Quantifying Quality for GxP Compliance

April 8, 2012

quantifying quality GxP

Quantifying Quality

GxP professionals understand the need for quality and quality system and we discuss quality with one another on a daily basis. But how do we measure it? How do we quantify our results? Once again we turn to Len Grunbaum and Emma Barsky, regular contributors to GxP Perspectives, for their insight on how to quantify quality for the development manufacture, and distribution of health products such as drugs, medical devices, and biologics.

Quantifying Quality

In its simplest form, the definition of “quality” is “how good something is.” But what exactly does this mean for the life science industry, whose frame of reference is defined by regulations which are often vague and which provide little or no guidance regarding how they should be implemented?

In light of this, we would like to offer some ideas regarding how to measure – quantify – how good your “quality” is in tangible and practical terms. We contend that such metrics are useful in order for company management to make sound decisions regarding whether and/or where the quality system (i.e., the operational infrastructure that promotes and facilitates “quality”) requires improvement. The following key indicators are not all-inclusive (nor are the items mutually exclusive), but they provide meaningful ways to assess your “quality”:

• Number of successful external and internal audits as a percentage of the total number of external and internal audits: the higher the percentage of successful external audits (e.g., by existing/potential clients, regulators), especially when you have a large number of them, the better your “quality.” Passing one audit with flying colors is great but passing multiple audits with few minor or no observations is way better. It not only sets a trend regarding “legitimate” quality but it also validates the company’s degree of quality from different perspectives. This scenario allows any company to claim that its quality system has withstood scrutiny from a variety of companies and/or regulatory agencies over a long period of time.

While “looking good” to the outsiders is great, “feeling good” about what is under the covers is even better. Therefore, if thorough internal audits do not find any issues that either directly (critical observation) or indirectly (major observation) impact subject/consumer safety and/or data/product integrity, then “quality” is inherent to the operations.

GxP quality quantify

Measurements for Success

You may wonder how a subjective term like “success” is defined in this context. Fair question. A result of “no audit findings” (e.g., no FDA 483s, no audit observations) is the clearest measure of success. A relative handful of “minor/cosmetic” issues is not perfect but is certainly acceptable in this context. To the extent that the number of observations may be “critical” or “major,” as defined above, the audit will certainly be viewed as less successful or even unsuccessful. One should also remember that it is a common thing in the industry to consider a large number of minor observations as a major issue because this scenario gives an impression of a negative trend, the latter of which is not conducive to having quality operations.

Number of “directed” (i.e., “for cause”) audits as a percentage of total audits: because directed audits are performed to follow up on actual or perceived regulatory compliance problems, the higher the number of “directed” audits, the more questions will be raised about your “quality.” “Directed” audits could be external (i.e., performed by existing clients or regulatory authorities) or internal (i.e., performed by internal quality staff). The higher the number of problems confirmed, the weaker the quality system. Even if these types of audits indicate in general that there are no actual problems, or a minimal number of problems, a large number of such audits should prompt questions regarding why the perception exists that the degree of “quality” is such that an investigation is required.

quality

Number of Investigations

Number of investigations/CAPAs: an investigation is a formal and documented process performed to gather information (e.g., root cause, impact) regarding a specific problem encountered (e.g., a customer complaint, a missing controlled document) and which, depending on the outcome of the investigation, may lead to corrective and preventive actions. An “excessive” number (the definition of which is admittedly subjective in nature) of investigations, even if satisfactorily completed and closed, gives an impression that the underlying cause has never been properly identified and/or corrected.

Number of repeating issues as a percentage of the number of audits performed: repeating issues are symptomatic of a quality system that does not correct or otherwise effectively address problems. While isolated incidents are not necessarily a reflection on the company’s overall quality, incidents that span multiple project teams and/or departments and/or are observed more than once may be indicative of quality-related problems. It is very difficult to convince anyone of the quality of operations when problems that are systemic in nature become evident.

The higher the percentage of audits that contain repeating issues, the more likely that this may be viewed as 1) management indifference, 2) lack of management involvement, 3) inappropriateness of personnel qualifications and/or 4) inability/unwillingness to invest in “quality.”

quantify quality GxP

Lost Business

Number of business opportunities lost due to unsuccessful external audits as a percentage of the number of external audits: audits are sometimes performed as a basis for determining whether a business relationship should be consummated or continued (e.g., you will be chosen as a vendor/supplier, an existing relationship will be sustained) or expanded (e.g., a company will be awarded additional projects). Some life science companies (e.g. pharma, biotech) have to get clearance from the FDA prior to being able to market their product. Support companies (e.g., CROs, contract manufacturers) may have to undergo due diligence inspections to establish/maintain/enhance a business relationship. The higher the percentage of such opportunities lost (e.g., loss of a potential or existing client, project cancelled/not awarded, FDA did not grant an approval) because of poor audit results, as a percentage of external audits performed, the stronger the indication that your “quality” is dangerously weak. This, in turn, has a financial “bottom line” impact on the company: loss of business opportunities can also be translated into wasted R&D cost and/or lost anticipated revenue, both of which become a major risk to the company’s financial health.

In addition to the items listed above, there is another important quantifiable component to “quality,” which is too often being overlooked or not being considered at all. This component is what we define as “the monetary expenditure associated with ‘quality.’” Namely, we are talking about an operationally quantifiable parameter – cost of establishing and maintaining “quality” operations. Most will argue that “quality” is very expensive no matter what. We firmly believe that it does not have to be that way if the underlying causes, which directly and unnecessarily contribute to the extra cost of doing business, are either eliminated or minimized. Here are a few examples to give you a flavor of what can contribute to increased costs when it comes to meeting the regulatory responsibility of instituting and sustaining “quality”:

Regulatory compliance decisions that are not defined in writing and/or are not defensible.

Cumbersome and inflexible procedures that require more resources than necessary to execute them without “procedural deviations.”

Inefficient procedures that require the same activity to be done more than once in order to be in compliance.

Ineffective procedures that do not reach the desired objective of being in compliance after the first execution.

Unclear procedures that result in too many on-going corrections in order to inject “quality” into operations.

Too many procedures that company staff must follow without any value added.

Contradictory procedures that lead to generating Notes-To-File, CAPAs, deviations, investigations, etc. because compliance to one procedure results in non-compliance with one or more other procedures.

GxP Quality

The Costs and Benefits of Quality

The above-listed activities not only translate into the need to spend more time and money in an attempt to have operational quality, but a number of these items translate into further quality-related costs to the company. Examples of the latter include, but are not necessarily limited to, taking the time to respond to observations or even worse yet, an FDA-483 or a Warning Letter. We think the point we are trying to make is clear…

Our bottom line is that you can make both your QA and CFO happy by quantifying “quality” in terms that will be understood and appreciated by both. This means that sound decisions can be made regarding whether and/or where to apply precious company time and resources help ensure that your “quality” is as good as it can be without putting the business out of business.

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

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In News from FDA: Yet another weight loss danger in Japanese “rapid weight loss” pills. Read the story: foodconsumer.org

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Clinical Labs & GCP

June 12, 2011

FDA lab GCP

GCP for Clinical Laboratories

How to assess clinical laboratories for GCP compliance is one of the more difficult issues facing GxP professionals. Is CLIA the gold standard? How do the good laboratory practice (GLP) regulations impact clinical labs? Isn’t there a handy checklist out there somewhere? What do people mean by “GCLP?” I have been dealing with this issue a lot of late and people are really all over the map. Here are some of the approaches I take, along with a handy-dandy reference list at the bottom of the post.

First, let’s look at the easy part. The primary regulation dealing with clinical laboratories is the Clinical Laboratory Improvement Amendments (CLIA). Wow, that’s simple. However, CLIA specifically states that it does not have jurisdiction over research. CLIA covers the day-to-day laboratory tests that your doctor orders to check up on your cholesterol or hematocrit. For these routine tests, FDA recognizes CLIA certification as an acceptable standard. FDA also recognizes other certifications such as from the College of American Pathologists (CAP). However, FDA does not have its own laboratory program. No, the GLP regulations (Part 58) just don’t apply here. My advice is to keep them on the shelf.

GCP Lab FDA

Research Continues into New Laboratory Methods

However, things can get more complex. Not all laboratory tests are CLIA certified, there is a whole lot of research going on out there. Research methods are being developed every day. To make matters worse, just because a lab is CLIA or CAP certified, it does not mean that they have clinical trial experience and knowledge of kit building or blinding procedures. You need to go to their laboratory and see if they are equipped to perform the tasks in your statement of work. You need to perform a chain-of-custody tour to determine that your samples will be handled and analyzed in an appropriate manner, if there is “quality control at each stage of data handling” (ICH E6 Section 5.1.3).

One document that will come in handy is the FDA Guidance for Industry: Bioanalytical Method Validation. If you have a new laboratory method, it should be validated. What about an audit plan? I use the European Medicines Agency (EMA) GCP Inspection Guidance on Clinical Laboratories (Annex II). Links to both of these documents are listed below. The important thing to remember is that you have critical safety and efficacy endpoints being evaluated by the lab and they are highly importance to your study. Give the laboratory the attention it deserves.

GCP lab clinical trials FDA

Tour the Laboratory

Chronological order is a useful tool in assessing a laboratory. Follow the route of the samples starting with kit building, shipment to the sites, receipt from the sites and how they make it through the laboratory. Remember, the majority of laboratory errors take place Before sample analysis, in the pre-examination phase (source: CDC). In addition, there are more errors reported in the post-examination phase than the examination phase itself. Reporting is of critical importance. Your NDA or PMA might depend on the accuracy of those reports.

I have seen many checklists for conducting clinical laboratory audits. Most of them have issues that can impact their effectiveness. Your audit should be protocol-specific. The lab needs to be able to conduct the analyses required by the protocol. That’s why I use the EMA GCP Inspection Guidance for Clinical Laboratories as a basic audit plan. EMA has a GCP inspection program for clinical labs. Another important point is that not only do you need to pre-qualify a lab, you need to go back during the trial and audit live data. This is true for any critical vendor.

GCP Lab

There are a number of resource documents available

Many organizations are working on the clinical laboratory dilemma. You will hear the term “GCLP” quite a bit (for good clinical laboratory practice). It is important to remember that there is not one consistent standard on what GCLP is. Wouldn’t it be nice if we did have a consistent GCLP standard recognized by the world’s regulatory authorities? Here are some important references for clinical labs and GCP. Feel free to make additions to this list in the Comments section below.

EMA GCP Inspection Guidance for Clinical Laboratories

FDA Guidance for Industry: Bioanalytical Method Validation

College of American Pathologists Website

Clinical Laboratory Improvement Amendments (CDC)
(This site has links for genetic testing and Waived Testing)

GCLP – UNICEF, UNDP, World Bank, & WHO

MHRA: Good Clinical Practice for Clinical Laboratories – (Please see the comments/discussion on this.)

On The Blogroll: Dark Daily: News for Clinical Laboratories & Pathology Groups

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Draft Guidance: Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology. This guidance is open for public comment for 60 days (approximately August 7).
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FDA has announced a new draft guidance document. Public comment is due by 25 July 2011:

Guidance for Clinical Investigators, Industry, and FDA Staff: Financial Disclosure by Clinical Investigators

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FDA

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GxP Audit Techniques & Etiquette

May 29, 2011

audit GxP

GxP Audit Techniques and Etiquette

Auditing for quality assurance purposes or for an independent quality assessment has become a necessity for GxP Professionals in the highly regulated life sciences industry. Many companies have highly developed SOPs for auditors but there is no consensus on the basic behaviors of auditors. In this Guest Commentary veteran GxP Consultants Emma Barsky and Len Grunbaum offer their perspectives on how auditors should behave when conducting audits that can easily impact people’s jobs and reputations. I firmly believe that auditors should take their approach very seriously. Recent experiences of my own indicate it is a topic well worth review.

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GxP Perspectives will be taking a break for a few weeks. Everyone should take a break now and then.
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Guest Commentary by Emma Barsky & Len Grunbaum

As consultants in the life science industry, we often serve in the capacity of audit hosts for companies and, as such, have a greater exposure than most to various audit behaviors. We therefore are rarely surprised by inappropriate audit conduct.

GxP audit technique and etiquette

"I put three people
in jail
."

But even our eyebrows were raised when a third-party auditor, who was representing a company doing business with our client, started the audit with, “I put three people in jail.” Was she showing off and justifying her credentials? Was she trying to intimidate our client and us? Both? The result was that no one in the room was impressed or made nervous by such an introduction. If anything, her attitude provided the inspiration for this blog Guest Commentary.

In light of having to conform to technical and ethical standards of one’s profession, an auditor represents himself/herself and group/department he/she belongs to for sure. More importantly, however, the auditor also represents his/her company as a whole, even if representing the auditing company in the role of a consultant. Given that the auditor is often viewed as the company’s due diligence “eyes and ears,” every word and every move that the auditor makes is a reflection on the company he/she represents and on the employees of that company.

So what should one consider when it comes to the audit preparation, conduct and follow-up? Based on our experience (both good and bad), the following tips regarding audit etiquette, if put into practice, will usually leave the auditee with positive impressions regarding the auditor and the company he/she represents, irrespective of the audit’s outcome:

Be prepared – learn as much as you can in advance about the company you will be auditing. At a minimum, this can be accomplished through:

1) reading about the company on its website,
2) having a discussion with those groups and/or individuals who intend to use the company to be audited,
3) doing an internet search to see if there is anything of interest regarding the company to be audited (e.g., warning letters, legal actions), and
4) reviewing previous audit reports if applicable and available.

audit technique GxP

Preparation:
"An audit agenda is the first document the auditee will see"

Stay focused – develop an audit agenda that will center on the business reason(s) for the audit (e.g., qualification/due diligence audit, “for cause” audit, follow-up of a previous audit, investigation). An audit agenda is the first document that the auditee will see, and from this will form an opinion regarding the auditor. Therefore, it is best to have a detailed agenda that is customized in terms of the basis for the audit. This will:

1) demonstrate the auditor’s understanding of the nature of the auditee’s actual and/or potential support as it relates to the auditor’s company,
2) be indicative of the fact that there is no hidden agenda on the part of the auditor, and
3) set the tone for the auditor’s own expectations regarding thoroughness of the auditee’s preparation for the audit.

Be timely – if possible (e.g., you are not conducting a “for cause” audit or an investigation), send the audit agenda to the auditee at least two (2) weeks in advance of the audit. While a company should be prepared for an audit at all times, a timely agenda:

1) allows the auditee time to gather correct and complete information in advance of the audit,
2) permits the auditee to identify and schedule the appropriate individuals who will provide information during the audit, and
3) establishes the auditor’s own standard regarding timeliness for the auditee to provide requested information.

Dress appropriately – while many companies have a casual dress code, we believe that an auditor should always be dressed in a suit because this is a sign of respect and professionalism even in today’s “less than formal” work environment.

GxP audit technique

Avoid Surprises

Avoid surprises – information regarding the number of people attending the audit should be communicated to the auditee as far in advance as possible. More than once, we have seen instances where more people than expected showed up for an audit without warning. Even if the number of people to be hosted changes at the last second, it is the auditor’s responsibility to let the auditee know about it. Anything less than that is viewed as unprofessional.

Be sensitive – recognize the fact that audits are stressful in that they take away from the auditee’s ability to do billable work. Therefore, to maximize on your own effort while being conscious of the auditee’s availability, have all of your questions prepared in advance of interviews (e.g., after reading SOPs or other documents so the questions can be detailed and specific) to minimize the interview time and be flexible if the times for the interviews have to be changed on the spot.

Be fair – sometimes issues are very complicated and overlap multiple processes and/or organizational groups. Thus it is only fair to split the responsibility for misunderstandings/miscommunication and activities “going amiss” between the auditee and the company on behalf of which the audit is being performed.

GxP Audit techniques

Be Fair
'From what we have observed, the auditees often get all the blame'

From what we have observed, the auditees often get all the blame, even though the fault may not be entirely theirs. If you position yourself as someone who takes no sides and listen to all parties involved, you will be in a better position to identify the root cause of the issue(s) and, as a result, help the company you represent to resolve/mitigate them no matter whose fault it is.

Know your stuff – be well-versed with respect to the applicable regulations and be versatile in how regulations can be applied operationally, while still maintaining compliance, in the areas you are auditing.

Be open-minded – if you have not seen a regulation being addressed in a certain way, it does not mean that it presents a regulatory compliance problem. If it ever happens, your only job is to determine whether the unconventional approach, chosen by an auditee, may result in potential data integrity issues.

GxP audit technique

Professionalism:
"exhibiting a courteous and business-like manner during the audit "

Be polite and tactful – is essential. And, therefore, the usage of language becomes a critical part of the audit conduct. Not only should one stay away from inappropriate introductions (such as that described above), but also from 1) arguments, 2) accusations and 3) exhibiting lack of patience. Even if you think the company you are auditing is wrong, stay away from heated discussions. Instead, include your point of view and an explanation, along with the auditee’s position, in the audit report and let the company’s “Operations” deal with the rest.

Also, the auditor’s authority should not be misused – we have seen cases where, due to the auditor’s lack of understanding, the auditees were wrongly charged with something they have not done.

Be open – audit observations and potential audit findings should be discussed with the audit host throughout the audit, rather than just at the close-out meeting or even worse yet, mentioned only in the audit report that the auditee has to respond to.

GxP audit techniques

"Transparency throughout the audit"

Transparency throughout the audit will give the auditee a chance to present additional documentation, provide clarifications and collect supplementary evidence before the end of the audit. Not only will such an approach prevent the auditee from feeling “cheated” or “blind-sided,” but it will also give you, the auditor, a much better idea regarding where the auditee really stands.

Be sensible – unlike many seem to believe, “minimal or no observations” is not necessarily a reflection on your competency. So don’t be afraid to walk out of the audit with “no findings” where findings are not warranted. Remember that even the FDA itself is comfortable to close-out its inspections with no FDA-483s. Furthermore, there should also be a clear difference between auditor’s preferences (e.g., recommendations) and findings that present deviations from the regulations and have a potential impact on the quality of the product and/or process(es).

Be factual – when writing observations, provide enough facts and details to substantiate your findings. It is best to stay away from ambiguities and generalities when describing an issue because nothing frustrates an auditee more than all-encompassing statements that make the issue look worse than it really is.

GxP audit techniques

Review Audit Findings
in a Timely Manner

Be responsive – just like you expect the auditee to respond within thirty (30) calendar days (or business days, depending on the individual company’s requirements) to the audit findings, the auditee is also expecting reasonably prompt feedback from you regarding the audit findings and feedback to the respective auditee’s responses. Therefore, the audit findings, audit responses and any follow-ups should be sent out and/or reviewed in a timely fashion. Not letting the auditee know what the audit status is, even if responses are acceptable, is not an option because contracts often depend on the auditee successfully passing the audit.

The “morale of the story” is that the auditor has a big responsibility towards the company he/she represents and towards the company he/she is auditing. In our opinion, the biggest compliment and validation that the auditor can get is for the auditee to say “you were fair,” findings notwithstanding. In this case, everyone wins.

Emma Barsky
Len Grunbaum
Partners
The Practical Solutions Group, LLC

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FDA has announced a new draft guidance document. Public comment is due by 25 July 2011:

Guidance for Clinical Investigators, Industry, and FDA Staff: Financial Disclosure by Clinical Investigators

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On the blogroll: ‘The Hill’ on defunding the health reform law: CBO States Danger to Medicare Drug Funding

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GxP Audit Techniques & Etiquette- Please Comment


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


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 Clinical Trials: Quality Considerations for Pivotal Studies

April 9, 2011

clinical trials considerations pivotal

When Should Quality Begin?

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

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

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

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

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

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

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

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

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

clinical trial consideration pivotal

QA for the Data Lifecycle

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

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

pivotal clinical trial

Increased Enforcement of
Part 11

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

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

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

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

pivotal considerations for phase III clinical trials

QA Audits of Clinical Sites

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

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

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

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

Pivotal clinical trial considerations

Conduct Regular GCP Training

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

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

Sponsor audits and mock FDA inspections

pivotl phase III clinical trials

Always Prepare for an FDA Inspection

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

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

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

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Society for Clinical Data Management

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

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

March 13, 2011

FDA inspections

"It's Not My Job"

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

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

FDA inspection

"I Know Who Has That Responsibility"

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

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

FDA Inspevtions

Frontloading Quality:
The Key to Success

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

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Here are some helpful articles and resources on FDA inspections:

Applied Clinical Trials on Mock FDA Inspections.

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

FDA Inspection Guides: How the FDA conducts inspections

BioJobBlog: What’s Up With FDA Inspections Anyway?

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

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A new feature from FDAzilla on FDA 483s

Read the Press Release on 483s

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

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Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.

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

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