Three Things That You Should Know About Part 11

June 4, 2012

Part 11

Three Tips on Part 11

What is FDA doing about Part 11? Is the regulation for electronic records and electronic signatures still in force? – The answer is YES – What, if anything, should my company or clinical site be doing about it. Strict compliance can be very expensive- almost as expensive as no compliance at all! Here are three tips on Part 11 compliance from veteran consultants and regular GxP Perspectives contributors, Emma Barsky and Len Grunbaum. I first met Len at the last FDA training course I attended as an FDA field inspector. He is still training FDA and Industry on computerized systems. Given that FDA is focusing more and more on the automated processes and integrity of the data collected using automated means, Part 11 is more important than ever.

Carl Anderson, GxP Perspectives

GUEST COMMENTARY
Three things you need to know about 21 CFR part 11
by Emma Barsky & Len Grunbaum

Fifteen years after becoming effective, 21 CFR part 11 seems to generate as much controversy as it did when it was first implemented. At this point in time, we cannot think of another regulation that sparks as many disagreements with respect to its interpretation and generates as many discussions. Why is that?

Since the inception of the regulation as of August 1997, compliance has been, in our view, analogous to the story of Goldilocks and the Three Bears: compliance in some companies has been too hot (i.e., too restrictive and expensive); compliance in some companies has been too cold (i.e., minimal if any at all); and, compliance in some companies has been just right (i.e., cost-beneficial and based on an effective risk assessment). So, while we do not in any way want to equate compliance with the regulation to a bowl of porridge, we hereby offer three main things that you need to know about 21 CFR part 11 to help you make your compliance just right:

PART 11

THE IMPORTANCE OF VALIDATION

1. You need to know how to assess risks when it comes to 1) developing a validation approach regarding a given system and 2) implementing controls (e.g., audit trails, logical/physical security) to help ensure the trustworthiness and reliability of the records. As indicated in the Scope and Application guidance, the FDA’s “current thinking” on the subject, the agency will expect you to have a justified and documented risk assessment regarding these items. However, in order for the respective strategies and controls to be cost-beneficial in context of the potential of the system to affect product quality and safety, and record integrity, a combination of knowledge of system functionality, regulatory understanding, financial prudence and a healthy dose of common sense are required. Take one of these elements out of the equation and the resulting risk assessment will be neither practical nor useful.

2. You need to know the minimum documentation that must be available to support compliance with 21 CFR part 11. Irrespective of the development model employed (e.g., waterfall, Agile/Scrum), the software delivery model employed (e.g., software-as-a-product, software-as-a-service) or data hosting model employed (e.g., internal data center, outsourced hosting), as applicable, a documentation suite that truly supports compliance should encompass the following:

• User/functional requirements, including 21 CFR part 11 requirements, to describe what the system is supposed to do;

• Technical specifications to define how the system is built and how it works, and which is the critical component in supporting effective system maintenance (e.g., troubleshooting problems, assessing the impact of planned bug fixes and enhancements);

• Development/validation SOPs, and evidence of compliance (e.g., required documentation, required approvals, developer-level and user acceptance testing), to define the process for developing and deploying a system that operates as intended and meets regulatory requirements;

• Traceability between test evidence and all requirements;

• Change control SOP and supporting change request/change control records to ensure that the system continues to operate as expected;

• Training SOP and supporting training records to support staff qualifications regarding system development, maintenance and use;

• IT infrastructure SOPs (e.g., logical/physical security, back-up and recovery, etc.) and supporting records to evidence on-going protection and availability of records.

3. You need to know that, for a given system, the quality of testing and quality of reviews are of paramount importance because they may compensate for ineffective development and/or validation SOPs. In other words, the devil (or in this case the saving angel) is in the details. Therefore, it is important that

• Testing is complete and reflective of true system risks;

• Test evidence is supportive of test results/conclusions and/or does not raise “red flags”;

• Reviews are timely and reasonable (e.g., only a realistic number of detailed test scripts should be reviewed in one day);

• Incident reports are reviewed and approved by appropriate individuals promptly.

If testing practices, testing evidence and/or testing reviews are questionable, they will constitute a serious gap from a risk-based perspective because 1) one may not be able to rely on the given system’s operation, results, etc., and/or 2) data quality and integrity may be viewed as being compromised.

Part 11

Is your Compliance Running Too Hot or Too Cold?

While there are other aspects to 21 CFR part 11 that one should know (e.g., how to determine if 21 CFR part 11 even applies to you and, if not, how to document such a conclusion), the three items discussed above represent those areas where, in our view, compliance tends to be too hot (i.e., potential business risk in that the cost of doing business may be higher than it should be) or too cold (i.e., a potential regulatory risk in that regularity requirements may not be met which, in turn, may result in business risks based on the operational impact of FDA enforcement actions).

Emma Barsky and Len Grunbaum
Partners of The Practical Solutions Group, LLC
609.683.0756
Practical Solutions

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FDA Guidance on Risk-Based Monitoring, Part II

September 17, 2011

FDA risk based monitoring

New FDA Draft Guidance Document

FDA’s new draft Guidance for Industry: Oversight of Clinical Investigations — A
Risk-Based Approach to Monitoring (August 2011) is the subject of a great deal of discussion among clinical trial professionals. On the GCP LinkedIn group some have written about their concerns that “centralized monitoring” would severely limit a sponsor’s involvement with clinical sites. Others have pointed out that the emphasis on developing a monitoring plan should ensure that appropriate resources are tageted to where they are needed.

Two weeks ago GxP Perspectives published a Guest Commentary by Lorraine Ellis on the new draft guidance. This Guest Commentary by Judith Lynn, continues the discussion about the new draft guidance. She looks at FDA Warning Letters in developing her review and analysis.

Guest Commentary: A Risk-Based Approach To Monitoring

I reviewed the Recent Draft Guidance From FDA- A Risk-Based Approach To Monitoring with several information points in mind:

• Warning letters from FDA, including the JNJ /ICON letter of 8/10/09
• My own experiences reviewing Clinical Study Reports, conducting TMF review and mock audits
• FDA Compliance Program Guidance Manual 7348.811, Clinical Investigators

I try to view the instruction as meant to be helpful rather than another obstacle to overcome. I found that much of the draft guidance centers on managing your study, having a sampling plan, and ensuring quality. FDA mentions that both good protocol and CRF design is critically important, as well as having a monitoring plan that takes into account the specific study, and sponsors prior experience with the investigational product.

Onsite monitoring:

FDA risk based monitoring guidance

Seriously Ill or Vulnerable Populations

I am not convinced that onsite monitoring will go away. The sponsor obligation is to ensure the protection of human subjects, that sites conduct trials appropriately, and the data is auditable and accurate. Note the point in the draft guidance under section IV/ C, Factors to consider when developing a monitoring plan: that “a population that is seriously ill and/or vulnerable may require more intensive on-site monitoring to be sure appropriate protection is being provided”. This point speaks volumes as to the value FDA places in onsite monitoring.

Early phase monitoring:

The guidance states “For a product that has either a significant safety concern or for which there is no prior experience in humans, may require more intensive monitoring to ensure appropriate investigator oversight.” It is interesting that FDA specifically encourages sponsors to be onsite in earlier phase studies, when the Agency does not typically send their own investigators- remember, they investigate either for cause or pre-approval.

In my experience with both bioavailability and first in man studies, the value of being on-site to observe unexpected safety and protocol issues, and make immediate decisions regarding study conduct, has been critical. Examples:

• safety issues a healthy subject (recent army recruit) collapsed at a blood draw (was excluded); a site had urine/blood test machine not work and had to test offsite, affecting dosing times/schedules
• dose issues, a nasal sprayer malfunctioned for an intranasal product; patches expected to be study for 12-24 hours fell off almost immediately

Electronic Data

risk based monitoring FDA guidance

Electronic Case Report Forms

Using electronic CRFs is a great boon to the industry. It gives almost instant access to data that used to take months to enter, review, check for consistency and plausibility.

Data Checks that used to come only at the end of a study are available throughout: such as missing forms; out of window visits; other inconsistencies. Immediate data availability can be used to track study progress, investigator compliance (with visits, data entry, inclusion/exclusion), and detect possible troublesome data fields/labels for a single site or throughout a protocol. However, only the data entered is available for central review (remote).

Use data to identify anomalies:

FDA risk based monitoring guidance

Questions Raised During Data Review

During an audit for a sponsor preparing for an FDA inspection, I focused on 2 critical efficacy evaluations (a 20 minute physician evaluation and MRI scan, done at select study visits). I requested data management to calculate the number of procedures performed on the same day at a specific site. I found it very interesting when data management responded:

• 22 physician evaluations were performed on a single day (by the same physician)
• 15 MRI scans were performed on one day.

None of the monitoring visit reports mentioned this kind of scheduling, the requirements for calibrating MRI machines, or whether there was more than 1 machine at a site.

It may be worthwhile to spend more time during the study reviewing available study data. You may need to create customized reports to follow the metrics on your study. Consider the value of team review rather than individual review, in order to understand what your data may be indicating.

FDA warning letters often include observations that may be found during onsite monitoring:

fda

FDA Warning Letters

• Problems with original signatures on informed consent documents. Informed consent documents are not usually submitted to sponsors/monitors, but are reviewed during onsite visits.
• Non-serious adverse events were present in source documents that were not reported to the sponsor. Without onsite review, the sponsor cannot know what is missing.
• Inadequate records, including remarks regarding inappropriate delegation (unqualified person performing procedure or not signed/dated by investigator). Many sites around the world have paper records, and without onsite review, the sponsor cannot be aware of inadequacies.
• Inadequate accountability of the test article.

Monitoring plan considerations:

You may decide to reduce the number of onsite visits. Do this wisely. Ideally the monitoring plan is another tool that helps confirm the validity of your study data. Have your monitors perform activities onsite that cannot be performed remotely.
Source data: Often, only limited source data is available remotely for centralized review.

Finally, remember what the FDA is instructing their inspectors to do, and develop your plan in anticipation. The FDA inspection manual requires inspectors to:

• review logs of onsite monitoring visits
• describe the investigators source documents for legibility and completeness
• review the informed consent process.

Ideally the sponsor will not be surprised what is found when a Regulatory agency goes to the study site.

Judith Lynn, Pharmaceutical Consultant, September 2011

Read the Draft Guidance Document

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How to comment to FDA: Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!

Location of Monitoring guidance FR

The Federal Register Docket Number is FDA-2011-D-0597

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Pacific Regional Chapter SQA Fall Training 10-11 November at Allergan in Irvine, CA. The training will feature a debate which should be an interesting development in training workshops: Debi Garvin, MS, RQAP-GLP and Paula Parsons: Debate: The role of CAPA in a GLP environment.

PRCSQA Fall Training

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Tufts Center for the Study of Drug Development: Article on Protocol Amendments: One Third can be avoided.

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Training Opportunity:

training GxP

Audits & Risk Management

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.

GxP Audit & Risk Management Brochure

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

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FDA vs. Dr. Oz: Should you be drinking apple juice? Television personality Dr. Oz says that there are dangerous levels of arsenic in apple juice. The FDA disagrees. They point out that the tests Dr. Oz conducts are for total arsenic, inorganic and organic, and only inorganic arsenic represents a danger to public health. Read the FDA press release for a detailed explanation.

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On The Blogroll: PharmTech Talk discusses the Top Ten FDA 483 Observations for drug GMP inspections. Angie Drakulich reports that Numero Uno concerns Quality Control Units (QCUs).

My Perspective by Kathryn Davis, Clinical Development. In this new blog on WordPress Kathryn Davis discusses relevant issues including social media, GCP, and recruiting minorities in clinical trials.

The Dark Daily Laboratory and Pathology News

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FDA Clinical Investigator Course,
7-9 November 2011, Silver Springs, MD

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clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the Draft FDA Risk-Based Monitoring guidance document and on protocol deviations. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

GxP Perspectives LinkedIn Group

GxP Perspectives on twitter: @GxPPerspectives

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Please comment on the new draft guidance on Risk-Based Monitoring.

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FDA Releases Draft Guidance for Monitoring Clinical Trials

September 4, 2011

FDA releases draft guidance document for monitoring clinical trials

FDA Draft Guidance Offers New Methods of Monitoring Clinical Trials

At long last, FDA has released a new draft guidance document for monitoring clinical trials. The previous FDA guidance document, Guideline for Monitoring Clinical Investigations (1988/1998) was withdrawn earlier this year. The new draft guidance document, FDA Guidance for Industry- Oversight of Clinical Investigations– A Risk-Based Approach (August 2011), discusses the changes in the way clinical trials are conducted and new methods of monitoring clinical trials. There is a 90-day comment period where members of industry, professional organizations, and the public can submit written commments to the agency for review and consideration.

In this Guest Commentary veteran monitoring specialist Lorraine Ellis gives her perspective on the new draft guidance for monitoring clinical trials.

Guest Commentary by Lorraine D. Ellis, MS, MBA

When I started monitoring, the Investigators completed CRFs from the source documents and there were few Clinical Research Coordinators (CRCs). Usually an office nurse or staff member would complete the forms when they had “free” time. Three decades later, sites, studies, and monitoring have changed significantly. Investigator sites must have significant study infrastructure (SOPs and facilities, etc) and trained/experienced staff to complete the complex trials of the 21st century. So it is significant that the 1988 Guidance document has been retired and the new guidance on monitoring describes FDA’s view on applying 21st century technology and methods to monitoring.

There are several key advances in this guidance. The guidance describes the term “centralized monitoring” for the many practices of using technology to review data off-site. This term and other FDA comments describe using “off-site” monitoring as one of the acceptable methods of monitoring data quality and study conduct. This guidance will intensify the discussions of “why do we need monitoring every 4 to 6 weeks with 100% source document verification” and “what is the best monitoring procedure for this study”. Also, FDA outlines more detailed monitoring plans as the risk based approach requires that monitoring approaches should be tailored to the trial.

clinical trial monitoring fda guidance document

Poorly Designed Protocols, CRFs, or Trial Instructions

FDA suggests a multi-factor approach to ensure data integrity, compliance and patient protection since there are many trial factors that can affect these trial elements besides monitoring. For example, poorly designed protocols, CRFs, or trial instructions could cause fatal trial errors despite extensive monitoring. Inadequate, incomplete or poor training of all involved in the trial, Investigators, staff, monitors etc., could also decrease study quality. The guidance encourages using various methods of study conduct review to assess these study elements as well as data quality.

The second half of the guidance provides information on monitoring plans and their expected content. Currently monitoring plan content and quality vary among Sponsors so this detailed section should increase monitoring plan quality and detail as it describes methods appropriate to the study. Since this guidance promotes custom monitoring plans based on variables of the study such as scope and complexity, these sections will assist Sponsors in designing and implementing those monitoring practices appropriate to the study.

FDA clinical trials guidance

"Greater Reliance on Centralized Monitoring"

One sentence will probably be surprising to some veteran monitors and Sponsors. “FDA encourages greater reliance on centralized monitoring practices than has been the case historically, with correspondingly less emphasis on on-site monitoring”. Many Sponsors that have instituted EDC and other technologies for data collection/review, have not decreased on-site monitoring time they continue to rely on the “gold standard” of visits every 4 to 6 weeks and 100% SDV. FDA does advise that at least one on-site monitoring visit should be done to ensure processes and procedures are in place at the site to ensure data quality. FDA continues that to use centralized monitoring properly, Sponsors need to develop methods and standard operating procedures so that site records, data entry, and data reporting follow well-defined procedures.

FDA guidance on clinical trials monitoring

Risk-Based Approach

FDA recommends that the monitoring plan is developed based on a risk assessment of the study complexity, study endpoints, disease complexity, geography, Investigator experience, EDC capabilities, Investigational product safety, study stage and quantity of data. After risk assessment, the Sponsor prepares a tailored monitoring plan for each study that will address that risk and outlines the multi-faceted approach to the trial. The plan, that includes monitoring procedures, monitoring responsibilities, and trial requirements, should be in sufficient detail so monitors and others involved can carry out their respective tasks correctly.

The plan should also include: monitoring methods, communication of monitoring findings, resolution of issues, training topics, training evaluation, and monitoring plan amendments.
It will be interesting to read the comments sent to FDA in the next 90 days. Some Sponsors will say “it’s about time” monitoring will be optimizing 21st century technology. Others may struggle with the changing of the “gold standard” of monitoring. In any case, this guidance may be the catalyst the industry needs to optimize monitoring methods and effectiveness.

FDA Guidance for Industry: Oversight of Clinical Investigations– A Risk-Based Approach

Visit Lorraine’s Website

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How to comment: Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!

Location of Monitoring guidance FR

The Federal Register Docket Number is FDA-2011-D-0597

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

Please take a short 3-question survey to help GxP Perspectives improve! Survey begins 22 SEP 2011

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On the Blogroll: Chromosome which features an excellent post on, “The Site’s Side,” by Jae Chung, founder of goBalto, Inc., located in San Francisco. The post discusses some of the problems clinical sites face with monitors.

On The Blogroll: On Biostatistics and Clinical Trials- Finally a blog on biostatistics that I can almost read:) It is written by Dr. Deng, 邓春勤 A Medical Doctor turned into Biostatistician in Clinical Trial and Drug Development Industry
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clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the draft guidance document. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

GxP Perspectives LinkedIn Group

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The FDA, Center for Drug Evaluation and Research (CDER) is announcing an industry workshop entitled ‘‘CDER Small Business Assistance – Clinical Trials and Electronic Submissions.” This two day event will be held in two California locations consecutively. The first workshop will be held in Los Angeles, CA, on September 26-27, 2011, followed by a second in San Francisco, CA, on September 28-29, 2011.
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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)
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FDA Warning Letter Cites Repeat Violations

August 28, 2011

FDA Warning Letter Repeat Violations

FDA Cites Repeat Violations on Reporting Adverse Events

A recent FDA Warning Letter to a clinical investigator shows the importance of implementing the corrective actions promised from previous inspections. FDA states; “Given that you have not implemented the corrective actions promised in response to the August 2008 inspectional observations, we have concerns about whether the corrective actions that you have currently outlined will be properly implemented and executed in a manner that will prevent the recurrence of this and similar types of violations in the future.” In this case the previous inspection had cited the clinical investigator for the failure to report adverse events and serious adverse events, the same violations that the 2011 inspection documented. The violations, combined with the failure to implement corrective actions from the previous inspection, earned the investigator a Warning Letter.

It is important to remember how an FDA investigator prepares for an inspection. First, they receive an assignment from the Center for Drugs, The Center for Devices, or the Center for Biologics to conduct the inspection. Then there is a review of the file that includes the previous inspection reports. Each inspection report notes the violations at the previous inspection, or if it is the initial inspection, and if the violations are ongoing or resolved. The fastest way from a Form FDA 483, Inspectional Observations, to a Warning Letter is if there are ongoing violations from the previous inspection.

repeat violations

Review of Previous Inspection Reports

Promising corrective actions is all well and good. However, it is important to note that FDA will actually check up on your proposed corrections the next time they conduct an inspection, even if the inspection is three years later.

The Warning Letter has an interesting feature as it is signed by “Leslie K. Ball, M.D., Acting Director, Office of Scientific Investigations, Office of Compliance, Center for Drug Evaluation and Research.” Up until recently this had been the Division of Scientific Investigations. At FDA an Office is a higher organizational unit than a Division (all emphasis by GxP Perspectives). Evidently there has been some form of reorganization. However, this hasn’t been reflected on CDER organizational charts. The most recent “CDER Key Officials List,” dated August 22, 2011, listss the following:

Division of Scientific Investigations (DSI)

Leslie Ball, M.D., Director
Joseph Salewski, Deputy Director
CT Viswanathan, Ph.D., Associate Director
Chris Howard, Project Management Officer (Acting) (co-located)
Tanya Clayton, Project Management Officer (co-located)
Kevin Prohaska, Human Subject Protection Team (Acting)
Alex Gorovets, International Policy Team (Acting)
Constance Lewin, M.D., Good Clinical Practice Branch I
Sherbet Samuels, Good Clinical Practice Team I (Acting)
Tejashri Purohit-Sheth, Good Clinical Practice Branch II
Jean Mulinde, Good Clinical Practice Team II (Acting)
Sam Haidar, Good Laboratory Practice and Bioequivalence Investigations Branch (Acting)
Martin Yau, Bioequivalence Team (Acting)
Jackie O’’Shaughnessy, Good Laboratory Practice Team (Acting)
Thomas N. Moreno, Information and Informatics Team (Acting)

Evidently there are some significant changes taking place. Perhaps we will learn more later.

Read the Warning Letter

Also: Read the recent Warning Letter from CBER to a Clinical Trial Sponsor

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On The Blogroll: Applied Clinical Trials Blog discusses Facebook.

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FDA warning letter

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FDA Warning Letters: How to Navigate FDA’s Website

May 10, 2011

FDA Warning Letter

One of the Many Exhibitors at the
ACRP Conference

FDA Warning Letters, and some thoughts on critical and creative thinking, conclude my reporting from the Global Conference for ACRP – the Association of Clinical Research Professionals – held last week at the Washington State Convention Center in Seattle. During the conference it became apparent that many people, including FDA employees, have a difficult time searching for Warning Letters on FDA’s website. The Warning Letter section is an absolute mess. So I thought I would provide a few simple search tips to help find Warning Letters for GCPs. Unfortunately cGMP Warning Letters are more difficult, but the tips still help. Then I would like to tell you about an interesting session I attended on critical and creative thinking.

When searching for FDA Warning Letters, the link is below, scroll down and choose to “Browse Warning Letters by SUBJECT.” You will be presented with the alphabet. Click on “C” and then scroll down past all the “cGMP” categories until you reach “Clinical Investigator” where you will find the majority of GCP Warning Letters.

FDA Warning Letters

Searching for FDA Warning Letters

They will be listed in alphabetical order. There is a “Sort by:” option. Choose “Letter issued DESC” from the drop down menu. You will then have most of the GCP Warning Letters with the most recent listed first. You can also choose as subjects: Clinical Investigator – Sponsor; Bioresearch Monitoring; IRBs; Sponsor Obligations; and “IDE….” for medical device Warning Letters. There are several ways of listing for each category. You can sort by “Letter Issued DESC” for each category. There are five GLP categories plus Good Laboratory Practices. Go figure.

FDA Warning Letters

There were a number of interesting sessions that I attended at the ACRP meeting. I wanted to tell you about Critical Thinking in a Regulated Environment, because it can be so darn difficult. Kirk Mousley described critical thinking as producing ideas and then evaluating ideas. Citing Iris Verdi he described creative thinking as original, imaginative, and uncommon. He discussed that creative thinking comes through different avenues: it is often a revisement of something that already exists (evolution); a combination of two or more ideas (synthesis); or just a different way of looking at things, asking yourself, “how else can I look at this?”

FDA Warning Letters

How Can I Look at This Differently?

Mousley also discussed the barriers to creative thinking including “not part of an approved process” (SOPs). He noted that the regulatory process itself discourages critical thinking by imposing a “process mentality.” He countered that by suggesting that you build into a process the encouragement of critical thinking. And he pointed out the myth that “every problem can only have one solution or one right answer.” One of the points that I emphasize when doing a root cause analysis of a problem identified during a CAPA process is that you should Always Look for More Than One Root Cause.

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On The Blogroll: The FDA Lawyers Blog discusses a variety of interesting issues including bioequivalence data, litigation tactics, and Victory for Embryonic Stem Cell Researchers.

Please join GxP Perspectives on LinkedIn at:

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FDA & OHRP Hold Regulatory Forum at ACRP Meeting in Seattle

May 1, 2011

FDA OHRP regulatory forum

Jerry Menikoff of OHRP & Jean Toth-Allen of FDA

FDA and OHRP both presented at a Regulatory Affairs Public Forum at the ACRP Global Conference on Sunday, May 1st.Speaking for FDA were Leslie Ball, MD, Director of the Division of Scientific Investigations (DSI) which initiates the majority of Bioresearch Monitoring inspections at FDA. Also from FDA was Jean Toth-Allen, PhD, Biophysicist, Office of Special Medical Programs. Jerry Menikoff, MD, JD, spoke on the panel as the Director of the US Office for Human Research Protection. The Association of Clinical Research Professionals hosted the forum in a setting more reminiscent of a TV game show than a professional panel that was complete with theme music and multi-colored columns highlighting the stage. However the questions posed were the ones on everyone’s minds and the speakers gave some good answers.

Please note that the Plenary Session on the Regulatory Affairs Public Forum was recorded and is available on the ACRP website for free.

One question brought up the issue of sponsor oversight of outsourced clinical trial responsibilities. Toth-Allen said that the sponsor is ultimately responsible for all of the clinical trial responsibilities and only CROs are specifically mentioned in the regulations. She emphasized the need to have SOPs in place covering how they are going to oversee contracts of vendors and what the contracts should cover. Leslie Ball said that DSI had an increased focus on sponsor and CRO inspections.

Dr. Ball said that she thinks sponsors should look at three qualities when selecting vendors:

1. The overall capability of the organization and staff.

2. That contracts clearly point out who is responsible for specific responsibilities.

3. That the sponsor oversees the vendor’s activities while the trial is ongoing.

OHRP FDA regulatory forum in Seattle

When Does FDA Inspect?

Another area of interest was when and where FDA would inspect. Both Leslie Ball and Jean Toth-Allen said that FDA was focusing more on inspections during the actual conduct of the study and not just when a sponsor makes an application to the agency.

Dr. Ball said that with the shift to more sponsor/CRO inspections that FDA inspections were looking at sponsor oversight of ongoing trials. She also said that DSI was developing a risk-based site selection tool that looked at three different levels. First, at the application level, did the application pose certain risks that FDA needed to consider. Then at the trial level, tending to focus on pivotal trials. Then at the site level, were there complaints or a history of non-compliance. She also said that they were looking at data from the application such as the rate of subjects dropping out or very high or very low rates of adverse events.

FDA OHRP regulatory forum

Dr. Leslie Ball, FDA

Dr. Ball also emphasized that FDA looked at what they considered important, specifically data integrity for primary efficacy endpoints or key safety indicators, and oversight by the sponsor. She noted that many things that are routinely listed on a Form FDA 483, Inspectional Observations, such as study drug accountability sometimes didn’t find their way to a Warning Letter that focused on items of significance to the approval of the application.

Another interesting discussion was on the topic of online informed consent forms, which are beginning to appear. Jerry Menikoff said it depended on the nature of the study when an online consent might be appropriate. Jean Toth-Allen spoke of the need for a verification process, that the online consent was given by a real person.

FDA regulatory forum Seattle

Discussion on Electronic Medical Records in
Clinical Trials

Finally the panel discussed electronic medical records (EMRs). All three panelists supported the use of EMRs. Toth-Allen said that if an EMR is used in a clinical trial then the institution needs to provide access to verify the record, that it was not acceptable to for monitors to be told that you can’t see it, which elicited a hearty round of applause from the many monitors in attendance. Dr. Ball noted that there were a lot of advantages to EMRS. “You can actually read them,” she said. She also emphasized that EMRs should have the same criteria for clinical trials, that they should be ALCOA- Attributable, Legible, Contemporaneous, Original and Accurate. She also said that although they may not need to be Part 11 compliant, they did need to have an audit trail so that all changes to the record could be traced.

To view the Regulatory Forum visit the
ACRP Website on the Plenary Sessions

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On the Blogroll: RegBlog on all things regulatory from the University of Pennsylvania Law School. Covers much more than FDA

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On The Blogroll: Applied Clinical Trials Blog discusses,
“It Takes a Village: Recruiting Latino and Hispanic Patients.”

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ACRP Meets in Seattle for 2011 Global Conference

April 29, 2011

ACRP Seattle

ACRP Meets in Seattle for 2011 Global Conference

Seattle, WA plays host to the Association of Clinical Research Professionals’ (ACRP) annual Global Conference. ACRP is one of the larger professional organizations focusing on clinical trials and expects 2,000 participants. It will be the first time I have attended their Global Conference and I am looking forward to it. There will be sessions on “Introduction to Imaging in Clinical Trials” and on “Distance-Based Learning for Foreign Study Coordinators.” GxP Perspectives will be there for the entire conference (the pre-conference workshops have already begun) and among the sessions I look forward to is “Comparative Effectiveness Trials.” I am going to try to blog at least twice during the conference on issues I think are of concern to GxP Perspectives readers. If I am super industrious maybe I will blog from the ACRP Global Conference every day.

Here is a new feature that ACRP is offering: “ACRP is pleased to announce that for the first time ever, two live-feed Plenary Sessions from the ACRP Global Conference & Exhibition will be broadcast FREE of charge. Join us May 1 for the Regulatory Affairs Public Forum featuring representatives from global regulatory agencies addressing issues facing clinical trials. Join us May 2 for Innovation & Global Health, a discussion by Tachi Yamada, MD, President, Global Health Program, Bill and Melinda Gates Foundation.”

For more information visit the ACRP Website on the Plenary Sessions

ACRP clinical trials

Do You Have a Guest Commentary for
GxP Perspectives?

Another highlight will be the May 1st session on “Your Site Doesn’t Need 60 SOPs, But How Many Does It Need?” The speakers are Christine Pierre, RN and Steven Steinbreuck, MPH and the author of a Guest Commentary on GxP Perspectives on Informed Consent Requirements. Remember, I am always looking for a good Guest Commentary. Send me a note and ask me how-

Leave a Comment to Submit a Guest Commentary!

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On the Blogroll: Top 40 Websites (and Tweeters) on the FDA, by FDAZilla (Yes, we made the list.)

Moriah Consultant’s Blog - Commentary by Michael Hamrell, one of the conference speakers
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Conferences: Pharma/Bio Boot Camp on the eTMF on 20-21 May 2011 in Philadelphia

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FDA Clinical Trials: Quality Considerations for Pivotal Studies

April 9, 2011

clinical trials considerations pivotal

When Should Quality Begin?

When should quality preparation begin for a pivotal phase III clinical trial? About once a month I get a call asking for help for a clinical trial because its time to get ready for FDA inspections. I ask “When will the application be filed?” The response? “Soon, very soon.”

It is a good thing to prepare for an FDA inspection. It is even better to prepare at the beginning, reviewing the quality considerations necessary to do the job right by “frontloading quality.” Here are some things I think you should consider. (Please take the survey at the end)

Phase III Considerations for Compliance with the FDA Bioresearch Monitoring Program: by Carl Anderson

The U.S. Food and Drug Administration conducts inspections of clinical trials as part of their Bioresearch Monitoring program. Although all FDA regulated clinical trials are subject to inspection, the large majority of inspections are the result of an application for the approval of an investigational product. Results of an FDA “Bimo” inspection can have a direct impact on the review and approval of an NDA, PMA, or BLA by the agency. FDA conducts inspections of clinical trials for two primary reasons:

1. To ensure the integrity of data submitted to the agency in support of an application.

2. To protect the safety, rights, and welfare of human participants in clinical trials.

The regulations that the FDA enforces for clinical trials are collectively known as the good clinical practice (GCP) regulations. They include 21 CFR Parts 11, 50, 54, 56, 312, 314, 601, 812, and 814. They can be found on the web at: http://www.fda.gov/oc/gcp/regulations.html. In particular FDA Bimo inspections cover the specific responsibilities required of sponsors and investigators covered by 21 CFR 312 Subpart D: Responsibilities of Sponsor and Investigators. For medical devices they are contained in Part 812.

The primary guidance document used for GCPs is the International Conference on Harmonization E6: Good Clinical Practice: Consolidated Guidance. This document is the international standard and the primary GCP regulation in many countries. ICH documents for clinical studies including E6 can be found at the link on the bottom

There are two types of GCP inspections that are of concern for sponsors. The first type is the inspection of clinical investigators at the sites where research is conducted. The majority of FDA inspections are of the investigators. The second type is the inspection of the sponsor or contract research organization. This is a routine inspection for medical device sponsors and is becoming more common at drug sponsors. Although most inspections are at clinical sites, in the event that serious deficiencies are documented, there can be directed inspections of sponsors that can result in serious regulatory action.

clinical trial consideration pivotal

QA for the Data Lifecycle

Prior to beginning a pivotal study the sponsor should establish a system of clinical quality assurance. This is a recommendation, not a requirement, of FDA. E6 defines quality assurance (QA) as: “All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with GCP and applicable regulatory requirement(s).” Among the most important QA activities are the following:

Clinical trial materials. They should be produced in compliance with good manufacturing practice (GMP) regulations and qualified by an onsite audit.

pivotal clinical trial

Increased Enforcement of
Part 11

Computerized systems including eCRFs. There are many forward looking systems available for electronic case report forms (CRFs) including systems that are internet based. These vendors are not regulated by FDA and do not receive regulatory inspections. The burden is on the sponsor to determine if the vendor provides GCP compliant services. All should be qualified by an onsite audit.FDA has started looking a lot closer at eCRF systems.

Site management organizations (SMOs). These are unregulated organizations that provide support for clinical investigators and recruit study subjects. FDA inspections of sites using an SMO have frequently been cited for noncompliance with GCPs. SMOs should also receive onsite audits.

Central IRBs. These commercial institutional review boards have a better record than SMOs. However, the protection of human participants in research is a central FDA concern. Commercial IRBs should be qualified by an onsite audit.

Randomization services. This might not require an onsite audit and qualification, but the sponsor needs to critically determine that the vendor can supply the required services.

pivotal considerations for phase III clinical trials

QA Audits of Clinical Sites

Audits of clinical sites. ICH E6 states that: “The sponsor’s audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities…” The sponsor should audit a pivotal clinical trial throughout the data lifecycle. In particular the sponsor should audit problematic sites during the study. It is the sponsor’s responsibility to “secure investigator compliance” if the investigator is violating GCPs. This was the first violation cited on the Sanofi-Aventis Warning Letter and has historically been a major violation cited on FDA Warning Letters to sponsors.

Top enrolling sites should always be audited during the course of the study because of their increased importance for a successful study and the likelihood that the site will receive an inspection by FDA. The sponsor should also audit sites that may be inspected by FDA at the conclusion of the study including data outliers, sites with a history of noncompliance, and sites that do not have a history of FDA inspections.

Database audits The sponsor’s data management activities should have independent QA review. This should include a qualification audit if data management is contracted out. An excellent resource for data management is the Society of Clinical Data Management. They publish a Good Clinical Data Management Practices Guide which is available for purchase on their website below.

Trial master file (TMF) audits: A TMF consists of the Essential Documents section of ICH E6. There should be QA review periodically throughout the study. The failure to adequately document a clinical trial will hinder any application to FDA. The agency field investigators have a saying that, “If it isn’t documented then it didn’t happen.” Take a look at the TMF page at the top of the blog for additional resources.

Pivotal clinical trial considerations

Conduct Regular GCP Training

GCP training: The sponsor should have a training program that includes initial and continuing training on good clinical practice. The training program should be in writing and training should be documented. At least once a year staff members should attend an outside conference, meeting, or workshop that includes clinical trial professionals that are not the sponsor’s employees.Peer-to-peer interactions are necessary to develop staff

GLP audits: The FDA conducts routine surveillance audits of nonclinical test facilities. An FDA inspector may randomly select a study of the sponsor to track as part of that inspection. Protocols and final reports are collected and sent to FDA headquarters as part of the inspection. The sponsor should always qualify a nonclinical laboratory used for GLP studies submitted to the agency. The new FDA Sponsor Compliance Program (see previous post) gives instructions for looking at nonclinical studies during GCP inspections at the sponsor.

Sponsor audits and mock FDA inspections

pivotl phase III clinical trials

Always Prepare for an FDA Inspection

Finally, a sponsor should conduct audits of their clinical management department and conduct “mock FDA inspections” in preparation for the regulatory audits that will inevitably take place after the NDA, PMA, or BLA is filed. Preparing for a regulatory inspection is invaluable for effectively hosting any regulatory agency, in particular FDA. Medical device sponsors need to remember that FDA typically inspects sponsors submitting a PMA. Drug sponsor inspections are on the increase. The “OAI” violation rate for inspections of medical device sponsors was 33% in fiscal year 2007. OAI stands for “official action indicated” the most serious classification.

An OAI classification can cause FDA to delay or reject an application.

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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)

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Society for Clinical Data Management

ICH Guidance Documents
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On the Blogroll: PharmTech Talk has had a number of interesting blog posts of late.
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FDA clinical trials pivotal studies

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FDA Issues New Guidance for Sponsor & CRO Inspections

March 19, 2011

FDA guidance sponsor CRO inspections

FDA Issues Updated Guidance on Sponsor & CRO Inspections

FDA is increasing their emphasis on Sponosr and CRO inspections with the release of an updated version of the Compliance Program Guidance Manual, CP 7348.810, Sponsors, Contract Research Organizations, and Monitors (CPGM). This FDA guidance document gives instructions to FDA personnel on how to conduct an inspection of a sponsor or CRO involved in FDA regulated research.

It significantly modernizes the previous CPGM, released over 10 years ago, introducing new sections and deleting sections that were obsolete or irrelevant.

There are new sections on the Registration of Studies on ClinicalTrials.gov; Review of Site Records; Financial Disclosure; Electronic Records and Electronic Signatures; Emergency Research; International Data; and GLP Studies. Other sections, such as Medical Devices, are substantially updated and clearer. The new CPGM should professionalize FDA’s approach to sponsor and CRO inspections and ensure closer review of a sponsor’s regulatory responsibilities. It is long overdue. I have done a brief analysis of Section III, Inspectional, of the new CPGM. There are also some helpful links to documents in Section VI, References and Contacts including several documents that I had never heard of before.

FDA inspection guidance on sponsors and CROs

Sponsor and CRO Inspections Usually Will be Scheduled

The first significant change is right at the beginning of Section III, Inspections, “under this program will be pre-announced unless otherwise instructed in the inspection assignment.” This formalizes a policy that began a few years ago under the Medical Devices Initiative. In addition, the new CPGM makes a point of emphasizing a statement routinely included in FDA inspection documents: Approaches that differ from those described in FDA’s Guidance documents should not be listed on the (Form FDA) 483 (Inspectional Observations) unless they constitute deviations from the regulations.” There are also instructions that the new CPGM “provides only the minimum scope of the inspection” for the field investigator to “expand the inspection as the circumstances warrant.” There are also specific instructions on how to document a violation:

“Any deviations from regulations should be thoroughly documented. For example, if the sponsor failed to review monitoring reports in a timely fashion and/or failed to bring non- compliant clinical investigators into compliance, monitoring reports, report review dates, and evidence of clinical investigator continued non-compliance should be documented and copied.” (original emphasis)

There are specific instructions that stem from FDA’s increased vigilance regarding falsification of data:

FDA sponsor inspection

Increased Emphasis on Falsification of Data

“Discuss potential violations involving fraud subject to Title 18 of the United States Code (18 U.S.C.) with your supervisor, District Compliance Officer, and assigning Center contact for appropriate referral to the Office of Criminal Investigations (OCI).” Reader’s should note that Title 18 violations are the ones that can put you into prison. Here are the new sections of the CPGM:

D. REGISTRATION OF STUDIES ON CLINICALTRIALS.GOV

“ClinicalTrials.gov is a website maintained by the National Library of Medicine (NLM). Its establishment was mandated by the 1997 FDA Modernization Act (FDAMA) to provide a public resource for information on studies of drugs, including biological drug products. The FDA Amendments Act of 2007 (FDAAA) mandated expansion of this data bank and included enforcement provisions to help ensure compliance.” There are specific guidance instructions in this section including a discussion of the Form FDA 3674, which we all will be paying closer attention to. Among the additional instructions to FDA field investigators are:

“6. Determine whether primary and secondary outcomes measures are listed on ClinicalTrials.govfor the study/studies. Determine if the outcome measures, if any, listed on ClinicalTrials.gov are generally consistent with the primary and secondary outcomes in the sponsor’s study protocol(s).

7. When examining informed consent documents related to an applicable clinical trial registered on ClinicalTrials.gov, determine if the appropriate required statement referencing ClinicalTrials.gov is included6. 21 CFR 50.25(c). The statement is:

‘’A description of this clinical trial will be available on http://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.’’’

For the section on Monitoring Procedures and Activities there is one significant change in recognition of the changes in the conduct of clinical trials: “With the prevalence of multisite clinical trials, traditional monitoring techniques – early and frequent on-site visits at all clinical sites – have become resource intensive. Regulations do not prescribe a specific monitoring technique, simply stating that sponsors are required to select monitors qualified by training and experience to monitor the investigational study (21 CFR 312.53(d), 511.1(b)(8)(ii), and 812.43(d)).”

FDA sponsor CRO inspections guidance

Monitoring of Clinical Trials is Evolving

In part, this statement recognizes that 100% source/CRF verification might not be practical or necessary, that sponsors may need to adapt new techniques, sometimes described as “Compliance Monitoring,” where monitoring records and reports are reviewed to determine outlier data. This could include no adverse events reported at a specific site. The CPGM goes on to state: “Determine if all CRFs are verified during monitoring visits. If a representative sample was selected, determine how the size and composition of the sample were selected.”

Financial Disclosure is discussed for the first time by FDA in a CPGM. Financial disclosure violations are very rarely cited by FDA during sponsor/CRO inspections. This may change with these instructions:

“1. Determine if the sponsor obtained financial disclosure information from each investigatorbefore his/her participation in the clinical trial, as required by 21 CFR Part 54 and 21 CFR 312.53(c)(4) and 812.2(b)(5) and 812.43(c)(5).

2. Determine if the sponsor received prompt updates regarding relevant changes in financialdisclosure information from investigators during the study and for one year after study completion.

3. Determine if the sponsor reported to FDA (on Form FDA 3454 and 3455, respectively), allpertinent investigator disclosures and certifications of financial information as required by 21 CFR 54.6.

4. Determine if the sponsor retained the documentation to support the certifications anddisclosures of investigators’ financial information that was reported to FDA.”

FDA inspection of sponsor

Updated Section on
Part 11

There is an updated section on Electronic Records and Electronic Signatures. The FDA guidance document, “Guidance for Industry Part 11, Electronic Records; Electronic Signatures – Scope and Application” (Part 11 Guidance) is discussed at length confirming that this document currently represents FDA’s enforcement policy regarding Part 11.

The CPGM emphasizes issues including the Scope of Electronic Records & Signatures; Procedures; Data Collection; & Security.

Finally there are new sections on Emergency Research; International Data; & Nonclinical Laboratories reflecting new regulations, guidance documents, or inspection policies. It is important to note that although FDA will not inspect GLP studies at every sponsor/CRO inspection, the possibility exists. The new CPGM gives the field investigator specific instructions on what to look for in non-clinical studies. (UPDATE: Read the recent Sponsor Warning Letter on Preclinical Studies on the link below.)

The new CPGM will significantly change how Sponsor/Contract Research Organizations, and Monitor inspections are conducted. It confirms a shift to review of sponsor responsibilities by FDA’s Bioresearch Monitoring program managers. It is a very important document for sponsors and CROs to review.

Read the New CPGM

Guidance for Industry on Financial Disclosure

Guidance on Certifications Required By FDAAA (including clinicaltrials.gov)

Compliance Policy Guide on Fraud and Untrue Statements…

Part 11: Scope & Application Guidance

Sponsor Warning Letter on Preclinical Studies from CDRH

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Please take a short 3-question survey to help GxP Perspectives improve! Survey begins 22 SEP 2011

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On the Blogroll:

Marc Stecker’s Photos

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On the Blogroll: FDA Matters once again discusses the importance of FDA’s contributions to public health. Please read Steven Grossman’s post on Change Takes Time.

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FDA Inspections: What NOT To Say & How Not To Say It

March 13, 2011

FDA inspections

"It's Not My Job"

FDA Inspections are Always stressful. How should you answer the FDA Investigator’s questions? What should you say or, more importantly, what should you NOT say? Two common answers are to tell the truth and to only answer the question asked. Both are good points. The FDA investigator is conducting a public health inspection so you should want to tell the truth. It also happens to be against the law to lie to a federal official so there are both positive and negative motivations to answer a question truthfully. It is also a good idea to give a brief, factual, and truthful answer to the question you are asked, not a question you think might be asked. And remember to use a complete sentence. Receiving a barrage of monosyllables in an interview is only going to irritate the FDA investigator. The one answer I recommend to never give to an FDA investigator is, “It’s not my job.”

What? Most people who answer, “it’s not my job” are telling the truth! Not only that, it is not a good idea to answer for someone else who actually has that responsibility. However, you have to remember that an FDA investigator has heard that response one hundred times before. People frequently give evasive answers and avoid responsibility when being interviewed by the FDA. It gets very old, very fast.

FDA inspection

"I Know Who Has That Responsibility"

A better approach is to say, “That isn’t my job but I know whose responsibility it is and let me see if she is available.” During an FDA inspection it is important to build trust. If an FDA inspector asks a reasonable question, let’s say, “How do you ship investigational product to clinical sites?” It is in your interest to see that the right person answers the question and that you find the right person in a timely manner.

FDA has begun a program to increase the types of GCP inspections it conducts. There will be more inspections of CROs and clinical trial vendors such as clinical laboratories. In fact, they have already started. That means that many more people will need training on how to participate in an FDA inspection. GxP Perspectives will be having some Guest Commentaries on the subject and try to provide some practical solutions.

FDA Inspevtions

Frontloading Quality:
The Key to Success

The first step in successfully hosting an FDA inspection is to have a quality system in place that monitors the data or product lifecycle. You don’t want to start your quality process after you lock your database! Then, when FDA does show up, you want to give a positive impression. You want to build trust with FDA. Think back to the last time you phoned your utility company or complained about a pothole on your street. When you finally got a live person and they told you, “that’s not my job,” how did you feel? That isn’t how you want FDA to feel either.

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Here are some helpful articles and resources on FDA inspections:

Applied Clinical Trials on Mock FDA Inspections.

Ten Steps for Improving GCP Inspections by Vernette Molloy and my late colleague, Sandy Mackintosh, also in Applied Clinical Trials

FDA Inspection Guides: How the FDA conducts inspections

BioJobBlog: What’s Up With FDA Inspections Anyway?

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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.

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A new feature from FDAzilla on FDA 483s-

Read the Press Release on 483s

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.

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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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On The Blogroll: Audrey’s Network- a great way to keep up with news from the San Francisco Bay Area Life Sciences Community

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