Terri P. Kelly, RN, MSQA, CQA President and Principal ... - FDA News

Terri P. Kelly, RN, MSQA, CQA 

President and Principal Consultant 

Achieve Quality, Inc. 

Tarpon Springs, FL

Clinical SOPs 

�What’s working and what’s not 

�SOP detail 

�Warning Letters 

�Sponsor/CRO and Investigator

Procedural Documents

SOP Format 

� Header 

� Purpose 

� Scope 

� Definitions 

� Responsibility 

� Procedure Steps 

� Revision History 

� References

Purpose 

�Reason for SOP 

�This Standard Operating 

Procedure (SOP) describes the 

process utilized for….

Scope 

�Range, capacity, extent 

�This SOP applies to all…. 

�Clinical trials with controlled drugs 

�All Phase I‐IV clinical trials utilizing 

non‐electronic data collection 

procedures (i.e., paper CRFs and other 

related documents)

Definitions 

�Terminology used in SOP 

�SOPs are training tools for 

new employees 

�Copy definitions from ICH 

GCP E6

Responsibility 

�Can be combined with Procedure 

Steps 

�Who is assigned responsibility for 

what tasks 

�Who has overall responsibility to 

oversee compliance to SOP

Procedure Steps 

�Step‐by‐step how‐to complete a task 

�Think about how you would train someone 

with no research experience to do this task 

�Don’t make SOP too detailed and box 

yourself in 

�New employees read SOP, then mentor on 

task with experienced staff member, and 

then read SOP again

Revision History 

�New SOP: N/A 

�Chronological listing of all 

version dates and overview 

of changes made with each 

version

References 

• Listing of Regulation or Guidance 

• Applicability to SOP 

• ICH GCP E6 on most all SOPs 

• Controlled Drugs (DEA Controlled Substances Act: 

21 CFR Chapter 13) 

• ICF (FDA 21 CFR Part 50) 

• HIPAA Privacy Rule (45 CFR 160 and 164) 

• Listing of forms noted within SOP or 

related SOPs and WIs

Expectations During 

Sponsor / CRO Inspection 

� Table of Contents 

� Corporate Level SOPs 

� Controlled Documents 

� Training 

� Suspected Misconduct and Serious Breach Mgt 

� Corrective and Preventative Action 

� System Access and Part 11 Compliance 

� Document Retention / Archival 

� Facility Security 

� Disaster Recovery and Business Continuity 

� Vendor Management 

� Department Level SOPs

Which Document Level? 

�Oracle Clinical Data Entry 

�Good Documentation Practices 

�MHRA Submissions 

�Review of Site‐Specific ICFs 

�Histopathology Process between Lab 

and Dermatopathologist

Sponsor/CRO Clinical Operations 

� Investigator Site Selection 

� Study Start‐Up 

� Monitoring 

� CRA Selection 

� Monitoring Visits 

� Monitoring Reports and Correspondence 

� Clinical Monitoring Plans 

� Essential Docs: Trial Master File/Investigator Site File 

� Project Management

Sponsor/CRO Clinical SOPs 

� Clinical Trial Documents 

� Protocol, CRF, ICF/HIPAA, Study Plans 

� Registering Clinical Trials 

� Pharmacovigilance / Clinical Safety 

� Investigational Product (IP) Management 

� IP Safety Profile Management 

� IDBs, IFUs, Safety Updates, CEC, DSMB, Steering 

Committees 

� Clinical Study Reports 

� Audit and Inspection Management

Sponsor Warning Letters 

•[21 CFR 812.43(c)]Failure to obtain a signed agreement from 

each participating investigator, which must contain a 

commitment from the investigator to promptly update the 

financial disclosure information if any relevant changes occur 

during the course of investigation and for one year following 

the completion of the study. 

•Response: SOPs instituted to monitor investigator financial 

involvement 

•FDA Response: Provided SOPs inadequate; do not include 

provision of monitoring, whereby investigators are required to 

provide a financial interest update following changes in their 

financial interests in the company for one year following the 

completion of the study.


•[21 CFR 812.46(a)] Failure to secure the investigator’s 

compliance. Interim monitoring reports document failure of 

Investigator to follow the Investigational Plan, with no 

evidence of communicating the issues to the Investigator, nor 

corrective action being instituted. 

•Response: SOP revised to include requiring the Monitor to 

give more feedback to Investigator. 

•FDA Response: Provided SOP inadequate; fails to include 

what steps are taken to secure compliance, process to take 

when non‐compliance continues, including CAPA investigation, 

potential Investigator termination and FDA notification.


•[21 CFR 312.50]failure to ensure proper monitoring of the 

investigation . Overdosing of six subjects at Dr A’s site was 

neither recognized nor reported by study monitors in a timely 

manner. Ultimately identified by Data Management query five 

months after overdosing occurred. 

•Response: SOP will be put into place to ensure compliance 

with the FDA regulations in the future. 

•FDA Response: We acknowledge your firm’s assurance that 

corrective actions will be taken. However, we note that the 

response did not contain a detailed outline of procedures or 

processes, as well as CRA and site staff training, that would be 

implemented to prevent the future occurrence of these 

observations.

Clinical Investigator SOPs 

� FDA Guidance for Industry ‘Protecting the Rights, 

Safety, and Welfare of Study Subjects ‐ Supervisory 

Responsibilities of Investigators’ published May2007 

� Correcting problems identified by study personnel, outside monitors or 

auditors, or other parties involved in the conduct of a study 

� Documenting the performance of delegated tasks in a satisfactory manner 

and, where appropriate, verifying findings (e.g., observation of the 

performance of selected assessments or independent verification by 

repeating selected assessments) 

� Ensuring that the consent process is being conducted in accordance with 2 1 

CFR Part 50 and that study subjects understand the nature of their 

participation, risks, etc. 

� Ensuring that information in source documents is accurately captured on the 

Case Report Forms 

� Dealing with data queries and discrepancies identified by the study monitor 

� Ensuring study staff comply with the protocol, adverse event assessment 

and reporting, and other medical issues that arise during the course of the 

study.

Clinical Investigator SOPs 

� Investigator and Staff Qualifications and Training 

� Financial Disclosure and Certification 

� IRB Evaluation and Submissions 

� Subject ICF/HIPAA Process 

� Subject Qualification Review 

� Source Documentation 

� Case Report Form Transcription and Query Administration 

� Adverse Events and Serious Adverse Events 

� Investigational Product Management 

� Monitoring Visits 

� External Audits and Regulatory Authority Inspections 

� Record Retention and Archive

CI Warning Letters 

• [21 CFR 312.60] failure to conduct the studies or ensure they were conducted 

according to the investigational plan. 

• Response: SOP generated and training provided. 

• FDA Response: Obtaining education serves as a positive step in helping to understand the 

regulatory requirements related to conducting clinical research covered by the regulations. FDA 

notes, however, that there were discrepancies identified in our review of your SOPs with your 

noted promised corrective actions. Specifically, in review of the SOP, the investigator’s individual 

responsibility does not include ensuring and verifying eligibility of the subject into the study. From 

this SOP, it appears that the responsibility for determination of eligibility is left to the research 

nurse/coordinator and/or the data manager. 

In addition, in review of Sections A and B of the SOP, FDA could not determine to whom you 

delegated the responsibilities for eliciting and documenting the subject’s medical history, 

performing a complete or directed physical examination, establishing a subject’s baseline signs and 

symptoms, ordering the tests/procedures that were directed by the protocol, assessing the subject 

for signs and symptoms of any intercurrent illness, documenting adverse events appropriately, and 

instituting appropriate therapy if required by the subject’s condition. Specifically, FDA was unsure if 

the responsibility was jointly delegated to the investigator and research nurse/coordinator, or if the 

investigator or the research nurse/coordinator could independently handle these responsibilities 

without the knowledge or oversight by the other. FDA notes that the latter, which would allow the 

research nurse/coordinator to perform these activities alone, is inadequate.


• [21 CFR 312.62(b)] failure to maintain adequate and accurate case histories. 

• Response: SOPs generated and training provided. 

• FDA Response: In review of your SOPs, we note that the responsibilities of (1) 

the collection of the clinical research data reside mainly with the research 

nurse/coordinator; (2) the transcription of the data to the CRFs is delegated to 

the research nurse/coordinator and/or support staff; and (3) the quality 

assurance to ensure adequate and accurate case histories of only the first sets 

of completed CRFs is delegated to either the research manager and/or the 

research nurse/coordinator. We note that these SOPs provide no requirement 

for the investigator to review the documents to ensure the accuracy and 

adequacy of the information in the source records. In addition, per the SOP, 

the only quality assurance performed at your site to ensure adequate and 

accurate case histories is limited to only the first sets of completed CRFs. We 

further note that given that the research nurse/coordinator is also delegated to 

collect the study data, this could lead to the situation whereby the individual 

who is collecting and recording the study data is also auditing their own source 

records.


� [21 CFR 312.66] failure to promptly report to the IRB all unanticipated 

problems involving risk to human subjects or others. 

• Response: SOPs generated and training provided. 

• FDA Response: Your SOP states that all communications about AEs and SAEs 

that occur during the course of the study are to be communicated to the IRB by 

either the research nurse/coordinator and/or support staff. Based upon the 

review of your SOP, FDA is unsure whether the responsibilities delegated in this 

SOP are shared responsibilities between the research nurse/coordinator and/or 

support staff or whether each could individually take on the responsibility 

without oversight or knowledge by the other. FDA further notes that this SOP 

does not provide a role for the investigator to review the AEs and SAEs and/or 

verify that the reports submitted to the IRB have accurate and adequate 

information, which would include information about whether or not the event 

was associated with the use of the investigational drug.

Thank you! 

Terri P. Kelly, RN, MSQA, CQA 

Achieve Quality, Inc. Inc 

(727) 808‐7860 808 7860 cell 

(727) 937‐7073 937 7073 office 

kellyt@tampabay.rr.com

Terri P. Kelly, RN, MSQA, CQA President and Principal ... - FDA News

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