs to ensure that trials  are conducted and data are generated, documented (recorded), and reported in  compliance with the protocol, GCP, and the applicable regulatory requirement(s).

5.1.2 The sponsor is responsible for securing agreement from all involved parties to  ensure direct access (see 1.21) to all trial related sites, source data/documents ,  and reports for the purpose of monitoring and auditing by the sponsor, and  inspection by domestic and foreign regulatory authorities.

5.1.3 Quality control should be applied to each stage of data handling to ensure that  all data are reliable and have been processed correctly.

5.1.4 Agreements, made by the sponsor with the investigator/institution and any  other parties involved with the clinical trial, should be in writing, as part of  the protocol or in a separate agreement.

5.2 Contract Research Organization (CRO)

5.2.1 A sponsor may transfer any or all of the sponsor's trial-related duties and  functions to a CRO, but the ultimate responsibility for the quality and  integrity of the trial data always resides with the sponsor. The CRO should  implement quality assurance and quality control.

5.2.2 Any trial-related duty and function that is transferred to and assumed by a  CRO should be specified in writing.

5.2.3 Any trial-related duties and functions not specifically transferred to and  assumed by a CRO are retained by the sponsor.

5.2.4 All references to a sponsor in this guideline also apply to a CRO to the extent  that a CRO has assumed the trial related duties and functions of a sponsor.

5.3 Medical Expertise

The sponsor should designate 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.

5.4 Trial Design

5.4.1 The sponsor should utilize 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.

5.4.2 For further guidance: Clinical Trial Protocol and Protocol Amendment(s) (see 6.), the ICH Guideline for Structure and Content of Clinical Study Reports,  and other appropriate ICH guidance on trial design, protocol and conduct.

5.5 Trial Management, Data Handling, and Record Keeping

5.5.1 The sponsor should utilize 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.

5.5.2 The sponsor may consider establishing an independent data-monitoring  committee (IDMC) to assess the progress of a clinical trial, including the safety  data and the critical efficacy endpoints at intervals, and to recommend to the  sponsor whether to continue, modify, or stop a trial. The IDMC should have  written operating procedures and maintain written records of all its meetings.

5.5.3 When using electronic trial data handling and/or remote electronic trial data  systems, the sponsor should:

(a) Ensure and document that the electronic data processing system(s)  conforms to the sponsor’s established requirements for completeness,  accuracy, reliability, and consistent intended performance (i.e. validation).

(b) Maintains SOPs for using these systems.

(c) Ensure that the systems are designed to permit data changes in such a  way that the data changes are documented and that there is no deletion of  entered data (i.e. maintain an audit trail, data trail, edit trail).

(d) Maintain a security system that prevents unauthorized access to the data.

(e) Maintain a list of the individuals who are authorized to make data changes

(see 4.1.5 and 4.9.3).

(f) Maintain adequate backup of the data.

(g) Safeguard the blinding, if any (e.g. maintain the blinding during data  entry and processing).

5.5.4 If data are transformed during processing, it should always be possible to

compare the original data and observations with the processed data.

5.5.5 The sponsor should use an unambiguous subject identification code (see 1.58)  that allows identification of all the data reported for each subject.

5.5.6 The sponsor, or other owners of the data, should retain all of the sponsorspecific essential documents pertaining to the trial (see 8. Essential Documents for the Conduct of a Clinical Trial).

5.5.7 The sponsor should retain 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).

5.5.8 If the sponsor discontinues the clinical development of an investigational  product (i.e. for any or all indications, routes of administration, or dosage  forms), the sponsor should maintain all sponsor-specific essential documents  for at least 2 years after formal discontinuation or in conformance with the  applicable regulatory requirement(s).

5.5.9 If the sponsor discontinues the clinical development of an investigational  product, the sponsor should notify all the trial investigators/institutions and  all the regulatory authorities.

5.5.10 Any transfer of ownership of the data should be reported to the appropriate  authority(ies), as required by the applicable regulatory requirement(s).

5.5.11 The sponsor specific essential documents should be retained until at least 2  years after the last approval of a marketing application in an ICH region and  until there are no pending or contemplated marketing applications in an ICH  region or at least 2 years have elapsed since the formal discontinuation of  clinical development of the investigational product. These documents should  be retained for a longer period however if required by the applicable regulatory  requirement(s) or if needed by the sponsor.

5.5.12 The sponsor should inform the investigator(s)/institution(s) in writing of the  need for record retention and should notify the investigator(s)/institution(s) in  writing when the trial related records are no longer needed.

5.6 Investigator Selection

5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s). Each  investigator should be qualified by training and experience and should have  adequate resources (see 4.1, 4.2) to properly conduct the trial for which the  investigator is selected. If organization of a coordinating committee and/or  selection of coordinating investigator(s) are to be utilized in multicentre trials,  their organization and/or selection are the sponsor's responsibility.

5.6.2 Before entering an agreement with an investigator/institution to conduct a  trial, the sponsor should provide the investigator(s)/institution(s) with the  protocol and an up-to-date Investigator's Brochure, and should provide  sufficient time for the investigator/institution to review the protocol and the  information provided.

5.6.3 The sponsor should obtain the investigator's/institution's agreement:

(a) to conduct the trial in compliance with GCP, with the applicable regulatory  requirement(s) (see 4.1.3), and with the protocol agreed to by the sponsor  and given approval/favourable opinion by the IRB/IEC (see 4.5.1);

(b) to comply with procedures for data recording/reporting;

(c) to permit monitoring, auditing and inspection (see 4.1.4) and

(d) to retain the trial related essential documents until the sponsor informs  the investigator/institution these documents are no longer needed (see

4.9.4 and 5.5.12).

The sponsor and the investigator/institution should sign the protocol, or an  alternative document, to confirm this agreement.

5.7 Allocation of Responsibilities

Prior to initiating a trial, the sponsor should define, establish, and allocate all trialrelated duties and functions.

5.8 Compensation to Subjects and Investigators

5.8.1 If required by the applicable regulatory requirement(s), the sponsor should  provide 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.

5.8.2 The sponsor's policies and procedures should address the costs of treatment of  trial subjects in the event of trial-related injuries in accordance with the  applicable regulatory requirement(s).

5.8.3 When trial subjects receive compensation, the method and manner of  compensation should comply with applicable regulatory requirement(s).

5.9 Financing

The financial aspects of the trial should be documented in an agreement between the  sponsor and the investigator/institution.

5.10 Notification/Submission to Regulatory Authority(ies)

Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator,  if required by the applicable regulatory requirement(s)) should submit any required  application(s) to the appropriate authority(ies) for review, acceptance, and/or  permission (as required by the applicable regulatory requirement(s)) to begin the  trial(s). Any notification/submission should be dated and contain sufficient  information to identify the protocol.

5.11 Confirmation of Review by IRB/IEC

5.11.1 The sponsor should obtain 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/favourable opinion and, if requested by the  sponsor, a current copy of protocol, written informed consent form(s) and  any other written information to be provided to subjects, subject recruiting  procedures, and documents related to payments and compensation  available to the subjects, and any other documents that the IRB/IEC may

have requested.

5.11.2 If the IRB/IEC conditions its approval/favourable opinion upon change(s) in  any aspect of the trial, such as modification(s) of the protocol, written informed  consent form and any other written information to be provided to subjects,  and/or other procedures, the sponsor should obtain from the  investigator/institution a copy of the modification(s) made and the date  approval/favourable opinion was given by the IRB/IEC.

5.11.3 The sponsor should obtain from the investigator/institution documentation  and dates of any IRB/IEC reapprovals/re-evaluations with favourable opinion,  and of any withdrawals or suspensions of approval/favourable opinion.

5.12 Information on Investigational Product(s)

5.12.1 When planning trials, the sponsor should ensure 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.

5.12.2 The sponsor should update the Investigator's Brochure as significant new  information becomes available (see 7. Investigator's Brochure).

5.13 Manufacturing, Packaging, Labelling, and Coding Investigational  Product(s)

5.13.1 The sponsor should ensure that the investigational product(s) (including active  comparator(s) and placebo, if applicable) is characterized as appropriate to the  stage of development of the product(s), is manufactured in accordance with any  applicable GMP, and is coded and labelled in a manner that protects the  blinding, if applicable. In addition, the labelling should comply with applicable  regulatory requirement(s).

5.13.2 The sponsor should determine, for the investigational product(s), acceptable  storage temperatures, storage conditions (e.g. protection from light), storage  times, reconstitution fluids and procedures, and devices for product infusion, if  any. The sponsor should inform all involved parties (e.g. monitors,  investigators, pharmacists, storage managers) of these determinations.

5.13.3 The investigational product(s) should be packaged to prevent contamination  and unacceptable deterioration during transport and storage.

5.13.4 In blinded trials, the coding system for the investigational product(s) should  include a mechanism that permits rapid identification of the product(s) in case  of a medical emergency, but does not permit undetectable breaks of the  blinding.

5.13.5 If significant formulation changes are made in the investigational or  comparator product(s) during the course of clinical development, the results of  any additional studies of the formulated product(s) (e.g. stability, dissolution  rate, bioavailability) needed to assess whether these changes would  significantly alter the pharmacokinetic profile of the product should be  available prior to the use of the new formulation in clinical trials.

5.14 Supplying and Handling Investigational Product(s)

5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with  the investigational product(s).

5.14.2 The sponsor should not supply an investigator/institution with the  investigational product(s) until the sponsor obtains all required documentation  (e.g. approval/favourable opinion from IRB/IEC and regulatory authority(ies)).

5.14.3 The sponsor should ensure that written procedures include instructions that  the investigator/institution should follow for the handling and storage of  investigational product(s) for the trial and documentation thereof. The  procedures should address adequate and safe receipt, handling, storage,  dispensing, retrieval of unused product from subjects, and return of unused  investigational product(s) to the sponsor (or alternative disposition if  authorized by the sponsor and in compliance with the applicable regulatory  requirement(s)).

5.14.4 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(s) (see 8. Essential Documents  for the Conduct of a Clinical Trial).

(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.

5.14.5 The sponsor should:

(a) Take steps to ensure that the investigational product(s) are stable over the  period of use.

(b) 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. To the  extent stability permits, samples should be retained either until the  analyses of the trial data are complete or as required by the applicable  regulatory requirement(s), whichever represents the longer retention  period.

5.15 Record Access

5.15.1 The sponsor should ensure 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.

5.15.2 The sponsor should verify 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.

5.16 Safety Information

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

5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s)  and the regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC's  approval/favourable opinion to continue the trial.

5.17 Adverse Drug Reaction Reporting

5.17.1 The sponsor should expedite the reporting to all concerned  investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the  regulatory authority(ies) of all adverse drug reactions (ADRs) that are both  serious and unexpected.

5.17.2 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.

5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates  and periodic reports, as required by applicable regulatory requirement(s).

5.18 Monitoring

5.18.1 Purpose

 The purposes of trial monitoring are to verify that:

(a) The rights and well-being of human subjects are protected.

(b) The reported trial data are accurate, complete, and verifiable from source  documents.

(c) The conduct of the trial is in compliance with the currently approved  protocol/amendment(s), with GCP, and with the applicable regulatory  requirement(s).

5.18.2 Selection and Qualifications of Monitors

(a) Monitors should be appointed by the sponsor.

(b) Monitors should be appropriately trained, and should have the scientific  and/or clinical knowledge needed to monitor the trial adequately. A  monitor’s qualifications should be documented.

(c) Monitors should be 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).

5.18.3 Extent and Nature of Monitoring

 The sponsor should ensure that the trials are adequately monitored. The  sponsor should determine the appropriate extent and nature of monitoring.  The determination of the extent and nature of monitoring should be based on  considerations such as the objective, purpose, design, complexity, blinding,  size, and endpoints of the trial. In general there is a need for on-site  monitoring, before, during, and after the trial; however in exceptional  circumstances the sponsor may determine that central monitoring in  conjunction with procedures such as investigators’ training and meetings, and  extensive written guidance can assure appropriate conduct of the trial in  accordance with GCP. Statistically controlled sampling may be an acceptable  method for selecting the data to be verified.

5.18.4 Monitor's Responsibilities

The monitor(s) in accordance with the sponsor’s requirements should ensure  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:

(a) Acting as the main line of communication between the sponsor and the  investigator.

(b) Verifying that the investigator has adequate qualifications and resources  (see 4.1, 4.2, 5.6) and remain adequate throughout the trial period, that  facilities, including laboratories, equipment, and staff, are adequate to  safely and properly conduct the trial and remain adequate throughout the  trial period.

(c) Verifying, for the investigational product(s):

(i) That storage times and conditions are acceptable, and that supplies  are sufficient throughout the trial.

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

(iii) That subjects are provided with necessary instruction on properly  using, handling, storing, and returning the investigational  product(s).

(iv) That the receipt, use, and return of the investigational product(s) at  the trial sites are controlled and documented adequately.

(v) That the disposition of unused investigational product(s) at the trial  sites complies with applicable regulatory requirement(s) and is in  accordance with the sponsor.

(d) Verifying that the investigator follows the approved protocol and all  approved amendment(s), if any.

(e) Verifying that written informed consent was obtained before each subject's  participation in the trial.

(f) Ensuring that the investigator receives the current Investigator's  Brochure, all documents, and all trial supplies needed to conduct the trial  properly and to comply with the applicable regulatory requirement(s).

(g) Ensuring that the investigator and the investigator's trial staff are  adequately informed about the trial.

(h) Verifying that the investigator and the investigator's trial staff are  performing the specified trial functions, in accordance with the protocol  and any other written agreement between the sponsor and the  investigator/institution, and have not delegated these functions to  unauthorized individuals.

(i) Verifying that the investigator is enroling only eligible subjects.

(j) Reporting the subject recruitment rate.

(k) Verifying that source documents and other trial records are accurate,  complete, kept up-to-date and maintained.

(l) Verifying that the investigator provides all the required reports,  notifications, applications, and submissions, and that these documents are  accurate, complete, timely, legible, dated, and identify the trial.

(m) Checking the accuracy and completeness of the CRF entries, source  documents and other trial-related records against each other. The monitor  specifically should verify that:

(i) The data required by the protocol are reported accurately on the  CRFs and are consistent with the source documents.

(ii) Any dose and/or therapy modifications are well documented for each  of the trial subjects.

(iii) Adverse events, concomitant medications and intercurrent illnesses  are reported in accordance with the protocol on the CRFs.

(iv) 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.

(v) All withdrawals and dropouts of enrolled subjects from the trial are  reported and explained on the CRFs.

(n) Informing the investigator of any CRF entry error, omission, or illegibility.  The monitor should ensure that appropriate corrections, additions, or  deletions are made, dated, explained (if necessary), and initialled by the  investigator or by a member of the investigator's trial staff who is  authorized to initial CRF changes for the investigator. This authorization  should be documented.

(o) Determining whether all adverse events (AEs) are appropriately reported  within the time periods required by GCP, the protocol, the IRB/IEC, the  sponsor, and the applicable regulatory requirement(s).

(p) Determining whether the investigator is maintaining the essential

documents (see 8. Essential Documents for the Conduct of a Clinical Trial).

(q) Communicating deviations from the protocol, SOPs, GCP, and the  applicable regulatory requirements to the investigator and taking  appropriate action designed to prevent recurrence of the detected  deviations.

5.18.5 Monitoring Procedures

 The monitor(s) should follow the sponsor’s established written SOPs as well as  those procedures that are specified by the sponsor for monitoring a specific  trial.

5.18.6 Monitoring Report

(a) The monitor should submit a written report to the sponsor after each trialsite visit or trial related communication.

(b) Reports should include the date, site, name of the monitor, and name of  the investigator or other individual(s) contacted.

(c) Reports should include a summary of what the monitor reviewed and the  monitor's statements concerning the significant findings/facts, deviations  and deficiencies, conclusions, actions taken or to be taken and/or actions  recommended to secure compliance.

(d) The review and follow-up of the monitoring report with the sponsor should  be documented by the sponsor’s designated representative.

5.19 Audit

If or when sponsors perform audits, as part of implementing quality assurance, they  should consider:

5.19.1 Purpose

 The purpose of a sponsor's audit, which is independent of and separate from  routine monitoring or quality control functions, should be to evaluate trial  conduct and compliance with the protocol, SOPs, GCP, and the applicable  regulatory requirements.

5.19.2 Selection and Qualification of Auditors

(a) The sponsor should appoint individuals, who are independent of the  clinical trials/systems, to conduct audits.

(b) The sponsor should ensure that the auditors are qualified by training and  experience to conduct audits properly. An auditor’s qualifications should be  documented.

5.19.3 Auditing Procedures

(a) 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.

(b) The sponsor's audit plan and procedures for a trial audit should be guided  by the importance of the trial to submissions to regulatory authorities, the  number of subjects in the trial, the type and complexity of the trial, the  level of risks to the trial subjects, and any identified problem(s).

(c) The observations and findings of the auditor(s) should be documented.

(d) To preserve the independence and value of the audit function, the  regulatory authority(ies) should not routinely request the audit reports.  Regulatory authority(ies) may seek access to an audit report on a case by  case basis when evidence of serious GCP non-compliance exists, or in the  course of legal proceedings.

(e) When required by applicable law or regulation, the sponsor should provide  an audit certificate.

5.20 Noncompliance

5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory  requirement(s) by an investigator/institution, or by member(s) of the sponsor's  staff should lead to prompt action by the sponsor to secure compliance.

5.20.2 If the monitoring and/or auditing identifies serious and/or persistent  noncompliance on the part of an investigator/institution, the sponsor should  terminate the investigator's/institution’s participation in the trial. When an  investigator's/institution’s participation is terminated because of  noncompliance, the sponsor should notify promptly the regulatory  authority(ies).

5.21 Premature Termination or Suspension of a Trial

If a trial is prematurely terminated or suspended, the sponsor should promptly inform  the investigators/institutions, and the regulatory authority(ies) of the termination or  suspension and the reason(s) for the termination or suspension. The IRB/IEC should  also be informed promptly and provided the reason(s) for the termination or  suspension by the sponsor or by the investigator/institution, as specified by the  applicable regulatory requirement(s).

5.22 Clinical Trial/Study Reports

Whether the trial is completed or prematurely terminated, the sponsor should ensure  that the clinical trial reports are prepared and provided to the regulatory agency(ies)  as required by the applicable regulatory requirement(s). The sponsor should also  ensure that the clinical trial reports in marketing applications meet the standards of  the ICH Guideline for Structure and Content of Clinical Study Reports. (NOTE: The  ICH Guideline for Structure and Content of Clinical Study Reports specifies that  abbreviated study reports may be acceptable in certain cases.)

5.23 Multicentre Trials

For multicentre trials, the sponsor should ensure that:

5.23.1 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/favourable opinion by the IRB/IEC.

5.23.2 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 that are designed to capture the additional data.

5.23.3 The responsibilities of coordinating investigator(s) and the other participating  investigators are documented prior to the start of the trial.

5.23.4 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.

5.23.5 Communication between investigators is facilitated.

(Ref : http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/ E6_R1__Guideline.pdf)

4. INVESTIGATOR

4.1 Investigator’s Qualifications and Agreements

4.1.1 The investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirement(s), and should provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant documentation requested by the sponsor, the IRB/IEC, and/or the regulatory authority(ies).

4.1.2 The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as described in the protocol, in the current Investigator’s Brochure, in the product information and in other information sources provided by the sponsor.

4.1.3 The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.

4.1.4 The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies).

4.1.5 The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.

4.2 Adequate Resources

4.2.1 The investigator should be able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of suitable subjects within the agreed recruitment period.

4.2.2 The investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period.

4.2.3 The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.

4.2.4 The investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and their trial-related duties and functions.

4.3 Medical Care of Trial Subjects

4.3.1 A qualified physician (or dentist, when appropriate), who is an investigator or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.

4.3.2 During and following a subject’s participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial. The investigator/institution should inform a subject when medical care is needed for intercurrent illness(es) of which the investigator becomes aware.

4.3.3 It is recommended that the investigator inform the subject’s primary physician about the subject’s participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.

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

4.4 Communication with IRB/IEC

4.4.1 Before initiating a trial, the investigator/institution should have written and dated approval/favourable opinion from the IRB/IEC for the trial protocol, written informed consent form, consent form updates, subject recruitment procedures (e.g., advertisements), and any other written information to be provided to subjects.

4.4.2 As part of the investigator’s/institution’s written application to the IRB/IEC, the investigator/institution should provide the IRB/IEC with a current copy of the Investigator’s Brochure. If the Investigator’s Brochure is updated during the trial, the investigator/institution should supply a copy of the updated Investigator’s Brochure to the IRB/IEC.

4.4.3 During the trial the investigator/institution should provide to the IRB/IEC all documents subject to review.

4.5 Compliance with Protocol

4.5.1 The investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies) and which was given approval/favourable opinion by theIRB/IEC. The investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm agreement.

4.5.2 The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone number(s)).

4.5.3 The investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol.

4.5.4 The investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC approval/favourable opinion. As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted: (a) to the IRB/IEC for review and approval/favourable opinion, (b) to the sponsor for agreement and, if required, (c) to the regulatory authority(ies).

4.6 Investigational Product(s)

4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution.

4.6.2 Where allowed/required, the investigator/institution may/should assign some or all of the investigator’s/institution’s duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution..

4.6.3 The investigator/institution and/or a pharmacist or other appropriate individual, who is designated by the investigator/institution, should maintain records of the product’s delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial subjects. Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor.

4.6.4 The investigational product(s) should be stored as specified by the sponsor (see 5.13.2 and 5.14.3) and in accordance with applicable regulatory requirement(s).

4.6.5 The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol.

4.6.6 The investigator, or a person designated by the investigator/institution, should explain the correct use of the investigational product(s) to each subject and should check, at intervals appropriate for the trial, that each subject is following the instructions properly.

4.7 Randomization Procedures and Unblinding

The investigator should follow the trial’s randomization procedures, if any, and should ensure that the code is broken only in accordance with the protocol. If the trial is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational product(s).

4.8 Informed Consent of Trial Subjects

4.8.1 In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB/IEC’s written approval/favourable opinion of the written informed consent form and any other written information to be provided to subjects.

4.8.2 The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised written informed consent form, and written information should receive the IRB/IEC’s approval/favourable opinion in advance of use. The subject or the subject’s legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject’s willingness to continue participation in the trial. The communication of this information should be documented.

4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial.

4.8.4 None of the oral and written information concerning the trial, including the written informed consent form, should contain any language that causes the subject or the subject’s legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence.

4.8.5 The investigator, or a person designated by the investigator, should fully inform the subject or, if the subject is unable to provide informed consent, the subject’s legally acceptable representative, of all pertinent aspects of the trial including the written information and the approval/ favourable opinion by the IRB/IEC.

4.8.6 The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to the subject or the subject’s legally acceptable representative and the impartial witness, where applicable.

4.8.7 Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the subject or the subject’s legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the trial should be answered to the satisfaction of the subject or the subject’s legally acceptable representative.

4.8.8 Prior to a subject’s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject’s legallyacceptable representative, and by the person who conducted the informed consent discussion.

4.8.9 If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. After the written informed consent form and any other written information to be provided to subjects, is read and explained to the subject or the subject’s legally acceptable representative, and after the subject or the subject’s legally acceptable representative has orally consented to the subject’s participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject’s legally acceptable representative, and that informed consent was freely given by the subject or the subject’s legally acceptable representative.

4.8.10 Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of the following:

(a) That the trial involves research.

(b) The purpose of the trial.

(c) The trial treatment(s) and the probability for random assignment to each treatment.

(d) The trial procedures to be followed, including all invasive procedures.

(e) The subject’s responsibilities.

(f) Those aspects of the trial that are experimental.

(g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant.

(h) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this.

(i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks.

(j) The compensation and/or treatment available to the subject in the event of trial-related injury.

(k) The anticipated prorated payment, if any, to the subject for participating in the trial.

(l) The anticipated expenses, if any, to the subject for participating in the trial.

(m) That the subject’s participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled.

(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject’s original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by theapplicable laws and regulations and that, by signing a written informed consent form, the subject or the subject’s legally acceptable representative is authorizing such access.

(o) That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the subject’s identity will remain confidential.

(p) That the subject or the subject’s legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject’s willingness to continue participation in the trial.

(q) The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom to contact in the event of trial-related injury.

(r) The foreseeable circumstances and/or reasons under which the subject’s participation in the trial may be terminated.

(s) The expected duration of the subject’s participation in the trial.

(t) The approximate number of subjects involved in the trial.

4.8.11 Prior to participation in the trial, the subject or the subject’s legally acceptable representative should receive a copy of the signed and dated written informed consent form and any other written information provided to the subjects. During a subject’s participation in the trial, the subject or the subject’s legally acceptable representative should receive a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to subjects.

4.8.12 When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject’s legally acceptable representative (e.g., minors, or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject’s understanding and, if capable, the subject should sign and personally date the written informed consent.

4.8.13 Except as described in 4.8.14, a non-therapeutic trial (i.e. a trial in which there is no anticipated direct clinical benefit to the subject), should be conducted in subjects who personally give consent and who sign and date the written informed consent form.

4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled:

(a) The objectives of the trial can not be met by means of a trial in subjects who can give informed consent personally.

(b) The foreseeable risks to the subjects are low.

(c) The negative impact on the subject’s well-being is minimized and low.

(d) The trial is not prohibited by law.

(e) The approval/favourable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/ favourable opinion covers this aspect.

Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.

4.8.15 In emergency situations, when prior consent of the subject is not possible, the consent of the subject’s legally acceptable representative, if present, should be requested. When prior consent of the subject is not possible, and the subject’s legally acceptable representative is not available, enrolment of the subject should require measures described in the protocol and/or elsewhere, with documented approval/favourable opinion by the IRB/IEC, to protect the rights, safety and well-being of the subject and to ensure compliance with applicable regulatory requirements. The subject or the subject’s legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate (see 4.8.10) should be requested.

4.9 Records and Reports

4.9.1 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.

4.9.2 Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained.

4.9.3 Any change or correction to a CRF should be dated, initialed, 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 (see 5.18.4 (n)). Sponsors should provide guidance to investigators and/or the investigators’ designated representatives on making such corrections. Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor’s designated representatives are documented, are necessary, and are endorsed by the investigator. The investigator should retain records of the changes and corrections.

4.9.4 The investigator/institution should maintain the trial documents as specified in Essential Documents for the Conduct of a Clinical Trial (see 8.) and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents.

4.9.5 Essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained.

4.9.6 The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.

4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records.

4.10 Progress Reports

4.10.1 The investigator should submit written summaries of the trial status to the IRB/IEC annually, or more frequently, if requested by the IRB/IEC.

4.10.2 The investigator should promptly provide written reports to the sponsor, the IRB/IEC (see 3.3.8) and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or increasing the risk to subjects.

4.11 Safety Reporting

4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator’s Brochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects’ names, personal identification numbers, and/or addresses. The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC.

4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol.

4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested information (e.g., autopsy reports and terminal medical reports).

4.12 Premature Termination or Suspension of a Trial

If the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and, where required by the applicable regulatory requirement(s), should inform the regulatory authority(ies). In addition:

4.12.1 If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of the termination or suspension.

4.12.2 If the sponsor terminates or suspends a trial (see 5.21), the investigator should promptly inform the institution where applicable and the investigator/institution should promptly inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or suspension.

4.12.3 If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see 3.1.2 and 3.3.9), the investigator should inform the institution where applicable and the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.

4.13 Final Report(s) by Investigator

Upon completion of the trial, the investigator, where applicable, should inform the institution; the investigator/institution should provide the IRB/IEC with a summary of the trial’s outcome, and the regulatory authority(ies) with any reports required.

(Ref : http://ichgcp.net/4-investigator)

 IRB / IEC Essential Documentation

3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)

3.1 Responsibilities

3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid to trials that may include vulnerable subjects.

3.1.2 The IRB/IEC should obtain the following documents:

trial protocol(s)/amendment(s), written informed consent form(s) and consent form updates that the investigator proposes for use in the trial, subject recruitment procedures (e.g. advertisements), written information to be provided to subjects, 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 fulfil its responsibilities.

The IRB/IEC should review a proposed clinical trial within a reasonable time and document its views in writing, clearly identifying the trial, the documents reviewed and the dates for the following:

- approval/favourable opinion;

- modifications required prior to its approval/favourable opinion;

- disapproval / negative opinion; and

- termination/suspension of any prior approval/favourable opinion.

3.1.3 The IRB/IEC should consider the qualifications of the investigator for the proposed trial, as documented by a current curriculum vitae and/or by any other relevant documentation the IRB/IEC requests.

3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year.

3.1.5 The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given to subjects when, in the judgement of the IRB/IEC, the additional information would add meaningfully to the protection of the rights, safety and/or well-being of the subjects.

3.1.6 When a non-therapeutic trial is to be carried out with the consent of the subject’s legally acceptable representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials.

3.1.7 Where the protocol indicates that prior consent of the trial subject or the subject’s legally acceptable representative is not possible (see 4.8.15), the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials (i.e. in emergency situations).

3.1.8 The IRB/IEC should review both the amount and method of payment to subjects to assure that neither presents problems of coercion or undue influence on the trial subjects. Payments to a subject should be prorated and not wholly contingent on completion of the trial by the subject.

3.1.9 The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts, and schedule of payment to trial subjects, is set forth in the written informed consent form and any other written information to be provided to subjects. The way payment will be prorated should be specified.

3.2 Composition, Functions and Operations

3.2.1 The IRB/IEC should consist of a reasonable number of members, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. It is recommended that the IRB/IEC should include:

(a) At least five members.

(b) At least one member whose primary area of interest is in a nonscientific area.

(c) At least one member who is independent of the institution/trial site.

Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter.

A list of IRB/IEC members and their qualifications should be maintained.

3.2.2 The IRB/IEC should perform its functions according to written operating procedures, should maintain written records of its activities and minutes of its meetings, and should comply with GCP and with the applicable regulatory requirement(s).

3.2.3 An IRB/IEC should make its decisions at announced meetings at which at least a quorum, as stipulated in its written operating procedures, is present.

3.2.4 Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or advise.

3.2.5 The investigator may provide information on any aspect of the trial, but should not participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.

3.2.6 An IRB/IEC may invite nonmembers with expertise in special areas for assistance.

3.3 Procedures

The IRB/IEC should establish, document in writing, and follow its procedures, which should include:

3.3.1 Determining its composition (names and qualifications of the members) and the authority under which it is established.

3.3.2 Scheduling, notifying its members of, and conducting its meetings.

3.3.3 Conducting initial and continuing review of trials.

3.3.4 Determining the frequency of continuing review, as appropriate.

3.3.5 Providing, according to the applicable regulatory requirements, expedited review and approval/favourable opinion of minor change(s) in ongoing trials that have the approval/favourable opinion of the IRB/IEC.

3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written approval/favourable opinion of the trial.

3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC approval/favourable opinion of an appropriate amendment, except when necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or number(s)) (see 4.5.2).

3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:

(a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7, 4.5.2, 4.5.4).

(b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2).

(c) All adverse drug reactions (ADRs) that are both serious and unexpected.

(d) New information that may affect adversely the safety of the subjects or the conduct of the trial.

3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution concerning:

(a) Its trial-related decisions/opinions.

(b) The reasons for its decisions/opinions.

(c) Procedures for appeal of its decisions/opinions.

3.4 Records

The IRB/IEC should retain 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 make 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.

The INDIAN / USA / EU Directives on GCP in Clinical Trials

The INDIAN Directives on GCP in Clinical Trials

INTRODUCTION

The history of Good Clinical Practice (GCP) statute traces back to one of the oldest enduring traditions in the history of medicine: The Hippocratic Oath.  As the guiding ethical code it is primarily known for its edict to do no harm to the patient.  However, the complexities of modern medicine research necessitate a more elaborate set of guidelines that address a Physician’s ethical and scientific responsibilities such as obtaining informed consent or disclosing risk while involved in biomedical research.

Good Clinical Practice is a set of guidelines for biomedical studies which encompasses the design, conduct, termination, audit, analysis, reporting and documentation of the studies involving human subjects.  The fundamental tenet of GCP is that in research on man, the interest of science and society should never take precedence over considerations related to the well being of the study subject.  It aims to ensure that the studies are scientifically and ethically sound and that the clinical properties of the pharmaceutical substances under investigation are properly documented.   The guidelines seek to establish two cardinal principles: protection of the rights of human subjects and authenticity of biomedical data generated.

 These guidelines have been evolved with consideration of WHO, ICH, USFDA and European GCP guidelines as well as the Ethical Guidelines for Biomedical research on Human Subjects issued by the Indian Council of Medical Research.  They should be followed for carrying out all biomedical research in India at all stages of drug development, whether prior or subsequent to product registration in India.

 DEFINITIONS

 Act

Wherever relevant, the Act means Drugs & Cosmetics Act 1940 (23 of 1940) and the Rules made thereunder.

 Adverse Event (AE)

Any untoward medical occurrence (including a symptom / disease or an abnormal laboratory finding) during treatment with a pharmaceutical product in a patient or a human volunteer that does not necessarily have a relationship with the treatment being given. Also see Serious Adverse Event

 Adverse Drug Reaction (ADR)

(a)   In case of approved pharmaceutical products:  A noxious and unintended response at doses normally used or tested in humans

(b)   In case of new unregistered pharmaceutical products (or those products which are not yet approved for the medical condition where they are being tested): A noxious and unintended response at any dose(s)

The phrase ADR differs from AE, in case of an ADR there appears to be a reasonable possibility that the adverse event is related with the medicinal product being studied.

In clinical trials, an untoward medical occurrence seemingly caused by overdosing, abuse / dependence and interactions with other medicinal products is also considered as an ADR.

Adverse drug reactions are type A (pharmacological) or type B (idiosyncratic). Type A reactions represent an augmentation of the pharmacological actions of a drug. They are dose-dependent and are, therefore, readily reversible on reducing the dose or withdrawing the drug. In contrast, type B adverse reactions are bizarre and cannot be predicted from the known pharmacology of the drug.

 Audit of a Trial

A systematic verification of the study, carried out by persons not directly involved, such as:

(a)   Study related activities to determine consistency with the Protocol

(b)   Study data to ensure that there are no contradictions on Source Documents.  The audit should also compare data on the Source Documents with the interim or final report.  It should also aim to find out if practices were employed in the development of data that would impair their validity.

(c)   Compliance with the adopted Standard Operating Procedures (SOPs)

 Blinding / Masking

A method of “control experimentation” in which one or more parties involved are not informed of the treatment being given.  Single blind refers to the study subject(s) being unaware, while Double blind refers to the study subject(s) and/or investigator(s), monitor, data analyst(s) are being unaware of the treatment assigned.

 Case Record Form (CRF)

A document designed in consonance with the Protocol, to record data and other information on each trial subject.  The Case Record Form should be in such a form and format that allows accurate input, presentation, verification, audit and inspection of the recorded data.  A CRF may be in printed or electronic format.

Clinical Trial (Clinical Study)

A systematic study of pharmaceutical products on human subjects – (whether patients or non-patient volunteers) – in order to discover or verify the clinical, pharmacological (including pharmacodynamics / pharmacokinetics), and / or adverse effects, with the object of determining their safety and / or efficacy.

Human/Clinical Pharmacology trials (Phase I)

The objective of phase I of trials is to determine the maximum tolerated dose in humans; pharmacodynamic effect, adverse reactions, if any, with their nature and intensity; and pharmacokinetic behaviour of the drug as far as possible. These studies are often carried out in healthy adult volunteers using clinical, physiological and biochemical observations. At least 2 subjects should be used on each dose.

Phase I trials are usually carried out by investigators trained in clinical pharmacology and having the necessary facilities to closely observe and monitor the subjects. These may be carried out at one or two centres.

Exploratory trials (Phase II)

In phase II trials a limited number of patients are studied carefully to determine possible therapeutic uses, effective dose range and further evaluation of safety and pharmacokinetics. Normally 10-12 patients should be studied at each dose level. These studies are usually limited to 3-4 centres and carried out by clinicians specialized on the concerned therapeutic areas and having adequate facilities to perform the necessary investigations for efficacy and safety.

Confirmatory trials (Phase III)

The purpose of these trials is to obtain sufficient evidence about the efficacy and safety of the drug in a larger number of patients, generally in comparison with a standard drug and/or a placebo as appropriate. These trials may be carried out by clinicians in the concerned therapeutic areas, having facilities appropriate to the protocol. If the drug is already approved/marketed in other countries, phase III data should generally be obtained on at least 100 patients distributed over 3-4 centres primarily to confirm the efficacy and safety of the drug, in Indian patients when used as recommended in the product monograph for the claims made.

Data on ADRs observed during clinical use of the drug should be reported along with a report on its efficacy in the prescribed format. The selection of clinicians for such monitoring and supply of drug to them will need approval of the licensing authority under Rule 21 of the Act.

Phase IV

Studies performed after marketing of the pharmaceutical product. Trials in phase IV are carried out on the basis of the product characteristics on which the marketing authorization was granted and are normally in the form of post-marketing surveillance, assessment of therapeutic value, treatment strategies used and safety profile. Phase IV studies should use the same scientific and ethical standards as applied in pre-marketing studies.

After a product has been placed on the market, clinical trials designed to explore new indications, new methods of administration or new combinations, etc. are normally considered as trials for new pharmaceutical products.

 Comparator Product

A pharmaceutical product (including placebo) used as a reference in a clinical trial.

 Confidentiality

Maintenance of privacy of study subjects including their personal identity and all medical information, from individuals other than those prescribed in the Protocol.  Confidentiality also covers the prevention of disclosure of sponsor’s proprietary information to unauthorised persons.

 Co-Investigator

A person legally qualified to be an investigator, to whom the Investigator delegates a part of his responsibilities.

 Co-ordinating Investigator

See Principal Investigator

 Clinical Research Organisation (CRO)

An organisation to which the sponsor may transfer or delegate some or all of the tasks, duties and / or obligations regarding a Clinical Study.  All such contractual transfers of obligations should be defined in writing.  A CRO is a scientific body – commercial, academic or other.

 Contract

A written, dated and signed document describing the agreement between two or more parties involved in a biomedical study, namely Investigator, Sponsor, Institution. Typically, a contract sets out delegation / distribution of responsibilities, financial arrangements and other pertinent terms. The “Protocol” may form the basis of “Contract”.

 Documentation

All records (including written documents, electronic, magnetic or optical records, scans, x-rays etc.) that describe or record the methods, conduct and results of the study, and the actions taken.  The Documents include Protocol, copies of submissions and approvals from the office of the Drugs Controller General of India, ethics committee, investigator(s)’ particulars, consent forms, monitor reports, audit certificates, relevant letters, reference ranges, raw data, completed CRFs and the final report. Also see: Essential Documents

Escape Treatment

A supplementary treatment, usually given to alleviate pain in placebo-controlled trials, to relieve the trial subject of the symptoms caused by the investigated disease in a study.

Essential Documents

The Documents that permit evaluation of the conduct of a study and the quality of the data generated.  See Appendix V.

Ethics Committee

An independent review board or committee comprising of medical / scientific and non-medical / non-scientific members, whose responsibility is to verify the protection of the rights, safety and well-being of human subjects involved in a study.  The independent review provides public reassurance by objectively, independently and impartially reviewing and approving the “Protocol”, the suitability of the investigator(s), facilities, methods and material to be used for obtaining and documenting “Informed Consent” of the study subjects and adequacy of confidentiality safeguards.

Final Report

A complete and comprehensive description of the study after its completion.  It includes description of experimental and statistical methods and materials, presentation and evaluation of the results, statistical analyses and a critical ethical, statistical and clinical appraisal. The Investigator’s declaration closing the study is a part of the Final Report.

Good Clinical Practice (GCP)

It is a standard for clinical studies or trials that encompasses the design, conduct, monitoring, termination, audit, analyses, reporting and documentation of the studies.  It ensures that the studies are implemented and reported in such a manner that there is public assurance that the data are credible, accurate and that the rights, integrity and confidentiality of the subjects are protected.  GCP aims to ensure that the studies are scientifically authentic and that the clinical properties of the “Investigational Product” are properly documented.

Impartial Witness

An impartial independent witness who will not be influenced in any way by those who are involved in the Clinical Trial, who assists at the informed consent process and documents the freely given oral consent by signing and dating the written confirmation of this consent.

Informed Consent

Voluntary written assent of a subject’s willingness to participate in a particular study and in its documentation.  The confirmation is sought only after information about the trial including an explanation of its status as research, its objectives, potential benefits, risks and inconveniences, alternative treatment that may be available and of the subject’s rights and responsibilities has been provided to the potential subject.

Inspection

An official review/ examination conducted by regulatory authority(ies) of the documents, facilities, records and any other resources that are deemed by the authority(ies) to be related to the study.  The inspection may be carried out at the site of the trial, at the sponsor’s / or CRO’s facilities in order to verify adherence to GCP as set out in these documents.

Institution

Any public or private medical facility where a clinical study is conducted.

 Investigator

A person responsible for the conduct of the study at the trial site.  Investigator is responsible for the rights, health and welfare of the study subjects.  In case the study is conducted by a team of investigators at the study site then the designated leader of the team should be the Principal Investigator. Also see Principal Investigator, Sub-investigator.

 Investigational Labelling

Labelling developed specifically for products involved in the study.

 Investigational Product

A pharmaceutical product (including the Comparator Product) being tested or used as reference in a clinical study. An Investigational Product may be an active chemical entity or a formulated dosage form.

 Investigator’s Brochure

A collection of data (including justification for the proposed study) for the Investigator consisting of all the clinical as well as non-clinical information available on the Investigational Product(s) known prior to the onset of the trial. There should be adequate data to justify the nature, scale and duration of the proposed trial and to evaluate the potential safety and need for special precautions. If new substantially relevant data is generated during the trial, the information in the Investigator’s Brochure must be updated. See Appendix IV.

 Monitor

A person appointed by the Sponsor or Contract Research Organisation (CRO) for monitoring and reporting the progress of the trial and for verification of data. The monitor ensures that the trial is conducted, recorded and reported in accordance with the Protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP) and the applicable regulatory requirements.

 Multi-Centric Study

A clinical trial conducted according to one single protocol in which the trial is taking place at different investigational sites, therefore carried out by more than one investigator.

 Non-Clinical Study

Biomedical studies that are not performed on human subjects.

 Non-Therapeutic Study

A study in which there is no anticipated direct clinical benefit to the Subject(s).  Such studies, unless an exception is justified, should be conducted in patient(s) having a disease or condition for which the Investigational Product is intended.  Subject(s) in these studies should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.

 Pharmaceutical Product(s)

Any substance or combination of substances which has a therapeutic, prophylactic or diagnostic purpose or is intended to modify physiological functions, and presented in a dosage form suitable for administration to humans.

 Principal Investigator

The investigator who has the responsibility to co-ordinate between the different Investigators involved in a study at one site or different sites in case of a multi-center study.

 Protocol

A document that states the background, objectives, rationale, design, methodology (including the methods for dealing with AEs, withdrawals etc.) and statistical considerations of the study. It also states the conditions under which the study shall be performed and managed.

 A list of items to be included in the Protocol is compiled in a subsequent chapter.

The content and format of the protocol should take into consideration the adopted SOPs, the regulatory requirements and the guiding principles of GCP.

The term Protocol, unless otherwise specified, relates to the latest amended version of the document, read in conjunction with all its appendices and enclosures.

 Protocol Amendment(s)

Any changes or formal clarifications appended to the protocol.  All Protocol Amendments should be agreed upon and signed by the persons who were the signatories to the Protocol.

 Quality Assurance (QA)

Systems and processes established to ensure that the trial is performed and the data are generated in compliance with GCP.  QA is validated through in-process Quality Control and in and post-process auditing of clinical trial process as well as data.

 Quality Control (QC)

The operational techniques and activities undertaken within the system of QA to verify that the requirements for quality of the trial related activities have been fulfilled.  QC activities concern everybody involved with planning, conducting, monitoring, evaluating, data handling and reporting. The objective of QC is to avoid exposure of study subjects to unnecessary risks and to avoid false conclusions being drawn from unreliable data.

 Randomisation

The process of assigning study subjects to either the treatment or the control group.  Randomisation gives all subjects the same chance of being in either group in order to reduce bias.

 Regulatory Authority

The Drugs Controller General of India or an office nominated by him is the regulatory authority for the purpose of carrying out Clinical Trials in India. The Regulatory Authority approves the study Protocol, reviews the submitted data and conducts inspections.

 Raw Data

It refers to all records or certified copies of the original clinical and laboratory findings or other activities in a clinical study necessary for the reconstruction and evaluation of the trial. Also see Source Data.

Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR)

An AE or ADR that is associated with death, inpatient hospitalisation (in case the study was being conducted on out-patients), prolongation of hospitalisation (in case the study was being conducted on in-patients), persistent or significant disability or incapacity, a congenital anomaly or birth defect, or is otherwise life threatening.

Schedule

Unless repugnant to the context, the Schedule means Schedule Y  to the Drugs & Cosmetics Rules.  (Reproduced here at Appendix II)

Source Data

Original documents (or their verified and certified copies) necessary for evaluation of the Clinical Trial.  These documents may include Study Subjects’ files, recordings from automated instruments, tracings, X-Ray and other films, laboratory notes, photographic negatives, magnetic media, hospital records, clinical and office charts, Subjects’ diaries, evaluation check-lists, and pharmacy dispensing records.

Sponsor

An individual or a company or an institution that takes the responsibility for the initiation, management and / or financing of a Clinical Study.  An Investigator who independently initiates and takes full responsibility for a trial automatically assumes the role of a Sponsor.

Study Product

Any Pharmaceutical Product or Comparator Product used in a clinical study.

Sub-Investigator

See Co-Investigator

Subject Files / Patient Files

A file containing demographic and medical information about a study subject.  It includes hospital files, consultation records or special subject files allowing the authenticity of the information presented in CRF to be verified and where necessary allowing it to be completed or corrected.  The conditions regulating the use and consultation of such documents must be honoured as prescribed under Confidentiality.

 Study Subject (Subject)

An individual participating in a clinical trial as a recipient of the Investigational Product.

A Study Subject may be a healthy person volunteering in a trial or a person with a medical condition that is unrelated to the use of the Investigational Product or a person whose medical condition is relevant to the use of the Investigational Product.

 Standard Operating Procedures (SOP)

Standard elaborate written instructions to achieve uniformity of performance in the management of clinical studies.  SOPs provide a general framework for the efficient implementation and performance of all the functions and activities related to a particular study.

 Subject Identification Code

A unique identification number / code assigned by the Investigator to each Study Subject to protect the Subject’s identity.  Subject Identification Code is used in lieu of the Subject’s name for all matters related to the study.

 Study Management

Steering, supervising, data management and verification, statistical processing and preparation of the study report.

 Validation

Validation of Study: The process of proving, in accordance with the principles of Good Clinical Practice, that any procedure, process equipment, material, activity or system actually leads to the expected results

Validation of Data: The procedures carried out to ensure and prove that the data contained in the final report match the original observations.  The procedure is applied to Raw Data, CRFs, computer software, printouts, statistical analyses and consumption of Study Product / Comparator Product.

(Ref : http://cdsco.nic.in/html/GCP.htm)

The USA Directives on GCP

Refer the following link

http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf

The EU Directives on GCP

Good clinical practice (GCP) is an international ethical and scientific quality standard for designing, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and wellbeing of trial subjects are protected and that clinical-trial data are credible.

The protection of clinical trial subjects is consistent with the principles set out in the Declaration of Helsinki. This is a statement of ethical principles developed by the World Medical Association.

Requirements for the conduct of clinical trials in the European Union (EU), including GCP and good manufacturing practice (GMP) and GCP or GMP inspections, are implemented in:

the 'Clinical Trial Directive' (Directive 2001/20/EC);

the 'GCP Directive' (Directive 2005/28/EC).

Information concerning the activities in EU Member States can be found via the Heads of Medicines Agencies.

EU harmonisation

The European Medicines Agency plays an important role in the harmonisation and co-ordination of GCP-related activity at an EU level. It is involved in: co-ordinating GCP inspections for the centralised procedure; preparing guidance on GCP topics through the work of the GCP Inspectors Working Group; co-ordinating advice on the interpretation of EU GCP requirements and related technical issues; developing of EU-wide guidelines on GCP inspections and related procedures for the centralised procedure.

For more information on clinical trial authorisation, safety monitoring, GCP inspections, and GCP and GMP requirements for clinical trials in the European Economic Area (EEA), see volume 10: clinical-trial guidelines of the rules governing medicinal products in the EU.

International clinical trials

Regardless of where they are conducted, all clinical trials included in applications for marketing authorisation in the EEA must be in accordance with: the GCP Directive (Directive 2001/83/EC Annex I, as amended by Directive 2003/63/EC); the ethical standards of the Clinical Trials Directive (Directive 2001/20/EC).

In July 1996, the EU adopted the guideline for good clinical practice, which lays out unified GCP standards for Europe, the United States of America and Japan.

the Council for International Organizations of Medical Science (CIOMS);

the World Medical Association.

Clinical trials conducted in countries outside the EU

The number of clinical trials and clinical-trial subjects outside Western Europe and North America has been increasing for a number of years. The Agency has been tracking the geographic origins of patients included in pivotal trials submitted in marketing authorisations to the centralised procedure.

In April 2012, the Agency published the final version of the reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of the EU / EEA and submitted in marketing authorisation applications to the EU regulatory authorities. The aim of the paper is to strengthen existing processes to provide assurance to regulators and stakeholders that clinical trials meet the required ethical and GCP standards, no matter where in the world they have been conducted.

The reflection paper is part of the Agency’s strategy developed to address the challenges arising from the increasing globalisation of clinical research. These challenges are addressed in a two-fold manner, by: putting forward concrete steps for international cooperation between regulatory authorities in the regulation of clinical trials, with a specific emphasis on capacity-building initiatives for a common approach to oversight of trials and to ensure a robust framework for the oversight and conduct of clinical trials; clarifying and determining the practical steps by which EU regulators will gain assurance that ethical and GCP standards are applied to clinical trials for human medicines, both during the development and during the marketing-authorisation-application phase.

The development of this paper followed on from the publication of the strategy paper on acceptance of clinical trials conducted in third countries and an international workshop in September 2010.

Working Group on Clinical Trials conducted outside of the EU / EEA

The Agency's Working Group on Clinical Trials Conducted Outside of the EU / EEA was established in 2009 to develop practical proposals for tasks and procedures or guidance  in the four areas identified in the strategy paper on the acceptance of clinical trials conducted outside of the EU/EEA: clarify the practical application of ethical standards for clinical trials, in the context of the Agency's activities; determine the practical steps to be undertaken during the provision of guidance and advice in the drug-development phase; determine the practical steps to be undertaken during the marketing-authorisation phase; international cooperation in the regulation of clinical trials, their review and inspection and capacity building in this area and to develop a reflection paper on ethical and GCP aspects of clinical trials conducted outside the EU / EEA.

The Working Group includes representatives of the Committee for Medicinal Products for Human Use (CHMP), Paediatric Committee (PDCO), Committee for Orphan Medicinal Products (COMP), Coordination Group for Mutual Recognition and Decentralised Procedures (CMD), Clinical Trials Facilitation Group, GCP inspectors, Patients' and Consumers' Working Party, Healthcare Professionals' Working Group, Agency secretariat and European Commission.

The Working Group meets on a regular basis at the Agency.

Collaboration with the Food and Drug Administration

The Agency and the United States Food and Drug Administration (FDA) agreed to launch a joint initiative to collaborate on international GCP inspection activities in July 2009.

The initiative forms an important contribution to ensuring the protection of clinical-trial subjects in the context of the increasing globalisation of clinical research. The initiative comes under the scope of the confidentiality arrangements between the European Commission, the European Medicines Agency (EMA) and the FDA. For more information on these arrangements, see United States.

EMA-FDA GCP initiative

The initiative's main objectives are to: conduct periodic information exchanges on GCP-related information, to streamline sharing of GCP inspection planning information, and to communicate on inspection outcomes effectively and in a timely manner; conduct collaborative GCP inspections by sharing information, experience and inspection procedures, co-operating in the conduct of inspections and sharing knowledge of best practice; share information on the interpretation of GCP, by keeping each other informed of GCP-related legislation, regulatory guidance and related documents, and to identify and act together to benefit the clinical research process.

The initiative began with a pilot phase that ran between September 2009 and March 2011. During the pilot, the EMA and the FDA exchanged more than 250 documents relating to 54 different medicines. They also organised 13 joint inspections of clinical trials in conjunction with the GCP inspectors of the EU Member States.

A report and question-and-answer document on the outcomes of the pilot are available, which detail the success of the information-sharing and collaboration on inspections relating to clinical trials:

Report of the EMA-FDA pilot GCP initiative

The pilot has laid the foundation for a more efficient use of limited resources, improved inspection coverage and better understanding of each agency’s inspection procedures. It demonstrates how the agencies can work together to improve human subject protection and better ensure the integrity of data submitted as the basis for drug approvals.

Based on the positive experience, the EMA and the FDA intend to continue with the initiative, incorporating lessons learned during the pilot. The agencies are updating the terms of engagement and procedures for participating authorities to reflect this.

Applicants interested in volunteering to take part in a collaborative inspection during the pilot phase should contact the EMA or the FDA.

(ref : http://www.emea.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_ 000072.jsp&mid=WC0b01ac05800268ad)

How will the introduction affect clinical research

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Extracts from the guidance documents Possible sanctions for non- compliance

Guidance documents accessible from this page represent the Agency's current thinking on good clinical practice (GCP) and the conduct of clinical trials. As with all guidance documents, they do not create or confer any rights for or on any person and do not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute and regulations. However, in many places throughout these documents, specific regulations are cited and the requirements of the regulations are reiterated. The regulations are enforceable.

Guidance Documents Grouped by Topic:

·         General

·         Institutional Review Boards (IRBs) and Informed Consent

·         Drugs and Biologics

·         Medical Devices

·         Manufacturing Requirements for Investigational Products

·         Electronic Data

General

21 CFR 50.54, Process for Handling Referrals to FDA under, Guidance for Clinical Investigators, Institutional Review Boards and Sponsors)

This guidance is intended to assist clinical investigators, Institutional Review Boards (IRBs), sponsors, and other interested parties in understanding the FDA's process for handling clinical investigations that include children as subjects and that have been referred to FDA for review under 21 CFR 50.54.

Data Monitoring Committees, Establishment and Operation of Clinical Trial, Guidance for Clinical Trial Sponsors

This guidance is intended to assist sponsors of clinical trials in determining when a data monitoring committee (DMC) is needed for study monitoring, and how such committees should operate.

Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials, Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors (PDF - 71KB)

This guidance describes FDA’s longstanding policy that already-accrued data, relating to individual who cease participating in a study, are to be maintained as part of the study data.  This pertains to data from individuals who decide to discontinue participation in a study, who are withdrawn by their legally authorized representative, as applicable, or who are discontinued from participation by the clinical investigator.

Exception from Informed Consent Requirements for Emergency Research, Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors

This guidance is intended to assist Institutional Review Boards (IRBs), clinical investigators and sponsors in the development, conduct, and oversight of investigations to determine the safety and effectiveness of FDA regulated products (e.g., drugs, including biological drug products, devices) in emergency settings when an exception from the informed consent requirements is requested under Title 21, Code of Federal Regulations, Section 50.24 (21 CFR 50.24).

Financial Disclosure by Clinical Investigators, Guidance for Clinical Investigators, Industry and FDA Staff (PDF- 165KB)

This guidance is intended to assist clinical investigators, industry, and FDA staff in interpreting and complying with the regulations governing financial disclosure by clinical investigators, 21 CFR part 54. 

Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subject Protection (PDF – 35 KB)

This guidance document, developed at the department (DHHS) level, applies to all human subject research conducted or supported by HHS agencies or regulated by the Food and Drug Administration.

Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects, Guidance for Industry (PDF - 163KB)

This guidance provides an overview of the responsibilities of a person who conducts a clinical investigation of a drug, biological product, or medical device (an investigator as defined in 21 CFR 312.3(b) and 21 CFR 812.3(i)).  It is intended to clarify for investigators and sponsors FDA’s expectations concerning the investigator’s responsibility (1) to supervise a clinical study in which some study tasks are delegated to employees or colleagues of the investigator or other third parties and (2) to protect the rights, safety, and welfare of study subjects.

Monitoring of Clinical Investigators, Guideline for the, Guidance for Industry (Document Removed)

FDA is currently revising this guidance.  If assistance is needed concerning monitoring of clinical investigators, please contact the appropriate Center or, for general monitoring questions, the Office of Good Clinical Practice (OGCP) via our GCP questions box at gcp.questions@fda.hhs.gov.

Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims (PDF - 295KB)

This guidance describes how FDA reviews and evaluates existing, modified, or newly created patient-reported outcome (PRO) instruments used to support claims in approved medical product labeling.  A PRO instrument (i.e., a questionnaire plus the information and documentation that support its use) is a means to capture PRO data used to measure treatment benefit or risk in medical product clinical trials. This guidance does not address the use of PRO instruments for purposes beyond evaluation of claims made about a medical product in labeling nor disease-specific issues.

Pharmacogenomic Data Submissions, Guidance for Industry (PDF - 96 KB)

The guidance provides recommendations to sponsors holding investigational new drug applications (INDs), new drug applications (NDAs), and biologics license applications (BLAs) on what pharmacogenomic data to submit to the agency during the drug development process, the format of submissions, and how the data will be used in regulatory decision making. The guidance is intended to facilitate scientific progress in the area of pharmacogenomics.

Race and Ethnicity Data in Clinical Trials, Collection of, Guidance for Industry

This guidance recommends using a standardized approach for collecting and reporting race and ethnicity information in clinical trials conducted in the United States and abroad for certain FDA regulated products. The recommended standardized approach was developed by the Office of Management and Budget (OMB). The guidance lists the OMB categories for race and ethnicity and describes FDA's reasons for recommending the use of these categories. In addition, this guidance recommends a format for race and ethnicity data within study data that are submitted in standardized data sets such as the Study Data Tabulation Model or in the electronic Common Technical Document (eCTD).

Institutional Review Boards (IRBs) and Informed Consent

Adverse Event Reporting to IRBs- Improving Human Subject Protection, Guidance for Clinical Investigators, Sponsors, and IRBs

This guidance is intended to provide assistance to the research community in interpreting requirements for submitting reports of unanticipated problems, including certain adverse events reports, to the IRB.

Centralized IRB Process in Multi center Clinical Trials, Guidance for Industry on Using a 

This guidance is intended to assist sponsors, institutions, institutional review boards (IRBs), and clinical investigators involved in multicenter clinical research in meeting the requirements of 21 CFR part 56 by facilitating the use of a centralized IRB review process (use of a single central IRB), especially in situations where centralized review could improve efficiency of IRB review.

HIPAA Authorizations Under FDA Regulations, IRB Review of Stand-Alone, Guidance for Industry (PDF - 614 KB)

This guidance provides clarification for IRBs of their responsibilities for reviewing and approving stand-alone authorizations under the HIPAA Privacy Rule.

Informed Consent Elements, 21 CFR 50.25(c), Questions and Answers on, Guidance for Sponsors, Investigators and Institutional Review Boards

This guidance is intended to help sponsors, investigators and Institutional Review Boards better understand the new informed consent requirement set forth in 21 CFR 50.25(c). The guidance will assist those involved in applicable FDA-regulated clinical trials better understand the new informed consent requirement, including small businesses.

IRB Continuing Review after Clinical Investigation Approval, Guidance for IRBs, Clinical Investigators, and Sponsors (PDF - 320 KB)

This guidance is intended to assist institutional review boards (IRBs) in carrying out their continuing review responsibility under 21 CFR 56.108(a) and 56.109(f) by providing recommendations regarding the criteria, process, and frequency of continuing review to assure the protection of the rights and welfare of human subjects enrolled in clinical investigations. This guidance should also help clinical investigators and sponsors better understand their responsibilities related to continuing review.
 

IRB Registration, Frequently Asked Questions, Guidance for Institutional Review Boards (IRBs) (PDF - 48 KB)

This guidance is intended to assist IRBs in complying with the requirement for IRB registration under amended 21 CFR 56.106, effective July 14, 2009.   Registration is accomplished through a modified version of the Internet-based registration system used by OHRP for registration of IRBs that are designated by institutions under FWAs.   This guidance document addresses basic information, such as why FDA issued a new rule requiring registration, which IRBs are subject to the regulation, the type of information to be provided when registering, and implications of non-compliance.

The Radioactive Drug Research Committee: Human Research Without An Investigational New Drug Application, Guidance for Industry and Researchers (PDF - 417KB)

This guidance is intended to provide information for those using radioactive drugs for certain research purposes to help determine whether research studies can be conducted under 21 CFR 361.1, Prescription Drugs for Human Use Generally Recognized as Safe and Effective and Not Misbranded: Drugs Used in Research, or whether research studies must be conducted under 21 CFR part 312, Investigational New Drug Application (IND).

The Radioactive Drug Research Committee: Human Research Without An Investigational New Drug Application - Guidance for Industry and Researchers (PDF - 276 KB)

This guidance is intended to provide information for those using radioactive drugs for certain research purposes to help determine whether research studies can be conducted under 21 CFR 361.1, Prescription Drugs for Human Use Generally Recognized as Safe and Effective and Not Misbranded: Drugs Used in Research, or whether research studies must be conducted under 21 CFR part 312, Investigational New Drug Application (IND).

Drugs and Biologics

Available Therapy, Guidance for Industry

This guidance is intended to provide guidance to industry on the meaning of the term "available therapy" as currently used by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) in the FDA in the specific circumstances described in the guidance.

Bioavailability and Bioequivalence Testing Samples, Handling and Retention of, Guidance for Industry (PDF - 166KB)

Inspection of clinical and analytical sites that perform bioavailability (BA) and bioequivalence (BE) studies frequently reveals the absence of reserve samples at the testing facilities where the studies are conducted. The guidance is intended to clarify how to distribute test articles and reference standards to testing facilities, how to randomly select reserve samples, and how to retain reserve samples.

Clinical Holds Following Clinical Investigator Misconduct, Guidance for Industry and Clinical Investigators on the Use of (PDF - 33KB)

This guidance for industry and clinical investigators provides information on one use by FDA of its authority to impose a clinical hold on a study or study site if FDA finds that human subjects are or would be exposed to unreasonable and significant risk of illness or injury.  Specifically, this guidance describes circumstances in which FDA may impose a clinical hold based on credible evidence that a clinical investigator conducting the study has committed serious violations of FDA regulations on clinical trials of human drugs and biologics.

Enforcement of Safety Reporting Requirements for INDs and BA/BE Studies, Guidance for Industry and Investigators (PDF - 41KB)

This document provides guidance to sponsors and investigators on enforcement of FDA’s final rule, "Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans" (75 FR 59935, September 29, 2010). This guidance contains information regarding the Agency’s intent to exercise enforcement discretion regarding the reporting requirements in the final rule until September 28, 2011.

Exploratory IND Studies, Guidance for Industry (PDF - 220KB)

This guidance describes the preclinical and clinical issues as well as chemistry, manufacturing and controls information that should be considered when planning exploratory studies including studies of related drugs or biologics under an investigational new drug (IND) application.

FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND, Frequently Asked Questions, Guidance for Industry and FDA Staff (PDF - 108KB)

This guidance document is intended to clarify for sponsors and applicants how they can demonstrate compliance with the requirements of 21 CFR 312.120.  It provides recommendations for the submission of information, whether in an IND or application for marketing approval for a drug or biological drug product, to demonstrate that a non-IND foreign clinical study was conducted in accordance with GCP.

Food-Effect Bioavailability and Fed Bioequivalence Studies, Guidance for Industry (PDF - 166KB)

This guidance provides recommendations to sponsors and/or applicants planning to conduct food-effect bioavailability (BA) and fed bioequivalence (BE) studies for orally administered drug products as part of investigational new drug applications (INDs), new drug applications (NDAs) and abbreviated new drug applications (ANDAs), and supplemental applications.

Gender Differences in the Clinical Evaluation of Drugs, Guideline for the Study and Evaluation of, Guidance for Industry (PDF - 1.83MB)

This guideline presents guidance on FDA's expectations regarding inclusion of both genders in drug development.

Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, Guidance for Industry (PDF - 220KB)

This guidance is intended to assist industry with risk management activities for drug products, including biological drug products, in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).

IND Exemptions for Studies of Lawfully Marketed Drug or Biologicial Products for the Treatment of Cancer, Guidance for Industry (PDF - 188KB)

This guidance is intended to assist sponsors in deciding whether a study of marketed drugs or biological products for treating cancer falls within the exemption under § 312.2(b)(1) (21 CFR 312.2(b)(1)) from the general requirement to submit an investigational new drug application (IND).

Premarketing Risk Assessment, Guidance for Industry (PDF - 91KB)

This guidance is intended to assist industry with risk management activities for drug products, including biological drug products, in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).

Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications, Guidance for Industry

This guidance discusses issues related to the electronic submission of new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), investigational new drug applications (INDs), master files, advertising material, and promotional labeling using the electronic common technical document (eCTD) specifications.

Safety Reporting Requirements for INDs and BA/BE Studies, Guidance for Industry and Investigators (PDF-228 KB)

This guidance is intended to help sponsors and investigators comply with the requirements for investigational new drug (IND) safety reporting and safety reporting for bioavailability (BA) and bioequivalence (BE) studies under 21 CFR 312.32, 312.64(b), and 320.31(d)(3). This document provides guidance to sponsors and investigators on expedited safety reporting requirements for human drug and biological products that are being investigated under an IND and for drugs that are the subjects of BA and BE studies that are exempt from the IND requirements. This guidance defines terms used for safety reporting, makes recommendations on when and how to submit a safety report, and provides advice on other safety reporting issues that have arisen from sponsors and investigators.

Safety Reporting Requirements for INDs and BA/BE Studies-Small Entity Compliance Guide, for Industry and Investigators (PDF-35KB)

This guidance is intended to help small businesses understand and comply with FDA’s safety reporting regulations for human drug and biological products that are being investigated under an investigational new drug application (IND) and for drugs that are the subjects of bioavailability (BA) and bioequivalence (BE) studies that are exempt from the IND requirements. The FDA has prepared this guidance in accordance with section 212 of the Small Business Regulatory Enforcement Fairness Act (Public Law 104-121).

Serious or Life-Threatening Diseases and Conditions, Information Program on Clinical Trials for, Guidance for Industry (PDF - 34KB)

This guidance is intended to assist sponsors who will be submitting information to the Clinical Trials Data Bank. It addresses statutory and procedural issues for submitting information to the data bank.

Medical Devices

Analyte Specific Reagents (ASRs): Frequently Asked Questions, Guidance for Industry and FDA Staff – Commercially Distributed (PDF - 139KB)

This guidance document is intended to clarify the regulations regarding commercially distributed analyte specific reagents (ASRs) (21 CFR 809.10(e), 809.30, and 864.4020), and the role and responsibilities of ASR manufacturers. This document is not intended to provide guidance on the role of clinical laboratories in the development of laboratory developed tests (LDTs). The guidance follows the substance, spirit, and meaning of the ASR regulations already in place.

Humanitarian Device Exemption (HDE) Regulation: Questions and Answers; Guidance for HDE Holders, Institutional Review Boards (IRBs), Clinical Investigators, and FDA Staff

This guidance document answers commonly asked questions about Humanitarian Use Devices (HUDs) and applications for Humanitarian Device Exemption (HDE) authorized by section 510(m)(2) of the Federal Food, Drug, and Cosmetic Act (the Act). It also reflects the additional requirements set forth in the Pediatric Medical Device Safety and Improvement Act of 2007.

Humanitarian Use Device (HUD) Designations, Guidance for Industry and Food and Drug Administration Staff (PDF - 92KB)

This guidance document is intended to assist applicants in the preparation and submission of Humanitarian Use Device (HUD) designation requests to the U.S. Food and Drug Administration’s (FDA or Agency) Office of Orphan Products Development (OOPD). It is also designed to assist FDA reviewers in their evaluation and analysis of HUD designation requests ("HUD requests" or "requests").

Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable, Guidance for Sponsors, Institutional Review Boards, Clinical Investigators and FDA Staff

This guidance informs sponsors, institutional review boards (IRBs), clinical investigators, and agency staff that the FDA intends to exercise enforcement discretion, under certain circumstances, with respect to its current regulations governing the requirement for informed consent when human specimens are used for FDA regulated in vitro diagnostic device investigations.

In Vitro Diagnostic (IVD) Device Studies -Frequently Asked Questions, Guidance for Industry and FDA Staff (PDF - 342KB)

This guidance document outlines FDA regulations applicable to studies for investigational IVD devices, including those regulations related to human subject protection. The guidance also explains data considerations that ultimately will affect the quality of the premarket submission. It includes a glossary, a reference list with related web addresses, and a quick-reference table.

Software Validation, General Principles of, Guidance for Industry and FDA Staff

The primary purpose of this guidance is to outline general validation principles that the FDA considers applicable to the validation of medical device software or the validation of software used to design, develop, or manufacture medical devices.  In addition, it contains useful validation principles applicable to software used in the conduct of clinical trials.

Manufacturing Requirements for Investigational Products

Current Good Manufacturing Practice for Phase 1 Investigational Drugs (PDF - 132KB)

This guidance is intended to assist in applying current good manufacturing practice (CGMP) required under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) in the manufacture of most investigational new drugs (IND) used in phase 1 clinical trials. These drugs, which include biological drugs, are exempt from complying with 21 CFR part 211 under 21 CFR 210.2(c) (referred to as phase 1 investigational drugs).

Design Control Guidance for Medical Device Manufacturers

This guidance is intended to assist manufacturers in understanding quality system requirements concerning design controls. Assistance is provided by interpreting the language of the quality systems requirements and explaining the underlying concepts in practical terms.  As discussed under Device Advice, devices approved under an investigational device exemption (IDE) are exempt from the Quality System (QS) regulation, except for the design control requirements under §820.30. However, the sponsor may state an intention to comply with other parts of the QS regulation. The extent to which the Quality System regulation will be followed in manufacturing the device must be documented in the sponsor’s IDE records [§812.140(b)(4)(v)].

INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing, and Controls Information (PDF – 193KB)

This guidance provides recommendations to sponsors of investigational new drug applications (INDs) on the chemistry, manufacturing, and controls (CMC) information that would be submitted for phase 2 and phase 3 studies conducted under INDs. This document applies to human drugs (as defined in the Federal Food, Drug, and Cosmetic Act). It does not apply to botanical drug products, protein drug products derived from natural sources or produced by the use of biotechnology, or other biologics. The goals of this document are to (1) ensure that sufficient data will be submitted to the Agency to assess the safety, as well as the quality of the proposed clinical studies from the CMC perspective, (2) expedite the entry of new drug products into the marketplace by clarifying the type, extent, and reporting of CMC information for phase 2 and phase 3 studies, and (3) facilitate drug discovery and development.
 

Electronic Data

Computerized Systems Used in Clinical Investigations, Guidance for Industry  (PDF - 53KB)

This guidance provides recommendations to sponsors, contract research organizations, data management centers, clinical investigators and institutional review boards regarding the use of computerized systems in clinical investigations.

Part 11, Electronic Records; Electronic Signatures--Scope and Application, Guidance for Industry on (PDF - 215KB)

This guidance is intended to describe the FDA's current thinking regarding the scope and application of part 11 of Title 21 of the Code of Federal Regulations; Electronic Records; Electronic Signatures (21 CFR Part 11).

(ref : http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformation SheetsandNotices/ucm219433.htm)