FDA & Politics: In the Interest of Science?

April 3, 2012

FDA and politics

Political Pressure at FDA?

FDA Regulates 25% of the U.S. economy and has long been the target of lobbyists from the food,drug, & tobacco industries.The question is always asked: “Is mixing the public health mission of FDA with politics in the current political climate advancing the interests of the American consumer?” Unfortunately, the answer is almost always no. Last December GxP Perspectives published a Guest Commentary on “when Politics and Science Collide,” by April Mayberry. In the 03 April 2012 New York Times there is an extensive page one article on the differences between the Obama White House and FDA on public health issues.

For most readers of this blog it is a question on the approval of health products; drugs, medical devices, and biologics, that come to mind. Is FDA providing the right balance in regulatory oversight? Is FDA making decisions based on science and not political pressure? The issue came to a head over the Plan B controversy that April Mayberry wrote about in her Guest Commentary. In this week’s FDA Matters, longtime FDA observer Steven Grossman talks about different plans to speed up FDA approvals noting that there are rarely initiatives to make sure that FDA scientists have the time and resources to make the right decisions. Grossman notes that former FDA Commissioner Dr. Andrew Von Eschenbach wrote an opinion piece in the Wall Street Journal where he states:

FDA and Politics

Dr. Andrew Von Eschenbach

“What will it take to realize the potential of the new medicine? The United States has the world’s most innovative drug and device companies and research universities, plus the unparalleled National Institutes of Health. What’s missing is a modernized Food and Drug Administration that can rapidly and efficiently bring new discoveries to patients.”

This places the burden, and blame, for new health product approvals squarely on FDA. The New York Times article points out that political pressure has often shaped FDA policy and that there have often been serious consequnces when FDA tries to assert its independence. For example, FDA Commissioner Dr. Jane Henney lost her job for allowing the approval of the controversial drug RU-486. Although then DHHS Secretary Donna Shalala guaranteed Dr. Henney that FDA would have independence to make scientific decisions, she was soon out of a job with the election of George W. Bush.

FDA and politics

Dr. Margaret Hamburg has Supported FDA Scientists on Plan B

Current FDA Commissioner, Dr. Margaret Hamburg has not had as supportive a relationship with the current DHHS Secretary, Kathleen Sebelius. They clashed on the restrictive measures insisted on by Secretary Sebelius for access to Plan B. Other areas of disagreement include labels on sunscreens and over the asthma drug Primatene Mist. In an election year the volatile mix of politics and science is even more apparent. In the New York Times article FDA historian Daniel Carpenter of Harvard University warns:

“In a globalized world , where trust is a huge part of what American manufacturers have to sell, the politicalization of the FDA’s reputation could hurt not only consumer protection but industry profits as well.”

It should be an interesting year for science and politics.

Carl Anderson, GxP Perspectives

Read the New York Times Article

FDA Matters

====

Join the GxP Perspectives Linkedin Group Here
Or get an email subscription (on the right sidebar)
====

Add your comments to the discussion on Politics and Science at FDA

Leave a Comment » | FDA | Tagged: , , , , | Permalink
Posted by GxP Perspectives

FDA Warning Letters for International APIs in 2011

January 8, 2012

API FDA Warning Letter International firms

API Warning Letters to International Manufacturers

FDA issued at least ten Warning Letters to international manufacturers of active pharmaceutical ingredients in FY-2011. Manufacturers in both China and India, the world’s largest exporters of APIs, received three Warning Letters each from FDA. Manufacturers in Spain, the UK, Canada, and Japan each received one Warning Letter from FDA. These metrics show both the domination of China and India in the API market as well as the continued dependence on international manufacturers for APIs destined for the U.S. market.

Deficiency Categories:

The violation that dominated the charges cited by FDA in FY-2011 related to quality control, cited in four Warning Letters, two to China and one each to Canada and Japan.

FDA API Warning Letters in 2011

Failure to Have Procedures for Cross Contamination

Another violation that is sure to cause concern with FDA is the failure to prevent cross-contamination. When I attended FDA API inspection training in 2000 cross-contamination, particularly with anti-biotics, was a major concern. It continues to be with API manufacturers in both India and China being cited for the “Failure to have appropriate procedures in place to prevent cross-contamination.”

Out of specification (OOS) laboratory results are always a concern of FDA and landed on Warning Letters to manufacturers in India and Spain. Other citations include:

= Water purification for APIs used in parenterals

= Failure to establish a stability program to monitor APIs

= Failure to perform at least one identity test of each batch of incoming material

= Validation of analytical methods used to test APIs

There are no big surprises here but it shows that regular surveillance of API vendors is an absolute necessity for the manufacture of quality drug products. What is of interest is that GxP Perspectives couldn’t find any domestic Warning Letters for APIs. That doesn’t mean they don’t exist, only that they couldn’t be easily located. Unfortunately, FDA lists API Warning Letters in any number of classifications for GMPs for finished pharmaceuticals. However, they don’t seem to list them for APIs. With all the razzle-dazzle taking place on FDA’s website, you would think they could come up with a consistent way to list API Warning Letters. Who knows, maybe next year.

by Carl Anderson, GxP Perspectives
Research by Francesca Carreras-Perez, GxP Perspectives

====

Two articles of interest regarding APIs:

Indian API Manufacturers want anti-dumping duties

API Product List (note countries of origin)

====

Please join us: GxP Perspectives LinkedIn Group

GxP Perspectives on twitter: @GxPPerspectives

Leave a Comment » | FDA | Tagged: , , , , | Permalink
Posted by GxP Perspectives

FDA Commissioner Margaret A. Hamburg’s Statement on the Passing of Dr. Charles Edwards 

September 1, 2011


FDA Commissioner Margaret A. Hamburg’s Statement on the Passing of Dr. Charles Edwards

FDA repeat violations warning letter

Former FDA Commissioner
Dr. Charles Edwards

The death of Dr. Charles Edwards is a great loss to the Food and Drug Administration and to Americans who enjoy the safest supplies of food and medicine in the world, thanks to his leadership. During his tenure as FDA commissioner, Dr. Edwards was one of the country’s most ardent drug safety advocates, ordering the extensive review of over-the-counter drugs for safety, effectiveness, and accuracy in labeling. In addition, he ordered that one of the first mandatory package inserts be included with oral contraceptives to warn patients about the possible risks.

Dr. Edwards led FDA from December 1969 to March 1973, taking the reins in a time of great change at the agency. Under his leadership, FDA’s budget doubled from 1970 to 1972 as the commissioner steered the agency towards a greater regulatory role. During these years FDA began regulating biologics and radiological health.

From FDA, Dr. Edwards continued serving his country as assistant secretary for health in the Department of Health, Education and Welfare. There he proposed major reforms in health care and gave greater standing to the Centers for Disease Control and Prevention.

In 1990, long after Dr. Edwards had left government service, Health and Human Services Secretary Louis Sullivan named him head of the Advisory Committee on the FDA to review the agency’s mission, structure, priorities, staffing, and budget.

In a warning that seems a foreshadowing of current concerns about FDA resources, the Edwards committee warned: “An agency charged with such a broad array of vital health protection responsibilities, yet one that lacks the tools to carry out those responsibilities, is in serious danger. And hence, so is the American public.”

While he was still commissioner, Dr. Edwards wrote in a journal article, “I firmly believe that the FDA today represents the soundest and most effective approach to carrying out the vital public functions with which it is charged. I also believe that we are constantly challenged to do a better job, and I can assure you that we intend to meet that challenge.”

His words echo today.

Serving during the turbulent Watergate years, Dr. Edwards was confronted with myriad crises and a skeptical public, but he met each with an integrity and dedication that did honor to his office, the agency, and his country. It is this dedication that I strive to emulate each day as I follow in his footsteps as commissioner. He will be greatly missed.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

I was just a wet behind the ears scientist when Dr. Edwards made the transition from FDA to being the ASH. I remember years later, he was the first ASH to whom I made a presentation (and wouldn’t you know it, I can’t remember the topic – probably laser safety). FDAAA alumni member Phil White worked for him as his special assistant in the OC in the early 70′s. Phil’s take is straightforward: “My favorite Commissioner.”

Read the New York Times Obituary

Leave a Comment » | FDA | Tagged: , , , , , | Permalink
Posted by GxP Perspectives

Major Reorganization at FDA

July 14, 2011

Dr. Margaret Hamburg

Dr. Margaret Hamburg, FDA Commissioner

Every organization needs to take stock of personnel and responsibilities, including FDA. The world of FDA regulaton is changing rapidly and in an effort to keep current Commissioner Margaret Hamburg has announced a major reorganization in an FDA-wide announcement reprinted below. She announced a new position, stating “I am establishing a new Deputy Commissioner for Medical Products and Tobacco.” The position will be filled by Dr. Steven Spielburg (no not That one) the former Dean of Dartmouth Medical School to fill the position. There are a number of other changes at the top. Here’s what the announcement said:

From: A Message from the Commissioner
Sent: Wednesday, July 13, 2011 3:41 PM
To: FDA-Wide
Subject: A Message from the Commissioner

Dear Colleagues,

I am writing today to let you know about some changes that I will be making to the agency’s management structure. As you probably recall, back in January, I told you that I was initiating a review of the Office of the Commissioner. As I explained at that time, this review was driven by the expanding and rapidly changing nature of the Agency’s responsibilities, and the need for a management structure that reflects these changes and best supports your efforts.

I consulted with former Commissioners, as well as with HHS Secretary Sebelius, and considered many options before arriving at the structure that I am announcing today.

The most important thing driving my consideration of this is the changing nature of both the Agency and the job of Commissioner. Today, the Agency faces several key challenges:

First, we are a very large agency, with an incredibly broad span of responsibility. We regulate products that account for between 20 and 25 percent of every consumer dollar spent in the U.S. and that total more than a trillion dollars annually. For the most part, these are products that people rely on in fundamental ways every day.

Second, as technology and science continue to evolve, we are faced with the challenge of making sure that new ideas translate into the products and opportunities that people need and count on to protect their health. Innovative products that are truly transformative create unique scientific and regulatory challenges, and FDA must be a consistently powerful catalyst for innovation.

FDA Change

The Challenges of Globalization

Third, we have seen the dramatic transformation of globalization – more products, more countries, more access by consumers and companies to global supplies – and this presents an enormous challenge to FDA in ensuring the safety and quality of the products we regulate.
Finally, we continue to be faced with administrative challenges. In these difficult economic times, our agency’s budget requires constant attention. And, simply providing the support and services for our 12,000 plus employees – everything from phones to IT to office space on our beautiful, growing White Oak campus – is a daunting job.

I take very seriously my responsibility to lead FDA along a path that will meet these challenges. One crucial part of this responsibility is to create a structure in the Commissioner’s Office that best supports your efforts and reflects the changing nature of the Agency.

FDA reorganization

'The structure of the Office of the Commissioner that I inherited was created in 1970'

The structure of the Office of the Commissioner that I inherited was created in 1970, when the FDA consisted of three Centers and a field office. By 2011, we had grown to seven Centers, and a Commissioner’s Office with more than 1,600 staff. Over the years, as Congress created new programs that cut across Center responsibilities, those programs were placed by default in the Office of the Commissioner.

The new organizational alignments more accurately reflect the agency’s responsibilities, subject matter expertise and mandates in an ever more complex world, where products and services do not fit into a single category. Let me begin by saying that, for most of the FDA, this organizational alignment will likely not have a significant impact on you or your day-to-day work.

The most obvious change you will see is that the Agency’s programs, in terms of a reporting chain to me, will be divided into “directorates” that reflect the core functions and responsibilities of the Agency. This new management structure will enable the Office of the Commissioner to better support the agency’s core scientific and regulatory functions, and help tie together programs that share regulatory and scientific foundations. I will rely on the leadership of these directorates to help provide the necessary direction and coordination needed by an Agency of this scope.

FDA changes

Dr. Steven Spielberg

I am establishing a new Deputy Commissioner for Medical Products and Tobacco, who will provide high-level coordination and leadership across the Centers for drug, biologics, medical devices, and tobacco products. The Centers will, of course, remain as discrete management entities under their current expert leadership. In addition to this strategic role with the Centers, this position will oversee our Special Medical programs.

I am pleased to announce that Dr. Steven Spielberg, former Dean of Dartmouth Medical School and currently Director of the Center for Personalized Medicine and Therapeutic Innovation at Children’s Mercy Hospital in Kansas City, has accepted this position. In this role, Dr. Spielberg will serve as both advocate and a support for Center Directors in their important work for FDA.

I will also be creating a directorate focused on grappling with the truly global nature of today’s world — food and drug production and supply, as well as the science that undergirds the products we regulate — so that the FDA can move from being a regulator of domestic products to one overseeing a worldwide enterprise.

fda reorganization

Global Regulatory Operations & Policy

To oversee this transformation, I have asked Deborah Autor, now Director of CDER’s Office of Compliance, to take on the role of Deputy Commissioner for Global Regulatory Operations and Policy. In this position, Deb will provide broad direction and support to the Office of Regulatory Affairs and to the Office of International Programs, with a mandate from me to make response to the challenges of globalization and import safety a top priority in the years to come. Dr. Murray Lumpkin, who has served with dedication and accomplishment as Deputy Commissioner for International Programs and Director of the Office of International Programs, will take on a new role as Senior Advisor and Representative for Global Issues. In this role, he will be charged primarily with special projects that draw on his expertise working with counterpart regulatory agencies on issues of global regulatory harmonization, governance and capacity-building.

The third directorate is the previously established Office of Foods, which we created to make our oversight of FDA’s food and feed program a more seamless enterprise. That task is even more important today as Mike Taylor leads the implementation of the Food Safety Modernization Act.

fda reorganization

Office of Operations

The fourth directorate will be a new Office of Operations, headed by a Chief Operating Officer. The COO will oversee the agency’s administrative functions, such as human resources, facilities, information technology, finance, and other activities that provide support to your organizations. Within this Office, I am bringing the budget formulation and budget execution functions together under a CFO position. We have initiated a search to fill the Chief Operating Officer position.

The Office of the Chief Scientist, charged with our important efforts to improve FDA’s science and address issues of cross-cutting scientific concern, will continue to do so. The National Center for Toxicological Research will report to the Chief Scientist, Dr. Jesse Goodman, and, like the other Centers, will remain a discrete management entity within this new directorate model.

fda reorganization

John Taylor

Within the new, smaller, immediate office of the Commissioner, John Taylor will remain as Counselor and will have the additional responsibility to oversee the policy and planning functions, the Office of Legislation, and the Office of External Affairs. I want to thank John for serving as acting Principal Deputy these past months, in addition to his duties as Counselor. He has tirelessly supported me and the Agency with enthusiasm, energy, expertise, and good humor.

You can find revised organizational charts, reflecting this realignment at http://inside.fda.gov:9003/AboutFDA/FDAStaffInformation/OrgCharts/default.htm. (This org chart could not be accessed at time of publication. You can also try here for Office of the Commissioner) In addition, I will share a video message of this announcement shortly. Your managers will be available to answer any questions you might have in the coming days.

In closing, I want to take a moment to thank you so much for all that you do. FDA is an extraordinary place, with so many highly-dedicated professionals and support staff who are committed to promoting and protecting public health. You accomplish a tremendous amount every day and I am grateful for all of your work. These organizational changes are intended to help further your important work and the mission of this remarkable Agency.

Sincerely,
Margaret A. Hamburg, M.D.
Commissioner of Food and Drugs

(Information from FDA Alumni Association)

====

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

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

====

On The Blogroll: I have updated the URL for RAPS, the Regulatory Affairs Professionals Society. It was at the 2009 RAPS Annual Meeting that I first heard Dr. Hamburg speak. RAPS has several conferences in the upcoming months.

====

FDA

On LinkedIn

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group
====
Please leave your comments on the FDA reorganization below
====

12 Comments | FDA | Tagged: , , , , , , | Permalink
Posted by GxP Perspectives

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.

=====
Interstate Conveyance Sanitation Warning Letter
=====
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.
=====

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.

============

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

=====

GxP Perspectives is now on twitter: @GxPPerspectives

Follow GxPPerspectives on Twitter
.

Leave a Comment » | FDA | Tagged: , , , , , , | Permalink
Posted by GxP Perspectives

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.

============
A new service: Please check out the Services page at the top of the Blog to learn more about GxP Services.
============

============
Take the GxP Survey! Only Ten Questions!
============

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?

#######

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.

##########
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.

##########

Follow GxPPerspectives on Twitter

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

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

1 Comment | FDA | Tagged: , , , , , , , , | Permalink
Posted by GxP Perspectives

Dr. Sharfstein to Leave FDA on Friday

January 5, 2011

FDA Joshua Sharfstein

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

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

///////////////////

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

Dear Friends and Colleagues,

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

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

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

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

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

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

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

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

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

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

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

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

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

Thank you, and take care,

Josh

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

///////////////////////

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

Leave a Comment » | FDA | Tagged: , , | Permalink
Posted by GxP Perspectives

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.

============
A new service: Please check out the Services page at the top of the Blog to learn more about GxP Services.
============

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

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

<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<

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.

Leave a Comment » | FDA, GxP, Warning Letters | Tagged: , , , , , , , , , , , | Permalink
Posted by GxP Perspectives

Response Letters to a Form FDA 483, Inspectional Observations

November 7, 2010

FDA 483 response

How Should You Respond to a Form FDA 483?

What is an adequate response to a Form FDA 483, Inspectional Observations? That question was discussed by two representatives of FDA at a training workshop hosted by the Pacific Regional Chapter of the Society for Quality Assurance and the Organization of Regulatory and Clinical Associates – Northwest. The workshop, held on 4-5 November 2010 in Seattle, featured discussions by Chrissy J. Cochran, PhD, from the Division of Bioresearch Monitoring (BIMO) at the Center for Devices and Radiological Health (CDRH) and Mihaly S. Ligmond, Consumer Safety Officer, Division of Domestic Field Investigations, Office of Regulatory Affairs (ORA). ORA is the field organization that conducts most FDA inspections. Both Cochran, who spoke by teleconference on the 4th, and Ligmond, who attended on the 5th, stressed the do’s and don’ts of responding to an FDA 483.

The Form FDA 483

Both FDA speakers stressed that the 483 is the preliminary observations of the field investigator, not the final compliance determination of the Agency. Both emphasized that there was no requirement to respond in writing to a 483. However, both told the training session that if there are issues identified on a 483, then a clear written response can help prevent enforcement action, including a Warning Letter, by FDA. Cochran discussed a few ineffective FDA 483 response letters received by CDRH. They included a clinical investigator who was using an informed consent form without all of the required elements required by 21 CFR 50.25. These elements include a clear statement of research; alternative procedures; a discussion of confidentiality and other important information. The clinical investigator complained that: “You cited us on a technicality.” This was a clear and significant violation of FDA clinical trial regulations and this was not an acceptable response.

Cochran gave an example of an adequate response to an FDA 483 for protocol violations. The response included a copy of a written procedure developed to prevent recurrence of the violation. The procedure was presented to a seminar for study staff with a sign-in sheet with the date of the seminar. It included implementation dates with a review scheduled after three months to determine the effectiveness of the corrective action.

The response to an FDA 483 should go to both the District Office and to CDRH, Cochran said. She stated that it is the assessment at BIMO that makes the final compliance determination for Bioresearch Monitoring inspections. She reviewed the issues that BIMO considers when reviewing an establishment inspection report (EIR) and a Form FDA 483, Inspectional Observations. These include:

• Are the FDA 483 observations actual violations of the regulations?
• Are there additional violations in the exhibits submitted with the EIR?
• Are the observations documented with exhibits or discussion in the EIR?
• Are the observations significant?
• Did the inspected party address the issue in their response?
• Is the response adequate? “We will carefully look at it.”

Ligmond, who is a National Expert for drug good manufacturing practice (GMP) inspections, gave the following recommendations for a response letter to an FDA 483:

• Set a reasonable timeline for taking action;
• Initiate a “Global Response” if the deficiency can impact other areas;
• Include details and attachments;
• Be comprehensive;
• Address disagreements with the observations;
• As a courtesy, copy the investigator

FDA 483

The FDA 483 is the Preliminary Observation of the FDA Field Investigator

Both Cochran and Ligmond restated the new FDA policy for written responses to an FDA 483 if the response is to be considered by FDA prior to issuing a Warning Letter. That response time is 15 business days from the date the FDA 483 is issued. Ligmond gave an excellent recommendation to avoid possible disputes on FDA 483 observations. “Address misunderstandings promptly, courteously, and with the facts,” he said. He discussed the importance of a daily wrap-up session o clear up any disagreements or inaccurate information that may have been given to the FDA field investigator.

CAPA

Corrective and Preventative Action, or CAPA, was discussed by both speakers. Ligmond said that a CAPA plan should address problems completely and in a timely manner. Cochran said that a good CAPA plan should assess the root cause of deficiencies; identify the problems; evaluate the extent of problems; give a clear timeline, describe the CAPA being taken; and reassess the root cause.

Inspection preparedness was also discussed. Ligmond said to spend each day as if you were going to be inspected by FDA. They stressed the importance of Mock FDA Audits in preparing staff for inspections.

FDA 483 response

ALWAYS Respond to a Form FDA 483

My own experience is that it is always a good idea to respond to an FDA 483. If there is a problem, then give clear details on how the problem is going to be fixed, with specifics such as a timeframe. If you disagree with the observation, then follow Ligmond’s advice to address it “with the facts” and with documentation of the facts. FDA rarely will accept excuses such as “I thought my study coordinator was going to do that.” However, if there is a legitimate response, you should make it in a clear, respectful manner. The 483 responses I have worked on always included specific actions, specific dates, and a specific person or department accepting responsibility for ensuring that the corrective action takes place. And they always include documentation of corrective actions. If it isn’t documented, then it’s just a rumor.

##########
A new feature from FDAzilla on FDA 483s-

Read the Press Release on 483s

##########

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\

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

2 Comments | FDA | Tagged: , , , , , , , | Permalink
Posted by GxP Perspectives

FDA Clarifies Adverse Event Reports for Clinical Trials

October 10, 2010

FDA adverse event reporting

FDA Final Rule Clarifies
AE Reporting for
Clinical Trials

On 28 September 2010 FDA announced that it was issuing a final rule that clarifies safety reporting for adverse events during clinical trials. The final rule impacts drug and biologic regulations for clinical trials conducted under an investigational new drug (IND) application (21 CFR 312) and bioequivalence studies (21 CFR 320). The draft rule was published in 2003 and received numerous comments. These comments, combined with increased concern over drug safety, led to significant changes by FDA. The new rule defines the separation of clinical trial safety adverse event reports and post-market safety reporting. The agency is working on new regulations for post-market safety reports. FDA stated that the separation was necessary to improve the quality of safety reporting, monitor the safety of drugs and biologics, and harmonize adverse event reports internationally. There are some significant differences between the draft rule of 2003 and the final rule published on 28 September 2010 including:

• Replace the defined phrase ‘‘associated with the use of the drug’’with the term ‘‘suspected adverse drug reaction (SADR),’’
• Require submission of expedited reports of ‘‘information sufficient to consider product administration
changes,’’
• Make it clear that safety reports of overall findings or data in the aggregate must be submitted in a narrative format,
• Permit the determination that an SADR is life-threatening to be based on the opinion of either the investigator orsponsor (as opposed to only the investigator),
• Require that the sponsor notify FDA and all participating investigators of each SADR that is both serious and unexpected, based on the opinion ofeither the investigator or sponsor (asopposed to only the sponsor),
• Require a ‘‘minimum data set’’ for each report of an SADR submitted toFDA, and
• Clarify the sources of information that sponsors must review for safety surveillance and reporting purposes.

FDA clarifies adverse events clinical trials

FDA Adopts ICH E2A Definitions

Perhaps the most significant change in the final rule is that FDA is adopting the terms and definitions in the ICH guidance document E2A that are used throughout the world. Prior to issuing the final rule FDA regulations did not specifically define the term “adverse event” although the term was referred to repeatedly in the regulations and there was a definition for “serious adverse event.” Using the ICH definitions will make it easier for clinical trial professionals to “speak the same language” when conducting research. As FDA clarifies definitions, communications between sponsors and investigators should become easier. Hopefully, researchers will now understand that it isn’t necessary to “report all SAEs immediately.” FDA is stating clearly that:

“… the revisions to the IND safetyreporting requirements will improve theoverall quality of safety reporting andthe agency’s ability to review critical safety information by ensuring that theinformation that FDA receives in an INDsafety report is relevant and useful.

Under former regulations, there may have been over-reporting of serious adverse events for which there was little reason to believe that the drug had caused the event, complicating or delaying FDA’s ability to detect a safety signal.

In this final rule, FDA clarifies definitions, provides examples of the types of evidence that suggest a causal relationship for purposes of reporting asuspected adverse reaction to the IND and participating investigators, and revises the requirements for expedited reporting of serious and unexpected suspected adverse reactions to the IND.”

The ambiguity over reporting adverse events has caused friction between many study coordinators and CRAs. Hopefully, FDA clarifying AE reporting will help researchers focus on issues of significance.

FDA Announcement of Final Rule

At the same time FDA issued a draft guidance on Safety Reporting Requirements which will be the topic of a future post. The comment period is OPEN!

Safety Reporting Requirements for INDs and BA/BE Studies

++++In news from GxP Perspectives++++

clinical trials adverse event FDA

TMF Webinar on Thursday, 14 October 2010

Special Announcement: TMF Webinar 14 October

Read the updated article on the Form FDA 1572 in:

Applied Clinical Trials “Closing Thought” on FDA 1572

ALSO: Please join me on LinkedIn at:

GxP Perspectives LinkedIn Group

Share/Bookmark

Leave a Comment » | Clinical Trials, FDA, GCP | Tagged: , , , | Permalink
Posted by GxP Perspectives

« Previous Entries
Follow

Get every new post delivered to your Inbox.

Join 601 other followers

%d bloggers like this: