GCP Training on Informed Consent: The Basics for Compliance

March 29, 2010

GCP Informed Consent Training

Informed Consent: Protecting Participants in Clinical Trials

The most serious GCP compliance concerns in a clinical trial are frequently regarding informed consent. FDA recently issued several Warning Letters about clinical sites failing to appropriately consent a clinical trial participant. Training that informed consent is a Process and not just a form to fill out is essential to a quality clinical trial. FDA looks closely at the Qualifications of research staff obtaining informed consent. In this guest commentary Mikki O’Neal discusses the importance of informed consent training from the perspective of a clinical site.

Guest Commentary:

By Mikki O’Neal, CCRP, CCRC
Regulatory Compliance Manager
Houston, Texas

Informed Consent Training: A Site Perspective

Lack of {adequate} training frequently seems to be a standard hot topic in research circles. What constitutes solid training? By what measures should a researcher be deemed qualified to obtain informed consent? While I feel that online training modules provide a good basic foundation, institutions are often relying on them as the sole requirement to satisfy the training process of a researcher. I like to refer to this as theory-based training. While online modules and classroom training do give a researcher a good grasp of how research evolved into what it is today, what is often missing from these training methods is application training. How do you take what you have learned in a module and apply it to every day research activity? Informed consent training is a perfect example. You can speak about informed consent theory until you are blue in the face, but until a researcher is able to see an actual consent process applied, how can they truly grasp the relevance of “it’s all in the details”? This is one of the first steps that foster the communication gap between a poor consenter and a well informed research subject.

More and more you see non-research clinical staff being burdened with the additional responsibility of consenting a subject for a trial while they are performing their basic job functions. Not only does it add extra responsibility to their plate, but obtaining proper research informed consent is typically not even a topic that gets entertained because they don’t understand the reasons, importance, or implications.

GCP Training

GCP Training for Informed Consent Compliance

What is more surprising is that very often these observations occur with “experienced” research personnel, which begs to question the methods in which they were trained. One of the largest mistakes that I think a site manager can make is to hire a researcher based on experience listed on paper and then assume that because of said experience, training will not have to occur (or that very minimal training will suffice). Taking it “back to the basics”, in my opinion, is a critical factor with this topic. It is very easy to start cutting corners and minimizing the importance of a true informed consent process when a study seems simple or the researcher is rushed.

Food for thought: Should researchers be required to demonstrate informed consent ability with an annual practical assessment? Would it be beneficial for sites to implement random “audit” shadowing of researchers during an informed consent process? Is there a “one size fits all” solution to solving informed consent issues? A vital piece of the puzzle is oversight. Know what is going on at your site. Assess the capability of your research personnel. Standardize your training so that all personnel are trained in the same manner regardless of experience. Require continued education. And most of all, never assume that someone is adequately trained just because they have worked in the field of research for an extended amount of time.

Please read other Guest Commentary on the page at the top of the Blog.

UPDATE 6 January 2011: Two Important New GCP Documents:

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

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

“Sec. 50.25 Elements of informed consent.

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


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FDA Warning to Pediatrician on Adverse Events

March 25, 2010

A pediatrician conducting a vaccine study received an FDA Warning Letter for failure to report adverse events as required by the protocol along with other GCP violations. The Warning Letter noted numerous adverse events not reported. Although the title of the study has been redacted, it is appears from the nature of the adverse events, such as ear infections, that it was for a pediatric vaccine. FDA prioritizes the review of studies when there are risks to children, a vulnerable population, in a clinical trial. The letter was issued by the Center for Biologics Evaluation & Research.

FDA Warning

Adverse Events in Vaccine Clinical Trial

The FDA Warning Letter, dated March 11, 2010, also cited the pediatrician for failure to record concomitant medications, failure to maintain adequate and accurate case histories, and records of the disposition of the investigational drug. These are the types of violations that FDA has cited time and again, following the protocol for reporting adverse events and other activities such as concomitant medications and serious recordkeeping errors. Protocol violations top the list of GCP violations. However there was an additional recordkeeping violation that is less common. The trial cited the clinical investigator for the failure to maintain records noting:

“At the time you signed the Form FDA 1572, Statement of Investigator, for Studies 1 and 2, you agreed to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make these records available for inspection in accordance with 21 CFR 312.68. In your letter, you explain that you do not have access to the study record because your affiliation with Sylva Pediatric Associates (SPA) ended in (b)(6). Our investigation revealed that after your departure from Sylva Pediatrics records of your completed studies were stored by (b)(4). After (b)(4) closed, your records were relocated to SPA and did not remain under your supervision at your current position at Western North Carolina Pediatric and Adolescent Care in Sylva, North Carolina.”

FDA Warning

The wrong place for study files

I have seen this happen on several occasions. A researcher will change their practice and lose control of their records. In the worst case I saw a breakup in the medical practice led to the study records being moved to a storage closet and then being thrown in a dumpster by a janitor. Bad news. However, the news is even worse when the research participants are children. Here is the Warning Letter:



50 Top Blogs for Biotech Students: No, I didn’t make the list but our friends at Compliance Zen did (see the Blogroll).


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CAPA Basics- Corrective And Preventative Action

March 22, 2010

CAPA Basics

CAPA Basics

When developing a quality management program you need to discuss the basics of CAPA: corrective and preventative action, and how to come up with a CAPA plan that resolves the root causes of violations. In a guest commentary, veteran GxP consultant Barb Immel discusses CAPA basics. I first met Barb when she was teaching a 3-day drug development course at UC Extension and had invited me as a guest speaker. I sat through the entire three days and learned a lot.

Guest Commentary:

CAPA Basics By Barbara K. Immel

Poor corrective and preventive action (CAPA) and investigations continue to be among top FDA Form 483 deficiencies issued to drug, biologic, and medical device manufacturers. And FDA has been issuing warning letters citing inadequate corrective action to clinical investigators, institutional review boards, contract research organizations, and sponsors. It’s in everyone’s self interest to improve the quality of investigations and CAPA. The most important point to remember?

The depth and intensity of an investigation should match the potential risk to the patient.

1. Start with the requirements. Always follow all applicable regulations and standards, and go above and beyond the minimum requirements. Although the only organizations that are required to establish a CAPA system are medical device manufacturers, it has always been either a requirement or an expectation that all organizations in our industry will perform thorough investigations and implement effective CAPA. Helpful passages include, but are not limited, to:

Device CGMPs. Establishing a CAPA system is a CGMP requirement for medical device manufacturers producing product for the US (21 CFR 820.100).

Drug CGMPs. Conducting certain investigations and documenting and justifying deviations is required for manufacturers making product for the US. Inadequate investigations are a frequent CGMP deficiency (21 CFR 211.192).

CAPA laboratory

Good Laboratory Practice

Preclinical Requirements. Taking corrective action is required in the GLPs (21 CFR 58) for testing facility management (21 CFR 58.31), the study director (21 CFR 58.33), Clinical Requirements. And taking effective corrective action is implied in the GCPs. Relevant sections include but aren’t limited to the Responsibilities of Sponsors (21 CFR 812.40) and Responsibilities of Sponsors and Investigators (21 CFR 312 Subpart D).

2. Establish good surveillance. Carefully think about the data you need, and the speed with which you will require being notified. A surveillance system is only as good as the information it receives.

• Conduct thorough, frequent audits (most internal operations should be audited at least once a year, and critical suppliers should be audited frequently, such as once every 12-18 months). Ensure audits are done by experienced personnel, and that any identified issues are promptly addressed.

• Require that all employees immediately report to their supervisor when they deviate, make a mistake, or notice something unusual. Require that sites notify you rapidly of any issues or potential issues.

• Set up an effective trending system, to identify potential issues before they become a fire.

• Regardless of where you work in the industry, check out the following documents for ideas:

o AdvaMed Points to Consider When Preparing for an FDA Inspection under the QSIT Corrective and Preventive Action Subsystem:

o Global Harmonization Task Force Proposed Document: Quality Management System — Medical Devices — Guidance on corrective action and preventive action and related QMS processes:


Laboratory Requirements:

If you work with a laboratory, see FDA’s Guidance for Industry: Investigating Out-of-Specification Test Results for Pharmaceutical Production

• Ensure your system will allow you to notify FDA of any problems concerning your product or clinical trial within FDA required reporting timeframes (i.e., a field alert, medical device report, biologic product deviation report, adverse event or serious adverse event, etc.).

• Always include a link between your investigation and CAPA procedures and your FDA reporting procedures, including your recall procedure.


Review Recall Procedures

Any potential recall situation should immediately be brought to the attention of your QA executive. For recall SOP ideas, see FDA’s regulation (21 CFR 7) and FDA’s Guidance for Industry: Product Recalls, Including Removals and Corrections. Test your recall system at least once a year.

Remember: Each FDA District Office has a Recall Coordinator.


3. Create (or improve) your SOP(s) and systems. Every organization should have a failure investigation procedure that states the threshold for initiating an investigation. The decision whether to investigate should always be made by an experienced QA employee, and documented.

• Periodically ask employees or others using your system what’s driving them crazy about it, and act on the results.

• Make sure your system requires the early categorization or determination of risk, and the ability to rapidly escalate the importance of items. Your system should include how management will be routinely informed of ongoing investigations and CAPA activities, and how they will be immediately informed of critical issues.

4. Define your terms. For medical device companies, ISO 13485, Medical devices – Quality management systems – Requirements for regulatory purposes, and ISO 9001, Quality management systems –


Define Your Terms!

Requirements, define corrective and preventive action. Since complying with these standards is required to sell devices in Europe, Canada, and Australia, it makes good business sense for device firms to use these definitions. Drug and biologic companies, and clinical groups, are under no such requirement, but define your terms and provide training to all employees so everyone is using the same terminology.

The ISO definitions are:

• Corrective Action: Action to eliminate the cause of a detected nonconformity or other undesirable situation.

• Preventive Action: Action to eliminate the cause of a potential nonconformity or other undesirable potential situation.

5. Train employees. Provide frequent, ongoing training to all employees or staff. Don’t forget to train sales representatives on what a customer complaint is, and how they should rapidly report any that they receive.

Provide training on the following to individuals performing investigations:

o Your investigation and CAPA procedure(s)
o All applicable regulations and standards
o Root cause analysis
o Solution criteria*
o How to perform an investigation
o Your documentation and reporting requirements
o Report writing (since employees may be moving from simply filling out a form to creating a written investigation report)
o Interviewing (since investigators will need to be able to interview individuals at all levels)

*All solutions should prevent the recurrence of the problem, should not cause an unacceptable problem, should be within the control of your organization to enact, and should provide good value for their cost.

Teach everyone the key stages of an investigation:

1) identification and definition of the problem,
2) determination of whether to do an investigation (categorization/risk analysis),
3) planning the investigation,
4) root cause analysis,
5) identifying appropriate corrective and preventive action,
6) implementing the action, and 7) measuring the effectiveness of the action.

• Train everyone to carefully evaluate and select possible CAPA actions before they are implemented, and to confirm the effectiveness of the CAPA – and that it didn’t cause a greater problem – after implementation (the effectiveness checks).

• And teach everyone how to do a basic or preliminary investigation. Only ask experienced investigators or employees to perform more serious or difficult investigations (follow-up investigations).

By Barbara K. Immel

For further information take a look at Barb’s website:



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In News from GxP Perspectives:

CAPA Plans for Clinical Trials

Protocol Violations: Root Cause Analysis

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

Public Comment Period is Open for New FDA Draft Guidance:
FDA Draft Guidance on Electronic Source Data in Clinical Investigations

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Keeping Protocol Deviations in Check: Part 1

March 17, 2010

protocol deviations

Keys to FDA Compliance

Recent FDA Warning Letters have shown serious concern about protocol adherence and the number of deviations documented. I am hearing the same things from colleagues monitoring sites. My fried Chris wrote me last night, “It is unbelievable how much this is still occurring even as we speak.” A clinical research associate confided in me Monday that “They had never heard of GCP!” Clinical sites have been experiencing their own issues regarding protocols which I will discuss in future posts. The only person who seems non-plussed by this is my colleague Judith Lynn. She has been writing protocols and monitoring sites for many years and offers us some sound advice. Needless to say, she begins with some very basic sponsor responsibilities.

Guest Commentary by Judith Lynn-

Manage your study

Recent warning letters from FDA remind us of a fundamental truth about running trials: Sponsors need to manage their studies.

We might do well to consider FDA guidance as a helpful guide, not another obstacle or checkbox. A monitoring plan is a useful exercise for the study manager, to help define critical timepoints, help predict manpower requirements, and data flow. Good monitoring helps ensure reliable data. This in turn helps sponsors make better decisions, either for the next study or for a marketing application. Hiding or ignoring safety or study conduct trends only builds in problems later.

Monitor the study

• Have a communication plan, if your monitor finds something of concern, make sure there is a mechanism to escalate concerns
• Expect monitors to look not only at each subject individually, but also pay attention. Electronic data collection, and review of lab reports over time help with this

Review monitoring visit reports.

protocol deviations FDA

Regular Review of Monitor Reports

Keeping current with review of reports helps the sponsor. If you don’t have time, consider asking for help. If nothing else, for financial reasons (if there is no report, why should you have an expense report)? Issues I have found, both during study conduct or during file audit, include:

~ Reports are delinquent or missing
~ Frequency of visits does not match monitoring plan
~ Different monitor each time (this can affect the ability to track issues over time, and site’s understanding of the protocol)
~ Protocol deviations at sites, pay attention to the number and type of deviations noted

Protocol Deviations

I have recently seen exhaustive notes and lists of protocol deviations at sites. While tabulation of numerous deviations can be tedious, deviations can be an indicator of problems with a site or with the protocol.

~ Inclusion/exclusion criteria are not realistic (if too many subjects enrolled, with sponsor approval, that don’t meet criteria)
~ Site does not understand the study (Retraining?)
~ Study is complex
~ Site may not have appropriate facilities (if procedures often not done, there may be an offsite laboratory or X-ray facility that is difficult for subject to get to)

I have worked in both large and small sponsor companies. Often we have a lot to do and limited time and budget. I encourage you to make the time, and dedicate the resources to manage your study. It will pay off.

Judith Lynn, 17 March 2010

Judith Lynn is a Pharmaceutical Consultant based in Redwood City, CA. Watch for future Guest Commentaries including Protocol Deviations: Part 2 by Sarah Wilson

Protocol Violations: Root Cause Analysis

A Head’s Up for Sponsor-Investigators:

FDA has just issued a Warning Letter for GCP violations to a “sponsor-investigator” someone who both initiates a clinical trial and conducts it. In this case the Warning Letter was sent to the researcher for Sponsor responsibilities as they had passed on the investigator role to another researcher. All of the same responsibilities Judith mentions hold true for academic research and “Investigator-Initiated Research.” Read for yourself:


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FDA Seeks Public Comment on Transparency

March 13, 2010

FDA public input

FDA Asks for Public Comments

The Food and Drug Administration is soliciting comments from the public and stakeholders regarding making the agency more transparent, The FDA issued a press release that said in part:

“As part of the final phase of its transparency initiative, the U.S. Food and Drug Administration is seeking comment from the public and other interested stakeholders on how the agency can increase transparency in its interactions with regulated industry.”

The Press Release Continues:

“For this final phase, the FDA is particularly interested in comments from all interested parties on how the agency can make improvements in the following areas:
~ Training and education for regulated industry about the FDA regulatory process in general and/or about specific new requirements
~ The guidance development process
~ Maintaining open channels of communication with industry routinely and during crises
~ Providing useful and timely answers to industry questions about specific regulatory issues”

GxP Perspective:

FDA periodically embarks on an effort to be more transparent to the public and to regulated industry. This time they are seeking public comment, which is a good thing. However, past efforts at transparency haven’t always born fruit. For example, when I was conducting inspections in the mid-90s the field organization, the Office of Regulatory Affairs, started distributing inspection reports, called EIRs for Establishment Inspection Report, to the inspected party under an initiative called a Field Management Directive: FMD-145. This effort has long fallen by the wayside and many clinical investigators and others in regulated industry don’t even know they can obtain their report. Here is a link to FMD-145:


The public also would like to know what types of source documents FDA expects to see for a clinical trial. Others ask what the definitions of common industry terms are, such as “trial master file.” So transparency is something FDA can improve on.

Final Compliance Determination:

FDA input

Final FDA Compliance Determination

Most people are aware of the Form FDA 483, Inspectional Observations. This form lists the preliminary observations made by the FDA Consumer Safety Officer (field investigator) at the conclusion of an inspection. However this is not the final compliance determination of the agency. This will usually come in post-inspectional correspondence. FDA writes letters to most inspected firms, not just the Warning Letters that are posted on the internet.

There are many FDA 483s requested under the Freedom of Information Act (FOIA) that are floating around and discussed by regulated industry. However, it is the letter that FDA writes after the EIR is reviewed by a compliance officer that is the final compliance determination of FDA. Sometimes it is quite different from the original 483. These letters should be made available when a 483 is requested under the FOIA . On several occasions I have, to no avail, attempted to request “post-inspectional correspondence” from the overworked Freedom of Information Act technicians that redact FOIA requests from the public.

The final compliance determination is what FDA really thinks, and a lot of “regulation by rumor” would be cut down if FDA released these letters along with a Form FDA 483. Sometimes these letters are called “informational” or “untitled.” FDA should have a uniform method of requesting post-inspectional correspondence. It would be a valuable compliance tool.

Some Bright Spots

FDA Seeks Public Input

Finding Information

In FDA’s defense they are about the only regulatory agency in the world that will release a regulatory inspection report under a law such as the Freedom of Information Act. Just try getting an inspection report from a European, Asian, or other regulatory agency. FDA also posts redacted Warning Letters on their website. That is also unique. And FDA has programs like GCP Questions that try to answer basic regulatory issues. Here is a link to email answers to many inquiries to GCP Questions:


All in all FDA is one of the more transparent regulatory agencies in the world, something it doesn’t get much credit for. However, there is certainly room for improvement.

How To Comment:

Electronic comments may be submitted to:


Submit written comments to the Division of Dockets Management (HFA–305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, Md., 20852. All comments should be identified with docket number FDA–2009–N–0247.

Posted in the March 12, 2010, Federal Register, the request for electronic or written comments has a deadline of April 12, 2010.

Read the FDA Press Release:



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Clinical Trial GCP Failures Spark FDA Warning Letter

March 11, 2010

FDA issued a new Warning Letter for the most common GCP failures: Informed consent; recordkeeping; and protocol adherence. The 24 February letter to a clinical investigator in Meridian, MS is a textbook case on how not to conduct a clinical trial. First, the investigator failed to recruit eligible subjects and it went downhill from there. This was not a case of Good Clinical Practice (GCP).

FDA GCP Warning Letter

Study Eligibility is a Major FDA Concern

The problem is that this is a psychiatric study and the subjects need to be diagnosed with bipolar disorder in order to participate. Protecting research subjects who may have diminished autonomy is a primary concern for FDA. Thee of six subjects randomized in the study did not meeting the eligibility criteria of having Bipolar I Disorder. FDA considers this “placed at risk for injury from participation in the study,” a serious GCP violation.

FDA has paid closer attention to meeting eligibility requirements of a protocol listed in the inclusion/exclusion criteria. It has been showing up on more Warning Letters in the past two years. And the problems continued from there. One subject was dosed three days before baseline. Not good.

Recordkeeping Errors:

FDA cited the investigator for numerous recordkeeping errors noting:

The records for Subject 1004 contained numerous errors in subject number, protocol number, and date or identity of study visit. For example:

i. Numerous records reflect that subject number 1002 was used instead of the correct subject number 1004.

ii. Forms marked “Screening Visit,” “Week 1 Visit,” and “Week 4 Visit” all are dated October 31, 2006.

iii. There are two forms marked “Week 1 Visit” documenting the Children’s Depression Rating Scale Revised (CDRS-R) evaluation with two different dates, October 31, 2006 and November 8, 2006.

Informed Consent:

FDA Clinical Trial

FDA Approval Requires Sound Data

The Warning Letter goes on to list informed consent violations and failure to inform the IRB of changes in research activity, something I believe you will be seeing more of. None of these violations involve fraud, the topic in the previous two posts. However, they seriously jeopardize the quality of the research data and fully deserve FDA’s attention. The Division of Scientific Investigations (DSI) in the Center for Drug Evaluation & Research issued the Warning Letter.

Read the Warning Letter here:




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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FDA to Increase Criminal Prosecutions

March 7, 2010

FDA plans to increase the number of criminal prosecutions by the agency along with other measures to curb criminal violations of the Food, Drug, and Cosmetic Act. These aren’t intended for your every day criminal. instead, FDA wants to go after top officials in regulated industry. In my previous post I discuss FDA proposing new regulations for reporting the falsification of research data in the first significat rule change regarding clinical trials by the new FDA leadership. It seems that FDA’s leadership is focused on

criminal prosecutions and FDA

Should FDA Focus on Criminal Prosecutions?

expanding its use of the criminal jurisdiction FDA has had for decades. According to Alicia Mundy in the Wall Street Journal:

The Food and Drug Administration plans to increase prosecutions of pharmaceutical and food industry executives as part of an effort to refocus its criminal division, which has been under attack in Congress and is criticized in a new government report.”

The Office of Criminal Investigations

The Office of Criminal Investigations (OCI) is technically part of the FDA’s field organization, the Office of Regulatory Affairs. However, there is little contact between the field employees that conduct Bioresearch Monitoring and other regulatory inspections and the criminal investigators of OCI. During the 13 years that I worked in ORA after the criminal group was formed I met an OCI official only once. She was a former Secret Service officer and a very smart professional. However, she did not have extensive knowledge about clinical trials, which is why we met. FDA seems to want to improve the relationship between OCI and the rest of the Agency. The Government Accountability Office (GAO) issued a critical report regarding OCI to Congress last Thursday, March 4th. Responding in a letter to Congress FDA stated it wanted to:

FDA office of criminal prosecutions

FDA Office of Criminal Investigations

improve procedures for information-sharing between OCI and other Agency components with the goal of enhanced allignment of criminal/regulatory priorities and activities.”

The FDA letter also mentions increasing the “appropriate use of misdemeanor prosecutions” the item that has gotten most of the attention. This seems like a good idea and I’m all for prosecuting people who submit false data and commit other crimes. People who commit crimes are called criminals and white collar criminals have been neglected all too often. The letter also discusses the debarment of clinical investigators. The last item mentioned by the letter hasn’t received very much press attention when it states:

“Finally, the committee recommended that FDA improve the coordination of its response to cargo theft of FDA-regulated products, such as pharmaceuticals and infant formula. Potential threats include counterfeiting, diversion, tampering, adulteration, misbranding, theft, and terrorist acts.”

That sounds like serious stuff. I’m not sure that I consider FDA the right federal agency to take on all of that, but I’m a regulatory consultant, not a criminal one. FDA has limited resources, even with the

FDA criminal prosecutions

Is FDA the right agency to pursue cargo theft of pharmaceuticals?

proposed increase in funding (see previous post). On one hand these developments seem that they are addressing critical needs.

On the other hand, FDA is a Public Health and regulatory agency and the regulation of critical industries, such as banking, insurance, food, transportation, and pharmaceuticals, has suffered in the past decade. Increasing criminal prosecutions may be a very good thing. But will it come at the expense of modernizing FDA’s other regulatory responsibilities? All too often public health has suffered due to an increase in funding for criminal prosecutions. I believe the primary focus of FDA should be a public health focus on the regulation of food, drugs, vaccines, and medical devices. FDA should look into updating regulations for clinical trials and other issues such as a recall authority for adulterated foods.

GxP Perspective:

FDA leadership has said, “In some cases, the agency may need to modernize existing standards in order to address ambiguities.” I would suggest that there are existing ambiguities in FDAs clinical trial regulations. There hasn’t been a substantive rewrite of the Investigational New Drug (IND) regulations since March 1987. This is an item that I consider to be of importance. There have been revisions of certain parts of the IND regulations, but we are basically working with regulations that are over 20 years old.

FDA regulations

Are FDA's regulations for clinical trials up to date?

Most clinical trial professionals I know are not criminals. They are dedicated, highly motivated, hard-working professionals who would like to do the right thing, if FDA would tell them. The IND regulations have overly vague specifications on what an “adequate and accurate case history” is and I can’t count the times people have asked me the requirements for source documents. Definitions for common industry and regulatory terms such as “trial master file” and “adverse event” cannot be found in FDA’s regulations.

In addition, the business of running a clinical trial has changed dramatically in the past 23 years. There has been an explosion of clinical trial vendors and outsourcing. The industry is qualitatively different than it was in the 1980s. It would be good if there was a concrete regulation telling a sponsor on how to provide oversight of a clinical laboratory or an eCRF vendor. I certainly am glad to see that FDA is taking on white collar criminals with increased criminal prosecutions. I think it is the right thing to do. I’m also in favor of federal law enforcement agencies, including FDA, taking on the problem of the theft of pharmaceuticals and infant formula. However, we also need to update the regulations for law-abiding researchers. I hope that Congress and FDA gives this some attention as well.

You can read the Alicia Mundy article here:



Remember- YOUR comments are always welcome

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FDA Proposed Rule on False Data

March 1, 2010

FDA has published a proposed rule, “Reporting Information Regarding Falsification of Data” in the February 19 Federal Register. FDA wants to require sponsors to submit reports to FDA about false data, or the possibility of false data, within 45 calendar days after the sponsor becomes aware of the information. The proposed rule is open for comment until May 20, 2010. (A proposed rule is an FDA proposal to change an FDA regulation.)

Sponsor Responsibility:

FDA states that sponsors are in the best position to determine if there has been falsification of data used in

FDA Proposed Rule

FDA Proposed Rule

clinical trials or in nonclinical (GLP) research. FDA notes that “through their monitoring, auditing, and reviewing of data,” sponsors can spot false data that FDA might not detect during a bioresearch monitoring inspection.

FDA issued the proposed rule because current regulations are unclear on the need to report falsification of data to FDA. The proposed rule states that sponsors are “reluctant or uncertain as to whether it is necessary to report the information (to FDA).” FDA notes that sponsors have excluded data of a clinical investigator suspected of data falsification or terminated their participation in a study without stating the reasons. FDA is concerned that persons suspected of data falsification then continue to participate in other studies. FDA states:

“Taking effective action in response to falsification could lessen the magnitude and impact of the falsification in a current study, reduce the potential for delays or compromise to other studies and applications (including studies and applications from other sponsors for whom such a person might also be working), and protect the rights, safety, and welfare of research subjects.”

FDA makes these comments in the “preamble” to the proposed rule. The preamble is FDA’s explanation of why the proposed rule is necessary with definitions and clarifications of those reasons. The preamble is followed by the actual proposed wording of the changed regulations.

A Closer Look:

Such a person” is nicely put, but the proposed rule doesn’t address whether clinical trial vendors are included in their concerns. There is not an actual mention of contract research organizations, clinical laboratories, IVRS vendors, eCRF systems, etc. There is a reference to, “any confirmed or possible falsification by any person involved in studies conducted by or on behalf of a sponsor or relied on by a sponsor.” FDA is very clear they want to include the possibility of falsification.

The proposed rule discusses the serious reasons FDA is concerned with the falsification of data. However, the

Propose Rule Falsification of Data

Falsified Data is a Roll of the Dice

distinct impression that I had from reading the proposed rule was that FDA is primarily concerned with the activities of a principal investigator at a clinical site. There is no discussion of the possible root causes of data falsification. During my career I have been asked to conduct “for cause” audits where data falsification was suspected. I primarily found a confused, undertrained staff member making unintentional mistakes.

Then there is the very real problem of overworked and/or undertrained staff deliberately altering data in an attempt to satisfy a supervisor and keep their jobs. This can happen not only at clinical sites or nonclinical laboratories, but at the many vendors participating in research that are seldom inspected by FDA.

GxP Perspective:

FDA asks, “How does a sponsor become aware of data falsification?” They offer a few brief examples including the “monitoring review and evaluation of study data (e.g., noticing unusual data on case report forms and/or analytical reports).” After issuing Warning Letters to J&J and ICON Clinical Research, Inc. (see previous posts) it is clear that GxP professionals working for sponsors need to develop the techniques necessary to determine fraud. FDA told ICON:

“Study monitors failed to identify that on multiple occasions, site personnel documented administration of study drug to different subjects at precisely the same time.”

FDA proposed rule

A Failure to Monitor?

Stop and think about this. It is entirely possible for monitors to review different charts at different visits andnot discover this possible fraud. When I conduct site audits I rarely compare things such as the time of administration of study drug across different charts. I usually review one chart at a time (maybe I should change).

These are issues that need review of data listings and biostatisticians who can look for funny numbers that aren’t necessarily evident to monitors and auditors (and FDA investigators). We need to utilize a variety of tools and not depend entirely on monitoring visits and site audits. One possible unintended consequence of this proposed rule is that clinical sites will be audited to the point it becomes a regulatory burden, not a safeguard for data integrity and the protection of study participants.

Consequences of Noncompliance:

FDA falsification dataIt is interesting to note that FDA asks, “What are the consequences of not reporting confirmed or possible data falsification?” The answer should be sobering. It includes the possibility of a violation of 18 U.S.C. 1001. You will note that Title 18 of the US Code is not specific to FDA. It is the section of Federal law that includes the basis for felony prosecutions. Tough stuff.

Request for Comments:

FDA offers definitions of falsification of data, a definition of “data,” and a definition of unintentional errors. FDA also explains why they consider 45 days to be appropriate and a number of other issues. The comment period is used to clarify and seek input for these definitions and issues of concern to stakeholders and the public. The proposed rule lists several ways to comment. This is an important proposal for changing FDA regulations for food, drugs, biologics, medical devices, and veterinary medicines. It is an attempt to address legitimate concerns for public health and consumer protection. It deserves our attention.

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