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 To summarize, in PDUFA V Commitment Letter 8-31-2011, the agency announced their intention of issuing draft guidance for required electronic submissions in eCTD format by December 31, 2012, with final guidance no more than 12 months after the close of the public comment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!

FDA Releases Draft Guidance on “Artificial Pancreas” to Fight Diabetes

June 21, 2011

FDA diabetes artificial pancreas

FDA Guidance for "Artificial Pancreas"

FDA released a draft guidace document for development of an “artificial pancreas,” a highly anticipated step in the fight against diabetes. At one time the onset of type 1 diabetes, where the body stops producing insulin, was always fatal. Then, in 1922, scientists from the University of Toronto gave the first injection of insulin to a 14 year old boy with type 1 diabetes. The experiment was a success and one of the major achievements in the history of medicine. However, this would be the first of many steps in fighting diabetes mellitus. Two of the scientists, Dr. Frederick Banting and Professor John Macleod won the 1923 Nobel Prize for Medicine which they shared with two other members of their team, Charles Best and Bertram Collip. And a new Nobel Prize winner may be working on an artificial pancreas right now.

The concept of an artificial pancreas or a “closed loop” system is that a diabetic could automatically have their blood sugar analyzed and in real time inject insulin to maintain a normal glycemic level.

artificial pancreas FDA

Researchers are Focusing on the "Artificial Pancreas"

Although there have been many advances with insulin pumps and continuous glucose monitors, the devil is in the details on how to regulate the amount of insulin supplied to the diabetic. It is hardly an easy matter.

Most diabetes researchers are looking into the concept of an artificial pancreas as opposed to replacing the islet cells in the diabetic’s pancreas that create insulin. It is the destruction of a diabetic’s islet cells that causes type 1, insulin dependent, diabetes. The Toronto researchers originally called their discovery “isletin.” Type 2 diabetes, once referred to as “adult onset” diabetes, is currently in epidemic proportions in the United States. It impacts the body differently than type 1 diabetes.

The development of an artificial pancreas requires the use of sophisticated medical devices, many of which are already approved. However, it requires the devices to communicate with each other and the development of an algorithm to measure the right amount of insulin to be administered at the right time. No easy task.

FDA guidance artificial pancreas

Draft Guidance Discusses Clinical Trials & Applications for Approval

It is also a difficult issue to regulate. FDA is responsible for ensuring that any artificial pancreas system is safe for the user. The new draft guidance lays out a step-by-step approach for researchers through the regulatory process, for “The Content of Investigational Device Exemption (IDE) and Premarket Approval (PMA) Applications.” The FDA press release states:

“Our goal is to provide a clear pathway for artificial pancreas development so that people with diabetes can benefit from innovative medical devices,” said Jeffrey Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health. “Getting a safe and effective artificial pancreas system to Americans with type 1 diabetes is an FDA priority.”

The draft guidance is for an “early version of an artificial pancreas system.” There is a 90 day comment period from the date the guidance is issued (22 June 2011). A seperate guidance on more autonomous artificial pancreas systems is expected to be released by FDA by the end of 2011.

FDA Press Release

Draft Guidance…Low Glucose Suspend (LGS) Device Systems


On the Blogroll: Top 40 FDA-Related Websites (and tweeters)


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SOPs in Europe: Required for GCPs?

April 1, 2011

SOP Europe requirements

SOPs for Clinical Trials in Europe

What are the differences in SOPs for clinical trials in Europe and the United States? Despite the fact that FDA and the European Medicines Agency are increasing their cooperation and collaboration there are still some formidable obstacles. One is the difference in regulations. The other is how much influence ICH E6: Good Clinical Practice: Consolidated Guidance has in different parts of the world. Today we have a Guest Commentary from The SOP Doctor, Dr Marie McKenzie Mills MICR, CSci, CBiol, MSB, a clinical scientist and trainer from the United Kingdom. She is here to give us a European perspective on SOPs. In 1996, Marie established McKenzie Mills Partnership (MMP), providing consultancy services including training, medical information, medical writing, and clinical research.

I will be publishing a post in Marie’s blog this weekend. Trans-Atlantic Cooperation!

Also: Please take the survey at the bottom of the post!

Guest Commentary

Is there a legal requirement to have SOPs for GCP in Europe?

by Dr Marie McKenzie Mills MICR, CSci, CBiol, MSB

Back in January, in his post “reflecting on the TMF”, Carl mentioned that the ICH Topic E6 Guideline for GCP may not appear to receive the same emphasis from some regulatory authorities as in the past. His post raised a flag about whether there’s a GCP standard other than ICH E6 GCP, which got me thinking. In Europe, a similar concern often pops up along the lines of: which GCP should we be following? So here goes with my answer, particularly for those of us affected by European legislation, with a wee bit of context to explain it.

In Europe, ICH GCP was adopted in July 1996, and became operational in January 1997. Despite having no uniform legal framework for implementation, it was largely adhered to within the European Community (EC) as a set of 13 internationally recognised principles for conducting clinical trials, founded in the bioethical principles that were established in the Declaration of Helsinki. But, its adoption as a regulatory standard was neither complete nor uniform.

SOP Europe

Does the Clinical Trials Directive Require SOPs?

In 2001, Directive 2001/20/EC – legislation known as the Clinical Trials Directive – eventually provided a common legal framework across Member States for monitoring and enforcing GCP standards applicable to clinical research implementation. However, Directives have to be transposed into national law, in each Member State (within three years of their publication). This created scope for differing interpretations of the intended regulatory requirements, somewhat at odds with the goal of harmonisation. Even so, ICH GCP is the cornerstone standard within both the Clinical Trial Directive (Article 1 (3)), and the GCP Directive (Directive 2005/28/EC: Introduction, points 1 and 8; Chapter 1, Article 1 (1a)). So, far from receiving less emphasis, its principles have been adopted in both Directives, where it provides a basic standard for the conduct of clinical trials in a “set of internationally recognised ethical and scientific quality requirements, which must be observed for designing, recording and reporting trials that involve the participation of human subjects”.

This then brings me to the question about requirements for SOPs. Even if this requirement isn’t explicitly stated in European legislation, the burden to satisfy it exists nonetheless, particularly for sponsors because, according to ICH GCP 5.1.1, they’re responsible for “QA and QC systems with written SOPs to ensure that trials are conducted in compliance with the protocol, GCP, and the applicable regulatory requirement(s)”. Likewise, IRBs or IECs – as they’re better known across Europe – also need to have SOPs for their functions (ICH GCP 3.2.2).

Europe SOPs require?

Requirements for EU
Member States

As it turns out, in the GCP Directive, the requirement for SOPs is emphasised less for sponsors, and more for Member States, since their inspectors need appropriate tools for verifying GCP compliance (Chapter 6, Inspection Procedures, Article 26: “Member States shall establish the relevant procedures for verification of good clinical practice compliance. The procedures shall include the modalities for examining both the study management procedures and the conditions under which clinical trials are planned, performed, monitored and recorded, as well as follow-up measures”.

So there you have it: SOPs are required tools for sponsors to ensure GCP compliance; and, for inspectors they’re required tools for verifying compliance. As an all-encompassing requirement in the GCP Directive it often seems to escape everyone’s notice, perhaps because it appears understated. But, it’s there in Chapter 2, entitled Good Clinical Practice for the design, conduct, recording and reporting of clinical trials in Section 1, Article 2 (4): “The necessary procedures to secure the quality of every aspect of the trials shall be complied with.” I don’t know about you, but I think that’s all about SOPs. What do you think?

Links to the Clinical Trials Directive, GCP Directive and the ICH GCP guideline can all be found on the European Medicines Agency website on the link below.

European Medicines Agency (EMA)

EMA GCP Inspections

Marie’s Blog on the Difference between ICH and WHO GCPs

Carl’s Guest Post on Marie’s Blog on Differences Between FDA & EMA Sponsor/CRO Requirements


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On the Blogroll: New from the UK: Assero UK
“Working to connect your data…”

And, an interesting development:

PharmTech Talk on EU Transparency Initiative


A new service: Please check out the Services page at the top of the Blog to learn more about GxP Services.


There are some important new FDA Warning Letters:

Warning Letter on Fraud at Clinical Site

Warning Letter for GMPs at Clinical Supplies Facility

Which brings us to a new feature from FDAzilla on FDA 483s

Read the Press Release on 483s

For more information about Europe you can read:

Applied Clinical Trials, View From Brussels by Peter O’Donnell
Jobs in Clinical Research? The April issue of the Journal of Clinical Research Best Practices just arrived on my doorstep (actually my email inbox) with a review by editor Norm Goldfarb on a new book, “Careers Opportunities in Clinical Drug Research” by Rebecca J. Anderson. At $59.00 it is a bit pricey but reading Norm’s journal always gives you a spectrum of information on clinical trials. You should consider an introductory Free Subscription to the Journal.

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GCP Protocol Deviations & Violations: Determining the Root Cause

March 6, 2011

protocol violations and deviations GCP

GCP Protocol Violations: Determing the Root Cause

The top violation cited during FDA inspections of clinical sites has consistently been the failure to follow the investigational plan- Protocol Deviations & Violations. Coupled with recordkeeping violations the failure to follow the protocol has been the mainstay of the Form FDA 483, Inspectional Observations, issued by FDA field investigators to clinical sites for decades. However, FDA has recently been pointing out that the root cause can just as easily be poorly designed protocols as noncompliance by a clinical investigator. In the previous post on GCP CAPA plans I note that at least two root causes that should always be investigated. This is particularly true when you find systematic protocol violations. Two areas that should always be reviewed are:

Protocol Design: Frequently you will find a Note to File in a clinical site’s regulatory binder saying that the study coordinator had been “retrained” in the importance of subject compliance. However, if subjects are routinely missing visits or protocol-required procedures you need to take a look at how well designed the protocol is. Were clinical sites consulted when the protocol was written? Is the visit schedule practical? Are the tests easily performed or do they require special efforts by research staff at a busy medical practice? And just how many protocol amendments do you have anyway? It is the clinical site that will receive an FDA 483 but the root cause very well might be found at the sponsor.

GCP Violations and protocol deviations

Protocol Violations are the Top GCP Violation at Clinical Sites

Protocol Adherence: Sometimes the clinical site is the cause of the deviation. There is a significant difference between the practice of medicine and the conduct of a clinical trial. I can’t count the times that I have been told, condescendingly, that “We’ve been doing this type of medical procedure for quite some time.” That’s all well and good but have you been reading the protocol for quite some time? A clinical trial is an experiment, and frequently requires activities that are not the usual practice of medicine. You may need to order a second blood test, or change the dose of the investigational product.

In cases like this a follow-up letter from the monitor to the clinical site might not be enough. If the root cause is the failure to understand the responsibilities of a clinical investigator then the issue may need to be escalated to someone with the letters “MD” after their name. Sometimes you need a physician to explain the protocol to another physician. Seldom does the “re-education” of support staff work as an effective corrective action.

Determining the root cause of systemic protocol deviations and violations isn’t always easy. However, if you don’t follow the investigational plan you can jeopardize your application. And remember, always investigate at least two possible causes of protocol violations.


In a recent FDA Warning Letter protocol violations are discussed at length.

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This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)

On the Blogroll: Cancer Sucks

Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.
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SPECIAL UPDATE: 18MAR2011: FDA has released an updated version of the Compliance Program Guidance Manual 7348.810, Sponsors/Contract Research Organizations/Monitors. There are new sections on registration of clinical trials on ClinicalTrials.gov, Financial Disclosure, the Part 11 Scope & Application Guidance Document, and other issues. If you work for a sponsor, a CRO, or are a contract CRA you MUST read this document. Review Section III, Inspectional.

I am in the process of writing an analysis of this updated compliance program. Please let me know if you have questions or suggestions for points to consider. Thanks!


CAPA Plans for Clinical Trials

February 22, 2011

GCP CAPA Plans for clinical trials

CAPA Plans: Corrective and Preventative Actions

CAPA- corrective and preventative action– Are CAPA plans for clinical trials different than a CAPA for a GMP quality system? Do GCP regulations require CAPA plans? Is a root cause analysis necessary to develop a CAPA plan? What are FDA’s expectations for CAPA plans? These are some of the questions that were asked at EXL Pharma’s conference on CAPAs in the clinical trial environment held last month in Virginia. I then had the opportunity to ask them all over again during a “for-cause” GCP audit. The results provided for some interesting insight into how sponsors, CROs, and clinical investigators can investigate errors in clinical trials and put in place a process to prevent the errors from continuing.

First we should define our terms:

Corrective Action: –Immediate action to a problem that has already occurred or has been identified.

Preventative Action= Taken to eliminate the root cause of a potential problem including the detection/identification of problems.

Root Cause Analysis: A class of problem solving methods used to identify the root causes of problems or events.

These definitions hold true for all GxP quality systems. However, there are some basic differences that set GCP CAPAs apart from the manufacturing or GLP arena:

= FDA regulations assign responsibilities to Investigators, Sponsors, & IRBs- there are NO regulatory responsibilities for human subjects participating in clinical trials

= GMPs involve a manufactured product- GCPs involve a clinical investigation, an experiment- The “products” are the integrity of the data and the protection of human subjects in clinical research.

= GMPs largely involve a manufacturing process- GCPs largely involve the interactions of People

CAPA Clinical Trials

What is the Root Cause of the Problem?

FDA has made it clear both in public presentations and in Warning Letters to sponsors and clinical investigators that they expect two responses to GCP problems once they have been identified. First, there should be an investigation regarding how widespread the problem is. In effect, conducting a root cause analysis and investigation into the problem. Next, FDA expects a description of efforts into the prevention of the problem in the future. This is essentially a plan of corrective and preventative action, a CAPA. So even though FDA’s GCP requirements don’t specify CAPA plans, if you receive a Form FDA 483, Inspectional Observations, you really need to put a CAPA plan into place. Here are two examples why:

= FDA Sponsor Warning Letter, January 2011 – “Your response is inadequate in that it does not describe your corrective and preventive actions in sufficient detail.”

= FDA NIDPOE letter to Clinical Investigator (potential disqualification warning) 2009: “…however, you failed to investigate for additional acts of falsification within the same clinical investigation or in other clinical investigations in which the study coordinator was involved.”

CAPA clinical trials

Always Look for at Least 2 Root Causes

The root cause analysis of a clinical trial problem should include an investigation into what happened. Different problems will need different levels of investigation depending on significance. In addition, the root cause analysis will need to determine if a CAPA plan is required. Not all problems or errors are both systemic and significant. You don’t want to institute a system of “Death by CAPA” by initiating a CAPA plan for each error that occurs. People make mistakes and a quality system should focus on the errors that matter. Sometimes you will see a “CAPA” that merely restates the error and then the ubiquitous note to file saying “retrained study coordinator.” This is not an appropriate CAPA plan and not an appropriate corrective action. Here are some points to include in a CAPA investigation:

= There can be multiple root causes- Always Look at Two Possible Root Causes

= “Always look at the raw data.” If you are not looking at original documents, then you are missing something of importance

= Why, why, why, why, why The “five why’s” of CAPA. Drill down to find the root cause.

= The “root cause” is not restating the error.

= PICCC: Problem, Investigate, Comparison, Clues, Cause

CAPA clinical trials

Problem Solving in Clinical Trials

PICCC is a useful tool in a root cause analysis. What does “comparison” mean? It means to compare the problem across protocols and across clinical sites. If you have the failure to follow a point in the protocol at one site, do other sites have the same problem? If that is the case, the root cause may very well be that the protocol is poorly written, it may need an amendment. The corrective action would not read, “retrained study coordinator on the importance of protocol adherence.” The CAPA plan would look in a different direction, towards the sponsor. The ubiquitous note to file may not be necessary.

There is a wealth of resources on CAPA, root cause analysis, and conducting an investigation. I am including some of those that I used for this post as well as for presentations. There is still a lot to be developed on CAPAs for clinical trials. However, it is clear that regulatory agencies want to know what you have done to investigate clinical problems and what you are doing to prevent them from recurring. In short, they want CAPA plans.

Barb Immel on CAPA Investigations

Essential Components of an Effective CAPA Plan by Jim Colyn

Root Cause Analysis by Edward Dunn, MD


You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives. I also encourage you to get an email subscription (on the sidebar to your right) or join the LinkedIn group (below).

GxP Audit & Risk Management Congress: 20-21 October 2011, Philadelphia, PA. This conference combines both GMP and GCP tracks to maximize the opportunity for cross training, shared best practices, and networking. Two members of the GxP Perspectives LinkedIn group, Janice Wilson and Adi Lampmann, are among the faculty. The conference is sponsored by ExL Pharma and GxP Perspectives is a media partner.

SPECIAL UPDATE: 18MAR2011: FDA has released an updated version of the Compliance Program Guidance Manual 7348.810, Sponsors/Contract Research Organizations/Monitors. There are new sections on registration of clinical trials on ClinicalTrials.gov, Financial Disclosure, the Part 11 Scope & Application Guidance Document, and other issues. If you work for a sponsor, a CRO, or are a contract CRA you MUST read this document. Review Section III, Inspectional.

On the Blogroll: GxP Perspectives made the list for Best 40 Blogs (and tweets) on the FDA. This comes from FDAZilla. I think it is a pretty good list.

Informed Consent: Questions on New FDA Requirement

February 13, 2011

FDA Requirements Informed Consent Questions

FDA Has New Requirements for Informed Consent

FDA has implemented a new informed consent requirement by updating their informed consent regulations (21 CFR Part 50). The principle of informed consent has been a central ethical factor for efforts to protect participants in clinical trials since the aftermath of World War II. This Guest Commentary by Steven Steinbrueck discusses the new FDA requirement and asks some basic questions about informed consent. I think they are questions well worth asking. What works and what doesn’t work in the informed consent process? Are informed consent forms understandable? Do research participants understand the concepts of the research? Are the right questions being asked? The new FDA regulation is copied at the bottom of Steven’s commentary.

Guest Commentary by Steven Steinbrueck

I was prompted to write by two things—a nice invitation from Carl and the soon to be implemented change to the informed consent regulations. As most of us are aware, there will be a new element required for those clinical studies subject to 21 CFR 50.25; notification that results of the trial will be published in clinicaltrials.gov.

Although I have very little against this requirement, I do find it interesting that the first substantial change in informed consent regulations in quite some time, while logical and required by FDAAA 2007, adds little to help potential research subjects make an informed risk assessment regarding the advisability of participating in a clinical trial.

I think we should stop and think about what we believe, and what we know, about informed consent.

Fundamentally, we believe that human research requires voluntary consent by the participant and that this consent may only be legitimately sought following the provision of required information. Without such consent, human research is thought to be unethical. We can all point to multiple publicized instances where this widely accepted tenet has been ignored.

informed consent questions

The Nuremberg Code was Adopted After the World War II Nuremberg Trials

More than 60 years ago, the Nuremburg Code began with the exhortation that “…voluntary consent is absolutely essential;” the guilt of the physicians on trial began with consent issues. We find similar and more detailed guidance in Belmont, Helsinki and ICH. Most countries have codified their requirements in multiple laws and regulation. In the US, these requirements are primarily found in 21 CFR 50.25 and 45 CFR 46, the so-called Common Rule.

I doubt that we have much argument about the fundamental requirement for truly informed consent, or even its major topics. So, what am I even talking about?

But, what do we know? Essentially, that a large portion of research participants do not understand one or more important concepts about the research they are involved in. Many researchers have documented what has been called therapeutic misconception, therapeutic optimism, and even therapeutic nihilism on the part of both participants and researchers. Although percentages vary between 40 and 70+%, we are aware that we have not fulfilled the obligation to ensure that the information provided is not only complete, that it contains all elements required by regulation or guidance, but also that the volunteer comprehends the information provided—prior to their participation.

Although compliance is necessary, it is insufficient. We must do something about the incomprehensibility of many consent forms. They must be shorter and the time between presentation of the information and consent must be longer. Additional information, including HIPAA authorizations and lengthy explanations of alternative treatments and non-experimental procedures must be provided in separate documents. And finally, we must routinely assess understanding before and during the trial. For, to enroll someone who does not understand, is to enroll someone who has not truly been given the opportunity “to decide what shall o r shall not happen to them.” And that is simply against our collective beliefs.

Steven Steinbrueck, MPH
Stonebridge Consulting


“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 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.”


MHRA and Clinical Trials– Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma

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New FDA Guidance Documents Planned for 2011

January 9, 2011

FDA Guidance Documents 2011

FDA Plans New Guidance Documents in 2011

FDA just issued a new draft guidance document for Electronic Source Documents in Clinical Investigations (see below) and has more in the works. In this Guest Commentary, John Avellanet, founder of Cerulean Associates LLC, takes a look at what is in store for 2011 as far as FDA Guidance Documents with a focus on new documents for postmarket surveillance. The article is excerpted from a lengthier article in John’s newsletter SmarterCompliance. John forecasts new guidance documents every year in his newsletter. There is a link to John’s website below.

Guest Commentary by John Avellanet:

FDA postmarket surveillance is the emphasis of at least six different guidance documents planned for publication in 2011. And these are in addition to the new International Conference on Harmonization (ICH) and Global Harmonization Task Force (GHTF) documents expected, including a GHTF guidance on the handling of recalls and field safety corrective actions (see below).

The list of FDA postmarket surveillance guidance documents includes:

1. Chemistry, Manufacturing, and Controls (CMC) – Postmarketing Plan
2. CMC Postapproval Changes Reportable in an Annual Report
3. Pharmaceutical Manufacturing Statistics and Trend Analyses
4. Best Practices for Conducting Pharmacovigilence Studies Using Electronic Healthcare Data (remember that since FDAAA of 2007, the term “study” explicitly means postmarket nonclinical study)
5. Medical Device Reporting for Manufacturers
6. Postmarket Surveillance and the National Competent Authority Report Exchange Criteria and Report Form
7. Types of Submissions for Postapproval Changes to Combination Products

FDA Guidance Documents

Expect New REMS Guidance from FDA

I also expect the agency to release a revised risk evaluation and mitigation strategies (REMS) guidance, at least in draft form, by year’s end. Part of this release will be the creation of a pilot program to test what a standard REMS could like as a default part of any new drug or biologic submission. This means one more step toward pushing the industry to create some type of REMS for every single new drug or biologic developed. The agency will maintain an approach to a standard REMS that will be harmonized with other regulatory member agencies in the ICH. And while such a revised draft REMS guidance may come as a separate document, I suspect the agency may take a newer tact: “guidance by FAQ.”

guidance documents

EMA is Also Releasing New Guidance & Clarifications

Both the European Medicines Agency (EMA) and the UK’s health agency (MHRA) have begun publishing clarifications and revisions to guidance documents and regulatory interpretations using question and answer formats posted on agency webpages. The FDA adopted this approach most recently in its “guidance” (for Buildings and Facilities) on avoiding moldy or musty odors in drugs. Might the agency harness the “guidance by FAQ” approach for its upcoming standardized REMS draft and pilot?

The standard REMS template – while seeming to add more requirements to drug development – will actually provide manufacturers and developers more flexibility, something already known to readers of Get to Market Now! Turn FDA Compliance into a Competitive Edge. While I do not expect the REMS guidance and template to be finalized until after the pilot program is complete, consider developing a high-level REMS as part of any late stage development today. Expect to be able to talk intelligently to FDA reviewers of your plans for a postmarket surveillance program. A high-level draft REMS strategy (you need not share the actual document with the agency) will only help.

Finally, be aware that in 2011, the HHS Office of Inspector General (OIG) will examine the FDA’s postmarket surveillance activities, with a report expected to be published in 2012. This will inevitably result in more postmarket guidance, and may give the FDA the backing it needs to make a basic REMS part of any new drug or biologic submission by 2014.

This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)
SmarterCompliance Newsletter

Global Harmonization Task Force focuses on medical devices

International Conference on Harmonization focuses on drugs and biologics

SPECIAL ANNOUNCEMENT: From the FDA Alumni Association (FDAAA): The WHO is seeking a pharmaceutical technical officer to work in China ondrug policy. The position looks very interesting. Please forward to anyone you think might be interested. Please contact WHO directly if you have questions. For info contact <a href="Florence Houn “>Florence Houn at FDAA. or view the WHO AnnouncementWHO Announcement


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Special Notice: The Blog was published in the Journal of Diabetes Science & Technology on the topic of Supervisory Responsibilities of Investigators with my colleagues Ann Berenbaum and Patti Young.

Access the Abstract Here


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