Tag Archives: Are you Practicing GCP?

How to Avoid Electronic Data Integrity Issues: 7 Techniques for your Next Validation Project

The idea of this article was taking (with permission from the original authors) from Montrium:  how-to-avoid-electronic-data-integrity-issues-7-techniques-for-your-next-validation-project

Regulatory agencies around the globe are causing life science companies to be increasingly concerned with data integrity.  This comes with no surprise given that Guidance Documents for Data Integrity have been published by the MHRAFDA (draft), and WHO (draft).  In fact, the recent rise in awareness of the topic has been so tremendous that, less than two years after the original publication, the MHRA released a new draft of its guidance whose scope has been broadened from GMP to all GxP data.

Is data integrity an issue of good documentation practices? You can read GCP information about this topic here.

Good Documentation Practices for SAS / EDC Developers

Are you practising GCP?

In computerised systems, failures in data integrity management can arise from poor or complete lack of system controls.  Human error or lack of awareness may also cause data integrity issues.  Deficiencies in data integrity management are crucial because they may lead to issues with product quality and/or patient safety and, ultimately may manifest themselves through patient injury or even death.

I recently was at the vendor qualification tool that uses a hand held device to read data while the physician or expert manually put pressure on someone’s body parts (e..g. pain related). I was not impressed. Even though it seems like a nice device with its own software, the entire process was manual and therefore, questionable data integrity. The measurement seems to be all over the place and you would need the right personnel at the clinical site to perform a more accurate reading since again, it was all manual and dependent of someone else used of the device.

I also questioned the calibration of this device. The sale’s person answer ? “Well, it is reading 0 and therefore, it is calibrated.”….Really? You mean to tell me you have no way of proving when you perform calibration? Where is the paper trail proving your device is accurate? You mean to tell me I have to truth your words? Or your device’s screen that reads ‘0’? Well, I have news for you. Tell that to the regulators when they audit the trial.

What is Data Integrity?

Data can be defined as any original and true copy of paper or electronic records.  In the broadest sense, data integrity refers to the extent to which data are complete, consistent and accurate.

To have integrity and to meet regulatory expectations, data must at least meet the ALCOA criteria. Data that is ALCOA-plus is even better.

Alcoa

 

What is a Computerised System?

computerised system is not only the set of hardware and software, but also includes the people and documentation (including user guides and operating procedures) that are used to accomplish a set of specific functions.  It is a regulatory expectation that computer hardware and software are qualified, while the complete computerised system is validated to demonstrate that it is fit for its intended use.

How can you demonstrate Electronic Data Integrity through Validation?

Here are some techniques to assist you in ensuring the reliability of GxP data generated and maintained in computerised systems.

Specifications

What to do

Why you should do this

Outline your expectations for data integrity within a requirements specification.

For example:

  • Define requirements for the data review processes.
  • Define requirements for data retention (retention period and data format).
Validation is meant to demonstrate a system’s fitness for intended use.  If you define requirements for data integrity, you will be more inclined to verify that both system and procedural controls for data integrity are in place.
Verify that the system has adequate technical controls to prevent unauthorised changes to the configuration settings.

For example:

  • Define the system configuration parameter within a configuration specification.
  • Verify that the system configuration is “locked” to end-users.  Only authorized administrators should have access to the areas of the system where configuration changes can be made.
The inspection agencies expect you to be able to reconstruct any of the activities resulting in the generation of a given raw data set.  A static system configuration is key to being able to do this.

 

Verification of Procedural Controls

What to do

Why you should do this

Confirm that procedures are in place to oversee the creation of user accounts.

For example:

  • Confirm that user accounts are uniquely tied to specific individuals.
  • Confirm that generic system administrator accounts have been disabled.
  • Confirm that user accounts can be disabled.
Shared logins or generic user accounts should not be used since these would render data non-attributable to individuals.

System administrator privileges (allowing activities such as data deletion or system configuration changes) should be assigned to unique named accounts.  Individuals with administrator access should log in under his named account that allows audit trails to be attributed to that specific individual.

Confirm that procedures are in place to oversee user access management.

For example:

  • Verify that a security matrix is maintained, listing the individuals authorized to access the system and with what privileges.
A security matrix is a visual tool for reviewing and evaluating whether appropriate permissions are assigned to an individual. The risk of tampering with data is reduced if users are restricted to areas of the system that solely allow them to perform their job functions.
Confirm that procedures are in place to oversee training.

For example:

  • Ensure that only qualified users are granted access to the system.
People make up the part of the system that is most prone to error (intentional or not).  Untrained or unqualified users may use the system incorrectly, leading to the generation of inaccurate data or even rendering the system inoperable.

Procedures can be implemented to instruct people on the correct usage of the system.  If followed, procedures can minimize data integrity issues caused by human error. Individuals should also be sensitized to the consequences and potential harm that could arise from data integrity issues resulting from system misuse.

Logical security procedures may outline controls (such as password policies) and codes of conduct (such as prohibition of password sharing) that contribute to maintaining data integrity.

 

Testing of Technical Controls

What to do

Why you should do this

Verify calculations performed on GxP data.

For example:

  • Devise a test scenario where input data is manipulated and double-check that the calculated output is exact.
When calculations are part of the system’s intended use, they must be verified to ensure that they produce accurate results.
Verify the system is capable of generating audit trails for GxP records.

For example:

  • Devise a test scenario where data is created, modified, and deleted.  Verify each action is captured in a computer-generated audit trail.
  • Verify the audit trail includes the identity of the user performing the action on the record
  • Verify the audit trail includes a time stamp
  • Verify the system time zone settings and synchronisation.
With the intent of minimizing the falsification of data, GxP record-keeping practices prevent data from being lost or obscured.  Audit trails capture who, when and why a record was created, modified or deleted.  The record’s chronology allows for reconstruction of the course of events related to the record.

The content of the audit trails ensures that data is always attributable and contemporaneous.

For data and the corresponding audit trails to be contemporaneous, system time settings must be accurate.

 

 

 

Who can delete data?

Adequately validated and have sufficient controls to
prevent unauthorized access or changes to data.

Implement a data integrity lifecycle concept:

  • Activate audit trail and its backup
  • Backup and archiving processes
  • Disaster recovery plan
  • Verification of restoration of raw data
  • Security, user access and role privileges (Admin)

Warning Signs – Red Flags

  • Design and configuration of systems are poor
  • Data review limited to printed records – no review
    of e-source data
  • System administrators during QC, can delete data (no proper documentation)
  • Shared Identity/Passwords
  • Lack of culture of quality
  • Poor documentation practices
  • Old computerized systems not complying with part 11 or Annex 11
  • Lack of audit trail and data reviews
  • Is QA oversight lacking? Symptom of weak QMS?
I love being audited

 

 

 

 

 

 

Perform Self Audits

  • Focus on raw data handling & data review/verification
  • Consider external support to avoid bias
  • Verify the expected sequence of activities: dates,
    times, quantities, identifiers (such as batch,
    sample or equipment numbers) and signatures
  • Constantly double check and cross reference
  • Verify signatures against a master signature list
  • Check source of materials received
  • Review batch record for inconsistencies
  • Interview staff not the managers

FDA 483 observations

“…over-writing electronic raw data…..”

“…OOS not investigated as required by SOP….”

“….records are not completed contemporaneously”

“… back-dating….”

“… fabricating data…”

“…. No saving electronic or hard copy data…”

“…results failing specifications are retested until
acceptable results are obtained….”

  • No traceability of reported data to source documents

Conclusion:

Even though we try to comply with regulations (regulatory expectations from different agencies e.g. EMA, MHRA, FDA, etc), data integrity is not always easy to detect. It is important the staff working in a regulated environment be properly trained and continuous refresher provided through their career (awareness training of new regulations and updates to regulations).

Companies should also integrate a self-audit program and develop a strong quality culture by implementing lesson learned from audits.

Sources:

You can read more about data integrity findings by searching the followng topics:

MHRA GMP Data Integrity Definitions & Guidance for the Industry,
MHRA DI blogs: org behaviour, ALCOA principles
FDA Warning Letters and Import Alerts
EUDRA GMDP database noncompliance

The Mind-Numbing Way FDA Uncovers Data
Integrity Laps”, Gold Sheet, 30 January 2015

Data Integrity Pitfalls – Expectations and Experiences

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Good Clinical Practice – The Bible

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. Compliance with this standard provides public assurance that the rights,
safety and well-being of trial subjects are protected, consistent with the principles that have
their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

Below is the link to the most common terms used in clinical trials (for reference). Use it as your leisure, during work hours and day-to-day work as a clinical researcher.

Good Clinical Practice Bible – Terminologies

Are you Practicing GCP?

You probably heard news or stories such as Misconduct Delayed Drug Approval or Duke Settles Negligence Suit.

The 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. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki.

The first is to ensure the protection of the patient. The subject’s consent should have been obtained before any study procedure were performed. Each subject is monitor to ensure accuracy and completeness of the data generated.  If an SAE occurred, the monitor will confirm that the SAE has been reported promptly and completely.

The objective of the ICH GCP Guideline is to provide a unified standard practice for the United States, Japan and the European Union (EU) to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.

So what are the essential documents during the conduct of a clinical trial?

1- Investigator Brochure documents relevant and current scientific information around the investigation product (IP) has been provided to the investigator.

2- Signed Protocol (including Amendments) and Case Report Forms (CRF) document investigator and sponsor agreements.

3- Informed Consent Form documents the information given to trial subjects.

4- Financial Aspects of the trial documents the financial agreement between the investigator/institution and the sponsor / research for the trial.

5- Signed agreement between involved parties. For example, sponsor and CRO.

6- Institutional Review Board (IRB) / Ethics committee (IEC) documents the trial has been subject to IRB/IEC review and given approval opinion. For example this includes but not limited to protocol and any amendments, CRF (if applicable), informed consent form, subject compensation.

7- Regulatory authority(ies) approval/notification of protocol documents approval/notification by the regulatory authority compliance with the applicable regulatory requirements(s).

8- Curriculum Vitae and/or other relevant document evidencing qualifications of investigator and sub-investigator as document eligibility to conduct trial and/or provide medical supervision of subjects.

9- Normal value(s)/range(s) for medical / laboratory technical procedures documents normal values of the tests.

10- Sample of label(s) attached to investigational product containers document compliance with applicable labeling regulations and appropriateness of instructions to the subjects.

11- Decoding procedures for blinded trials documents how, in case of an emergency, identify of blinded investigational product without breaking the blind for remaining subject’s treatment.

12- Master randomization list documents method for randomization of trial population.

13- Pre-trial monitoring report documents the site is suitable for the trial.

Note: Any or all documents listed in this guidelines may be subject to, and should be available for audit by the sponsor’s auditor and inspection by the regulatory authority(ies). Any revision to any of the above documents should be added to the files during the trial as evidence.

After completion of a trial, some other documents such as completed subject identification code list, audit certificate, clinical study report and final trial close-out monitoring report shall be available to document completion of the trial.

Research and practice may be carried on together when research is designed to evaluate the safety and efficacy of a therapy. Basic Ethical principles refers to those general judgements that serve as a basic justification for the many particular ethical evaluation of human actions. Respect for persons where persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well being.

Do not harm – hippocratic maxim

 Who ought to receive the benefits of research and bear its burdens?

An injustice occurs when some benefit to which a person is entitled to or when ought to be treated equally. This principle applies to the rights, safety and well-being of the trial subjects with most considerations and should prevail over interests of science and society.

Conducting clinical trials, in accordance with this principles of good clinical practice (GCP), makes it possible to test the effectiveness and safety of medicines, hence, it is important the understand the principles established in the guidelines.

Source:

http://www.ich.org/home.html and http://www.the-scientist.com/

Anayansi is an EDC Developer Consultant and clinical programmer for the Pharmaceutical and Biotech industry with more than 13 years of experience.

Available for short-term contracts or ad-hoc requests. See my specialties section (Oracle, SQL Server, EDC Inform, EDC Rave, OpenClinica, SAS and other CDM tools)

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