eSolutions to Meet FDA Requirements to Maintain Adequate Records (Part 5 of 6)

This post is Part 5 of a 6 part series. Visit weekly or enter your email to subscribe.

FDA guidance suggests sponsors should include information about the intended use of computerized systems in their data management plan. Compliant with 21 CFR part 11, this data management plan should also describe the “security measures employed to protect the data and a description of the flow of electronic data”1. In the workflow demonstrated in the Figure below, note that a unique user name and password is required to access the system. Each user is associated with a user group and each user group is limited to specific roles/functions within the eSource. The user activity is date and time stamped in real time and an audit trail serves as the automated documentation of who did what, to whom and when.

Figure 3 

eSource systems/vendors should:

  • support controlled and secure access typically by
    • a username/ ID and password,
    • user roles,
    • role-specific privileges,
    • data encryption, and
    • workflow
  • create and maintain an audit trail of data entry and data revisions including
    • the “old” value,
    • the “new” value,
    • date and time stamp,
    • and the user who entered/changed the data
    • reason for the data edit
  • have a provision for data transfer and storage for the time required by the regulations

to be continued…

1 Guidance for Industry Electronic Source Documentation in Clinical Investigations Draft Guidance. U. S. Department of Health and Human Services, Food and Drug Administration, Office of the Commissioner. November 2012. Retrieved December 18, 2012 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM328691.pdf

 

 

 

 

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eSolutions to Meet FDA Requirements to Maintain Adequate Records (Part 4 of 6)

This post is Part 4 of a 6 part series. Visit weekly or enter your email to subscribe.

Electronic diary solutions are typically customized software programs built with rules and edit checks that can track compliance, facilitate efficiencies and significantly reduce queries. Electronic boundary and edit checks should be used to minimize errors and omissions at the time of data entry. Additionally, an eDiary solution can include a subject dosing screen to capture required investigational product administration as well as software customization to prompt the subjects to complete missing data before allowing them to move from one question or screen to the next. Electronic diaries can include fields to “record storage temperatures of study medication that was stored in subjects’ refrigerators”1 in compliance with storage condition requirements specified by the protocol. Likewise, drug administration screens can be linked to drug inventory management systems to meet the FDA requirement to maintain adequate records of the disposition of the investigational drug (21 CFR §312.62(a)).

When implementing electronic edit checks, user acceptance testing should be a priority to ensure business logic and protocol driven rules fit the purpose, prevent duplicate entry, make sense to the user and do not conflict. For example, it would be confusing for a patient who identifies himself in the eDiary as male to be asked about his pregnancy status. Data elements that are captured more than once should auto populate when the data is static (i.e. date of birth), but require a new entry for data expected to change (i.e. weight). Electronic triggers should be tested to avoid conflict and verify missing or out of range data. Device logic that requires the patient to answer a question about climbing stairs before moving on to the next question should have an option to indicate a reason for leaving the question blank. In this example, the patient may be in a wheelchair, or may not have climbed any stairs in the applicable timeframe for the interval questionnaire. In another example, an electronic rule that requires the patient to complete a “visit 2” diary before allowing access to “visit 3” diary data entry could be problematic when the patient may have missed or skipped their second visit or the allowable time window to enter the visit 2 information. Sponsors should include information on electronic prompts, flags, and data quality checks that are designed to address data inconsistencies, missing data, and entries out of range in their data management plan so that it is available for FDA inspection.2

to be continued…

1 FDA Warning Letter Ref. No. 06-HFD-45-11. Retrieved October 25, 2012 at http://www.fda.gov/ICEPI/EnforcementActions/WarningLetters/2007/ucm245744.htm

2 Guidance for Industry Electronic Source Documentation in Clinical Investigations Draft Guidance. U. S. Department of Health and Human Services, Food and Drug Administration, Office of the Commissioner. November 2012. Retrieved December 18, 2012 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM328691.pdf

 

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eSolutions to Meet FDA Requirements to Maintain Adequate Records (Part 3 of 6)

This post is Part 3 of a 6 part series. Visit weekly or enter your email to subscribe.

eSource solutions must allow PI access to electronic data. Developing and planning eSource solutions should also address data transfer to the sponsor in an effort to protect the rights, safety, and welfare of subjects. Sean Kassim of the FDA recently pointed out that in the world of eDiary and DCDC, direct transfer of ePRO to the sponsor is NOT appropriate. As part of their oversight, the Principal Investigator (PI) needs to have access to this data typically via site access to an online portal (See Figure).

Figure

eSource Manuscript Figures 1_2

In addition, “To comply with the requirement to maintain accurate case histories (21 CFR 312.62(b)) and 812.140(a) (3)), investigators should review and electronically sign the eCRF for each subject before the data are archived” and released to the parties (IRB, Data Management Center, SMO/CRO, Regulatory authority).Data that goes directly to the sponsor may contain information wholly relevant to patient care and human subject protection (HSP). For example, PROs with multiple entries of shortness of breath should be reviewed by the PI to determine whether or not clinical intervention is indicated. Compliance with this requirement for PI oversight can be in the form of a formal process for review of the data or the electronic instrument can alert the PI to review certain criteria specified at the onset of the study – either way, the PI needs to have access to the data.

In the process of data management, data entered into the diary by the subject should be available primarily for subject safety, but also to review and query for accuracy. In the figure above, the electronic model indicates PRO questionnaires are accessible as view only data and not editable by the site staff while the PI/designee with a specific user role is able to modify concomitant meds (CM), infusion data, and untoward events in response to a query. Some have suggested only the originator, in this case the subject via the eDiary,  should be allowed to change or modify the “original source”. The most recent FDA draft guidance however, suggests someone other than the “originator” can modify original electronic source so long as the modifications meet the standards in the guidance:

  • Modified or corrected data carry a new data element identifier
  • Identifier includes date, time and originator of the change
  • Both the modified data element and the identifier is write-protected (read only)
  • The original data element with its original data element identifiers is preserved and available for FDA investigators

Additionally, when it makes sense to wipe out data to recycle the device, the local information including the audit trail of data modifications needs to be saved, and a data file (CD or pdf) serves as the certified copy representative of data collected in compliance with the standards in the guidance as well as  21 CFR§11.1.2

1 Guidance for Industry Electronic Source Documentation in Clinical Investigations Draft Guidance. U. S. Department of Health and Human Services, Food and Drug Administration, Office of the Commissioner. November 2012. Retrieved December 18, 2012 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM328691.pdf

2 Helfgott, J., Kassim, S. 2012. Drug Information Association Clinical Management Teleconference “FDA on FDA Perspective on ePRO”. October 19, 2012.

to be continued…………..

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eSolutions to Meet FDA Requirements to Maintain Adequate Records (Part 2 of 6)

This post is Part 2 of a 6 part series. Visit weekly or enter your email to subscribe.

In the event of an inspection or an audit, sponsors may be asked to show evidence the eSource selected for a clinical trial has been vetted as fit for purpose. Specific to ePRO, the FDA intends to “examine the final version of an instrument in light of its development history, including documentation of the complete list of items generated and the reasons for deleting or modifying items…whether the PRO instrument’s final conceptual framework (e.g., the hypothesized relationships among items, domains, and concepts measured) is confirmed in the appropriate study population and is consistent with the endpoint model of the planned clinical trials.”1 Documentation of eSource solutions as compliant with FDA “fit for purpose” expectations would include evidence of:

  • software and system development according to protocol required specifications
  • sponsor user acceptance training as part of the system development life cycle
  • screen shot validation showing the electronic tool does not influence or alter the user ability to consistently use or gather the data because of variability in the user display
  • equivalency testing when the solution platform varies from user to user
  • consideration for cultural practices when studies are global (i.e. a VAS scale read from right to left in Hebrew instead of traditional left to right practice)
  • a “demo” device the inspector can use to evaluate the functionality

Sponsors should verify and validate they chose the right ePRO solution and it was built correctly.   For example, a web-based ePRO application, dependent on varying web-browsers, may pose a challenge for data consistency across all modalities when there is variation in operating system and content format that may or may not require scrolling to see the entire question. “When a PRO instrument is modified, sponsors should provide evidence to confirm the new instrument’s adequacy. That is not to say that every small change in application or format necessitates extensive studies to document the final version’s measurement properties.”1 However, moderate and substantial modifications may require additional validation when the PRO instrument is altered in item content or format. ISPOR (International Society for Pharmacoeconomics and Outcomes Research) suggests examples of moderate and substantial modifications to a validated paper and pencil PRO as:

  • Moderate – changes in item wording, splitting a single item into multiple screens, significantly reducing font size so that a subject would need to scroll or change screens to see all the possible responses, significant changes that alter interpretability, changing the order of items
  • Substantial – removing items or making significant changes to item text to fit the PRO to an electronic screen2

According to ISPOR, validated ePRO questionnaires that have been adapted from paper do not require equivalence studies if the data produced is superior (higher reliability), has comparable psychometric properties, and there is no modification to content from the original paper questionnaire.  Sponsors need to decide whether or not to invest in customized software to accommodate the chosen validated PRO instrument; or the potential need for equivalency analysis or full psychometric validation before implementing an electronic tool for widespread use.

  1. Guidance for Industry Patient Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. December 2009. Retrieved October 25, 2012 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf
  2. Recommendations on Evidence Needed to Support Measurement Equivalence between Electronic and Paper-Based Patient-Reported Outcome (PRO) Measures: ISPOR ePRO Good Research Practices Task Force Report* Value in Health 12 (4). 2009.

to be continued…………

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eSolutions to Meet FDA Requirements to Maintain Adequate Records (Part 1 of 6)

This post is Part 1 of a 6 part series. Visit weekly or enter your email to subscribe. 

Technology is important in the product development life cycle as well as the clinical trial workflow. The regulations are flexible in allowing sponsors and CROs to choose electronic solutions for data collection either home grown or vendor purchased. In any case, however, the electronic systems should meet the sponsor needs and the sponsor should vet and document the system capabilities and functionality. First let’s define the “e” terms.

to be continued….

  1. Guidance for Industry Electronic Source Documentation in Clinical Investigations Draft Guidance. U. S. Department of Health and Human Services, Food and Drug Administration, Office of the Commissioner. November 2012. Retrieved December 18, 2012 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM328691.pdf
  2. CDISC Clinical Research Glossary.  Applied Clinical Trials 20(12): 11-43. 2011.
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