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

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



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).


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

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

to be continued…………..


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
  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…………


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
  2. CDISC Clinical Research Glossary.  Applied Clinical Trials 20(12): 11-43. 2011.

Paper Diaries – Risky Business


Many in our industry refer to the “parking lot syndrome” when describing patients rushing to complete days’ worth of their paper diaries for their clinical trial just before their site visit.

Did you know that this “syndrome” was actually captured in a study published by the British Medical Journal (BMJ2002;324:0.6)?

It found that although 90% of subjects reported completing the paper diary on time, only 11% actually completed it as instructed.  They were able to track paper diary entries by embedding photo sensors into the diary binder (to determine when the binder was actually opened).   This compares to a 94% compliance rate with an electronic diary.

The complete article can be read here.

Equally as interesting, the FDA PRO guidance(published in 2009) states the following:

“If a patient diary or some other form of unsupervised data entry is used, we plan to review the clinical trial protocol to determine what steps are taken to ensure that patients make entries according to the clinical trial design and not, for example, just before a clinic visit when their reports will be collected.” (pg. 14)

This guidance indicates the regulatory authorities are keenly aware of the non-compliance associated with paper diaries, and intend to monitor patient compliance with diary entries according to protocol requirements.

If your study is designed to collect patient reported outcomes, study endpoints, symptoms, or undesirable events from patients at home, consider using an electronic diary with an automatic date and time stamp, to facilitate regulatory compliance.

You can learn more about assisTek’s Patient eDiaries by clicking here, and see pictures here.



Email Alerts in Clinical Trials Improve Study Team Efficiency

Look what assisTek can do to help your study team manage compliance, undesirable events, site visits, etc more effectively and proactively! 

 Patient Non-Compliant?

  • Email alert directly to Study Team for follow-up.
  • Email reminder sent directly to patient to complete diary entry.


Nurse Records AE?

  • Email alert directly to Investigator for Review and Assessment.


Patient records undesirable symptom, event, medication, etc?

  • Email alert directly to Study Team for review and follow-up.


Site Visit coming up?

  • Email reminder sent directly to patient.


When used correctly, email alerts can help study teams manage critical issues more efficiently, and help gain compliance from patients before it’s a problem.

assisTek’s email alert system is linked directly to specific events based on protocol requirements and study team needs.

Questions about how this can work in your study? Find out more:  (and yes we do reply!)



Top 10 List – Why is eSource preferred?

Top 10 List – Why is eSource preferred by Clinical Trial teams?

10.  Transcription costs are expensive

9.    Transcription requires source data verification.   Anytime data is duplicated, errors are introduced.

8.    eSource eliminates parking lot syndrome.  FDA requires proof that data was collected as described in protocol!

7.    eSource technology gives study teams access to data in real-time – compliance, symptoms, QOL, etc.

6.    eSource lowers burden on site team (transcription, monitoring, etc).

5.    eSource lowers burden on data managment team if alerts, logic, etc designed to improve protocol compliance

4.    Data sharing and follow-up are dramatically improved between patient, study coordinator and investigator.

3.    Real-time access to undesirable and adverse events.    Safety monitoring no longer relegated to site visits.

2.    Patient visits with electronic source records are more meaningful – nurse & investigator can view history, trends, etc of past visits.

1.     eSource saves money and time.


eSource in Clinical Trials: A brief overview

Many clinical trial teams are tiptoeing into the world of eSource, anxious to reap the benefits, yet uneasy about the impact.  To many, the unknowns seem daunting and overwhelming, and maybe not worth the effort.  To those who have taken the plunge, the value to the study team has far outweighed the initial investments.  This blog is geared to address the typical concerns: What is Source? Why eSource?  What problems are solved with eSource?  What are the potential gotchas?  What is the impact on the study team? and What does the FDA say about all this?

According to the FDA, “initial documentation of data in a clinical study is considered Source documentation or Source data”.1  This is a fairly straight-forward concept.  The source data and documentation is the original record of a data element, and integrity is maintained by using an audit trail to track any changes and modifications.

Now, introduce electronic source “eSource”.  For all intents and purposes, the definition is the same, except the original record is captured electronically.  This excludes source data that was captured on paper and transcribed into an electronic database.  eSource is true to its name and the source data element itself must be electronic; and must be followed with a detailed audit trail as well.

On the face, the benefits are obvious.   The FDA promotes eSource in clinical studies because it will help to:

  • “eliminate unnecessary duplication of data,
  • reduce the opportunity for transcription errors,
  • promote the real-time entry of electronic source data during subject visits, and
  • ensure the accuracy and completeness of data (e.g., through the use of electronic prompts for missing or inconsistent data).” 1

The advantages can go further than even those stated above.  Let’s take a few examples:

Example 1:  A patient receives an infusion treatment for a study drug.  During her visit, all data (vital signs, concomitant medications, infusion data, etc) is captured electronically.  That night the patient has a serious adverse event which results in a trip to the emergency room, and the study investigator is contacted.  The beauty of having the patient’s most recent visit captured electronically is that the investigator has immediate access to the day’s treatment details (along with previous treatments) directly at his fingertips.  If data relating to the infusion treatment was captured on paper, the investigator, at best, might have access to a chart at the infusion clinic.   When time is critical, paper is not the answer, and can potentially jeopardize the patient’s safety.  Using eSource allows the data to be accessed and assessed in real time.  Any subsequent events relating to the emergency room visit can too be captured electronically and automatically disseminated to key team members.

Example 2:  A patient reports symptoms on an electronic diary that are undesirable.  The study staff is automatically notified via email.  If this were collected on paper, the patient would report the symptom, and would likely not get any resolution until a site visit sometime in the future.  Their recollection of the undesirable symptom or event will not be as clear as it was when originally reported.  Using eSource allows the study staff to determine the severity in real-time and follow-up as needed.  Any subsequent contact with the patient regarding the undesirable symptom can too be captured electronically and automatically shared with key team members.

From a data manager’s point of view, eSource can solve a multitude of problems, most notably consistency of data (pre-defined medication lists for example) and access to data as described above. The key is to avoid any potential gotchas relating to the integration of data with an existing study database (or EDC system).  Every study team desires consistency and is not necessarily gung-ho about introducing another system/website/database into a study.  This is one area where things can get complicated.  If it is the study teams’ wish to use eSource, there must be a backend designed to integrate the eSource data into the existing database or EDC system.  Audit trails must remain intact, and query processes must be clearly defined.  What good is an eSource system if team members cannot use it seamlessly with study data reported into other system(s)?

The obvious benefit to any study using eSource is quality and access to data.  The access to ongoing, real-time data can speed the overall process an average of 6 months.  Since drug approval is what sponsors are after, this cannot be ignored.   Equally as interesting is the substantial cost savings.  If a true eSource solution is used, all transcription and source data verification costs are eliminated.  This can cost upwards of $15 per page (CRF and non-CRF data).  You do the math; the savings are significant.  Just as noteworthy is the fact that data can be monitored remotely and queries fall, on average, by 70% (headaches and frustration decrease at the same rate!).

Although the FDA’s guidance on eSource is still in its “draft” stage, the implication is clear.  The FDA appears to support the collection of source data electronically as a means to promote accuracy, integrity, traceability, and completeness of data.  If your team is still tiptoeing around this powerful movement in clinical trials, consider starting with an eSource solution that collects primary endpoints electronically and integrates directly with a database that your team is confident using.  Work out the kinks and transition to using eSource to capture all data elements once you’ve gotten your feet wet.

  1.  U.S. Department of Health and Human Services, Food and Drug Administration (December 2010).  Guidance for Industry:  Electronic Source Documentation in Clinical Investigations.  Available at