RECONSTRUCTION under US FDA 21 CFR -Part 58(k) and OECD GLP Principles - An Analysis
- General
Any pre-clinical study conducted as per OECD GLP Principles and supporting documents complying to Indian GLP regulations MHFW ( Ministry of Health and Family Welfare), Drugs and Cosmetic Rules, 1945, as amended 31 Dec 2016, Schedule L-1 and claiming compliance to USFDA GLP 21 CFR Part 58 regulations needs to demonstrate properly on demand in terms of reconstruction and traceability of study documents as detailed below (item 2) during the GLP regulatory investigations . The OECD GLP framework also has formally incorporated data reconstruction adherence under Advisory No. 22 as detailed in item 2 below and has integrated this global best practice. This alignment between US FDA GLP and OECD GLP underlines the growing regulatory focus on traceability and data transparency in preclinical research.
This concept of reconstruction seems to be very basic but still all the facilities following GLP Principles should ensure it is a fundamental tenet. Maintaining raw data integrity is not just a regulatory requirement, it is fundamental to the credibility of study results. It enables investigators and reviewers to reconstruct and validate study reports, ensuring that findings are accurate, reproducible, and trustworthy. This also helps regulatory agencies / sponsors to make appropriate safety assessments to protect patients using trustworthy data. For organizations committed to GLP compliance and high-quality research, robust data reconstruction processes are essential to meeting both regulatory expectations and scientific rigour.
2. Reconstruction
According to US FDA raw data refers to any laboratory worksheets, records, memoranda, notes, or exact copies thereof, that result from the original observations and activities of a nonclinical laboratory study. These records are necessary for the reconstruction and evaluation of the submitted final study report. In cases where the exact transcripts of raw data have been prepared (e.g., tapes which have been transcribed verbatim, dated, and verified accurate by signature), the exact copy or exact transcript may be substituted for the original source as raw data.
According to OECD Advisory no.22, raw data is all original test facility records and documentation, or verified copies thereof, which are the results of the original observations and activities in a study and allow complete reconstruction and evaluation of the GLP activities. Raw data also may include, for example, photographs, microfilm or microfiche copies, computer readable media, dictated observations, recorded data from automated instruments or any other data storage medium that has been recognized as a capable of providing secure storage of information for a time period.
Broadly we shall summarize reconstruction as below:
- It means using the evidence generated during a study (raw data) to demonstrate (prove) the study was executed according to the protocol and SOPs.
- It is a process in which an event or series of events is carefully examined in order to create an understanding of exactly what happened in the past.
- It is a technical process by which scientific principles and techniques are applied to carefully examine the physical evidence (raw data), in order to confirm that the reported results are accurate and trustworthy.
3. Learnings
While science is important, we need the raw data records to be properly aligned to reconstruct the sequence of events that previously occurred, on a deep dive concept.
- When data are collected manually and then retrospectively entered in a computer system, the paper or electronic version that contains the original observations remains the raw data and must be retained.
- Certified true copies of the raw data (such as copies of logbooks and other related documents) are to be included in the study file for the ease of reconstruction.
4. Discussion points:
There are a few differences between OECD GLP and USFDA GLP (21 CFR Part 58). These are outlined below to support a better understanding and to help ensure the test facility remain compliant with both the frameworks:
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Feature |
OECD GLP (Principles) |
US FDA GLP (Regulations) |
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Scope |
Applies to global, non-clinical studies of chemicals and chemical products |
Applies when a nonclinical laboratory study tests a regulated article in a test system, for the purposes of assessing safety, and is intended to be included in a submission. |
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Purpose and requirements under regulatory submission |
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Nature |
Guidelines |
Regulations |
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Enforcement |
NGCMA, India which enforces OECD Principles |
US FDA |
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Differences between OECD GLP and US FDA /EPA GLP |
a) study-based, b) facility-based, and c)process-based inspections and QA has to maintain copies of SOPs.
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Inspection and Certification
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Facilities are certified by national monitoring authorities and receive a certificate of compliance with the period of validity. In addition, NGCMA assesses the facility compliance maintenance through their surveillance / surprise inspections as when required. For non-compliances accreditation are withdrawn/ discontinued or not renewed. The status is published in the website |
The FDA conducts announced or unannounced study-based inspections and does not issue certificates of compliance. Instead, evidence of inspection includes documents like Form 483 and Establishment Inspection Reports (EIR). In the recent period , USFDA is not directly auditing ( Palamur was an exception & rare case ) and is nominating the NGCMA to conduct the audit and report to them |
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Raw data |
“Raw data means all original test facility records and documentation, or verified copies thereof, which are the result of the original observations and activities in a study. Raw data also may include, for example, photographs, microfilm or microfiche copies, computer readable media, dictated observations, recorded data from automated instruments, or any other data storage medium that has been recognised as capable of providing secure storage of information for a time period as stated in section 10, below.”
OECD Advisory no.22 states “The Principles of GLP define raw data as all original test facility records and documentation, or verified copies thereof, which are the result of the original observations and activities in a study and allow complete reconstruction and evaluation of the GLP activities.” "Therefore the concept of reconstruction was added in advisory 22 to bring in the alignment between US FDA GLP and OECD GLP to integrate global best practices to emphasize the growing regulatory focus on traceability and data transparency in preclinical research.. |
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Documentation and Record-Keeping |
Requires comprehensive documentation to ensure data integrity and traceability. |
Requires detailed documentation, with specific requirements for raw data and its reconstruction and requires exact copies or transcripts for reconstruction in study files.
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How Companies Comply with Both FDA regulations and OECD Principles
1. Understanding Both FDA GLP Regulations and OECD Principles:
Familiarizing the staff with the specific requirements and differences of each set of documents by conducting a gap analysis helps facilitate their understanding of their obvious and subtle differences through a tabular format as explained above, so that all personnel understand both FDA GLP regulations and OECD Principles.
2. Harmonizing SOPs
Work practices are defined in standard operating procedures that comply with both OECD Principles and FDA GLP regulations at the same time. Therefore, separate SOPs are not required for studies that claim FDA GLP compliance
3. Training and Education
Conduct regular training sessions to educate all staff who work on GLP studies on the differences and similarities between OECD Principles and FDA GLP regulations, with particular reference to reconstruction as defined in Part 58. This helps ensure that all personnel are aware of the compliance requirements.
4. Quality Assurance Units (QAU)
Establishing a robust Quality Assurance Unit (QAU) is crucial. The QAU monitors compliance with both OECD Principles and FDA GLP regulations, conducts internal audits, and ensures that practices for documentation meet the requirements of the OECD Principles and FDA regulations. They should audit on a deep dive concept with an objective to traceability/ reconstruction on a full circle.
- Documentation and Record-Keeping Maintain detailed and accurate records that comply with both OECD Principles and FDA GLP requirements. This includes keeping raw data, certified true copies, and ensuring that all data can be reconstructed and verified. It is the responsibility of TFM to ensure all practices and documents are GLP compliant.
- Regular Audits and Inspections Conduct regular internal audits to ensure ongoing compliance with both OECD Principles and FDA GLP regulations. This helps identify and address any discrepancies.
By understanding the practical implications and implementing these compliance strategies, companies can effectively navigate the requirements of both OECD Principles and FDA GLP regulations, thereby helping sponsors to make appropriate safety assessments to protect patients using such data.
