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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Drug Accountability in Clinical Trials

January 19, 2012

clinical trials study drugs

Drug Accountability in Clinical Trials

Drug Accountability Is the one thing that everyone looks at and everyone ignores in clinical trials. I don’t know how many times I have read in a monitor’s report that “drug accountability not done due to time restraints.” Yet consistently “test article accountability” (as FDA refers to it) is one of the top findings on a Form FDA 483, Inspectional Observations, issued for clinical trials. In this Guest Commentary pharmacist Roberta Wong outlines the basics for clinical trial professionals. She concludes with six issues for clinical trial sites to consider. She is a consultant to biopharmaceutical companies and teaches at the Pharmaceutical BioEngineering Program at the University of Washington.

Guest Commentary by Roberta Wong, PharmD

Drug Accountability in Clinical Trials

It’s not exciting, it’s not cutting edge. It may be the last thing you think about when preparing for an FDA audit. You might scan the records and figure if all the lines are filled in, it must be okay. Or, the auditor might not look at it, so I will trust that the pharmacist did it correctly. After all, aren’t pharmacists one of the most trusted professions? Consider this: if drug accountability is in question, then the whole study could be in jeopardy. Proving that the drug was administered to the patient that resulted in the effects seen from study drug is a key factor in determining the merit of a product candidate. The FDA has listed drug accountability as #3 in a list of top 5 pitfalls.

drug accountability in clinical trials

What FDA Considers

The FDA uses these categories for determining the seriousness of a deficiency. Sometimes, minor sloppiness is due to poor record keeping. This can be corrected with training, and close follow-up to insure consistency amongst staff. Sloppiness, if bad enough, can cause removal of data from study results, impacting the overall quality of the data, and the integrity of the study conduct. Often unintentional, lack of attention to detail, and not understanding the importance of accurate recordkeeping in the drug application can contribute to a clinical trial site’s data being thrown out of a sponsor’s application. Training staff at the study initiation visit and checking the quality of the work during the course of the study is critical for good record keeping to be maintained during the clinical trial. Staff can change, so retraining may be needed as new staff members are added to an ongoing study.

drug accountability in clinical trials

Intent to Deceive?

On the other hand, some inconsistencies in drug accountability can be due to a true intent to deceive. Drug supplies that are listed as destroyed, lost, or dropped, can be traced to individuals diverting supplies for themselves, or with the intent on selling study drug to other individuals. Investigational drugs can also be switched in an attempt to give drug preferentially to certain patients, if there is also a placebo as part of the study. Limiting access to investigational drugs is a key role for the pharmacist in studies conducted at large institutions. At smaller sites, or individual physician’s offices, study drug may be held by research or nursing staff. In these situations, limiting access and providing locked security for study drugs is required by the study sponsor.

So, what happens when a clinical trial site has drug accountability problems? If this occurs during a clinical trial, the Sponsor will stop new drug shipments, and may suspend study enrollment temporarily. Visits to the site by the sponsor will ascertain the cause of the problem, and determine if re-training will prevent future issues. During this investigation, reviewing the records with the study coordinator and the prinicipal investigator are imperative. And of course, documentation of any meetings with site staff summarizing the corrective action is essential. Ongoing audits for the remainder of the trial will demonstrate that the interventions were successful, and the site is now compliant in maintaining accurate drug accountability.

drug accountability in clinical trials

"Shooting the Dice" with Your Clinical Trial?

Drug accountability is more than just counting pills and vials. Site staff must insure that the study subject receives the study drug, and receives the correct dosage. There should be documentation to support drug administration. If the patient self-administers study drug, often diaries and pill vials are collected to validate the administration of study drug. If the drug is administered at a clinic visit, there are often forms to complete to verify the dosage that was given to a study subject.

How can you avoid problems with drug accountability? First, make sure that all involved in the study are consistent with their documentation. Make sure that the records are completed with the drug dose, patient, date, time and individual removing drug from the central inventory. If study drug is administered in the clinic, the worksheet should note the date, and actual time that the drug was given. If drug is not administered, even though a dose was prepared, then a note should record that drug was destroyed. If study drugs require refrigeration, then the accountability records should have a place to note the temperature.

Lastly, issues with accountability need to be addressed quickly and a solution determined. Vigilance in accurate documentation will insure minimal issues. Making sure the patient received the proper dose is one more way to insure that well-run clinical trials produce good quality data.

How do you know if your system is set up to produce good drug accountability? Here are some questions that you can answer about your study.

Questions to consider:

1. Did the patient receive the proper dose? How do you know?

2. Did the Physician calculate the correct dose? Who double checked the calculation? Is it weight-based? Is the dose calculated at study enrollment? Is the dose recalculated based on the patient’s baseline weight or dose the dose change only if the weight changes by 10%?

3. Drug was sent to the clinic to prepare a dose, and the patient was a no show. Should the drug be signed back into the central inventory? (If the drug should be refrigerated, and you are unsure of how the drug was stored, what should you do?)

4. Drug was prepared for a patient who was a no show, but promised to come in the next day. Can you save the prepared dose and administer it the next day?

5. Does your clinical trial allow documentation of these issues in the study records?

6. For study drug accountability, who resolves new issues? Where do you record your answer? How do you train the rest of the staff regarding this issue?

Contact Robbie!

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FDA 483s: Effective Responses to Avoid Warning Letters

October 16, 2011

Responding to FDA 483

Effective Responses to Form FDA 483

An FDA inspection can result in a Form FDA 483, Inspectional Observations, being issued by the FDA field investigator. How you respond can determine whether the 483 will result in a Warning Letter, the primary form of FDA enforcement actions. How to respond to a 483 is a topic of discussion for regulated industry since the 483s arose in the early 1950s, originally as an attempt by FDA to respond to industry complaints that FDA didn’t inform industry about the field investigator’s findings prior to initiating an enforcement action (at the time primarily seizures, injunctions, and prosecutions). In this Guest Commentary regular GxP Perspectives contributors Emma Barsky and Len Grunbaum list the problems that FDA has found with responses to 483s and some proposed solutions.

Guest Commentary: One Way to Avoid a Warning Letter … Maybe

The following sentence fragments represent but a very small sample of trumpet calls heralding that a firm may have fumbled an opportunity to avoid a Warning Letter after receiving an FDA-483:

• “We have reviewed your response and have concluded that it is not adequate because…”

• “The adequacy of the response cannot be determined because the response did not include…”

• “Your response does not address…”

• “We have reviewed your firm’s response and note that it lacks sufficient corrective actions regarding…”

• “We have reviewed your firm’s responses; however we continue to have concerns related to your firm’s compliance…”

• “The adequacy of your firm’s response cannot be determined at this time…”

• “Your response is inadequate because…”

We say this because of the following: while a response to an FDA-483 is not mandatory and does not represent a final Agency determination regarding firm’s compliance, a firm’s voluntary response often does impact the Agency’s conclusion of the need for follow-up actions, one of which may be the much feared and dreaded Warning Letter. How so, you ask? Here is how….

FDA 483s and Warning Letters

"FDA will conduct a detailed review"

As the FDA indicates in section 5.2.7 of the Investigations Operations Manual, “If FDA receives an adequate response to the FDA-483 within 15 business days of the end of inspection [emphasis added]”, FDA will conduct a detailed review of the response before determining whether to issue a Warning Letter. Alternatively, responding late negates any chance that the FDA will consider the firm’s responses in its resolution regarding whether a Warning Letter is warranted and not responding at all, of course, has the same outcome as responding late.

This brings us to the quality of the response itself. In this context, the higher the “quality” of the response, the more likely the FDA will consider the response as “adequate” and, as a result, may not issue a Warning Letter. Since the firm’s management controls the quality and timeliness of everything that goes on, we suggest that the following guidelines be used to craft the response to the FDA-483 to increase the firm’s chances of avoiding the Warning Letter:

• Train the individuals involved in the FDA-483 response effort regarding what information should be included in the response and the format chosen to present the response.

• Assign someone to review recent FDA Warning Letters to identify those items where the FDA indicates that the response to the respective FDA-483 was not adequate and include these items in the training to ensure that known mistakes/failures are not repeated.

FDA 483 response

Focus Your Response

• Focus on evaluating the extent of the observation in terms of whether the issue could have potentially impacted data integrity, and, if so, whether the issue is systemic (e.g., how many studies, batches, sites, etc. could be possibly affected). This is the most important point to address in terms negating the observation or softening the impact of the observation. If an observation points to actual data integrity issues, these issues need to be brought to the attention of the respective sponsors, where applicable, and responses to the FDA should be discussed with them first.

• Establish the true root cause of the observation. In doing so, look for the operational gap (e.g., inefficient project management oversight) that resulted in the regulatory deficiency (e.g., lack of timely document reviews and/or approvals) so that it can be fixed properly and permanently.

• Provide specifics regarding any corrective actions taken or proposed. It is not adequate to state that the problem was or will be corrected. Details regarding 1) what was/will be corrected (e.g., development of a remediation plan), 2) when it was/will be completed and 3) if applicable, the timeframe for training (e.g., as in case of a revised procedure) should be provided.

• Describe preventive actions that will minimize or eliminate the chance of recurrence of the problem in the future.

• Provide supporting documentation for every claim made.

• Show commitment regarding implementing all of the proposed activities by 1) specifying activities to be taken and target dates for their completion, 2) assigning accountability for the actions, 3) ensuring proper completion of each respective activity though internal audits.

effectively responding to a 483

The Importance of a Quality Response to FDA 483s

The quality of the response to the FDA-483 is also important for another reason: groups like FOI Services request the Establishment Investigation Reports (EIR) and FDA-483s through the FOIA, so this information eventually winds up in the public domain.

The firm can request that its FDA-483 response be published along with the FDA-483 itself, in which case the response should be such that it gives confidence not only to the FDA but also, where applicable, to existing and potential clients, that non-conformities have not and do not impact data integrity.

The bottom line is this: Do not ever get yourself in trouble with the FDA. But if you do, avoid unforced errors by 1) taking the time and making the effort to respond to the FDA-483, if you get one, in a timely fashion, 2) using the guidelines above in doing so, or 3) consulting with an expert to assist.

By Emma Barsky and Len Grunbaum, the partners of The Practical Solutions Group, LLC

Contact Emma & Len

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ExL Pharma has announced that FDA’s Dr. Leslie Ball will give the Keynote Address at the 2nd annual Developing CAPAs in the GCP Environment conference held 19-20 January in Arlington, VA. GxP Perspectives is a media sponsor.

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Read FDA Warning Letters A suggested practice is to search Warning Letters by topic or issuing office. Then sort by “Letter Issue Date – Desc” to find the most recent Warning Letters.

19 October 2011 update: FDA posted a Warning Letter to SmithKline Beecham (GSK), West Sussex, UK for serious cGMP violations stating: “Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile.”

Read the Warning Letter

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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. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

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On The Blogroll: Rebar Interactive (twitter: @rebarinte) has an excellent blog for clinical sites. If nothing else you MUST check out their post on:
“Patient Recruitment: Think That You Might Be Wrong,”
if for nothing else than the photo. A great blog post by Rahlyn.
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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 Enforcement: The Four Elements of Proof

April 16, 2011

The four elements of Proof FDA

FDA Enforcement:
The Four Elements
of Proof

What is FDA required to document to initiate an enforcement action? What proof is necessary to establish clear and significant violations of the regulations? What elements of noncompliance do FDA field investigators need to establish that a Warning Letter, seizure, injunction, consent degree, or prosecution is required? FDA has basic requirements that should be documented during an inspection: they are called the Four Elements of Proof. When reviewing a Form FDA 483, Inspectional Observations, it should be compared against these basic required elements for consistency, relevancy and significance. Let’s look at the Four Elements of Proof, sometimes referred to with the acronym JIVR.

FDA four elements of proof

Does FDA Have Jurisdiction?

JURISDICTION: For FDA to take an enforcement action, it needs jurisdiction. We know that FDA regulates drugs, medical devices, and biologics/vaccines. However, It isn’t always simple. There is a strict definition of “drug” in the Food, Drug & Cosmetic Act. That is the reason FDA lost at the Supreme Court with the first attempt at asserting jurisdiction over tobacco in the 1990s. It was “a question of intent,” which is also the title of former Commissioner Dr. David Kessler’s fascinating book on his time at FDA. Laws and regulations usually have a section for “definitions.” Take some time to read them. It will help you understand the way FDA interprets inspections and when to seek enforcement actions.

FDA enforcement four elements of proof

An Early FDA Inspection: Railroad Watering Points

INTERSTATE COMMERCE: One of the principal functions of the United States government is to regulate interstate commerce. Railroads were the principal means of interstate transportation when FDA was founded and an important area of FDA concern. And just try to document medical oxygen in interstate commerce. I once had a promotion delayed for three months because as a Bioresearch Monitoring investigator, I was dealing with the biopharmaceutical and medical device industries where interstate commerce is basically assumed. So I had to go out to a couple of medical gas repackers and collect DOC Samples (a DOC sample consists of paperwork, not a product) to establish that I could document interstate commerce. (See Warning Letter Below for Interstate Conveyance Sanitation.)

four elements of proof

What is the Violation?

VIOLATION: There should be a “clear and significant” violation of the regulations to put something on a 483 or Warning letter. If the laboratory normal range for the inclusion/exclusion criteria for blood glucose is 80-120 Mg/DL and the result is 121 that is a clear violation. Is it significant? I think not. Determining significance is not an easy task. It is something that may need discussion during an FDA inspection. Patient, professional discussion of the issue is usually the best approach. Your FDA field investigator may not have experience in the specific therapeutic area or technical issues of the inspection. It isn’t always easy conducting an FDA inspection and establishing the four elements of proof and the significance of the violation. And remember, You cannot determine the root cause of a problem if you don’t know what the violation is. What is the Violation? Find it in the regulations.

FDA four elements of proof

Regulations Assign Responsibility

RESPONSIBILITY: Regulations assign responsibility. In clinical trials they are assigned to sponsors, investigators, and IRBs. In GMPs and postmarket activities responsibilities are assigned to the “applicant” and the manufacturer of a regulated product. In the GLP regulations, responsibility is assigned to the testing facility. Responsibility is a Big Deal to an FDA investigator. It is just as important to ask, “Whose regulatory responsibility is it?” as it is to ask, “What is the Violation?” Without regulatory responsibility you cannot determine who should recommend the actions necessary to correct a regulatory error.

There you have it. The four elements of proof. The basic requirements for FDA enforcement.

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Interstate Conveyance Sanitation Warning Letter
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News from FDA: There is a new Proposed Rule (proposed change in regulations) from FDA on the Disqualification of Investigators. This proposed rule modernizes and harmonizes current regulations. The Final Rule will probably look quite similar.
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On the Blogroll: GxP Perspectives made the list for Top 40 Websites (and tweets) on the FDA. This comes from FDAZilla. I think it is a pretty good list.

Also: David Spero has an excellent post called The Art of Motivation on his blog. This isn’t about regulations, its about people.

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FDA Warning Letters to International Companies for CAPAs & Complaints

November 28, 2010

FDA warning letter CAPA complaint

Warning Letters for CAPAs & Complaint Investigations

In the past 90 days FDA issued five Warning Letters to international firms for GMP failures to adequately investigate complaints. Whether it is GMPs, GCPs, or GLPs FDA is making the case that when things go wrong, it is a company’s responsibility to investigate and implement the necessary corrective and preventative action (CAPA), In the past, FDA was hesitant to issue Warning Letters to firms outside the United States. That clearly is changing as both the Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation and Research (CDER) have issued Warning Letters to companies in Canada, Switzerland, China, Sweden, and India. Although the companies are from diverse locations and range from medical devices, active pharmaceutical ingredients (APIs), and finished pharmaceuticals, one issue connects them all: the failure to adequately address complaints. For the medical device Warning Letters, corrective and preventative actions (CAPAs) figured prominently.

FDA first opened international offices in 2008 in India and China and now has offices in Europe and Latin America as well. The international offices are predominantly focused on GMPs for food, drugs, and medical devices. FDA has also stepped up its inspections of clinical trials in international locations including Russia and Eastern Europe. However, there has not been the corresponding surge in Warning Letters. At least not yet. Here are charges that FDA made in the international Warning Letters:

CAPA complaint FDA warning letter

Failure to Investigate Bacterial Contamination

Claris (India): On April 15, 2010, your firm received a complaint from a U.S. distributor (Sagent Pharmaceuticals) informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a swirling mass, which the complainant identified as the fungus Cladosporium species. There is no information in the Complaint Investigation Report to show that Claris initiated an investigation to determine the root cause and extent of the problem until April 26, 2010, when Claris received this contaminated large volume parenteral and examined it.

Storz Medical (Switzerland): Failure to establish and maintain adequate procedures for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4). For example, no protocol, including acceptance criteria, was established for the validation of Change Request (b)(4). Additionally, there was no documentation showing that this change was validated. The change was implemented to fix cracked cooling pumps in the Modulith SLX-F2.

The Warning Letter goes on to say:

international complaint investigation failure FDA

Failure to Establish Procedures for Complaints

Failure to establish and maintain adequate procedures to ensure that any complaint involving the possible failure of a device, labeling, or packaging to meet any of its specifications shall be reviewed, evaluated, and investigated unless such investigation has already been performed for a similar complaint and another investigation is not necessary, as required by 21 CFR 820.198(c).

Neoventa Medical AB (Sweden): 1. Failure to establish and maintain adequate procedures for implementing corrective and preventive action that include requirements for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device and that all activities required under this section and their results be documented, as required by 21 CFR 820.100(a)(4) and (b).

2. Failure to establish and maintain adequate procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).

Once again the direct connection between the failure to investigate complaints and the failure of a system of CAPA.

FDA Warning Letters CAPA

Chinese API Manufacturer Hit with FDA Warning Letter

Yunnan Hande (China): Failure to thoroughly investigate complaints for APIs batches that do not meet the United States Pharmacopeia (USP) compendial requirements that may have been associated with the specific failure or discrepancy. In addition, your investigation was not extended to other batches that may also be affected.

Pega Medical (Canada): Failure to establish and maintain the requirements, including quality requirements, that must be met by suppliers, contractors, and consultants, as required by 21 CFR 820.50(a)… For example, Complaint NCR No. (b)(4) reported…”

Read the Warning Letters:

Storz Medical, AG Warning Letter

Yunnan Hande Biotech Warning Letter

Claris India Warning Letter

Pega Medical Warning Letter

Neoventa Medical AB

FDA International Resident Posts

And What About Clinical Trials?

At a recent FDANews conference FDA representative Ann Meeker-O’Connell, M.S., Division of Scientific Investigations, Office of Compliance CDER/FDA, said,

FDA warning letter international complaint investigations

Clinical Trial CAPAs Face Different Challenges

“But, clinical trials are inherently variable systems with a goal of producing reliable data for regulatory decision-making . . . How can this be reconciled with a quality system framework originating in mass manufacturing?”

That is a very good question and one that many of us have been wrestling with. However, it is clear that FDA has been taking on the question of the international nature of the drug and device industry, including manufacturing and clinical trials.

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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.

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

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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.

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.

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FDA Guidance: FAQ for In Vitro Diagnostic Devices (IVDs)

September 27, 2010

FDA FAQ IVD

FDA Guidance: FAQ for
In Vitro Diagnostic
Medical Devices

In Vitro Diagnostic medical devices (IVDs) have long occupied a poorly understood sector of clinical trials. Now, a recent FDA document, Guidance for Industry and FDA Staff: In Vitro Diagnostic (IVD) Device Studies- Frequently Asked Questions (June 25, 2010) clears up many questions. The FAQ offers resources including the definition of many basic IVD and medical device terms. Examples include the FDA definition of the difference between Invasive and Non-Invasive and the difference between a Significant Risk and Non-Significant medical device. The FAQ gives FDA contact information for IVD review divisions and the conduct of clinical trials. Most importantly, the FAQ discusses how IVDs meet the criteria for exemption from most requirements under medical device clinical trial regulations.

The FAQ discusses the requirements for the emergency use of investigational IVDs. It also discusses the differences in informed consent requirements between FDA and the U.S. Department of Health and Human Services which funds NIH studies. Frequently researchers think that if a study is exempt under DHHS regulations (Title 45 Part 46) that the study is exempt from FDA informed consent regulations found in 21 CFR Parts 50 and 56. FDA requires IRB and informed consent even if studies are exempt from most requirements of 21 Part 812.

The FAQ also discusses use of data collected from studies conducted outside the United States. The FAQ gives the following guidance:

“… the PMA regulation, 21 CFR Part 814, allows foreign data to be used as the sole support of a marketing application but only if (1) the data are applicable to the U.S. population and to U.S. medical practices, including laboratory practices, (2) the studies have been performed by clinical investigators of recognized competence, and (3) the data may be considered valid without the need for an on-site FDA inspection or, if necessary, FDA can validate the data through an on-site inspection or other appropriate means (21 CFR 814.15(d)).

For IVD devices, FDA would consider differences in population demographics, disease prevalence, disease presentation, laboratory practices, and medical standards of care. If the sponsor plans to submit an application based solely on foreign data, FDA recommends that the sponsor consult with the reviewing division prior to submission of the application.“

FAQ FDA IVD

ICH Good Clinical Practice Can Also Apply to Medical Device Studies

The FAQ endorses ICH E6: Consolidated Guidance on Good Clinical Practice as a sound guidance document with sections applicable to medical devices as well as pharmaceuticals. It also discusses the draft ISO 14155 document:

“Although the ICH document was written for studies of pharmaceuticals, sections of the guidance address study issues common to all investigational products. Thus, these sections of the ICH GCP provide a useful reference regarding the proper conduct of studies.

The draft ISO document specifically states that it does not apply to IVD devices. The draft ISO document is an international document intended to reflect basic practices appropriate to clinical trials worldwide. It does not include all of FDA’s specific requirements for clinical studies and is not presently a standard that FDA has officially recognized; therefore, we do not recommend that you rely on it.“

IVD In Vitro FDA FAQ

Appendix 2 Shows Requirements for IRB Approval and Informed Consent

The FAQ has two charts, Appendix 1 and Appendix 2, that clear up decision making for IVD exeption criteria as well as informed consent requirements. And in keeping with current FDA clinical trial policy the FAQ emphasizes the use of quality systems for IVDs. The FAQ and two other relevant FDA guidance documents are below:

FAQs for In Vitro Diagnostic Devices

FDA Guidance on Informed Consent for IVDs Using Leftover Human Specimens

Comparison of FDA (21 CFR 50 & 56) and DHHS (45 CFR 46) Regulations

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UPDATE: My favorite industry magazine, Applied Clinical Trials, now has a LinkedIn Group:
Applied Clinical Trials LinkedIn
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Read the updated article on the Form FDA 1572 in:

Applied Clinical Trials “Closing Thought” on FDA 1572

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Part 11: It’s Back

July 14, 2010

Part 11 FDA

FDA To Resume Enforcement of Part 11

FDA has announced that “The Agency (FDA) will be conducting a series of inspections in an effort to evaluate industry’s compliance and understanding of Part 11 in light of the enforcement discretion described in the August 2003 ‘Part 11, Electronic Records; Electronic Signatures — Scope and Application’ guidance (Guidance).” This is a big deal. It has been seven years that FDA has debated Part 11 and began using “Enforcement Discretion.” The Agency announced that: “The Agency expects to begin conducting the Part 11 focused inspections soon.” Part 11, Electronic Records; Electronic Signatures has been one of the most confusing and controversial regulations FDA has ever written. I am now trying to find a Part 11 specialist to let us know the meaning of it all. Read what FDA has to say:

FDA Part 11 Announcement

UPDATE: Read the 25 July Guest Commentary on Part 11 by Len Grunbaum & Emma Barsky

The early report: The best report so far: Angie Drakulich goes into further detail on the changes including an interview with FDA in her report in the blog, PharmTech Talk

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The Blog has just been put on the expanded Top 50 Health Blogs list, which I truly appreciate. However, they constantly change their links to keep it current. Currently I am not there although there are other interesting posts. I now have two “Top Fift” links on the Blogroll.

50 Top Health Blogs

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Problems With FDA: Process for Complaints

July 8, 2010

FDA complaint process

How Do You File a Complaint About FDA?

Lately I have encountered colleagues and clients who have had problems with an FDA inspection. One result is that they do not know the process to file a complaint or they fear retribution if they do complain about an FDA inspection. I discussed this briefly in a previous post on how long an FDA inspection should take. But it is more than the length of the inspections. It is that some FDA field investigators are not prepared for conducting an inspection in a clinical trial’s therapeutic area and that a few field investigators (a very small minority) use abusive inspection tactics. Fortunately FDA has a process for fielding complaints. Here is what they say, in FDA’s inimitable manner:

“If you believe an FDA employee is not following FDA’s Good Guidance Practice regulations (21 CFR 10.115) or the Office of Management and Budget’s Bulletin No. 07-02(M-07-07) Final Bulletin for Agency Good Guidance Practices (January 18, 2007), you should contact the employee’s supervisor in the issuing office or Center. If the issue is not resolved, contact the next highest supervisor or the Center’s Ombudsman. If the issue is still not resolved, contact the FDA’s Office of the Ombudsman at:

FDA Office of the Ombudsman
5600 Fishers Lane, Rm. 13B-07
Rockville, MD 20857
Phone: 301-827-3390
Fax: 301-480-8039
Email: Ombuds@oc.fda.gov

We have redesigned the FDA Web site. As a result, some Web links (URLs) embedded within guidance documents are no longer valid. If you find a link that does not work, please try searching for the document using the document title. For more assistance, go to Contact FDA.”

I would like to note that you can use the Office of the Ombudsman confidentially if you choose.

UPDATE: I have had two very good comments on this topic. You can read both, with my responses on the comments page. I welcome your comments as well. One comment is from a European colleague, Eldin Rammel, and the other is from former FDA National Expert Bob Coleman, who certainly has more experience on this than I do. I thought it should come up from the comments page. Here is Bob’s advice:

Carl, I am painfully aware that there are some FDA personnel that often overstep their authority while conducting investigations/inspections. While I was with the FDA, I often would receive information to that effect from various companies, many of the complaints for the most outrageous allegations. My response to them was that they needed to arrange for a meeting (face-to-face) with the Director of Investigations (if it was a foreign firm) or the District Director for domestic facilities to discuss the details of what happened for resolution. Unfortunately, many do not choose to do so (perhaps out of a sense of retribution – which if that ever occured would be intolerable). I have advised those impacted that unless they take their complaint directly to FDA, then nothing can or will be done.

Bob

On a different note I am going to discontinue the “Facebook Fans” site because of privacy concerns. I have started a LinkedIn Group which I hope you will join. LinkedIn is a more secure site than Facebook currently is.

GxP Perspectives LinkedIn Group

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