FDA & EMA Regulatory Developments for eSubmissions

May 14, 2012


Regulatory Developments for eSubmissions

A few months ago, GxP Perspectives discussed eCTD as a Required Format for FDA Submissions. To summarize, in PDUFA V Commitment Letter 8-31-2011, the agency announced their intention of issuing draft guidance for required electronic submissions in eCTD format by December 31, 2012, with final guidance no more than 12 months after the close of the public comment period. Twenty-four months after publication of the final guidance, electronic submissions will be required for all new NDA and BLA submissions (originals, supplements and amendments) with a few specified exceptions. In this update, Kathie Clark discusses upcoming requirements, developments, and incentives for sponsors of clinical research.

Recent eSubmission-Related Regulatory Developments and the Impact on Sponsors
by Kathleen Clark

The regulatory authorities have been busy announcing plans and issuing new guidance related to eSubmissions in recent months. Legislation has been proposed to expedite review of generic drug applications and improve communication between FDA and industry – Generic Drug User Fee Act Program (GDUFA). GDUFA includes goals for FDA such as reviewing and acting on 90% of complete ANDAs within 10 months after the date of submission – but these goals only apply to submissions made electronically, following the eCTD format.

New Initiatives in Europe

regulatory developments for eSubmissions

New Developments in Europe

In Europe, the big news has been the eXtended EudraVigilance Medicinal Product Report Message (XEVPRM). XEVPRM is an XML-based message format that defines the structure and data elements required to unambiguously identify a medicinal product. European Medicines Agency requires that by July 2, 2012, information on medicinal products for human use authorized or registered in the Union is submitted electronically in this format. Sponsors are scrambling to meet this mandate as guidance has been finalized only recently.

Sponsors are often challenged to locate the data needed for submission, and ensure that it is complete and accurate. Vendors have been following the initiative closely, but even so, deploying and validating systems to publish the new message and putting in place the business processes around their use is a significant effort. Some aspects of the mandate remain unclear.

Another ongoing initiative in Europe is the pilot program for the new electronic Application Form, or eAF. The eAF is actually a collection of electronic Application Forms for human and vet med MAAs as well as variations and renewals. These are PDF fillable forms requiring extensive, detailed information for completion. Use of the electronic application forms is expected to yield the following benefits:

• Improvements to data quality and consistency during data entry

• Access to the underlying data entered into the forms in an XML format

• Integration with dynamic lists of controlled terminologies

The eAF pilot commenced on March 12th 2012 and is expected to run for four months.

FDA’s New Validation Criteria and Module 1

The FDA has finalized new eCTD Validation Criteria. They have not yet announced an implementation date, which will be set at least one month in advance of enforcement. The validation criteria represent a major overhaul:

• 56 new validation checks (5 high, 36 medium, 15 low) – 12 checks will be removed

• 161 unique error conditions – of which 22 errors can cause a technical rejection
In the past, the FDA has not validated the actual PDFs that make up the majority of an eCTD submission. The new criteria require extensive validation of the PDF files themselves. This includes validation of

• Fonts (use of standard fonts embedded where required)

• PDF format (1.4 or 1.7)

• Absence of applied security (either password protection or restrictions such as preventing the selection of text)

• Generation of PDFs in a manner that allows them to be text selectable (from electronic sources as opposed to scanned)

regulatory Developments for eSubmissions

FDA’s New eCTD Validation Criteria

The FDA will also be validating bookmarks and hyperlinks to ensure that they are valid and don’t point to external or non-relative locations. Finally, the FDA has provided rules to help sponsors correctly name and place their PDF fillable forms. This is essential as the FDA reads data from these forms that allows submissions to be processed by their automated software, without manual intervention. This is also important to sponsors, as failing to supply valid forms can result in up to five days delay in processing a sequence.

A fillable form should always be submitted, and should be named properly. As FDA requires forms to be signed, if sponsors have trouble applying digital signatures, they should still fill out a PDF form, print, sign, scan, and submit both forms. For details, see the FDA presentation CDER Update: eCTD & Gateway Submissions.

FDA’s Draft Module 1 Guidance

The FDA plans major changes for Module 1, and have issued new draft US Module 1 and Comprehensive Table of Contents Headings and Hierarchy Guidance. These guidances are still subject to change and not likely to be implemented until early 2013. The changes include:

• Allowing for bundled submissions (one sequence submitted to multiple applications). Examples of bundled submissions include new manufacturing site, change in API source, a drug substance change that applies to multiple dosage forms of the same drug, changes in packaging, etc.

• Ability for attribute display values to be updated without having to update the Specifications, eCTD TOC, and DTD .

• Revision of heading elements.

• Addition of new headings and sub-headings, including detailed definition under m1.15 Promotional material. These additions are too numerous to mention but are summarized in Appendix 2 of the comprehensive Table of Contents. (The FDA has emphasized that promotional materials are still not accepted in eCTD format at this time.)

• Addition of new attributes in Module 1 (under m1-forms and m1-15-promotional-material).

• Additions and changes to Module 1 metadata. These are too numerous to mention but are summarized in Appendix 2 of The eCTD Backbone Files Specification for Module 1.

Finally, the FDA has updated the way it organizes regulatory activities within an application. (A regulatory activity is a set of sequences that together constitute a claim, e.g. an original application, supplement or annual report). There are three levels of organization:

Application (e.g., NDA, BLA, IND)

Submission Type (e.g. Original Application, Efficacy Supplement, Safety Reports)

Submission Sub-Type (e.g. Application , Amendment, Resubmission)

Valid Submission types will be based on the Application Type, e.g., an efficacy supplement can be associated with an NDA or BLA but not an IND. The FDA provided a figure to illustrate how the approach works in comparison with the previous approach.

You can see a number of FDA presentations on the topic of Module on the Electronic Submissions Presentations page.

Health Canada Updates

Health Canada is also planning extensive changes. They have issued new draft guidance for CTD, eCTD and Module 1. Health Canada is formalizing the concept of Regulatory Activities through use of the related-sequence metadata. Their regulatory activities are defined in their Module 1 guidance and include New Drug Submission, Supplement to a New Drug Submission, Abbreviated New Drug Submission, Clinical Trial Application and many more. Clinical Trial Applications are not yet being accepted in eCTD format but that is expected to start around the end of 2012.

There are many changes to the table of contents, including correspondence organized under 1.0, much more granularity around 1.2 Administrative Information, more headings under Product Information (IB, more labeling elements, PV/Risk Management plans and information), change of 1.6 Electronic Review Documents into Regional Clinical Information, a new section 1.7 for CTA information, and a new regional quality section, 2.2.R.4 Yearly Biologic Product Report.

eSubmissions regulatory updateHealth Canada is also making major changes in its Module 1 metadata, including adding elements applicant, product-name, dossier-identifier, dossier-type, regulatory-activity-type, regulatory-activity-lead and removing elements submission-identifier, and submission-date.

Finally, on the technical front, the eCTD guidance calls for a technical change to the use of a Schema instead of DTD.

What Can Sponsors Do to Prepare?

Although some of these changes are only in draft or pilot stages, preparation should begin now. Suggested preparation steps include:

• Review the guidance documents and agency presentations

o Ask questions – esub@fda.hhs.gov is a great resource for FDA issues if you need clarification

• Understand the new documents required in the CA/US M1

o Do they already exist and are just not submitted? Or must they be created? Under which circumstances?

o Are they being created using high quality templates authored to the correct granularity?

o How will you handle promotional materials with non-traditional formats (movies, artwork, etc.)?

• Review the new validation criteria

o Are PDFs being created in a compliant manner?

o Are US Fillable Forms being created and published correctly?


EudraVigilance Medical Product Dictionary

FDA Electronic Submissions Page

Kathie Clark is Director, Product Management for NextDocs, a leading provider of SharePoint based content and quality management systems for Life Sciences. Kathie has an extensive background in document management and electronic submissions for the global life sciences industry and has written extensively about industry challenges in blog posting, journal articles and white papers. You can reach her at kclark@nextdocs.com or follow her on twitter at @kathie_clark.

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Also this marks three years for the great blog by Steven Grossman, FDA Matters. Congratulations Steven! You can read his post on FDA, Me, and Maybe the Mafia!

Clinical Labs & GCP

June 12, 2011


GCP for Clinical Laboratories

How to assess clinical laboratories for GCP compliance is one of the more difficult issues facing GxP professionals. Is CLIA the gold standard? How do the good laboratory practice (GLP) regulations impact clinical labs? Isn’t there a handy checklist out there somewhere? What do people mean by “GCLP?” I have been dealing with this issue a lot of late and people are really all over the map. Here are some of the approaches I take, along with a handy-dandy reference list at the bottom of the post.

First, let’s look at the easy part. The primary regulation dealing with clinical laboratories is the Clinical Laboratory Improvement Amendments (CLIA). Wow, that’s simple. However, CLIA specifically states that it does not have jurisdiction over research. CLIA covers the day-to-day laboratory tests that your doctor orders to check up on your cholesterol or hematocrit. For these routine tests, FDA recognizes CLIA certification as an acceptable standard. FDA also recognizes other certifications such as from the College of American Pathologists (CAP). However, FDA does not have its own laboratory program. No, the GLP regulations (Part 58) just don’t apply here. My advice is to keep them on the shelf.


Research Continues into New Laboratory Methods

However, things can get more complex. Not all laboratory tests are CLIA certified, there is a whole lot of research going on out there. Research methods are being developed every day. To make matters worse, just because a lab is CLIA or CAP certified, it does not mean that they have clinical trial experience and knowledge of kit building or blinding procedures. You need to go to their laboratory and see if they are equipped to perform the tasks in your statement of work. You need to perform a chain-of-custody tour to determine that your samples will be handled and analyzed in an appropriate manner, if there is “quality control at each stage of data handling” (ICH E6 Section 5.1.3).

One document that will come in handy is the FDA Guidance for Industry: Bioanalytical Method Validation. If you have a new laboratory method, it should be validated. What about an audit plan? I use the European Medicines Agency (EMA) GCP Inspection Guidance on Clinical Laboratories (Annex II). Links to both of these documents are listed below. The important thing to remember is that you have critical safety and efficacy endpoints being evaluated by the lab and they are highly importance to your study. Give the laboratory the attention it deserves.

GCP lab clinical trials FDA

Tour the Laboratory

Chronological order is a useful tool in assessing a laboratory. Follow the route of the samples starting with kit building, shipment to the sites, receipt from the sites and how they make it through the laboratory. Remember, the majority of laboratory errors take place Before sample analysis, in the pre-examination phase (source: CDC). In addition, there are more errors reported in the post-examination phase than the examination phase itself. Reporting is of critical importance. Your NDA or PMA might depend on the accuracy of those reports.

I have seen many checklists for conducting clinical laboratory audits. Most of them have issues that can impact their effectiveness. Your audit should be protocol-specific. The lab needs to be able to conduct the analyses required by the protocol. That’s why I use the EMA GCP Inspection Guidance for Clinical Laboratories as a basic audit plan. EMA has a GCP inspection program for clinical labs. Another important point is that not only do you need to pre-qualify a lab, you need to go back during the trial and audit live data. This is true for any critical vendor.


There are a number of resource documents available

Many organizations are working on the clinical laboratory dilemma. You will hear the term “GCLP” quite a bit (for good clinical laboratory practice). It is important to remember that there is not one consistent standard on what GCLP is. Wouldn’t it be nice if we did have a consistent GCLP standard recognized by the world’s regulatory authorities? Here are some important references for clinical labs and GCP. Feel free to make additions to this list in the Comments section below.

EMA GCP Inspection Guidance for Clinical Laboratories

FDA Guidance for Industry: Bioanalytical Method Validation

College of American Pathologists Website

Clinical Laboratory Improvement Amendments (CDC)
(This site has links for genetic testing and Waived Testing)

GCLP – UNICEF, UNDP, World Bank, & WHO

MHRA: Good Clinical Practice for Clinical Laboratories – (Please see the comments/discussion on this.)

On The Blogroll: Dark Daily: News for Clinical Laboratories & Pathology Groups


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Draft Guidance: Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology. This guidance is open for public comment for 60 days (approximately August 7).
FDA has announced a new draft guidance document. Public comment is due by 25 July 2011:

Guidance for Clinical Investigators, Industry, and FDA Staff: Financial Disclosure by Clinical Investigators



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Reflecting on the Trial Master File, the TMF

February 5, 2010

Post updated 28 January 2011: Just what is a trial master file or TMF? What are “Essential Documents?” How does FDA expect to see researchers document a clinical trial? Are there differences between FDA and EMA, the European Medicines Agency in TMF requirements? UPDATE: Read the Final version of the “EMA Reflections” Document on EDC, released after this post was originally published.

Reflecting on TMF

Documentation Requirements for Clinical Trials

It is interesting to note that although “TMF” is a standard industry term in the United States and is used by regulators around the world, the FDA doesn’t actually have a TMF inspection and rarely uses the term. FDA regulations are vague about the exact documents required for a clinical trial. In a response to an inquiry about documents answered by “GCP Questions,” a program within the Office of the Commissioner, FDA stated on 02 November 07:

“FDA’s regulations are intentionally pretty general, the reason for this is that the agency believes that sites and sponsors should have the necessary flexibility to adopt procedures that will comply with the regulatory requirements, and make sense (given the complexity of the study and available staff), without being unnecesarily burdensome.”

While this may be a commendable intent, it isn’t particularly helpful. I understand that regulations and guidance documents can’t be overly specific, but vague guidance on regulatory compliance leads to what I call, “regulation by rumor.” People will use an anecdote they have heard about what they think an FDA investigator wants in order to determine what documents FDA considers essential to a clinical trial. This can cause real problems between a clinical site and a monitor or auditor. There are genuine differences on how to document protocol deviations and other issues.

trial master fileThe term “trial master file” comes from the ICH E6 Guidance Document on Good Clinical Practice (E6). (Links to E6 and other documents related to this post are listed at the conclusion of the post.) Section 8 of E6 is called, “Essential Documents for the Conduct of a Clinical Trial.” In the introduction to Section 8 the Trial Master File is discussed. I consider E6 to be the authoritative document on the subject. Section 8 has a comprehensive list of Essential Documents, their location and what is necessary before, during, and after a clinical trial. When I define “TMF” I use the documents listed in Section 8 as my primary guidance. The only significant addition to this list (that I am aware of) is the FDA requirement for a Final Report, from the investigator to the sponsor. (I have an article on Final Reports at the conclusion of this post.)

TMF Trial Master File

ICH E6 Sets the Standard for Essential Documents

However, some regulatory authorities don’t seem to be emphasizing E6 as much as they may have in the past. It has been suggested that there might be additional “Essential Documents” although no regulatory agency that I know of has published a comprehensive list that could complement E6. Also, it has been suggested that there may be a “Good Clinical Practice” standard other than E6. FDA stated this when they rewrote the requirements for Foreign Clinical Studies Not Conducted Under an IND (21 CFR 312.120). Where you can find an alternative GCP isn’t discussed.

I think that E6 gives sound recommendations for GCP compliance. We should be using it more, not less. It has been published in the Federal Register as official FDA Guidance. It is the only guidance that FDA has on the TMF.

When discussing the TMF one of the trickiest issues involves electronic records, including electronic medical records (EMRs) at a hospital or medical center. There is a lot of grey area as far as protecting privacy, access to EMRs, and the validation of an institution’s EMR system. Unfortunately there isn’t a definitive guidance document on the topic of EMRs. FDA does have a guidance document on “Computerized Systems Used in Clinical Investigations.” It is found in the Important References section on your right, along with E6. Another resource that I recently became familiar with is a document from EMEA with the clever name of “Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials.” I’ve attached a PDF copy for your viewing pleasure at the bottom of the post. It contains some excellent recommendations. (Also attached is the final document released after this post was originally written. It is very similar: See “EMA Reflections”)

TMF electronic records

Electronic Medical Records

The “Reflections” document discusses Assigning Responsibility for maintaining clinical trial records. FDA regulations assign responsibility to either the sponsor or the clinical investigator. The “Reflections” document notes that the clinical site needs to maintain control over source documents and not hand over the responsibility to a sponsor. Source documents are the responsibility of the clinical investigator. This includes worksheets or standardized forms that a sponsor might prepare for a site in order to conduct the study according to the protocol. Even though the worksheets are written by the sponsor, they become the Responsibility of the Investigator. Lately FDA has taken to making this point on Warning Letters. Here’s an example from a recent FDA Warning Letter to a clinical investigator on the subject of “adequate and accurate subject case histories.”

“Your site chose to use the sponsor’s standardized forms as source documents to record and document information related to the subjects’ study visits. Per the standardized form, your site was to “Complete the Inclusion/Exclusion Criteria Worksheet to evaluate for study eligibility.” In the FDA investigator’s review of 16 of 65 subject records at your site, there was no Inclusion/Exclusion Criteria Worksheet found for any of these subjects.”

TMF FDA warning letters

Notice FDA's Wording in Warning Letters

Notice that FDA considers that the site “chose” to use the sponsor’s forms. These records are the responsibility of the clinical investigator. As such, if there is a problem with them during an FDA inspection, then the problem belongs to the clinical site. In this case, the problem was significant enough to result in a Warning Letter. Having solid documentation of a clinical baseline, including recording the Inclusion/Exclusion Criteria are Very Essential Documents. It should be noted that this clinical investigator had a lot of additional problems, not just the sponsor’s standardized forms, or worksheets.

The EMA “Reflections” document gives some good advice for clinical trial recordkeeping. They use the old FDA guidance ALCOA- Attributable, Legible, Contemporaneous, Original, and Accurate and add four additional elements. They are Complete, Consistent, Enduring, and Available When Needed. The last point is particularly important. If you can’t show the document to a regulatory inspector, then for the purposes of the inspection, it doesn’t exist. I would add one additional element; QUALITY. People sometimes place importance on fax coversheets, which are not Essential Documents, instead of the quality of the source documents that document a clinical baseline and protocol-required activities.The quality of the documents used to support an application for a new drug or medical device is sometimes overlooked, to the detriment of Good Clinical Practice. These are the documents used to protect human subjects in research and ensure data integrity. Their quality should allow them to “stand alone.”


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Updates posted 28 JAN 2011- Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma

UPDATE 28 JAN 2011: There is a very interesting Important Notice to IRBs that is on the FDA website. Sort of a Coast IRB redux.

UPDATE 6 January 2011: Two Important New GCP Documents:

There is a Draft Guidance on Electronic Source Documentation in Clinical Investigations. The comment period is for 90 day (April 4, 2011 ?)

There is a new Final Rule on required elements of Informed Consent. You can read the Federal Register Announcement here that includes FDA comments in the preamble. The exact change in 21 CFR Part 50 is:

“Sec. 50.25 Elements of informed consent.

* * * * *
(c) When seeking informed consent for applicable clinical trials,
as defined in 42 U.S.C. 282(j)(1)(A), the following statement shall be
provided to each clinical trial subject in informed consent documents
and processes. This will notify the clinical trial subject that
clinical trial information has been or will be submitted for inclusion
in the clinical trial registry databank under paragraph (j) of section
402 of the Public Health Service Act. The statement is: “A description
of this clinical trial will be available on
http:[sol][sol]www.ClinicalTrials.gov, as required by U.S. Law. This
Web site will not include information that can identify you. At most,
the Web site will include a summary of the results. You can search this
Web site at any time.”


Update: Read the Final Reflections Paper from the European Medicines Agency on Electronic Data Capture:

EMA Reflections

Also: There are a couple of very good comments to this post by experienced professionals. They are well worth reading.

Here is the E6 document:

Here is the FDA guidance document on “Computerized Systems Used in Clinical Investigations.

Here are some links that will be of use in researching original data and certified copies:

Compliance Policy Guide 130.400 (equivalent to 7150.13)

Applied Clinical Trials: CDISC Clinical Research Glossary

And finally on Notes to File:


Please remember, your comments, questions, complaints, and advice are always welcome !!!

++++In news from GxP Perspectives++++

Announcement: The 18th and 19th of January 2011 I will be at the conference for Developing CAPAs in the GCP Environment, Arlington, VA. And Again in 2012!

2012 CAPAs in the GCP Environment

Read the updated article on the Form FDA 1572 in:

Applied Clinical Trials “Closing Thought” on FDA 1572

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Read additional posts on Good Clinical Practice- GCP:


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