FDA sends J & J another letter

August 28, 2009

Johnson and Johnson seems to be having their troubles with the Food and Drug Administration. First they received a Warning Letter for their oversight of clinical trials (see previous post). Now they are accused of false advertising for their Ertaczo cream to fight athletes foot and jock itch. J&J’s scientific ads said the product would “Crush, Kill, Destroy” the offending fungus. Of all the things to get nailed for.

According to Forbes.com:

“In an Aug. 21 letter released by the FDA Wednesday, the agency said the journal advertisement broadens the approved indication, contains unsubstantiated effectiveness claims about the product, and omits important risk information. Also, the FDA said J&J failed to submit the journal advertisement under current FDA regulations.”

And how is their stock doing? They seem to be shrugging it off. It’s down 0.23%.

GxP Perspectives LinkedIn Group

FDA Sends J&J a Warning Letter for Clinical Trial Failures

August 19, 2009

Johnson and Johnson received a Warning Letter from FDA for their failure to properly supervise clinical trials. The letter, issued by the Center for Drug Evaluation and Research’s Division of Scientific Investigations (DSI) on 10 August 2009, was addressed to the J&J Pharmaceutical Research & Development group in Raritan, NJ and cited failures for sponsor responsibilities.FDA Warning Letter

It is pretty rare for a pharmaceutical company to get a Warning Letter for clinical trial sponsor activities (called “Sponsor-Monitor” inspections). Approximately 10 were issued in fiscal year 2008 and most of those were to small medical device firms or to sponsor-investigators, physicians who both sponsor and conduct a clinical trial. The last major Warning Letter to a large pharmaceutical company was to Sanofi Aventis in October 2007 for research misconduct in the Aventis clinical trials for the drug Ketek. So DSI sending a Warning Letter to an industry giant like J&J is a pretty big deal. It certainly is in keeping with Commissioner Margaret Hamburg’s new emphasis on enforcement (see previous posts).

The Warning Letter cites J&J for “Failure to ensure proper monitoring of the clinical investigations.” This is the most common citation for a Sponsor-Monitor Warning Letter and has been for many years. DSI charges that J&J’s monitors failed to identify that drug infusions were given at the same identical time to multiple subjects. The drug is administered by an IV infusion and the source documents were contradictory and should have alerted the monitors of possible fraud. The Warning Letter cites detailed violations for study drug administration, shipments, and the necessary refrigerated storage.

The lengthy Warning Letter also cites J&J for “Failure to ensure that an investigation was conducted in accordance with the general investigational plan and protocols” and “Failure to secure investigator compliance.” These are also common violations for a Sponsor-Monitor Warning Letter. You can read the letter for yourself on the Blogroll: 1 FDA Warning Letter to J&J.

It will be interesting to see if the new enforcement climate will deal new Warning Letters to pharmaceutical and medical device sponsors or if this was an aberration. The one thing that it has in common with the Sanofi Aventis Warning Letter is that there is a suggestion of fraud. There are many things other than fraud that can go wrong in a clinical trial. Is this FDA’s standard?

I am attaching an article that I wrote for RAPS Regulatory Focus magazine in July 2008. It deals with the topic of quality systems in monitoring clinical trials.

July 08_Anderson_RAPS Focus_Monitoring

Update: FDA also sends a Warning Letter to the CRO involved, ICON Clinical Research. Read the Post:


GxP Perspectives LinkedIn Group

Dr. Hamburg and Dr. Sharfstein confront FDA’s “Invisible Line”

August 17, 2009

New FDA Commissioner Dr. Margaret Hamburg and her top deputy Dr. Joshua Sharfstein have made an impressive start and have announced a new era of “effective enforcement” for the Agency. They have done some house cleaning at the top and headquarters bureaucrats are beginning to get the message. Many FDA enforcement actions originate from headquarters and effective actions can be taken. But the bulk of FDA enforcement actions come from the hard working FDA field investigators (CSOs- consumer safety officers), compliance staff, and laboratory scientists distributed throughout the country in FDA’s field organization, ORA- the Organization for Regulatory Affairs. The CSOs are the inspectional force who carry out the Agency’s mission to ensure safe food, drugs, medical devices, and blood products for the American people. They’re the ones conducting the inspections on a day-to-day basis. (full disclosure: I worked for ORA for 17 years) They are hampered by an obsolete inspectional system and poorly trained supervisors and middle managers. And there is an invisible line that separates them from Drs. Hamburg and Sharfstein.

ORA, The FDA field organization, is divided geographically into twenty District Offices each headed by a District Director. In addition there are 13 laboratories and over 150 “Resident Posts.” My last job at FDA was as a CSO at the Tacoma, WA Resident Post, a part of the Seattle District. In reality, few CSOs or other field personnel communicate with anyone higher that a District Director. They have few interactions with FDA headquarters personnel unless it is very directly related to their specific job function. The District Directors form the Invisible Line between the field force and the rest of FDA. They filter all communication between the two sections. And their word is law.

To make matters worse, CSOs have little communication with their counterparts in other districts. This means that if there is a New Drug Application (NDA) filed and headquarters issues Bioresearch Monitoring (BIMO) assignments for clinical trial inspections to the Denver, Dallas, Chicago, Atlanta, and Florida Districts there is almost no communication between the CSOs conducting the inspections. If a CSO issues a Form FDA 483, Inspectional Observations, in Chicago, it is highly unlikely that the information will be shared with colleagues in the other districts. There is no project management, no conference calls, no training on the therapeutic area, the protocol, issues of concern to the review division, There is nothing of the sort for BIMO.

A large part of the problem is a question of turf. ORA is supposed to conduct inspections, all inspections, whether they know how to do them or not. There are no requirements that a BIMO CSO knows how to read medical records. Many do and are excellent inspectors. Many don’t and the quality suffers. Time after time I am questioned about an FDA 483 and why it was issued. Many times I just don’t have an explanation. Of course, I don’t have the report and exhibits in front of me. But there is a lot of poor judgement being shown. Many FDA inspectors do not have the appropriate qualifications, receive adequate training, and understand the significance of their observations.

It starts with the management of the BIMO program at the district office. There is no requirement that a BIMO supervisor have any BIMO experience. It does not matter if they have ever conducted a BIMO inspection. One supervisor once told me that it wasn’t necessary that a CSO know how to read medical records. They were conducting the inspection for compliance with FDA regulations and the regulations were all that mattered. I asked how the CSO was supposed to locate adverse events that weren’t reported if they couldn’t read the medical records. All I received was a shrug of the shoulders.

Another supervisor, who was responsible for IRB inspections in five states, once asked me, “What’s the Belmont Report.” This is the basic bioethics document produced by the United States Government. You might know what it is (you can google it) but the person responsible for making IRB inspection assignments, reviewing reports, recommending promotions, assigning training, THAT person should know. If there is a poorly written FDA 483, it is the fault of the supervisor and other FDA managers for allowing it to continue. However FDA supervisors don’t do inspections. They sit behind a desk and figure out work plans. They are not in touch with what is happening in the field. They receive no technical training on the increasingly complex world of drug and device development. NONE. And that is one of the primary reasons that industry complains about inconsistent FDA inspections and inconsistent Form FDA 483 observations. It is a very big problem.

The majority of FDA field employees are very dedicated and outstanding. The country is very lucky to have them on the job. The majority of FDA field managers are not. Standing at the head of the field managers are the District Directors, the Invisible Line separating the FDA field from the excellent new leadership of FDA at headquarters. If Dr Hamburg and Dr. Sharfstein want effective enforcement of FDA regulations, then they are going to have to take a Hard Look at the Office of Regulatory Affairs.

Ethics and the debate on health care

August 15, 2009

The media coverage on debate regarding health care reform has been a non-stop display of people protesting “death panels” and “socialized medicine.” What hasn’t happened has been a discussion of the ethics of not providing health care to millions of people and bioethics in general. This hasn’t always been the case. Bioethics were very much the focus when the country discussed “The Tuskegee Syphilis Study” and the U.S. government issued the Belmont Report in 1978. This was the basis for the protection of human participants in research in the United States and very much should be a part of the health care policy debate. The Belmont Report’s core principles are:

(1) respect for persons: protecting the autonomy of all people and treating them with courtesy and respect and allowing for informed consent;

(2) beneficence: maximizing benefits for the research project while minimizing risks to the research subjects; and

(3) justice: ensuring reasonable, non-exploitative, and well-considered procedures are administered fairly (the fair distribution of costs and benefits to potential research participants.)

The “Tuskegee Study” was actually sponsored by the U.S. Public Health Service and studied syphilis in poor African American men in the South during the Jim Crow era of segregation. The men were not treated even after the discovery that penicillin could effectively treat syphilis in the 1940s. The study was carried out from 1932 until 1972. President Clinton officially apologized to the survivors and family members for the government’s participation in the study.

All of the bioethical principals for medical research are applicable to the debate on the reform of health care and bioethics is entering the debate. Justice, which hasn’t received enough attention to say the least, is also being discussed. According to an article in today’s NY Times (attached as “11: Debate over health policy” on Blogroll” The “dramatic advances in health care pose questions for bioethicists.” The article discusses the fact that the debate has centered on the organizational management of healthcare and ideological debates and not How do we think about the ultimate goals of te health care system and even about health itself.” (Daniel Callahan)

Most importantly to me is that the bioethics concerned in health care is not being discussed. What does it mean when there are multi-tiered levels of health care? What role is the pharmaceutical and medical device industries playing? What does end of life counseling really mean? There should be a number of questions regarding ethics for the nation as a whole including, how do we work “Justice” back into the discussion.

Another viewpoint on the post: A Question of Significance

August 12, 2009

I received this comment on my post A Question of Significance (scroll down) from another clinical trials consultant. Since comments on posts are pretty well hidden, I thought I would post this response. It is regarding the need for a well-trained and supervised FDA inspectional workforce. There is also a thoughtful question/comment on the post regarding Dr. Schultz along with my reply. Here are the comments of Tania Issa who has years of experience as a clinical trial monitor:
Tania Johnstone Issa
August 10, 2009 at 5:47 pm

I fully agree with your position. Over the years I have worked closely with sites as a CRA/monitor, project manager, program manager, and QA auditor. I have seen investigators who have been terribly negligent in regards to patient safety. Just as bad, I have seen investigators who enroll marginally eligible or ineligible subjects or keep subjects on drug/device beyond the safety parameters in the protocol, enticed by enrollment incentives and other site payments. Yet when these same sites were inspected by FDA, many of the obvious and dangerous deficiencies went unnoticed, allowing the drug to be approved and the investigator to continue managing patients in other clinical trials. I have also seen excellent investigators receive 483s for minor deficiencies which had no impact on patient safety or data integrity. Enforcement is terribly absent and, at the same time terribly misplaced.

Carl has correctly emphasized that the FDA workforce inspecting sites and sponsors needs a thorough overhaul. Many of the basic principles of site monitoring, which are focused on (and quite adept at)ensuring patient safety and data accuracy, should be incorporated into FDAs inspection program. Well-trained monitors/CRA regularly identify lack of protocol adherence and patient safety issues, documenting these in reports. Because these reports are ultimately buried in paperfiles into perpetuity, rarely requested by the FDA, the agency charged with ensuring we have a safe drug supply, inspects sites but does not bother to read the eye-account written story of the site’s participation and the experience of their patients. Absurd, considering the FDA requires biopharmaceutical companies to perform this monitoring.

Many FDA inspectors lack any clinical experience and cannot comprehend what is written in study protocols, case report forms, medical charts, and monitoring reports. If biopharmaceutical companies are bound by FDA to select monitors “qualified by training and experience”, the FDA should do even better with the FDA staff responsible for Site/Sponsor inspections.

Because the clinical trials industry continues to express sincere concerns about the safety of investigational products, and bemoans lack of meaningful regulation from FDA, the industry has been self-disciplined enough to collaboratively identify and incorporate best practices (beyond regulations) truly designed to protect patient safety. Now it is time (pastdue) for REAL REFORM which should include a serious review of existing regulations against industry best practices.

Luckily, the ICH has by and large, has avoided the many constaints of political party affiliations, changing administrations, and lobbyists, using their efforts along with public input to provide meaningful guidance/regulation. Since the FDA references ICH as guidance instead of adpoting ICH as regulation, drugs and other investigational products approved for commercialization in the US are not approved against the highest standards already in use by many countries around the world. Luckily, however, many US companies have adopted the higher standards of ICH while they wait and wait for FDA to……..

Dr. Schultz resigns as head of FDA’s medical device center

August 12, 2009

The industry newsletter, The Gray Sheet and the Wall Street Journal both reported that Daniel Schultz, MD, Director of the Center for Medical Devices and Radiological Health (CDRH) offered his resignation to Dr. Margaret Hamburg, the new FDA Commissioner. Schultz said that the resignation was an agreement between him and Hamburg stating that Dr. Hamburg agreed his resignation “would be in the best interest of the center and the agency.” That doesn’t look good on your CV.

Dr. Schultz was under many clouds of suspicion. There have been serious charges leveled at the management of CDRH by employees conducting scientific review of new medical devices submitted to FDA. This is actually a very big deal. The Gray Sheet article is attached on the Blogroll as, “2: Schultz resigns.” I am very curious who else will be resigning in the Hamburg Era.

UPDATE: The Wall Street Journal reports on Dr. Janet Woodcock, Dr. Schultz’ counterpart at the Center for Drug Evaluation and Research, having conflict of interest problems. Read their coverage on the Blogroll: “11WSJ: Drug chief accused of conflict.”

The Blog Discloses All

August 11, 2009

Today’s NY Times had an interesting article on blog advertising in the business section. A link is on the Blogroll under “Blog Ads.” Some blogs are getting into trouble for basically being advertising shills for a specific product, some of which border on health fraud. The F.T.C. would like to see disclosure of gifts or money for product placement or articles on a blog. Sure, you betcha, here’s full disclosure by the Blog: No one has ever given me a nickel to post an article or link on the Blog. No one has ever given me anything, not even a souvenir coffee mug, for a post or link on the Blog. Carl’s Blog on FDA Stuff is definitely not a money making proposition.

FDA to revamp process for debarment and disqualification of researchers

August 10, 2009

In a press release dated August 7 the FDA announced that it was going to enhance the speed and transparency of actions taken against research misconduct in drug and medical device development. FDA stated that the revamped debarment and disqualification proceedings would increase protection of participants in clinical trials and ensure data integrity. Debarment and disqualification of a clinical investigator are the most serious enforcement actions that FDA can take short of criminal prosecution.

GxP Perspectives on LinkedIn

A Question of Significance: Dr Hamburg & FDA Enforcement

August 9, 2009

Since January of 2001 FDA has been lax in protecting the public and enforcing their regulations. I will let you put 2 and 2 together to figure out why. However, FDA enforcement needs to be relevant and meaningful. It needs to be for the right reasons, not just because someone wants to come across as tough.

Saturday I had a disturbing phone call from a client and friend who had just received a Form FDA 483, Inspectional Observations, at the conclusion of an FDA inspection. In reviewing the 483 with my client it was obvious that the FDA inspector had overstepped his bounds and that the 483 should not have been issued. However it is now part of the public record and available through the Freedom of Information Act. Without knowing the background, one of the observations could seem very serious and could result in FDA issuing a Warning Letter. The Warning Letter would then be posted on the internet for the entire world to see.

I am one of those that feel that FDA enforcement was lax during the past eight years. Part of the reason I left FDA after 17 years was a concern that the Agency just wasn’t doing its job. However, I also spent the summer of 2004 working at FDA headquarters reviewing inspection reports (EIRs) and found many of them to be lacking. Many field investigators were not technical experts in the area they were inspecting and cited violations that were not “clear and significant” violations of the regulations. Since leaving FDA I have seen a number of FDA 483s written that just didn’t rise to the level of significance necessary for a 483 to be issued or enforcement action taken. Many times this is because the front line supervisors do not have the technical and legal skills to properly review the 483s.

In the previous post (see below) I discuss the new enforcement climate at FDA. Although I am happy that Dr. Hamburg is taking her job seriously I have some concerns. We all want safe drugs, medical devices and food. We all want clinical trials to adequate and well-controlled. But we need clear enforcement standards and a well trained inspectional force for that to happen. And I fear that small companies and clinical trial sites will bear the brunt of a tough new enforcement climate. The larger firms have the legal resources to prevent Warning Letters and other enforcement actions. A small firm bringing their first product to market or a clinical investigator who has never been inspected by FDA may find themselves in a lot of trouble. This could be an unintended consequence of the new “effective enforcement” that Dr. Hamburg mentions in her recent speech to FDLI (see below).

The country needs a well-financed FDA to protect consumers from fraudulent and unsafe products. But we also need modernized regulations and a well-trained workforce to accomplish this. Dr. Hamburg needs to first look inside FDA before a wholesale enforcement campaign. She needs to take on the really significant problems, including internal problems, first. I would suggest quality control of FDA 483s as a good place to start. And that means properly training supervisors and middle management in the Office of Regulatory Affairs (the FDA field organization that conducts inspections).

UPDATE: An interesting comment is listed under: Enforcement

Dr. Hamburg says that FDA will step up “effective enforcement”

August 7, 2009

In a speech to the Food and Drug Law Institute Dr. Margaret Hamburg, the new FDA Commissioner, outlined a six step program to increase enforcement of FDA regulations. Stating that there had been a steep decline in enforcement actions, coupled with unreasonable delays in following through on serious public health problems, Hamburg stated in unequivocal terms that things were changing immediately to increase consumer protections and change the direction of FDA.

A review of recent FDA Warning Letters shows that there has indeed been an increase in enforcement and that there is a new emphasis on enforcement actions and a change in the climate at FDA from the previous administration. My hunch is that food good manufacturing practice (GMP) inspections will lead the way in receiving FDA attention with other GMP programs not far behind. However, when there is a change in the FDA enforcement climate it impacts all inspectional programs. Dr. Hamburg also signaled an increased scrutiny of internet health fraud. She emphasized the need to follow-up when FDA has found serious problems.

In some cases, serious violations have gone unaddressed for far too long,” Hamburg said. “These include violations involving product quality, adulteration, and misbranding; false, misleading, or otherwise unlawful labeling; and misleading advertising,” Hamburg stated. The entire address is available on the FDA homepage at http://www.fda.gov

Here is an outline of Dr. Hamburg’s six step program which is excerpted from the FDA website, with my comments in parenteses:

“First, the FDA will set post-inspection deadlines (for violative inspections).

Second, the FDA will take responsible steps to speed the issuance of warning letters (the exact opposite of 2001).

Third, the FDA will seek to work more closely with our regulatory partners (local, state, and international regulatory agencies) to develop effective risk control and enforcement strategies. (FDA has long worked closely with the states but has a poor history of international cooperation)

Fourth, the FDA will prioritize enforcement follow-up. After a warning letter is issued or a major product recall occurs, we will make it a priority to follow up promptly with appropriate action.

Fifth, the FDA will be prepared to act swiftly and aggressively to protect the public. The FDA will no longer issue multiple warning letters to noncompliant firms before taking enforcement action (this is a dramatic change from current practice).

A sixth new practice is a little different from the others. It relates to our response to firms after they have made necessary corrections.

At my direction, the FDA is developing a formal warning letter “close-out” process. If the FDA can determine, usually based on a re-inspection, that a firm has fully corrected the violations raised in a warning letter, we will provide to the firm a “close-out” letter, indicating that the issues in the warning letter have been successfully addressed. To keep the public informed, we will indicate on our website when a firm has received a “close-out” letter.” (lose out letters for warning letters is something very new. It might help give a warning letter more clout and ce rtainly gives industry a motivation to clean up their act.)

CThen Dr. Hamburg gave two examples of FDA’s new enforcement posture. The quick action issuing Warning Letters to internet websites selling fraudulent products for the H1N1 influenza virus (swine flu) and a crackdown on “nutritional supplements” that contained illegal anabolic steroids.

Now here are my two complaints regarding Dr. Hamburg’s speech. While cracking down on the sales of clearly fraudulent products is commendable and something FDA has not done effectively for years, it is not a bold initiative. In fact, it is picking the low hanging fruit. These are easy enforcement actions to obtain because the violations are so blatant. Large food companies and big pharma seem to be left out of this push towards tougher enforcement standards. Or maybe I am being impatient.

Second, during the question and answer period, a food and drug attorney asked Dr. Hamburg about the lack of regulations for an increasingly complex regulated industry. She side-stepped the question and instead spoke of greater government transparency. That is too bad. FDA’s clinical trial regulations were written 35 years ago for a very different clinical trial industry. There are no regulations or enforcement for the huge clinical trial services industry including clinical laboratories and site management organizations. Computerized systems and part 11 compliance is something FDA rarely discusses. Combination products don’t have the level of regulatory oversight they need. There are a lot of areas that FDA needs to modernize and address.

Still, Dr. Hamburg only has been in office for eight weeks. She is certainly setting a different tone than in the past eight years. She mentioned Congressional support and increased funding for inspections and enforcement. This sounds like large steps in the right direction.

%d bloggers like this: