How to Write an Effective Response for Sponsor Site Audits and Site Inspections

1. Introduction

The purpose of this guideline is to provide guidance on how to manage and respond to audit observations resulting from sponsor site audits or Regulatory Authority (RA) site Inspections.

2. Managing Observation Responses

All responses should include the following four elements:

1. Issue explanation / investigation: explanation of the issue and supporting information on identified of the issue previously (if applicable).
2. Root Cause: outcome of the root cause analysis and Human Factor.
3. Corrective action: actions taken to correct the immediate issue.
4. Preventive action: actions taken to prevent reoccurrence (may not be necessary for all CAPAs i.e. if action had already been taken or for isolated minor issues).

Note: the investigation and resulting actions, should consider, where appropriate, possible impact to other sites on the study and /or studies within the portfolio.

Further guidance on each of the elements can be seen below, including examples based on the following 3 observation case scenarios.

1. Observation 1: A copy of the follow-up letter for MV 3 was not filed in the onsite investigator file.
2. Observation 2: Only photocopies of the signed ICF were available at site for patients 1-3.

• Observation 3: The IMP logs had been completed incorrectly.

2.1 Issue Explanation / Investigation:

The response should include a brief and concise explanation relating to the chronology of events which led to the finding. Depending on the issue, a certain amount of investigation may be necessary to clarify why a non-conformance (NC) was not previously identified and/or in order to provide evidence of actions that have already been taken:

• Review previous MVRs for evidence of deviation detections and/or site retraining
• Review training slides for evidence of previous trainings related to the NC
• Review correspondence with the site and/or sponsor for evidence of previous escalation, etc.

Avoid too wordy responses and do not provide information if not strictly required. Stay focused on the finding.

If you refer to a SOP/WP/ SSP/ Project Plan, be sure to include the title, the code and, if appropriate, the version of the procedure/ plan.

Below are examples of potential responses:

1. Observation 1: The follow-up letter was sent by the CRA to the site on 03 Jan 2016 and a copy was filed in the in-house file (see attached email). The letter was sent only to the PI’s email box and not to the site coordinator who had responsibility for filing at the site. No further FULs were found missing in the onsite investigator file.

 

1. Observation 2: In accordance with the hospital’s local procedure, the original ICF was given to the patients and a copy was filed in a separate clinical trial folder. The CRA had identified this at MV1 and the site was retrained the same day (see the attached training log and the MVR). The CRA asked the site staff to retrieve the originals, but they were not available.

 

• Observation 3: The pharmacist responsible for completing the IMP logs was not aware of the correct way of completing the IMP forms. The pharmacist had not attended the SIV training on 20 Dec 2015 and subsequent training by the lead pharmacist had not taken place. This was the CRA’s first visit to the pharmacy and therefore she had not had the opportunity to review the pharmacy training log.

2.2 Root Cause Analysis (RCA):

A root cause analysis should be completed in order to identify the real Root Cause for the non-conformance and the associated Human Factor to ensure appropriate Corrective and Preventive Actions are put in place (CAPA). The Root Cause and the associated Human Factor should always be present in your response. The Root Cause must be a clear and concise statement. If the observation is due to an individual mistake/ human error this should be clearly stated.

1. Ask why, and then why and then why again until you identify the true root cause.
2. Consider if SOPs are clear and/or if the study-specific procedures are clear.

• Consider if the study-specific training provided to CRAs / sites was adequate.

1. Consider if there is a risk of the non-conformance occurring at other sites and /or across the entire study.

Examples of Root Causes:

1. Observation 1: The CRA had not CC’ed the study coordinator who was responsible for filing of the follow-up letter distribution email at the site because she was not on the site contact list. The PI had not forwarded the email to the study coordinator. Human factor: Communication.

 

1. Observation 2: The site’s local procedure incorrectly required that the site only maintain a copy of the signed ICF and provide the original to the subject. Human factor: Process.

 

• Observation 3: The pharmacist responsible for completing the logs had not received any study- specific training and was therefore not aware of the study-specific form requirements. Human Factor: Training.

 

 

 

2.3 Major / Critical Observations Impact Assessment:

Minor observations are often isolated incidences of non-compliance that may only need corrective actions and/or minimal preventative actions. Major and critical observations require a more thorough investigation, including an impact assessment where necessary.

For major or critical observations, ensure the wider impact is investigated, for example:

1. Observation 1: This was an isolated case as confirmed during the Investigation phase.
2. Observation 2: Are other sites in that country also not filing ICFs appropriately? What was the CRA’s knowledge and understanding?

• Observation 3: Were patients dosed correctly?

If wider impact is noted, then other corrective and/or preventive actions will need to be considered to correct any process / system failures. For studies that are part of a wider portfolio, lessons learnt and/or wider preventative actions at a portfolio level should be considered. 

2.4 Corrective Actions:

Corrective actions are the actions taken to correct the immediate non-conformance and should be clearly linked to the finding. Completion dates of the actions or the completion target dates for pending actions, the action owner and any evidence of the action completion/ implementation need to be included.

Examples of corrective actions:

1. Observation 1: The missing follow-up letter was filed by the SC in the on-site ISF on the 15th April 2016 (see MVR action item 2).
2. Observation 2: Copies of the ICFs were filed with the patient notes as the originals were not available. A NTF was completed and signed/ dated by the PI and was filed in the site file on the 15^th April 2016 explaining the reason for missing original versions of the signed ICFs (see attached NTF).

• Observation 3: The IMP logs were corrected by the pharmacist responsible for completing them at the next MV on the 15th April 2016 (see MVR).

2.5 Preventive Actions:

Preventive Actions are actions taken to prevent future reoccurrence of the non-conformance and should be clearly linked to the Root Cause and Human Factor. If this link is not evident, it might be that the root           cause has not been properly identified or the preventive action is not appropriate. Preventive actions      should include a due date and an action owner. If the action is complete, evidence of completion should be available.

Examples of preventive actions:

1. Observation 1: The CRA added the study coordinator’s email address to the contact list and will ensure that she is cced on all future correspondence (see study contact list attached).
2. Observation 2: The site updated their Clinical Trial Procedure for management of ICFs to require that the site maintain an original signed ICF filed with the patient notes and a signed copy to be given to patients for their records. This will be effective on 01 May 2016.

• Observation 3: The pharmacist responsible for completion of study IMP logs was trained by the CRA on the 10^th Jan 2016 and the training was documented on the pharmacy training log. On the same day, the lead pharmacist was also retrained by the CRA on his roles and responsibilities to ensure that assigned pharmacy staff receives appropriate study-specific training before completing any study-related documentation.  Copies of the training logs are attached.

2.6 Action timelines and follow-up:

For each corrective and preventive action, a target completion date should be provided along with the person responsible, i.e. an owner for its implementation. Ensure the target date is feasible. It is always better to have a longer due date than to be overdue.

Be prepared to provide evidence of the action completion/ implementation to the client. Therefore, ensure that your actions are objective, specific, measurable and can be documented.  No mention of an audit or inspection should be included in any documentation that is to be retained in the ISF or TMF (e.g. Monitoring Visit Report, Follow Up Letter).

3. DOs and DON’Ts

• Don’t enter full names in your responses, just roles and/or initials.
• When using acronyms, such as for the department (i.e. SSU, MW, DM) or the roles (e.g. PM, CTM, SSUA…), be sure to enter them in full the first time in the response document. The inspector/external auditor might not be familiar with them.
• The response must be written in a professional style using complete sentences. Don’t use a friendly language in writing and avoid abbreviations.
• The response must be written in correct English. Thoroughly review the response for errors and typos.

Frequently Asked Questions

What are the four elements that all responses to audit observations should include?

All responses should include issue explanation/investigation, root cause analysis, corrective action, and preventive action.

What should root cause analysis aim to identify?

Root cause analysis should aim to identify the real root cause for non-conformance and associated human factors to ensure appropriate corrective and preventive actions.

What should be included in corrective actions?

Corrective actions should be clearly linked to the finding and include completion dates, action owners, and evidence of completion.

What should preventive actions be linked to?

Preventive actions should be clearly linked to the root cause and human factor, include due dates and action owners, and have evidence of completion if the action is completed.

What should be considered when addressing process/system failures?

Consider wider impacts and potential corrective and preventive actions to address process/system failures.

How should responses be written?

Write responses in a professional style using complete sentences, avoiding friendly language and abbreviations.

What should be done to ensure clarity when using acronyms?

When using acronyms, enter them in full the first time in the response document to ensure clarity for inspectors/external auditors.

What should be avoided in documentation retained in the ISF or TMF?

Avoid including any mention of audits or inspections in documentation retained in the ISF or TMF.