good documentation practices in clinical research

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Good documentation practice in clinical research

Chitra bargaje.

Department of Clinical Trials and Safety, Global Quality and Regulatory Compliance, Bristol Myers Squibb, Mumbai, India

One of the most common inspection findings in investigator site inspections is lack of reliable, accurate and adequate source documentation. This also happens to be the most common pitfall identified during sponsor audits. The importance of good documentation practice needs to be emphasized to investigator sites to ensure that the study results are built on the foundation of credible and valid data. This article focuses on the key principles of good documentation practice and offers suggestions for improvement.

INTRODUCTION

Inadequate/inaccurate case histories form the second most commonly cited deficiency in US-FDA inspections of clinical investigator sites.

Similarly, source documentation issues ranked 5th among the top 10 findings from European Medicines Agency (EMA) inspections of investigator sites in 2009[ 1 ] and in some instances the findings were classified ‘critical’. Not surprisingly, clinical trial monitors and auditors also report documentation issues as a frequent area of GCP concern.

I would like to share an experience at a recent investigator site audit.

During the audit opening meeting we were informed that all the source data is on paper and no electronic documentation is used. The site was actually using MS word to document the data collected during the study. In normal practice the site did not use MS word to generate medical records. This method was adopted only for clinical trial subjects. For the trial subjects there were no other hand-written progress notes which the site would normally use for routine patients.

There were two underlying potential issues here:

• First, the site was following a different practice for documenting progress for clinical research subjects. Were the subjects’ records missing any elements of standard care because of the deviation from routine practice?
• Second, the site thought they had no electronic documentation, although MS word was used to record all subject data.

This example, illustrates a common occurrence in clinical trial research where a lack of understanding of basic GCP principles may have a negative impact on the quality of the study.

WHAT IS THE PURPOSE OF SOURCE DOCUMENTATION?

To understand the importance of good source documentation we should first review the purpose of source documentation. The most important purpose of source documentation in a clinical trial is to reconstruct the trial as it happened. It should enable an independent observer to reconfirm the data. Documentation should be such that it is able to provide audit trail to permit investigation if and when required.

Source documentation is the medical record of the subject before, during and after the trial.

It is the tool which confirms the eligibility criteria of the subject in the given trial.

It documents the progress of the subject from consenting till the subject completes the study. It records the accountability of the investigational product dispensed, consumed and returned by the subject. It serves as the complete medical record of the subject as the reference to the treating physician at any point of time.

Finally it forms a strong foundation for the data that gets transcribed into a CRF which ultimately gets translated into a clinical study report.

Irrespective of clinical trial, accurate documentation supports the fundamental principle of protecting subject’s rights, safety and well-being.

There can not be two thoughts to emphasize the need for reliable and quality documentation.

PRINCIPLES OF GOOD DOCUMENTATION PRACTICE

So, what does it mean when we say ‘Good Documentation’ and how do we practice it?

Any basic training in clinical research will definitely include these phrases:

‘What is not documented is not done!’

‘Document what is done as well as what is not done!’

Roots of good documentation principles are in the ICH-GCP where source data and source document is first defined.

ICH E6 1.51 source data

All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).

The words in italics describe some inherent qualities of source data.

ICH E6 1.52 source documents

Original documents, data and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, X-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial).

This definition describes the various types of documents which collectively form the source document.

Key attributes for good documentation were first described by US-FDA in the form of ALCOA -attributable, legible, contemporaneous, original and accurate. These are also adapted by World Health Organization (WHO). These criteria evolved with time. EMA has added some more ‘letters’ to describe qualities of good source documentation particularly for electronic documentation.[ 2 – 4 ]

Let‘s look at these attributes described by different authorities collectively.

Attributable

It should be clear who has documented the data.

Readable and signatures identifiable.

Contemporaneous

The information should be documented in the correct time frame along with the flow of events. If a clinical observation cannot be entered when made, chronology should be recorded. Acceptable amount of delay should be defined and justified.[ 4 ]

Original, if not original should be exact copy; the first record made by the appropriate person. The investigator should have the original source document.

Accurate, consistent and real representation of facts.

Long-lasting and durable.

Available and accessible

Easily available for review of treating physicians and during audits/inspections. The documents should be retrievable in reasonable time.

Complete till that point in time.

Demonstrate the required attributes consistently.

Based on real and reliable facts.

Corroborated

The data should be backed up by evidence.

Interestingly, it should be noted that the Drug Controller General India (DCGI) would emphasize on the condition in addition to the completeness, legibility and accessibility of investigator source data file as noted in DCGI’s guidance document for inspections.[ 5 ] My understanding of ‘condition’ is the state of the source documents, in terms of filing, storing and readability.

The degree to which the data fulfills the data quality criteria establishes acceptability of the data. It also determines the degree of excellence of the data quality. Qualities like consistency, credibility and corroboration help establish data integrity along with the data quality.

These are the expectations from clinical trial documentation however in reality many issues are observed in terms of quality of source documentation.

COMMON FINDINGS WITH RESPECT TO SOURCE DOCUMENTATION

‘Failure to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation’ is cited in 6 out of the 10 warning letters issued by US-FDA to clinical investigators in 2010.[ 6 ]

At one investigator site source documents were not available because the computer ‘crashed’ . So in the absence of availability, adequacy of the records could not be evaluated. The investigator was warned for ‘failure to retain records required to be maintained for the required timeframe per regulations’ .

I would like to highlight some of the findings from the warning letters in detail here. These findings give an idea of regulatory expectations and lacunae in documentation noted during inspections. I am sure readers would be able to relate to some of these findings with their personal experience.

• Eligibility criteria could not be confirmed. For e.g., (a)IVRS user manual states “Complete call worksheets prior to contacting the IVRS; then file completed worksheets with each subject’s source documentation.” The IVRS worksheets were not kept in the subjects’ files or maintained at the site and as such it could not be confirmed that patients were stratified in the right arm and received the medication they were assigned to. (b) All the items in the exclusion criteria checklist are checked except for the exclusion criterion related to the history of thrombocytopenia, including heparin-induced thrombocytopenia, or a platelet count <100,000 cells/microliter. In the absence of lab report this exclusion criteria could not be confirmed on the basis of the incomplete checklists.
• Multiple records for same data points making it unable to determine which served as the accurate source record, for e.g., multiple versions of visual analog scales completed for same visit with different values.
• Discrepancies in records to confirm primary efficacy endpoint of the study, for e.g., the total administered dose of morphine, as reflected in hospital records was different from the Case Report Form. The primary efficacy endpoint of the protocol was to measure the reduction in the requirement for morphine use in the 24 hours following surgery measured by total morphine usage compared to placebo.
• Clinical significance for out of range lab values not documented on the lab reports or conflicting information found in the source documentation-e.g., significant high glucose value marked as clinically nonsignificant on the lab report although the subject was referred to for primary physician for further follow-up.
• Missing pages from subject interview scales, numerous unexplained corrections months after the initial entries and conflicting information; incorrect subject identifiers, incorrect date e.g., same date on screening visit, visit week 1 and week 4.
• Numerous AEs not reported in CRFs, delays in transcribing data in CRFs, discrepancies between source and the CRF. Lack of timely reporting of AEs in eCRFs jeopardizes subject safety and reliability and integrity of data captured at the site.
• Incorrect/incomplete documentation regarding the disposition of drugs-dates, quantity and use by subjects.

Although some of these issues may appear minor prima facie such as some checkboxes not checked, a lab report not marked for significance for out of range value, some discrepancies in source and CRF, unexplained corrections, these issues point toward lack of understanding of good documentation requirements. For an independent observer such data would fail to provide confidence and assurance of data quality and safety of the subjects enrolled. The data may be deemed unfit for use. All exposure of patients to new drugs and the efforts and time spent by the investigator team would be wasted.

Systematic deficiencies in documentation can lead to questions about the integrity of the data, potentially resulting in health authority decisions to exclude the data from analysis.

In essence, we can definitely say that the quality of documentation can make or break the study at a given site.

WHAT ARE THE POSSIBLE ROOT CAUSES FOR REPEATED DEFICIENCIES IN SOURCE DOCUMENTATION?

Clinical research documentation involves a variety of documents from various sources and is often completed by several people. Thus rendering this process to be complicated and posing challenges to meet requirements. Moreover clinical research happens over a long period of time which adds to the challenge of maintaining continuity in the documentation practice.

Inadequacies in documentation could be the result of lack of training and experience in good understanding of clinical research and documentation requirements. As a result the principal investigator (PI) and staff may continue documentation per the routine medical practice. In India, the documentation in routine medical practice may not be as extensive as what would be expected for clinical research.

Additional unmonitored medical records are discovered at the time of audits/inspections. Such as: Diaries of coordinator, inpatient records of the hospital, electronic records, etc., for the simple reason that the staff does not realize that these form a part of source record. These unmonitored records may have important data which do not find its way to the CRF. This would have an impact on the availability of important information in CRFs. Reliability and integrity of data might me affected as a result.

In many FDA warning letters one can observe that inadequate case histories, consenting or drug disposal records are often attributed to the lack of investigator’s supervision in ensuring compliance. The PI delegates responsibilities to the study team and may not provide adequate time to review the source data due to lack of time or commitment. The study documentation is completely left on the shoulders of study coordinator’s.

Various tools are used for data collection. At times sponsor provides source document worksheets to ensure complete documentation. If these worksheets are not designed accurately to align with the protocol and CRF source data quality is directly impacted. These worksheets are often completed as checkboxes without any additional notes, comments or supporting documents. Source document worksheets sometimes also result in multiple records. The sites continue to maintain the clinical practice routine documentation and worksheets are completed in addition for the study. As such, these worksheets are no longer a primary source and thus no source document.

Workload of the existing staff can be another important reason leading to poor documentation. This may cause errors like source data for one subject entered in another subject record, pages misfiled, use of incorrect consent forms and similar issues.

Study coordinator/PI work with various sponsors/CROs at a time. These different sponsors/CROs communicate different level of expectations regarding source documentation. If the site is not experienced enough and they do not have a standard procedure to follow they may get confused with variations in guidance they receive. This may negatively impact the quality of data.

Certain technical inadequacies may also lead to poor source documentation. For e.g., the ECG machine is old and does not print the date, time and subject identifiers, printer or fax machine does not work. If the fax is not working it may result in not receiving important data i.e., lab reports, data queries, investigational product allocation confirmations, SAE transmission confirmations, etc. Important email correspondence with sponsor/CROs if not printed and archived may get lost.

HOW CAN THE DOCUMENTATION BE IMPROVED?

Based on the various causes noted above, I would like to offer some suggestions to improve the quality of source documentation at sites.

• PI should delegate responsibilities to staff adequately trained in protocol and GCP. Particular training should be provided on ALCOA and other good documentation practice requirements. Medical decisions should be delegated to medically qualified staff. Training of site staff should be repeated at defined frequency. New hires should be adequately trained before trial participation.
• PI should commit for involvement, and supervision throughout the entire duration of the study. There should be an agreed and documented procedure for PI to ensure supervision of the study by meetings with site staff, monitors; review of documentation, timely resolution of medical, ethical or GCP issues. The PI or designated subinvestigators should validate the medical data. The PI should also supervise the work of SMO staff and external facilities if used. In case there are performance issues with SMO staff or external facility PI should immediately inform the supervisor as well as sponsor.
• Site should develop a SOP for good documentation. This SOP should be shared with the sponsor/CRO and agreed upon before the start of the trial. This SOP should address aspects including but not limited to consenting process, verifying eligibility, use of right tools such as diaries, source document worksheets, OPD papers, copies of prescriptions, etc; ways to avoid multiple records and in case of multiple records should define the source for the study, method of corrections, review of safety labs and other reports. Documented procedure at site level should encompass management, maintenance, archival and retrieval of source documentation. Sites should have measures for continuous improvement and maintaining high-quality data. Sites should develop process for quality control.
• Before the trial commences all technical aspects such as for e-CRFs, fax, printers, etc. should be clarified and issues resolved. In case of any difficulties during the trial, sponsor should be informed and back-up plans agreed upon till the issue is resolved. In case when original lab records or investigational records are sent to central location for assessment, process should be in place to ensure a duplicate copy or certified copy is available in the site source records.
• Sponsor/CRO also plays an important role in ensuring quality of source documentation. Sponsor/CRO should ensure PI’s commitment and involvement throughout the study. Sponsor/CRO should assess the site’s documentation practice during pre-study visit and during the study; provide training to the site staff to reinforce expectations. Time spent effectively during pre-study evaluation on source documentation would help a great deal to minimize documentation issues later. The source data and their respective capture methods should be clearly defined prior to trial recruitment i.e. in the protocol or study specific source data agreement.

CONCLUSIONS

Source documentation should demonstrate the ALCOA and other attributes as described by regulatory authorities and GCP. Source documentation related findings are the most commonly cited during inspections and audits. PI’s commitment and involvement in the trial makes a huge difference. Efforts to train the sites, understand the sites practices right from the pre-study visit and continuous monitoring and training would definitely help in improving and maintaining the quality of site source documentation practices.

Ultimately the source document should speak for itself. It should narrate the medical journey of the patient as it happened to an independent observer-an auditor or inspector and thus form a strong foundation for a good clinical research.

Acknowledgments

I would like to thank Jessica Parchman (Group Director) and Kristel Van De Voorde (Director) from Global Quality and Regulatory Compliance, Bristol Myers Squibb for reviewing the article and providing valuable suggestions in shaping this article.

Good Clinical Practice Study Documentation

The Department of Medicine Clinical Research Unit has prepared this document is to provide guidance to all faculty and staff involved in the conduct of research on the  best practices related to documentation .

Good study documentation will allow for an individual with basic knowledge of the particular project to recreate the events of the study.

General Information

• Maintain records of all data and observations pertinent to the research subject.  These records should be identifiable to a particular participant.
• Remember that source documents are where the information is first recorded.
• All data must be verifiable.
• Study documentation should be able to recreate the study for any reviewer.
• Attributable – Can you tell who wrote and/or did this
• Legible – Can it be read?
• Contemporaneous- – Is the data current, and in the correct time frame?  The notation, signature and date should occur at the same time.
• Original – Has the data been altered?
• Accurate – Are there conflicting data elsewhere?  Content should precisely reflect the event.
• Use a signed Note to File to explain any discrepancies, missing or incomplete data.
• The same standards maintained for medical documentation should be followed for research documentation
• All documents require 2 identifiers on each page. 
• All entries are to be signed and dated in real time.
• Error corrections are made by drawing a single line through the incorrect entry, initial and date.
• Never obliterate entries that require correction.
• Subject records need to be secure but accessible.
• Do not alter past-dated notes by writing alongside or adding to prior entries.  Updates may be made through addenda.
• Use dark ink, do not use pencil.
• Never use whiteout.
• If the source data is incomplete or deficient, it may be completed or corrected using an addendum.  This late entry must be signed and dated at the time it is created.

Note to File

• May be used to correct errors, or as an explanation to a departure from the protocol.  Reasons for any departure should be documented and attempts to correct or prevent in the future should be included.
• This should not be used as a panacea to correct any error.

Informed Consent

• The process requires documentation and should reflect the process approved by the IRB in a narrative form or through the use of a checklist.
• Signature and date and time must be of the person obtaining the consent, at the time of the process. (Not added later)

Case Report Forms as Source

Case report forms may be used as source only when this practice is clearly outlined in the protocol, and they represent the data collected for the research are where the data were initially recorded.   

Medical Records From Outside Source

• Copies of records from an outside source may be used if they support endpoints, inclusion/exclusion criteria or adverse events.
• Attempts to obtain medical records should be recorded in the research chart.

Questionnaires

• Documentation must reflect who completed the questionnaire, in compliance with the protocol.
• For questionnaires completed by staff, a note should reflect how the information was obtained ie: direct interview with participant, phone call, chart abstraction.

Documentation: Essential Documents and Standard Operating Procedures

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Documentation is a critical component of clinical trials. There are requirements not only to be able to verify that the data being analyzed is accurate but that it was collected and processed in a consistent way. Anyone involved in a trial has to recognize the documentation requirements and ensure that they are met. The International Conference on Harmonization (ICH) Guidelines on Good Clinical Practice E6 provides details of standards to be met along with relevant definitions. This chapter provides guidance on identifying essential documents for a trial and also on how to develop and maintain systems for standard operating procedures.

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Good Clinical Practice Guidelines, E6 (R2) (2016). Retrieved from: http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/integrated-addendum-good-clinical-practice.htmlICH GCP Guidelines/

McFadden E et al (2015) The impact of registration of clinical trials units: the UK experience. Clin Trials 12(2):166–173

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Bloomberg School of Public Health, Johns Hopkins Center for Clinical Trials Bloomberg School of Public Health, Baltimore, MD, USA

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McFadden, E., Jackson, J., Forrest, J. (2020). Documentation: Essential Documents and Standard Operating Procedures. In: Piantadosi, S., Meinert, C. (eds) Principles and Practice of Clinical Trials. Springer, Cham. https://doi.org/10.1007/978-3-319-52677-5_45-1

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ICH Guidance Documents

ICH E3: Guideline for Industry Structure and Content of Clinical Study Reports (PDF - 240KB)

This International Conference on Harmonization (ICH) document makes recommendations on information that should be included in a core clinical study report of an individual study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects. The guideline is intended to assist sponsors in the development of a report that is complete, free from ambiguity, well organized and easy to review.

ICH E3 Questions and Answers (PDF - 141KB)

ICH E5: Ethnic Factors in the Acceptability of Foreign Clinical Data (PDF - 89KB)

This International Conference on Harmonization (ICH) document makes recommendations for strategies to permit clinical data collected in one region to be used to support drug and biologic registrations in another region while allowing for the influence of ethnic factors.

ICH E5 Questions and Answers (PDF - 48KB)

ICH E6: Good Clinical Practice: Consolidated Guidance (R2- Integrated Addendum) (PDF - 484 KB)

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human subjects. Compliance with GCP assures that the rights, safety, and well-being of trial subjects are protected and that the clinical trial data are credible. This International Conference on Harmonization (ICH) guidance provides a unified standard for the European Union, Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in those jurisdictions.

ICH E7: Studies in Support of Special Populations: Geriatrics Questions and Answers

This ICH guidance provides recommendations on special considerations that apply in the design and conduct of clinical trials of medicines that are likely to have significant use in the elderly. This question and answer (Q&A) document is intended to clarify key issues.

ICH E10: Choice of Control Group and Related Issues in Clinical Trials (PDF - 93KB)

This International Conference on Harmonization (ICH) guidance addresses the choice of control group in clinical trials, discussing five principal types of controls, two important purposes of clinical trials, and the issue of whether a trial could have detected a difference between treatments when there was a difference (assay sensitivity).

ICH Q9: Quality Risk Management (PDF - 113KB)

The purpose of this document is to offer a systematic approach to quality risk management. It serves as a foundation or resource document that is independent of, yet supports, other ICH Quality documents and complements existing quality practices, requirements, standards, and guidelines within the pharmaceutical industry and regulatory environment. It specifically provides guidance on the principles and some of the tools of quality risk management that can enable more effective and consistent risk-based decisions, by both regulators and industry, regarding the quality of drug substances and drug products across the product lifecycle. It is not intended to create any new expectations beyond the current regulatory requirements

VICH GL9: Good Clinical Practice (PDF - 64KB)

The objective of this document is to provide guidance on the design and conduct of all clinical studies of veterinary products in the target species. It is directed at all individuals and organizations involved in the design, conduct, monitoring, recording, auditing, analysis and reporting of clinical studies in target species and is intended to ensure that such studies are conducted and documented in accordance with the principles of Good Clinical Practice (GCP). Good Clinical Practice is intended to be an international scientific quality standard for designing, conducting, monitoring, recording, auditing, analyzing and reporting clinical studies evaluating veterinary products. This guidance has been developed under the principles of the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) and will provide a unified standard for the European Union (EU), Japan and the United States of America (USA) to facilitate the mutual acceptance of clinical data by the relevant regulatory authorities. This guidance was developed with consideration of the current practices in the EU, Japan and the USA together with those of Australia and New Zealand.

Good Documentation in Clinical Trials

WHAT IS GOOD DOCUMENTATION IN CLINICAL TRIALS?

The medical record of the subject before, after, and during the clinical trial is  a Source Document.   

Characteristics of Source document:

It helps to confirm whether the individual is eligible for a clinical trial or not.

It documents the progress of the subject from consenting till the completion of the given clinical study.

It helps to record how much investigational product is dispensed, used, and returned by the subject.

At any point of the treatment, the source document is a complete medical record of the subject as a reference.

Finally, it forms well-built data. Then it is transcribed to CRF that translates into a clinical study report.

The source document is the one that supports the fundamental principles which are necessary for the protection of subjects’ rights, safety, and well-being. ( Chitra Bargaje., 2019)

ALCOA-C  covers all the main aspects of a source document that include some crucial definitions and documentations., first introduced by the U.S. FDA. 

The reason why it got implemented in medical practices; is to ensure confidentiality, credibility, accuracy, and validation. ALCOA-C is the abbreviation of some crucial terms in clinical trials that are as follow,

Figure no. 1: ALCOA-C

Attributable

Contemporaneous

Available and accessible

Corroborated

Types of a Source Document:

There are two types of Source Documentation:

Electronic record means any combination of text, graphics, data, audio, pictorial, or other information representation in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system.

Paper Source Documents can be:

Handwritten data on the pre-printed forms have been prepared in advance.

Handwritten records.

In both cases, the source documents are only the records, either handwritten or printed out, with the original handwritten Investigator's signature.

The most common type of Source Documentation (SD) is official medical documentation used in medical institutions regularly:

Medical History

Outpatient Medical Chart

Various Logs / Hospital Charts

Table no. 1: examples of source document in clinical trials.

Examples of Source Document in Clinical Trial:

Participant’s medical reports

Phone encounters or notes

Report Participants diaries 

Specific research worksheets

Figure no. 2: general flow chart for clinical data management.

Clinical Data Management:

The process of collecting, cleaning, and management of subject’s data following regulatory standards is known as clinical data management (CDM).

Table no. 2: tools for CDM.

Main Objectives of CDM:

To provide high-quality data.

To keep the number of errors and missing data as low as possible.

Try to get maximum data for analysis.

Table no. 3: minimum requirement for CDM team.

The electronic information obtained from the CDM must comply with the Code of Federal Regulation (CRF), 21 CRF Part 11. CRF operates the existing records in an electronic format that we created, modified, stored, archived, retrieved, or transferred. ( binny et al., 2012)

Case Report Form:

CRF is the first step in the translation of protocol-specific activities into the data being generated. It should be concise, user friendly, and self-explanatory. (binny et al., 2012)

References: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121265/ - Good documentation practice in clinical research https://conductscience.com/portfolio/alcoa-c/ - ALCOA-C https://www.appliedclinicaltrialsonline.com/view/targeting-source-document-verification - Targeting Source Document Verification https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326906/ - Data management in clinical research: An overview https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170533/ - Basics of case report form designing in clinical research https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857788/ - Remote Source Document Verification in Two National Clinical Trials Networks: A Pilot Study https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386950/ - Impact of source data verification on data quality in clinical trials: an empirical  post hoc  analysis of three phase 3 randomized clinical trials

The Clinical Trials Team - Roles & Responsibilities

The importance of ich gcp.

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Good documentation practice in clinical research.

Author information, affiliations.

• Bargaje C 1

Perspectives in Clinical Research , 01 Apr 2011 , 2(2): 59-63 https://doi.org/10.4103/2229-3485.80368   PMID: 21731856  PMCID: PMC3121265

Abstract 

Free full text , good documentation practice in clinical research, chitra bargaje.

Department of Clinical Trials and Safety, Global Quality and Regulatory Compliance, Bristol Myers Squibb, Mumbai, India

One of the most common inspection findings in investigator site inspections is lack of reliable, accurate and adequate source documentation. This also happens to be the most common pitfall identified during sponsor audits. The importance of good documentation practice needs to be emphasized to investigator sites to ensure that the study results are built on the foundation of credible and valid data. This article focuses on the key principles of good documentation practice and offers suggestions for improvement.

INTRODUCTION

Inadequate/inaccurate case histories form the second most commonly cited deficiency in US-FDA inspections of clinical investigator sites.

Similarly, source documentation issues ranked 5th among the top 10 findings from European Medicines Agency (EMA) inspections of investigator sites in 2009[ 1 ] and in some instances the findings were classified ‘critical’. Not surprisingly, clinical trial monitors and auditors also report documentation issues as a frequent area of GCP concern.

I would like to share an experience at a recent investigator site audit.

During the audit opening meeting we were informed that all the source data is on paper and no electronic documentation is used. The site was actually using MS word to document the data collected during the study. In normal practice the site did not use MS word to generate medical records. This method was adopted only for clinical trial subjects. For the trial subjects there were no other hand-written progress notes which the site would normally use for routine patients.

There were two underlying potential issues here:

First, the site was following a different practice for documenting progress for clinical research subjects. Were the subjects’ records missing any elements of standard care because of the deviation from routine practice?

Second, the site thought they had no electronic documentation, although MS word was used to record all subject data.

This example, illustrates a common occurrence in clinical trial research where a lack of understanding of basic GCP principles may have a negative impact on the quality of the study.

WHAT IS THE PURPOSE OF SOURCE DOCUMENTATION?

To understand the importance of good source documentation we should first review the purpose of source documentation. The most important purpose of source documentation in a clinical trial is to reconstruct the trial as it happened. It should enable an independent observer to reconfirm the data. Documentation should be such that it is able to provide audit trail to permit investigation if and when required.

Source documentation is the medical record of the subject before, during and after the trial.

It is the tool which confirms the eligibility criteria of the subject in the given trial.

It documents the progress of the subject from consenting till the subject completes the study. It records the accountability of the investigational product dispensed, consumed and returned by the subject. It serves as the complete medical record of the subject as the reference to the treating physician at any point of time.

Finally it forms a strong foundation for the data that gets transcribed into a CRF which ultimately gets translated into a clinical study report.

Irrespective of clinical trial, accurate documentation supports the fundamental principle of protecting subject’s rights, safety and well-being.

There can not be two thoughts to emphasize the need for reliable and quality documentation.

PRINCIPLES OF GOOD DOCUMENTATION PRACTICE

So, what does it mean when we say ‘Good Documentation’ and how do we practice it?

Any basic training in clinical research will definitely include these phrases:

‘What is not documented is not done!’

‘Document what is done as well as what is not done!’

Roots of good documentation principles are in the ICH-GCP where source data and source document is first defined.

ICH E6 1.51 source data

All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).

The words in italics describe some inherent qualities of source data.

ICH E6 1.52 source documents

Original documents, data and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, X-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial).

This definition describes the various types of documents which collectively form the source document.

Key attributes for good documentation were first described by US-FDA in the form of ALCOA -attributable, legible, contemporaneous, original and accurate. These are also adapted by World Health Organization (WHO). These criteria evolved with time. EMA has added some more ‘letters’ to describe qualities of good source documentation particularly for electronic documentation.[ 2 – 4 ]

Let‘s look at these attributes described by different authorities collectively.

Attributable

It should be clear who has documented the data.

Readable and signatures identifiable.

Contemporaneous

The information should be documented in the correct time frame along with the flow of events. If a clinical observation cannot be entered when made, chronology should be recorded. Acceptable amount of delay should be defined and justified.[ 4 ]

Original, if not original should be exact copy; the first record made by the appropriate person. The investigator should have the original source document.

Accurate, consistent and real representation of facts.

Long-lasting and durable.

Available and accessible

Easily available for review of treating physicians and during audits/inspections. The documents should be retrievable in reasonable time.

Complete till that point in time.

Demonstrate the required attributes consistently.

Based on real and reliable facts.

Corroborated

The data should be backed up by evidence.

Interestingly, it should be noted that the Drug Controller General India (DCGI) would emphasize on the condition in addition to the completeness, legibility and accessibility of investigator source data file as noted in DCGI’s guidance document for inspections.[ 5 ] My understanding of ‘condition’ is the state of the source documents, in terms of filing, storing and readability.

The degree to which the data fulfills the data quality criteria establishes acceptability of the data. It also determines the degree of excellence of the data quality. Qualities like consistency, credibility and corroboration help establish data integrity along with the data quality.

These are the expectations from clinical trial documentation however in reality many issues are observed in terms of quality of source documentation.

COMMON FINDINGS WITH RESPECT TO SOURCE DOCUMENTATION

‘Failure to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation’ is cited in 6 out of the 10 warning letters issued by US-FDA to clinical investigators in 2010.[ 6 ]

At one investigator site source documents were not available because the computer ‘crashed’ . So in the absence of availability, adequacy of the records could not be evaluated. The investigator was warned for ‘failure to retain records required to be maintained for the required timeframe per regulations’ .

I would like to highlight some of the findings from the warning letters in detail here. These findings give an idea of regulatory expectations and lacunae in documentation noted during inspections. I am sure readers would be able to relate to some of these findings with their personal experience.

Eligibility criteria could not be confirmed. For e.g., (a)IVRS user manual states “Complete call worksheets prior to contacting the IVRS; then file completed worksheets with each subject’s source documentation.” The IVRS worksheets were not kept in the subjects’ files or maintained at the site and as such it could not be confirmed that patients were stratified in the right arm and received the medication they were assigned to. (b) All the items in the exclusion criteria checklist are checked except for the exclusion criterion related to the history of thrombocytopenia, including heparin-induced thrombocytopenia, or a platelet count <100,000 cells/microliter. In the absence of lab report this exclusion criteria could not be confirmed on the basis of the incomplete checklists.

Multiple records for same data points making it unable to determine which served as the accurate source record, for e.g., multiple versions of visual analog scales completed for same visit with different values.

Discrepancies in records to confirm primary efficacy endpoint of the study, for e.g., the total administered dose of morphine, as reflected in hospital records was different from the Case Report Form. The primary efficacy endpoint of the protocol was to measure the reduction in the requirement for morphine use in the 24 hours following surgery measured by total morphine usage compared to placebo.

Clinical significance for out of range lab values not documented on the lab reports or conflicting information found in the source documentation-e.g., significant high glucose value marked as clinically nonsignificant on the lab report although the subject was referred to for primary physician for further follow-up.

Missing pages from subject interview scales, numerous unexplained corrections months after the initial entries and conflicting information; incorrect subject identifiers, incorrect date e.g., same date on screening visit, visit week 1 and week 4.

Numerous AEs not reported in CRFs, delays in transcribing data in CRFs, discrepancies between source and the CRF. Lack of timely reporting of AEs in eCRFs jeopardizes subject safety and reliability and integrity of data captured at the site.

Incorrect/incomplete documentation regarding the disposition of drugs-dates, quantity and use by subjects.

Although some of these issues may appear minor prima facie such as some checkboxes not checked, a lab report not marked for significance for out of range value, some discrepancies in source and CRF, unexplained corrections, these issues point toward lack of understanding of good documentation requirements. For an independent observer such data would fail to provide confidence and assurance of data quality and safety of the subjects enrolled. The data may be deemed unfit for use. All exposure of patients to new drugs and the efforts and time spent by the investigator team would be wasted.

Systematic deficiencies in documentation can lead to questions about the integrity of the data, potentially resulting in health authority decisions to exclude the data from analysis.

In essence, we can definitely say that the quality of documentation can make or break the study at a given site.

WHAT ARE THE POSSIBLE ROOT CAUSES FOR REPEATED DEFICIENCIES IN SOURCE DOCUMENTATION?

Clinical research documentation involves a variety of documents from various sources and is often completed by several people. Thus rendering this process to be complicated and posing challenges to meet requirements. Moreover clinical research happens over a long period of time which adds to the challenge of maintaining continuity in the documentation practice.

Inadequacies in documentation could be the result of lack of training and experience in good understanding of clinical research and documentation requirements. As a result the principal investigator (PI) and staff may continue documentation per the routine medical practice. In India, the documentation in routine medical practice may not be as extensive as what would be expected for clinical research.

Additional unmonitored medical records are discovered at the time of audits/inspections. Such as: Diaries of coordinator, inpatient records of the hospital, electronic records, etc., for the simple reason that the staff does not realize that these form a part of source record. These unmonitored records may have important data which do not find its way to the CRF. This would have an impact on the availability of important information in CRFs. Reliability and integrity of data might me affected as a result.

In many FDA warning letters one can observe that inadequate case histories, consenting or drug disposal records are often attributed to the lack of investigator’s supervision in ensuring compliance. The PI delegates responsibilities to the study team and may not provide adequate time to review the source data due to lack of time or commitment. The study documentation is completely left on the shoulders of study coordinator’s.

Various tools are used for data collection. At times sponsor provides source document worksheets to ensure complete documentation. If these worksheets are not designed accurately to align with the protocol and CRF source data quality is directly impacted. These worksheets are often completed as checkboxes without any additional notes, comments or supporting documents. Source document worksheets sometimes also result in multiple records. The sites continue to maintain the clinical practice routine documentation and worksheets are completed in addition for the study. As such, these worksheets are no longer a primary source and thus no source document.

Workload of the existing staff can be another important reason leading to poor documentation. This may cause errors like source data for one subject entered in another subject record, pages misfiled, use of incorrect consent forms and similar issues.

Study coordinator/PI work with various sponsors/CROs at a time. These different sponsors/CROs communicate different level of expectations regarding source documentation. If the site is not experienced enough and they do not have a standard procedure to follow they may get confused with variations in guidance they receive. This may negatively impact the quality of data.

Certain technical inadequacies may also lead to poor source documentation. For e.g., the ECG machine is old and does not print the date, time and subject identifiers, printer or fax machine does not work. If the fax is not working it may result in not receiving important data i.e., lab reports, data queries, investigational product allocation confirmations, SAE transmission confirmations, etc. Important email correspondence with sponsor/CROs if not printed and archived may get lost.

HOW CAN THE DOCUMENTATION BE IMPROVED?

Based on the various causes noted above, I would like to offer some suggestions to improve the quality of source documentation at sites.

PI should delegate responsibilities to staff adequately trained in protocol and GCP. Particular training should be provided on ALCOA and other good documentation practice requirements. Medical decisions should be delegated to medically qualified staff. Training of site staff should be repeated at defined frequency. New hires should be adequately trained before trial participation.

PI should commit for involvement, and supervision throughout the entire duration of the study. There should be an agreed and documented procedure for PI to ensure supervision of the study by meetings with site staff, monitors; review of documentation, timely resolution of medical, ethical or GCP issues. The PI or designated subinvestigators should validate the medical data. The PI should also supervise the work of SMO staff and external facilities if used. In case there are performance issues with SMO staff or external facility PI should immediately inform the supervisor as well as sponsor.

Site should develop a SOP for good documentation. This SOP should be shared with the sponsor/CRO and agreed upon before the start of the trial. This SOP should address aspects including but not limited to consenting process, verifying eligibility, use of right tools such as diaries, source document worksheets, OPD papers, copies of prescriptions, etc; ways to avoid multiple records and in case of multiple records should define the source for the study, method of corrections, review of safety labs and other reports. Documented procedure at site level should encompass management, maintenance, archival and retrieval of source documentation. Sites should have measures for continuous improvement and maintaining high-quality data. Sites should develop process for quality control.

Before the trial commences all technical aspects such as for e-CRFs, fax, printers, etc. should be clarified and issues resolved. In case of any difficulties during the trial, sponsor should be informed and back-up plans agreed upon till the issue is resolved. In case when original lab records or investigational records are sent to central location for assessment, process should be in place to ensure a duplicate copy or certified copy is available in the site source records.

Sponsor/CRO also plays an important role in ensuring quality of source documentation. Sponsor/CRO should ensure PI’s commitment and involvement throughout the study. Sponsor/CRO should assess the site’s documentation practice during pre-study visit and during the study; provide training to the site staff to reinforce expectations. Time spent effectively during pre-study evaluation on source documentation would help a great deal to minimize documentation issues later. The source data and their respective capture methods should be clearly defined prior to trial recruitment i.e. in the protocol or study specific source data agreement.

CONCLUSIONS

Source documentation should demonstrate the ALCOA and other attributes as described by regulatory authorities and GCP. Source documentation related findings are the most commonly cited during inspections and audits. PI’s commitment and involvement in the trial makes a huge difference. Efforts to train the sites, understand the sites practices right from the pre-study visit and continuous monitoring and training would definitely help in improving and maintaining the quality of site source documentation practices.

Ultimately the source document should speak for itself. It should narrate the medical journey of the patient as it happened to an independent observer-an auditor or inspector and thus form a strong foundation for a good clinical research.

Acknowledgments

I would like to thank Jessica Parchman (Group Director) and Kristel Van De Voorde (Director) from Global Quality and Regulatory Compliance, Bristol Myers Squibb for reviewing the article and providing valuable suggestions in shaping this article.

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