GxP Quality- Building a Culture of Compliance

January 24, 2011

GxP culture compliance quality

Building a Culture of Compliance

Building a “culture of compliance” is almost a cliche in GxP Quality Assurance circles. However, time and again major problems occur when we discover that a “culture of shortcuts” has set in. In this Guest Commentary veteran GxP consultants Emma Barsky and Len Grunbaum cover the basics of how to build a culture of quality and compliance from the ground up. I first met Len Grunbaum in 2004 when he was on the faculty of an Advanced GLP course for FDA field investigators. This was the last FDA training I took before leaving. I was impressed with Len’s knowledge of validation processes and we’ve kept in touch. I’m still impressed.

This will be the last post for two weeks as I go traveling for a bit. I wanted to let readers know of two important recent articles (with links at the bottom of the post.)

The first is about a report issued earlier this month by the British Academy of Medical Sciences. The report was commissioned by the British government to try to pare back some of the bureaucracy involved with clinical trials in the U.K. An article on the report by Nick Taylor in Outsourcing-Pharma there are some interesting revelations about the British regulatory agency, MHRA. I strongly recommend reading this article.

In addition, I would like to refer readers to last week’s FDA Matters for interesting issues of concern at FDA. Now, here are Len & Emma:

Guest Commentary by Emma Barsky & Len Grunbaum

Implementing a “Culture of Compliance”: Practical Steps

Establishing a “culture of compliance” is not a “paint-by-numbers” exercise; it must be injected into the DNA of a company. In our experience, many companies strive to create a “culture of compliance” but few approach it from the perspective of a mindset of “shared attitudes, values, goals and practices that characterizes an institution or organization,” which is the essence of a “culture.” The ideas that follow are intended to provide a roadmap and practical steps towards implementing a company-wide “culture of compliance” in the life science industry, across any GXP area.

1. Develop a quality policy statement and quality objectives

culture compliance GxP

Developing a Quality Statement

Every company should set quality-related expectations for its employees and contractors. The policy that establishes an environment where employees and contractors are made knowledgeable of, and held accountable for, good quality practices pertinent to the company’s business should not only be visibly displayed but also discussed with/explained to those parties who will be required to adhere to it. Company management should emphasize the details of the quality policy that are outlined in item number 2.

2. Identify and document quality criteria
Company management should identify and document the criteria for “good quality practices.” These components may include, but may not necessarily be limited to, adherence to written policies and procedures, exercising good documentation practices (e.g. initialing and dating cross-outs, using a single line to for corrections), promptly bringing any deficiencies and/or deviations to the attention of company management, documenting unplanned deviations, providing explanations/justifications when planned deviations occur and correcting them in a timely fashion.

GxP culture compliance

Defining Expectations for Quality

To successfully implement staff adherence to the company’s quality policy, it may be beneficial for a company, in part, to tie staff members’ annual reviews, promotions and/or salary increases to the effectiveness of the adherence to, and application of, good quality practices. In other words, it should be made clear to the employees that everyone, including those responsible for a given department/operation where a quality deficiency is identified, will be held tangibly accountable.

3. Establish a robust quality baseline

Through performing internal audits and assessing CAPAs, the company’s Quality function (e.g., Quality Assurance) should identify quality-related issues based on the criteria regarding the components of “good quality practices” outlined in item number 2.

While performing the internal audits and through capturing the findings in the CAPA system, the Quality function should focus on identifying trends and themes related to non-compliance. In order to achieve this objective, the company’s CAPA system should be such that it allows the company to collect information regarding appropriate metrics to assess the success of the “culture of compliance” initiative.

Lack of compliance should be tracked not only on an issue-by-issue basis, but also across departments, individuals and operations/processes. Collecting information on these items will help to identify the root cause of the issue, which may stem from a larger issue related, but not necessarily limited to,

1. Cumbersome and, therefore, ineffective processes
2. Lack of appropriate supervision
3. Procedures that lack clarity (e.g., poorly worded documentation; lack of guidance, contradictory information)
4. Lack of documented procedures
5. Lack of an individual’s attention to detail and common sense
6. Lack of effective training

The list of potential root causes of the deficiencies encountered is limitless, but one thing always remains clear: unless quality-related issues are addressed and remedied at the root cause level, the fix to compliance issues will not be permanent, nor will the company be able to create and maintain the “culture of compliance.”

4. Maintain a robust quality baseline

Every internal audit should focus on the effectiveness of the established CAPA system. Specifically, the Quality function should determine whether:

1. The nature and impact of the deficiency on data has been properly identified
2. Effective corrective and preventive actions have been implemented
3. Appropriate follow-ups have been performed
4. The system is robust enough to trend and track quality-related issues accurately and completely
5. The system is robust enough to identify weaknesses with processes, documentation practices, personnel, etc.

The company’s Quality function should investigate all instances where the above has not been achieved for improvements within the quality system. This includes the defined metrics of the CAPA system.

In conclusion, we would like to emphasize that many factors, including but not limited to, new staff, acquisitions/mergers, new lines of business, staff reductions and/or new management have an impact on the “culture of compliance.” Therefore, in order to be successful, a “culture of compliance” should be a “living” initiative, which is constantly assessed for its effectiveness in light of changes that every company experiences during the normal course of events.

Emma Barsky
Len Grunbaum
The Practical Solutions Group, LLC


Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma

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


Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

See the page Guest Commentaries (at the top of the blog) for the previous article by Len & Emma on Part 11 compliance.

On FDA’s Website there are Two New Warning Letters from FDA to Clinical Investigators that show the need to effectively respond to a Form FDA 483, Inspectional Observations, with a well thought out CAPA Plan.

Contracts: Basics for Clinical Trial Sites

January 16, 2011

clinical trial contract

Some Practical Suggestions for Contracts

Negotiating contracts isn’t fun for clinical trial sites (or consultants). Contracts define the terms of how a sponsor and clinical trial site interact, who the parties are, and important issues for every clinical trial site to consider. One of the hardest issues for me has been indemnification; what to ask for and when to ask for it.

This Guest Commentary by Jill Petro helps to demystify some of the issues that clinical trial sites face when looking over a contract.Jill works for Aureus Research in New Orleans and has some practical issues for you to consider including checklists, spreadsheets, and templates.

Guest Commentary

Clinical Trial Contracts, by Jill Petro

Whether you are an Investigator, a study coordinator, a site manager, a CRA, or a member of the Contracts and Grants department, you probably have responsibility for some aspects of the contract and budget process. Most of us in these areas have had little, if any, formal legal or financial training. This is unfortunate, because the contract is the critical document that defines the expectations and legal obligationsof the Sponsor and Site (and sometimes the CRO).

Now you may say the protocol is more critical, but most contracts have a statement that the agreement supersedes with the protocol merely an attachment to the agreement. Shouldn’t we then spend as much effort making sure the contract is good for both parties as we do getting the protocol right? Reviewing contracts and budgets is time-consuming and can be frustrating.

This is NOT our area of expertise, and yet we are expected to negotiate asound agreement. It is possible to reduce the stress associated with this task if you develop a reasonable process forreview. This might include the use of checklists, templates, or spreadsheets.


clinical trial contract

Templates and Checklists Can Help

It’s not uncommon for Sponsors and Sites to have an “elements of the informed consent checklist” against which the Informed Consent Form for each study is compared to ensure none of the required elements are missing. Most Sponsors and CROs provide sites with a contract for review. The contract has probably already undergone a check of some sort by their legal staff. Wouldn’t it be nice for the site to have a “checklist of required elements” to use during the contract review process? This checklist will likely take some time to develop for a site. It should involve input from the Investigator, the Institution, the Site Manager/Study Coordinator, and Lawyer(s). All topics
that must be present should be listed and might include:

(A) Who the parties are,

(B) Indemnification,

(C) Subject injury, etc.


Now that the Site has its list of “required elements in a contract,” the group should decide on acceptable and unacceptable language within each topic. These could be your templates when reviewing a contract. If it matches your template (or the intent of your template), everything is fine. If it doesn’t, you have some template language which you can suggest as an alternative.

For instance, with regard to the parties, sometimes the contract is between the CRO and the site. If this is the case, your group would have to decide if this is acceptable or if it has to include the Sponsor. Maybe it would be acceptable if it says “CRO on behalf of the Sponsor,” but not if it is just says “CRO”. When it comes to indemnification, it is almost a universal expectation that the Sponsor will provide indemnity to the Site in some manner. It is likely that this will be a “required element” in the contract. As you discuss this area, your group will probably need to establish expectations on what will and will not be covered by indemnity.

Most Sponsors indemnify for njuries due to study product, but not for injuries caused by negligence. That seems straightforward enough, but what about indemnifying for a procedure that would not have been done except per study requirements? Next, your group will have to carefully check its insurance policies. Most contracts include a statement that the Site will also indemnify the Sponsor. Although some Sites may be able to extend their coverage to another party, many will not be allowed to do that by their insurance carrier. Check this out. If your insurance will not allow this, make sure your checklist includes this “Site indemnifies Sponsor” language in the “unacceptable language.”

clinical trial contract

Subject Safety in Clinical Trials

Our final example is subject injury. Consent forms must explain to the subject what compensation is available in the event of a research-related injury. In my experience, many contracts do not address this issue at all. To ensure all parties agree to their obligations in this area, the contract should include language that mirrors that of the informed consent form. A Site might also want details in the contract that explain how that process will work (how to request and obtain reimbursement).

Did I mention that this was a complex and lengthy process? It will probably take your site some time to develop its checklist and templated language, but it will speed up future negotiations. Why not make it one of your business resolutions for 2011 to bring this issue forward to those involved and try to have the task completed by the end of the year? It will make every contract easier in 2012!

Aureus Research Consultants, LLC


Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma

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

On the Blogroll: Diabetes Self Management, well organized and informative

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

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


Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group


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


Dr. Sharfstein to Leave FDA on Friday

January 5, 2011

FDA Joshua Sharfstein

Dr. Joshua Sharfstein to Leave FDA on Friday, January 7th

Dr. Joshua M. Sharfstein, Principal Deputy Commissioner of the U.S. Food and Drug Administration, will be leaving FDA this Friday, January 7. Since joining FDA two years ago, Dr. Sharfstein has brought much needed energy and a passion for public health to FDA. Together with Dr. Margaret Hamburg, he has revitalized the agency, in my viewpoint, for the better. There are a lot of opinions about his leaving to become the Director of Maryland’s Department of Health and Mental Hygiene. I’ll let you scour the web for interpretations. I don’t have a clue. However, I would like to share his message to FDA employees about his departure:


From: A Message from the Principal Deputy Commissioner
Sent: Wednesday, January 05, 2011 1:30 PM
To: FDA-Wide
Subject: Thank You

Dear Friends and Colleagues,

Just over two years ago, I was led through the Parklawn Building to a small, windowless room known as 15B08. Over the next few weeks, our small group on the Obama transition team met there for many hours with dozens of FDA staff, and then elsewhere with industry representatives and patient and consumer advocates.

Amidst hundreds of individual notes, we heard one melody: broad support for a strong FDA that protects and promotes public health.

Two years later, this melody can be heard at White Oak and in the agency’s offices around the country and across the globe. FDA now has the public health responsibility of tobacco regulation, a new law that will transform the food safety system, a renewed commitment to innovation in regulatory science and the regulatory process, and a growing reputation for transparency, accountability, and action.

In these two years, I have come to understand that FDA can succeed beyond everyone’s expectations by developing and explaining the public health logic underlying key regulatory steps.

I have found that by communicating like a public health agency – directly, clearly, and with credible partners – FDA can generate support and make further progress.

And I have seen that good judgment is as important as good data. It is good judgment that can answer the essential question of when the agency has enough data for action.

Through FDA-TRACK, the transparency initiative, numerous crises du jour, trips to regional and district offices, and other settings, I have had the pleasure of working with many remarkable FDA staff. I appreciate all of your patience and understanding during my first few months, and all of your dedication and accomplishments over the last two years. I know that even more progress and innovation is in store to benefit patients and consumers across the country.

It has been an honor to serve in the Administration of President Obama and Secretary of Health and Human Services Kathleen Sebelius.

And it has been a special pleasure to work for and learn from Dr. Margaret A. Hamburg, a leader with extraordinary judgment, kindness, and vision.

My tour at FDA is, however, coming to an end this Friday. Recently, Governor Martin O’Malley offered me the opportunity to serve as Secretary of Maryland’s Department of Health and Mental Hygiene, and I accepted. I will start next week in time for the state’s legislative session. My new role will span a wide range of exciting and important areas, including public health, mental health, substance abuse, developmental disabilities, Medicaid, and healthcare reform.

I would say good-bye — except that I will not be far away.

Dr. Hamburg has even invited me to run in the upcoming White Oak Classic, the annual 5K run around the campus. This has been an annual event that celebrates health and fun, and involves, for me, no small amount of personal humiliation.

I am in training for the race . . . and I hope to see you there.

Thank you, and take care,


Joshua M. Sharfstein, M.D.
Principal Deputy Commissioner
U.S. Food and Drug Administration


GxP Perspectives wishes Dr. Sharfstein all the best at his new job.

FDA Warning Letters in 2010 for GCP Failures

January 1, 2011

FDA Warning Letters GCP

FDA Maintains Pace for GCP Warning Letters
in 2010

After a significant rise in Warning Letters issued for GCP failures the past few years, FDA seems to have leveled off in the number of Warning Letters issued in 2010. I have not seen FDA metrics for Fiscal Year 2010 but my own review of Warning Letters issued to clinical investigators in 2010 doesn’t show a sharp increase, only more of the same. In particular, the primary deficiency categories are quite similar as they were 15 years ago when I attended my first FDA Bioresearch Monitoring course. Although the terminology has modernized over the years it can be summed up in four words: protocol adherence and recordkeeping.

UPDATE: I have posted below the BIMO FY-2010 Metrics below, courtesy of the Office of Good Clinical Practice- FDA/OC (many thanks). They are the people responsible for the Clinical Trials link on the FDA website. The metrics essentially confirm some of the conclusions of this post.

When looking at an FDA Warning Letter I am always curious about the very first charge that is listed. You will note that FDA does not use categories such as Critical, Major, or Minor as many company QA departments do. MHRA, the United Kingdom’s regulatory agency for health products, also uses a rating system, Major, Minor, and “Other.” However, FDA lists violations in the order of significance and the first item listed on either a Warning Letter or Form FDA 483, Inspectional Observations, is supposed to be the most significant. In ten Warning Letters I reviewed that were issued to clinical investigators in 2010 “failure to follow the investigational plan” was listed first on Warning Letters issued by the Center for Drugs four times. “Failure to conduct the investigation according to the signed agreement, the investigational plan, and FDA regulations was listed first in two Warning Letters issued by the Center for Devices and Radiological Health. The lesson here is that FDA pays close attention to protocol adherence.

FDA Warning Letters GCP

Keeping on Top of Records and the TMF

Recordkeeping violations were listed first on one Warning Letter but were included on eight of the ten Warning Letters I reviewed. Perhaps this is one of the reasons for the strong interest in the trial master file, the TMF. This pattern of violations has been happening a very long time. The first article I wrote after leaving FDA (six years ago) was called, “Protocol Adherence and Recordkeeping: The Twin Pillars of GCPs.” A typical Warning Letter was issued on 30 September 2010 (there is a link below). So the good news is that many researchers are paying attention to the increase in FDA Warning Letters the past few years and are instituting changes. The bad news is that there are still some people that keep repeating the same mistakes.

FDA GCP Warning Letter: 30 SEP 10

BIMO metrics – FY-2010

A new feature from FDAzilla on FDA 483s

Read the Press Release on 483s


Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

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.


In news from GxP Perspectives.

On the Blogroll: Catalyst Biomedical – A blog that I recently discovered and that you may find of interest

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

“Sec. 50.25 Elements of informed consent.

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

Your comments are welcome on FDA Warning Letters

%d bloggers like this: