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Good Clinical Practices (GCP) Guideline

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. This guideline provides the procedure for Handling and Reporting of serious breaches of Good clinical practices (GCP).

GOOD CLINICAL PRACTICES (GCP) – HANDLING AND REPORTING OF SERIOUS BREACHES

1.0   OBJECTIVE : 

    • This Standard Operating Procedure (SOP) provides the procedure to be followed when a serious breach of Good Clinical Practices (GCP) is suspected and provides a course of action for the documentation, investigation, remediation, and reporting of the same to the applicable Regulatory agencies.

2.0   SCOPE – SOP for Good Clinical Practices :

    •  This SOP is applicable to pharma employees/contract staffs/sites/ CROs/ service providers involved in Good Clinical Practices (GCP) studies conducted by or on behalf of the company for/in countries [e.g. United Kingdom (UK) & Singapore] where reporting obligations exist for serious breaches of Good Clinical Practices (GCP).

3.0   RESPONSIBILITY – Good Clinical Practices (GCP):

    • Personnel involved in the support/ conduct of Good Clinical Practices (GCP) studies shall be responsible for:

    • Documenting and reporting observations of suspected serious breaches of Good Clinical Practices (GCP) in studies conducted for/in countries where reporting obligations exist for serious breaches of Good Clinical Practices (GCP) to the Functional Area Management (FAM)/ Sponsor/ Sponsor representative and Head – Corporate R&D Quality/designee.

    • Head  – Corporate R&D, Quality/designee shall be responsible for:

    • Documenting all reported serious breaches of Good Clinical Practices (GCP).Good Clinical Practices (GCP)
    • Performing an initial assessment of reported serious Good Clinical Practices (GCP) breaches (examples provided in Attachment – I) and determining regulatory reporting requirements in consultation with the Head – of the Regulatory Affairs department/designee.
    • Convening a meeting with the management (as defined in section 9) when a serious breach of Good Clinical Practices (GCP) is reported.
    • Ensure that the minutes of the meetings with management are prepared and circulated to all meeting attendees.
    • Ensure that the investigation plan is prepared and investigations are conducted and reported.
    • Maintaining and updating the tracking log for serious Good Clinical Practices (GCP) breaches.
    • Compiling and maintaining serious Good Clinical Practices (GCP) breaches files.
    • Providing periodic status reporting of outstanding cases of serious breaches of Good Clinical Practices (GCP) to the senior management and relevant functional area management.

    • Functional   area management/sponsor/sponsor representative shall be responsible for:

    • Facilitating and supporting the investigation of serious breaches of Good Clinical Practices (GCP).
    • Participating in the collection and review of requested documents, determination and preparation of CAPA to be pursued, and submission of CAPA responses to Head – Corporate R&D Quality/designee.
    • Notifying the IRB/IEC of serious breaches of Good Clinical Practices (GCP) (as applicable).
    • Implementing/providing the CAPA plan to the person responsible at the place of the event.
    • Drafting and sending the last chance letter to the investigator site/ Contract Research Organization (CRO)/Service provider if the decision is taken to pursue remediation.
    • Drafting and finalizing the termination notification in consultation with the Legal department.

    • Company Management shall be responsible for :

    • Performing the assessment of serious breaches of GCP.
    • Discussing the scope of the investigation regarding a serious breach of GCP.
    • Reviewing the investigation report to ascertain if the evidence substantiates the claim of a serious breach of GCP.

    • The legal Department shall be responsible for :

    • Reviewing investigator, CRO, and service provider contracts to include clauses for notification requirements of serious breaches of Good Clinical Practices (GCP).
    • Reviewing any draft termination notice before it is sent out.

    • Regulatory Affairs shall be responsible for:

    • Notifying the applicable Regulatory agency /units of serious breaches of Good Clinical Practices (GCP) in consultation with the Legal Affairs department.
    • Facilitating communications with appropriate Regulatory agencies (as applicable) regarding termination of investigator site/ CRO/service provider.

4.0   ABBREVIATIONS AND DEFINITIONS

Term Definition
CAPA Corrective Action and Preventive Action
CRO Contract Research Organization
CTU Clinical Trial Unit (MHRA)
FAM Functional Area Management
GCP Good Clinical Practices
HSA Health Sciences Authority (Singapore)
IEC Independent Ethics Committee
IMP Investigational Medicinal Product
IRB Institutional Review Board
MHRA Medicines and Healthcare Products Regulatory Agency (UK)
NRES National Research Ethics Service
R&D Research and Development
REC Research Ethics Committee
Serious breach A “serious breach” is a breach that is likely to affect to a significant degree –(a) The safety or physical or mental integrity of the subjects of the trial; (b) The scientific value of the trial”.

5.0   PROCEDURE FOR HANDLING OF GOOD CLINICAL PRACTICES BREACHES :

    • All personnel involved in supporting or conducting Good Clinical Practices (GCP) studies of/on behalf of the company shall be sensitized towards the possibility of serious breaches of Good Clinical Practices (GCP) in studies conducted for/in countries where reporting obligations exist for serious breaches of Good Clinical Practices (GCP) (hereafter referred to as Good Clinical Practices (GCP) studies in this global SOP). Some examples (but not limited to) of what may be serious breaches of Good Clinical Practices (GCP) as provided by MHRA are given in Attachment I, 
    • For investigator sites / CRO/ service providers, the contracts shall include the requirement to notify the company (FAM/ Sponsor/ Sponsor representative and Head – Corporate R&D Quality /designee) of serious breaches of Good Clinical Practices (GCP) in GCP studies.
    • The legal department shall review the Investigator, CRO, and Service provider contracts to include such notification requirements of serious breaches of Good Clinical Practices (GCP), wherever applicable.
    • When there is a suspicion that a serious breach of Good Clinical Practices (GCP) has occurred, the individual making the observation or receiving the information shall immediately report it to the FAM/ Sponsor/ Sponsor representative and Head – Corporate R&D Quality/designee within one business day.

    • Verbal communications shall be promptly followed by written communication.

    • If issues related to serious breaches of Good Clinical Practices (GCP) in Good Clinical Practices (GCP) studies are raised through the whistle-blower policy of the company, the reporting obligations of the same shall be handled as per this guideline.
    • Head – Corporate R&D Quality/designee shall maintain a tracking log for serious Good Clinical Practices (GCP) breaches (as per Attachment II) and shall log in the reported suspected serious Good Clinical Practices (GCP) breaches.
    • Head – Corporate R&D Quality/designee shall perform the initial assessment to confirm potential serious Good Clinical Practices (GCP) breach and shall also determine Regulatory reporting requirements in consultation with the Head of the Regulatory Affairs department /designee.
    • If the initial assessment does not conclude a serious Good Clinical Practices (GCP) breach, the Head of Corporate R&D Quality/designee shall document the conclusions along with the justification and file in the serious Good Clinical Practices (GCP) breach file. Head – Corporate R&D Quality/ designee shall also update the tracking log for serious Good Clinical Practices (GCP)
    • If a serious breach of Good Clinical Practices (GCP) is suspected and further action is warranted, the Head – Corporate R&D Quality/designee shall convene a meeting with the appropriate company management within one business day to discuss the scope of the investigation and the further course of action as per applicable regulations and guidelines.

    • The head Corporate R&D Quality/ designee shall chair this meeting.

    • This meeting shall also be attended by the Head R&D Quality/ designee, Head of R&D, FAM / Sponsor / Sponsor representative, Head of the bioequivalence and clinical trials department(s), Head regulatory affairs, Legal department representative, and additional personnel as deemed necessary.
    • During this meeting, the company management shall evaluate all available The assessment and reason for whether further action will be taken or not shall also be documented.
    • Head – Corporate R&D Quality/designee shall ensure that the detailed minutes of the meeting are prepared and circulated to all the meeting attendees and a copy of the minutes of the meeting is maintained in the serious Good Clinical Practices (GCP) breach.
    • Head – Corporate R&D Quality/designee shall ensure that an investigation plan is developed in consultation with the relevant FAM / Sponsor / Sponsor representative to confirm the serious Good Clinical Practices (GCP) breach and to determine the root cause.
    • Head – Corporate R&D Quality/ designee shall ensure that the investigation is conducted according to the investigation plan and that an investigation report is prepared.
    • The company management shall review the investigation report to ascertain if the evidence substantiates the claim of a serious breach of Good Clinical Practices (GCP).
    • If the investigation rules out a serious Good Clinical Practices (GCP) breach, the Head Corporate R&D Quality/designee shall document the conclusions along with the justification and file in the serious Good Clinical Practices (GCP) breach file.

    • Head – Corporate R&D Quality/ designee shall also update the tracking log for serious Good Clinical Practices (GCP) breaches.

    • If the evidence substantiates the claim of a serious breach of Good Clinical Practices (GCP), the applicable country regulations shall be followed for reporting obligation.
    • The Regulatory Affairs department in consultation with the Legal department shall notify the applicable Regulatory agencies. Initial telephonic notification, if done, shall be followed up with a written notification.
    • If reporting templates are provided by the Regulatory agencies, the same shall be used else Attachment-III shall be used for reporting (initial and follow-up) of serious breaches to the Regulatory agency, whenever these need to be reported.
    • All reporting timelines shall be observed. E.g. MHRA and HSA: within seven days of the FAM/ Sponsor/ Sponsor representative becoming aware of a Good Clinical Practices (GCP) breach.
    • The notification shall also be sent out to any other relevant Regulatory units (e.g. Defective Medicines Report Centre of MHRA if the breach involves defective medicines or IMP recall), as applicable.

    • The FAM / Sponsor/ Sponsor representative shall inform the respective IRB / IEC as applicable.

    • The relevant FAM / Sponsor / Sponsor representative shall draft a CAPA plan for obtaining voluntary compliance from the person responsible at the site of the event e.g. Investigator.
    • The Head – Corporate R&D Quality/designee shall review the CAPA plan to ensure that the serious Good Clinical Practices (GCP) non-compliance issues will be remediated and prevented in the future with the proposed CAPA If required, the relevant FAM / Sponsor / Sponsor representative shall modify the CAPA plan.
    • If no modification is required, the relevant FAM/ Sponsor / Sponsor representative shall ensure that the CAPA plan is provided to the person responsible at the site of the event (e.g. investigator) with clear timelines given for implementation.

    • If investigations or corrective or preventive actions are ongoing at the time of reporting of serious breaches of Good Clinical Practices (GCP) to the Regulatory agencies.

    • The Regulatory Affairs department in consultation with the Legal department shall notify the Regulatory agency regarding the updates/ follow ups on the investigations or details regarding the closure of the CAPA.
    • Head – Corporate R&D Quality / designee shall periodically monitor the progress and effective implementation of the CAPA by either reviewing the related documents or by conducting follow up audits.
    • If CAPA is not effectively implemented or if post implementation of the CAPA, compliance could not be achieved, Head – Corporate R&D Quality/ designee shall convene a meeting with company management to determine whether to pursue further actions and communications for the purpose of remediation or to terminate the Investigator site/ CRO/ Service provider.
    • If the decision is taken to pursue remediation, the FAM / Sponsor / Sponsor representative shall send a last chance communication to the Investigator site / CRO / Service provider outlining the serious Good Clinical Practices (GCP) breach, corresponding corrective actions, current status (with a copy to IRB/IEC, if necessary).
    • The relevant FAM / Sponsor / Sponsor representative shall document the proposed remediation measures in a CAPA plan and send for review to the Head – Corporate R&D Quality / Post acceptance, the FAM/ Sponsor/ Sponsor representative shall provide the CAPA plan to the person responsible at the site of event e.g. Investigator for implementation.

    • Head – Corporate R&D Quality / designee shall ensure effective implementation and closure of CAPA.

    • If the decision is taken to terminate the Investigator site / CRO/ Service provider, the FAM / Sponsor / Sponsor representative in consultation with Legal department shall draft a termination communication within five business days of the decision being taken.
    • The termination communication shall include details of the project / study status, detailed description of the serious Good Clinical Practices (GCP) breach, record of efforts made to secure compliance prior to termination, clarification of outstanding issues etc.
    • The FAM / Sponsor/ Sponsor representative shall send out the termination communication to the Investigator / CRO / Service provider with a copy to Head – Corporate R&D Quality / designee and Regulatory affairs department.
    • The IRB/IEC shall also be informed. The Regulatory affairs department shall facilitate all communications with the appropriate Regulatory agencies, as applicable.
    • Head – Corporate R&D Quality / designee shall compile and maintain a Serious Good Clinical Practices (GCP) breach file containing all the documentations and communications pertaining to the GCP breach.
    • Head – Corporate R&D Quality /designee shall also maintain and periodically review the tracking log of serious Good Clinical Practices (GCP) breaches to verify whether outstanding cases have been brought to Periodic status report of outstanding cases shall be submitted to the company management and relevant FAM / Sponsor / Sponsor representative.

6.0   ATTACHMENTS

    • Attachment I –   Notification examples provided by MHRA.
    • Attachment II –  Format of tracking log for serious Good Clinical Practices (GCP) breaches.
    • Attachment III  –   Format for Notification of Serious Breach of Good Clinical Practices (GCP).

7.0      PRESERVATION OF GOOD CLINICAL PRACTICES (GCP) RECORDS

    • All documents generated as per this SOP shall be compiled and maintained in a serious Good Clinical Practices (GCP) breach file.
    • This file shall be treated as highly confidential and shall be maintained with secure access.
    • These records shall be archived and shall be retained for an infinite period.
    • A copy of the documents or a reference of these documents shall also be filed in the Trial Master File / study binders of the respective studies.

8.0   REFERENCES

    • MHRA – Guidance for the Notification of Serious Breaches of Good Clinical Practices (GCP) or the Trial Protocol, Version 5 (060114)
    • HSA – Guidelines on Notification of Serious Breaches, February 2015.
    • Integrated addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2), 09 November 2016.
    • Guidance for Industry Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects, October 2009.
    • Whistle Blower Policy for company and its Indian Subsidiaries.
    • Whistle Blower Policy for Global Subsidiaries.

ATTACHMENT – I

Notification examples provided by MHRA

Notified by Details of Breach Reported Is this a Serious Breach?
Sponsor Dosing errors reported:

1) A subject was dosed with the incorrect IMP, which was administered via the incorrect route (the IMP used was from a completely different clinical trial to the one the subject was recruited to).

2) A subject was dosed with IMP from the incorrect treatment arm. In addition, some months later, the subjects in an entire cohort were incorrectly dosed with IMP three times daily when they should have been dosed once daily.

3) One subject was administered 6 additional doses of IMP. The subject was to receive IMP on day 1 and 8 but instead received IMP on days 1 to 8. The subject experienced a severe adverse event as a result.

4) A subject took IMP that had expired two days ago. The subject did not experience any adverse events and this issue was not likely to affect the data credibility of the trial.

 Yes, there was significant potential to impact the safety or physical or mental integrity of trial subjects.

Yes, there was impact on the safety or physical or mental integrity of trial subjects or on the scientific value of the trial

this issue was systematic and persistent leading to a constant breach of the conditions and principles of Good Clinical Practices (GCP) in connection with that trial or the trial protocol

This issue persisted despite the implementation of a corrective and preventative action plan.

Yes, there was impact on the safety or physical or mental integrity of trial subjects and on the scientific value of the trial

No, there was no impact on the safety or physical or mental integrity of the trial subject or on the scientific value of the trial. In addition, the assessment of the breach identified this as a single episode and a detailed corrective and preventative action plan was implemented.
Sponsor IMP temperature excursions reported. Yes, if the situation was not managed and subjects were dosed with IMP assessed as unstable, which resulted in harm/potential to harm subjects.
Sponsor Multiple issues with the Interactive Response Technology (IRT) system across several clinical trials leading to the dispensing of expired IMP and a shortage of IMP at investigator sites in time of subject visits. Yes, there was impact on the safety or physical or mental integrity of trial subjects and this issue persisted leading to a constant breach of the conditions and principles of GOOD CLINICAL PRACTICES (GCP) in connection with that trial or the trial protocol, despite          the implementation of a corrective and preventative action plan.
Sponsor On two separate occasions the Sponsors identified issues with the same organization. First with consenting and then with potential fraud in recruitment and consenting. However, there was not unequivocal evidence of fraud at the time of reporting. One of the studies involved pediatric subjects. Yes, this subsequently led to enforcement action against the organization in question.
Sponsor Concerns were raised during monitoring visits about changes to source data for a number of subjects in a trial, which subsequently made subjects eligible with no explanation. An audit was carried out by the Sponsor and other changes to source data were noted without explanation, potentially impacting on data integrity. Follow-up reports sent to MHRA confirmed the Sponsor concerns over consenting and data changes made to source without an adequate written explanation.

Yes

Note: not all of the information was provided in the original notification, the Sponsor provided follow-up updates.
Sponsor A clinical trial subject attended A&E who attempted to contact the pharmacy department (using the phone number listed on the emergency card issued to the subject) in order to break the unbinding code. Pharmacy were unable to code break in a timely manner, as a result, the subject withdrew from the clinical trial feeling unhappy that the pharmacy was not available in an emergency situation. Yes, as this had significant potential to harm the subject if unbinding would have affected the course of treatment
CRO A cohort had invalid blood samples as they were processed incorrectly. As a result one of the secondary endpoints could not be met. Therefore, a substantial amendment was required to recruit more subjects to meet the endpoint. Subjects were dosed unnecessarily as a result of this error. Yes
CRO Subject safety was compromised because repeat ECGs were not performed, as required by the protocol. Also, there was inadequate QC of the interim safety reports used for dose escalation which has potential for stopping criteria to be missed. Yes
Contractor The Investigator failed to report a single SAE as defined in the protocol (re- training provided).

 

 

 

 

 No, if this did not result in other trial subjects being put at risk, and if it was not a systematic or persistent problem.

In some circumstances, failure to report a SUSAR could have a significant impact on trial subjects. Sufficient information and context should be provided for the impact to be assessed adequately.
Identified during inspection Investigator site failed to reduce or stop trial medication, in response to certain laboratory parameters, as required by the protocol. This occurred with several subjects over a one year period, despite identification by the monitor of the first two occasions. Subjects were exposed to an increased risk of thrombosis. Yes

Identified during inspection

 A potential serious breach was identified, but not reported (documentation in the Sponsor’s TMF identified that there may have been fraud at an investigator site, re-use of previous time point data in later time points). The Sponsor had investigated and the issue was subsequently found to be a genuine error and not fraud.

No, on this occasion.

However, had this been identified as fraud impacting on the integrity of the data, then this serious breach would not have been notified within the regulatory timeframe (i.e. 7 day window).
Sponsor Patient Information Leaflet and Informed Consent updated, but at one trial site this was not relayed to the patients until approximately 2-3 months after approval. More information on the potential consequences of the delay should have been provided. No, if this was not a systematic or persistent problem and if no harm to trial subjects resulted from the delay.

Yes, if there was a significant impact on the integrity of trial subjects (e.g. there was key safety information not relayed to subjects in a timely manner).
MHRA (CTU) The GOOD CLINICAL PRACTICES (GCP) Inspectorate was notified that a substantial amendment had been submitted regarding changes to dosing on a first in human study, as a result of an SAE after dosing the initial subject. The sponsor had temporarily halted the trial and only after further investigation had assigned the SAE as unrelated. The sponsor had not notified the CTU of the “urgent safety measure” implemented or reported the SAE as a potential SUSAR. Yes
NRES The early destruction of investigator site files (i.e. one study had only been completed a year earlier and one study was still ongoing). Yes
Member of public A member of public received a named invite to  a volunteer in a clinical trial (no specific trial mentioned). However, this person was not on the organization’s volunteer database and had not participated previously in a study. On further investigation by MHRA, it was revealed that the organization had contracted the use of a mail shot organization to send a generic mail shot to a list of people in a specific location, over a certain age. This had been approved by the REC. No

 

ATTACHMENT – II

Tracking log for serious Good Clinical Practices (GCP) breaches

S.No.

 Notification Date Details of Serious Non Compliance Issue Responsible FAM/Sponsor/Sponsor Representative Follow-up Status Corrective Action Status Notification (IRB / IEC / Regulatory) Closure

Remarks

 

ATTACHMENT – III

Notification of Serious Breach of GCP

Organization Name :
Contact Details : Date Breach Identified by Sponsor :
Date Breach Identified by Regulatory Agency :
Details of Individual or Organization committing breach : Details of related study (if applicable):
Report: Initial report {  }      Follow-up report   {  }
Details of the breach:
Potential impact to patient safety and/or data credibility :

{  }  Patient safety                                                        {  }  Scientific value / data credibility

{  }  Patient confidentiality                                         {  }  None

{  }  Approval issues                                                     {  }  Other non-compliance (specify)

{  }  IMP
Background : 
Other relevant information:

(i.e. study status, site(s), ethics, trust, CRO/sponsor details etc.)
Please give the details of the action taken:

This should include : Any investigations by your organizations, details of investigations by other organizations (e.g. CRO/ethics/trust), the results and outcomes of the investigations (if known or details of when they will be available/submitted), how it will be reported in the final report/publication, the corrective & preventive action implemented to ensure the breach does not occur again.
Actual impact to patient safety and/or data credibility :

{  }  Patient safety                                                        {  }  Scientific value / data credibility

{  }  Patient confidentiality                                         {  }  None

{  }  Approval issues                                                     {  }  Other non-compliance (specify)

{  }  IMP

 

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Janki Singh is experienced in Pharmaceuticals, author and founder of Pharma Beginners, an ultimate pharmaceutical blogging platform. Email: [email protected]

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