Drug Injury Watch

Can New FDA Transparency Task Force Acheive Its Lofty Objectives?

While Need For Greater Disclosure By FDA Is Evident, Drug Maker Trade Secrets May Be Difficult Obstacle To Overcome

(Posted by Tom Lamb at DrugInjuryWatch.com)

In early June 2009 it was announced that the FDA would begin to set up a task force within the agency whose purpose is to recommend ways by which there could be more timely disclosure about FDA regulatory and safety decisions.

From a June 2, 2009 FDA press release titled "FDA Forms Transparency Task Force" we get these laudable "sound bytes":

• Health and Human Services Secretary Kathleen Sebelius: "The Transparency Task Force will give the American people a seat at the table and make the FDA more open and accountable."
• FDA Commissioner Margaret A. Hamburg, M.D.: "I have asked the Transparency Task Force to deliver recommendations to me for ways to make more information available and foster better understanding of decision-making."
• Principal Deputy Commissioner Joshua Sharfstein, M.D.: "Implementation of the Transparency Task Force’s recommendations should make agency actions and decisions, and their underlying processes and bases, more transparent to the public."

This new FDA task force, which will be chaired by Principal Deputy Commissioner Sharfstein, consists of FDA center directors as well as the associate commissioner for regulatory affairs, chief scientist, and the chief counsel at the agency.

The FDA issued a June 3, 2009 Federal Register notice regarding the formation of its new Transparency Task Force in which the agency announced a June 24, 2009 public meeting intended to solicit recommendations on how the FDA can make more available, useful, and understandable information on its activities and decisions.

The agency has also established a "temporary" blog -- simply named "FDA Transparency Blog" -- which will run for the next six months, June through November 2009.

Two leading members of the medical community who have been involved with various drug-safety issues over time -- Dr. Steven Nissen, a cardiologist at the Cleveland Clinic, and Dr. Catherine DeAngelis, editor of The Journal of the American Medical Association -- both impliedly endorsed this move by the FDA according to a June 2, 2009 article, "Drug Agency May Reveal More Data on Actions", by New York Times (NYT) reporter Gardiner Harris. 

This same June 2 NYT article, however, points out that this new FDA task force will likely have a difficult time when it comes to the issue of any future disclosure of now secret data about drugs and devices under study:

The task will be complicated. Agency confidentiality decisions are governed by several interconnected laws, including the Federal Trade Secrets Act. Changing them would “involve more than one Congressional committee and impact thousands and thousands of companies, and thus would be an extremely difficult legislative path,” said Peter Barton Hutt, a former general counsel to the agency....

Ken Johnson, a spokesman for the Pharmaceutical Research and Manufacturers of America, said any agency plan to “disclose information about medicines during the F.D.A. review process should be carefully considered to ensure that the competitive development process remains intact to serve patients and the public health.”

According to the June 3 Federal Register notice, anyone interested in attending the June 24 public meeting -- which will be held at the National Transportation Safety Board (NTSB) Conference Center, 429 L'Enfant Plaza, SW., Washington, DC 20594 -- must register by June 17, 2009.

The Federal Register notice also provides information about how to make written and electronic comments, which must be submitted by August 7, 2009.

Beware The Potential Dangers Of Free Drug Samples

Some Ways That Free Drug Samples Can Harm Patients

(Posted by Tom Lamb at DrugInjuryWatch.com)

PLoS Medicine-- which is a peer-reviewed open-access journal published by the Public Library of Science -- published an essay by Susan Chimonas and Jerome P. Kassirer in May 2009 called "No More Free Drug Samples?" which provides a fresh perspective on a well-established practice in doctors office across the U.S.

This essay starts with the ideas that many of us may have about this practice:

Everybody likes something free, and free prescription drug samples are no exception. Patients love to receive them, and doctors feel good about handing them out. The practice of providing free drug samples is based on the tacit assumption that “sampling” does much more good than harm.

Chimonas and Kassirer go on from there to deconstruct these preconceptions, working at various levels:

In this essay, we question the assumption that good trumps harm when prescription drugs are provided free to practicing doctors. We argue that “sampling” is not effective in improving drug access for the indigent, does not promote rational drug use, and raises the cost of care.

I want to focus on the drug-safety aspect of this free drug samples issue. 

In their May 2009 PLos Medicine essay, Chimonas and Kassirer make these points in support of their contention that samples can have "negative consequences" when it comes to patient-health:

• In drugstores, pharmacists often identify potentially harmful drug interactions, intercept inadvertent medication errors, and offer a patient-friendly printout of instructions. In doctors' offices, however, detailed patient education regarding sample use rarely occurs, and when it does, it usually lacks information about drug interactions or instructions on how the drug should be taken. [footnote omitted]

• Moreover, if distribution is inadequately documented in patients' records, some people who receive samples in doctors' offices may not be notified or told to discontinue the medication in the event of a product recall or the emergence of new drug complications.

• The samples that drug representatives offer are almost never time-worn and well-tested drugs, nearly never generics, and usually comprise the newest agents on the market. As such, they expose patients to risks not yet identified in clinical trials. The experience with Vioxx is a case in point.

Chimonas and Kassirer discuss in this insightful essay, also, several other concerns they have with the seemingly "generous" practice of doctors dispensing free drug samples to patients.  It total, the authors conclude that:

The tradition of physicians dispensing samples has many serious disadvantages and is as anachronistic as bloodletting and high colonic irrigations. As the profession begins to slowly extract itself from the influential grip of industry, it must also deal with the undue influence of free samples.

If this topic interests you, "No More Free Drug Samples?" is a relatively short essay that is worth reading when you have an opportunity.

The Tale Of Merck's Fake Medical Journal As Told At A Vioxx Trial In Australia

Drug Company Paid Scientific Publisher Elsevier To Produce What Was Essentially A Marketing Publication For Vioxx And Fosamax

(Posted by Tom Lamb at DrugInjuryWatch.com)

In early April 2009 we heard that there had been some testimony at an Australian Vioxx personal injury trial about a "medical journal" which Merck had created and distributed to doctors in Australia apparently to tout the benefits of its (now recalled) blockbuster drug Vioxx.

Now an April 30, 2009 article, "Merck publishes fake journal", published online by The Scientist (free site registration required), gives us some additional information about what Merck was doing in Australia back in 2003:

Merck paid an undisclosed sum to Elsevier to produce several volumes of [Australasian Journal of Bone and Joint Medicine,] a publication that had the look of a peer-reviewed medical journal, but contained only reprinted or summarized articles--most of which presented data favorable to Merck products--that appeared to act solely as marketing tools with no disclosure of company sponsorship.

"I've seen no shortage of creativity emanating from the marketing departments of drug companies," Peter Lurie, deputy director of the public health research group at the consumer advocacy nonprofit Public Citizen, said, after reviewing two issues of the publication obtained by The Scientist. "But even for someone as jaded as me, this is a new wrinkle."

According to this article by Bob Grant, The Scientist obtained two issues of the Australasian Journal of Bone and Joint Medicine, Volume 2, Issues 1 and 2, both dated 2003.  Those issues were reviewed by Public Citizen's Peter Lurie, and the article some comments by Mr. Lurie about his review:

"I've never seen anything quite like this," he said. "Reviews are usually swimming in references." For example, one article on osteoporosis labeled above the title as a "meta-analysis" cites two references -- one itself a meta-analysis. "To the jaundiced eye, [the journal] might be detected for what it is: marketing," he said. "Many doctors would fail to identify that and might be influenced by what they read."

This April 30 article also draws upon testimony given at the trial of the civil suit filed by Graeme Peterson -- who suffered a heart attack in 2003 while on Vioxx -- against Merck and its Australian subsidiary, Merck, Sharp & Dohme Australia (MSDA):

In testimony provided at the trial last week, which was obtained by The Scientist, George Jelinek, an Australian physician and long-time member of the World Association of Medical Editors, reviewed four issues of the journal that were published from 2003-2004. An "average reader" (presumably a doctor) could easily mistake the publication for a "genuine" peer reviewed medical journal, he said in his testimony. "Only close inspection of the journals, along with knowledge of medical journals and publishing conventions, enabled me to determine that the Journal was not, in fact, a peer reviewed medical journal, but instead a marketing publication for MSD[A]."

He also stated that four of the 21 articles featured in the first issue he reviewed referred to Fosamax. In the second issue, nine of the 29 articles related to Vioxx, and another 12 to Fosamax. All of these articles presented positive conclusions regarding the MSDA drugs. "I can understand why a pharmaceutical company would collect a number of research papers with results favourable to their products and make these available to doctors," Jelinek said at the trial. "This is straightforward marketing."

As mentioned above, there was no disclosure of Merck's funding found anywhere in the two issues of the Australasian Journal of Bone and Joint Medicine obtained by The Scientist.  But reporter Bob Grant established that this "journal" was, in fact, paid for by Merck:

Elsevier acknowledged that Merck had sponsored the publication, but did not disclose the amount the drug company paid. In a statement emailed to The Scientist, Elsevier said that the company "does not today consider a compilation of reprinted articles a 'Journal'."

"Elsevier acknowledges the concern that the journals in question didn't have the appropriate disclosures," the statement continued. "It is worth noting that project in question was produced 6 years ago and disclosure protocols have evolved since 2003. Elsevier's current disclosure policies meet the rigor and requirements of the current publishing environment."

Mr. Grant's article also includes statements by a spokesman for Merck's Australian subsidiary, MSDA, as well as a rheumatologist in Australia who was one of the members of a "Honorary Editorial Board" for this Australasian Journal of Bone and Joint Medicine journal.

Last but not least:  Mr. Grant's article -- "Merck publishes fake journal" (free site registration required) -- provides links for you to view PDFs of the two issues of Australasian Journal of Bone and Joint Medicine from 2003 which were obtained by The Scientist.

P.S.  A new article, "Fresh questions raised about prominent cardiologist's role in "ghostwritten" 2001 meta-analysis of Vioxx trial", published April 30, 2009 by heartwire, is worth a look if this matter intrigues you.  (5/1/09)

Internal Glaxo Emails Show Drug Company Was Concerned In 2007 About Avandia's Heart Attack Risks

Senator Grassley's Report On How Glaxo Defended Avandia In Wake Of 2007 NEJM Article By Nissen And Wolski Is Expected To Be Released Soon

(Posted by Tom Lamb at DrugInjuryWatch.com)

On May 21, 2007, in our post titled "Glaxo's Diabetes Drug Avandia May Cause Significant Heart Attack Risk", we reported about the Los Angeles Times publishing a May 21 article which broke the story about a new analysis of Avandia data that had been published online earlier this same day by the New England Journal of Medicine (NEJM).

This now relatively well-known NEJM Avandia article, "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death", was written by Steven E. Nissen, M.D., and Kathy Wolski, M.P.H.; it was published in the June 14, 2007 print edition of the NEJM.

It turns out, however, that GlaxoSmithKline PLC -- the drug company that makes Avandia -- had some (improper) advanced notice of the Nissen and Wolski NEJM article and (surprise, surprise) the drug company tried to do something about it. 

For the telling of this still-developing story, we turn to a January 14, 2009 Wall Street Journal (WSJ) article, "Glaxo's Emails on Avandia Reveal Concern", by reporters Alicia Mundy and Jared Favole.  We start by setting the stage:

The study by Dr. Nissen for the New England Journal was supposed to be kept under wraps until its release on May 21, but Glaxo obtained a copy on May 3 from a doctor, Steven Haffner of the University of Texas, who was reviewing it for the medical journal. Dr. Haffner had been a Glaxo consultant on Avandia since 2000 and received $433,000 from Glaxo between 2000 and August 2007. He confirms giving Glaxo the study, though he says doing so was "a terrible mistake."...

As soon as Glaxo got Dr. Nissen's draft, its researchers began a detailed analysis, according to the email excerpts. On May 4, one wrote, "There is no statistical reason for disregarding the [Nissen] findings as presented."...

In a May 8, 2007, email, Moncef Slaoui, the director of Glaxo research, told several executives: "FDA, Nissen and GSK all come to comparable conclusions regarding increased risk for ischemic events, ranging from 30% to 43%!"

The January 14 WSJ article suggests that there is more to come, soon, regarding Glaxo's conduct back in 2007, this time from Washington:

A leading Republican senator, Sen. Chuck Grassley of Iowa, has been pushing the FDA to ask Glaxo to withdraw the drug. He is preparing a report that may be released soon containing excerpts from Glaxo documents about the company's efforts to defend its drug from the New England Journal study, according to people familiar with the situation.

We will be watching for the release of Senator Grassley's report about Avandia and Glaxo.

If you know anything more regarding this apparent attempt by Glaxo to head-off the 2007 NEJM article by Nissen and Wolski that first revealed the increased heart attack risk associated with Avandia -- or you want to express an opinion about Glaxo's conduct in this instance -- please submit a Comment below.

(Posted by Tom Lamb at DrugInjuryWatch.com)

On May 21, 2007, in our post titled "Glaxo's Diabetes Drug Avandia May Cause Significant Heart Attack Risk", we reported about the Los Angeles Times publishing a May 21 article which broke the story about a new analysis of Avandia data that had been published online earlier this same day by the New England Journal of Medicine (NEJM).

This now relatively well-known NEJM Avandia article, "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death", was written by Steven E. Nissen, M.D., and Kathy Wolski, M.P.H.; it was published in the June 14, 2007 print edition of the NEJM.

It turns out, however, that GlaxoSmithKline PLC -- the drug company that makes Avandia -- had some (improper) advanced notice of the Nissen and Wolski NEJM article and (surprise, surprise) the drug company tried to do something about it. 

For the telling of this still-developing story, we turn to a January 14, 2009 Wall Street Journal (WSJ) article, "Glaxo's Emails on Avandia Reveal Concern", by reporters Alicia Mundy and Jared Favole.  We start by setting the stage:

The study by Dr. Nissen for the New England Journal was supposed to be kept under wraps until its release on May 21, but Glaxo obtained a copy on May 3 from a doctor, Steven Haffner of the University of Texas, who was reviewing it for the medical journal. Dr. Haffner had been a Glaxo consultant on Avandia since 2000 and received $433,000 from Glaxo between 2000 and August 2007. He confirms giving Glaxo the study, though he says doing so was "a terrible mistake."...

As soon as Glaxo got Dr. Nissen's draft, its researchers began a detailed analysis, according to the email excerpts. On May 4, one wrote, "There is no statistical reason for disregarding the [Nissen] findings as presented."...

In a May 8, 2007, email, Moncef Slaoui, the director of Glaxo research, told several executives: "FDA, Nissen and GSK all come to comparable conclusions regarding increased risk for ischemic events, ranging from 30% to 43%!"

The January 14 WSJ article suggests that there is more to come, soon, regarding Glaxo's conduct back in 2007, this time from Washington:

A leading Republican senator, Sen. Chuck Grassley of Iowa, has been pushing the FDA to ask Glaxo to withdraw the drug. He is preparing a report that may be released soon containing excerpts from Glaxo documents about the company's efforts to defend its drug from the New England Journal study, according to people familiar with the situation.

We will be watching for the release of Senator Grassley's report about Avandia and Glaxo.

If you know anything more regarding this apparent attempt by Glaxo to head-off the 2007 NEJM article by Nissen and Wolski that first revealed the increased heart attack risk associated with Avandia -- or you want to express an opinion about Glaxo's conduct in this instance -- please submit a Comment below.

2008 Emory Law Journal Article Presents Ketek As A Case Study In FDA Regulatory Failure

Discusses The Dire Consequences Of Fraudulent Science, Federal Preemption, And Corporate Deregulation

(Posted by Tom Lamb at DrugInjuryWatch.com)

Thomas O. McGarity, of the University of Texas School of Law, is uniquely positioned to give us a history of the beleaguered antibiotic Ketek in his 2008 article, "Corporate Accountability for Scientific Fraud: Ketek and the Perils of Aggressive Agency Preemption", which was published in the Emory Law Journal, Volume 58, Number 2 (58 EMORY L.J. 287, 2008).

From an introductory footnote we get this background information about Professor McGarity and this 2008 law review article about Ketek:

This Article lies at the intersection of three major projects on which the author has labored for the past several years and will continue to pursue during the next two years. The first, an inquiry with my colleague Professor Wendy Wagner into the strategies that advocates in the private sector employ to “bend science” to support predetermined policy agendas, resulted in a recently published book....  The second project describes and analyzes the efforts of common law defendants, joined more recently by some regulatory agencies, to persuade courts to find that state common law claims against the manufacturers of federally licensed products and activities are preempted by federal regulatory action....  The final project, a forthcoming book, Freedom to Harm, examines the thirty-year project of free market advocates in corporate America, conservative think tanks, and academia to free companies of “unnecessary and burdensome” regulatory responsibilities and common law obligations.

I understand not many of you may have the appetite nor the time to consume all that Professor McGarity has to offer in his 58-page law review article.  Anyone wanting to learn about the various "irregularities" in how Ketek was approved by the FDA, however, should at least be aware that this McGarity article is available as a resource.

To give one a sense of what this Ketek law review article by Professor McGarity has to offer, I have excerpted the following from the Introduction section:

• Part I briefly describes the new drug approval process through which a manufacturer of a prescription drug must obtain approval from the Food and Drug Administration (FDA) for new products and for new uses of existing products.

• Part II provides a case study of the dramatic failure of this process to protect consumers by using recently uncovered information concerning the antibiotic Ketek.

• Part III briefly describes the role that state common law can play in providing a backup for ensuring that manufacturers behave responsibly during the drug approval process and are held accountable when they do not.

• Part IV describes the Supreme Court’s decision in Buckman Co. v. Plaintiffs’ Legal Committee, in which the Court held, in a fairly unique factual setting, that the plaintiffs’ common law claims based upon the fraud allegedly perpetrated by a consultant for a medical device manufacturer was preempted by federal law.  [footnote omitted]

• Part V analyzes the arguments for and against preemption of fraud-on-the-agency claims in light of the Ketek experience and concludes that, on balance, preemption is a bad idea because federal enforcement alone provides inadequate incentives to companies that, because they face powerful economic pressures to show large profits to their shareholders, are inclined to cut corners.

• Part VI offers suggestions on how the lower courts should react to Buckman, how the Supreme Court can avoid extending Buckman when it next takes up the issue, and how Congress might go about reversing or limiting Buckman and empowering common law courts to reassume the vital backstop role that they have played in the past.

One may wonder why Professor McGarity chose Ketek as his example for depicting what is currently wrong with the FDA and its drug-approval process.  From the Conclusion section:

Why does Ketek matter? Because FDA broke its own rules and allowed Ketek on the market; because dozens of patients have died or suffered needlessly; because FDA allowed Ketek’s maker to experiment with it on children over reviewers’ protests; because FDA ignored warnings about fraud; and because FDA used data it knew was false to reassure the public about Ketek’s safety.  [footnote omitted]

For those of you who are not familiar with Ketek (telithromycin), it is in a class of drugs called ketolide antibiotics and is to be prescribed only for community-acquired pneumonia. Ketek has been associated with adverse side effects such as liver damage, liver disease, liver failure, and hepatitis.

What Is The Proper Relationship Between Doctors, Patients, And Drug Companies

Consider These Five Different Points Of View Presented By The British Medical Journal In Its February 3, 2009 Edition

(Posted by Tom Lamb at DrugInjuryWatch.com)

On February 4, 2009, the Royal College of Physicians of London (RCP) published a report entitled "Innovating for Health: Patients, Physicians, the Pharmaceutical Industry and the NHS", prepared by a working group chaired by Richard Horton (editor of the Lancet), which consists of 70 pages with 42 recommendations.

The British Medical Journal (BMJ), in its February 3, 2009 edition, took the occasion of this report's publication to present five different and distinguished perspectives on the issue of what is the proper relationship between doctors, patients, and drug companies.  In the preface to each of these five articles in its February 3 edition, the stage is set by BMJ in this manner:

The relationship between the drug industry, academia, healthcare professionals, and patients is widely held to be at an all time low, and it is in the interests of all parties to improve it. A recent report from the Royal College of Physicians gives 42 recommendations aimed at forging a more productive partnership with industry. Here we set out five views on what the ideal relationship between industry and prescribers and patients should be and what steps need to be taken to achieve it. [citations omitted]

To give you a sense of the five different positions advocated in these BMJ "Analysis" section articles, below we are providing the first paragraph of each item.  Of course, if interested, you are encouraged to click-thru to the full version of these relatively short articles and continue reading.

We start with "Relationships with the drug industry: More regulation, greater transparency", by Harlan M, Krumholz, of Yale University School of Medicine, and Joseph S. Ross, of Mount Sinai School of Medicine, in New York:

The relationship between drug and device companies, the medical profession, and the public is at a critical juncture. Individuals who have placed their interests in profit and influence over patients and public health have overshadowed much of the good work and reputations of those who have engaged in constructive interaction. As a result, public perception of the drug industry, doctors and scientists is at an historic low. The public is well served when industry, clinicians, and academicians work together for the common good, generating new knowledge and ensuring appropriate and rapid dissemination of effective products to save lives and improve quality of life. To restore the public’s trust we must set a path forward that encourages ethical collaboration and discourages activities by industry, researchers, or practising doctors that are largely self serving or place financial benefit above patients and the public good. Setting explicit standards of conduct for interactions between industry and both patients and physicians can assist all parties. We propose six.  [footnotes omitted]

Next -- and we are following the order in which the BMJ set them forth in its print publication -- is "Relationships with the drug industry: Keep at arm’s length", by Marcia Angell, a senior lecturer in social medicine at Harvard Medical School:

I believe there should be no relationship between the drug industry and either prescribers or patients. Drug companies are investor owned businesses with a responsibility to maximise profits for their shareholders. That is quite different from the mission of the medical profession, which is to provide the best care possible for patients. I start with this simple fact, because it is so often obscured by the industry’s public relations.  Drug companies are not confused on this score. Their major output now consists of "me-too" drugs for mild or ill defined conditions in essentially healthy people. This is because that market is big and more easily expanded than the market for innovative drugs for serious diseases.  [footnote omitted]

The third article is "Relationships with the drug industry: Collaboration to improve care", by Gordon Coutts, a vice president and general manager of Schering Plough UK:

Healthcare professionals and patients need to have the most up to date information on all the treatment options available to them, including medicines. There is therefore a legitimate place for a responsible relationship between the drug industry and the NHS, prescribers, and patients. This relationship should support the promotion of good medical care, improve health outcomes, and reduce health inequalities. It should include the provision of information to guide valid patient choice.

For a fourth perspective, we look to "Relationships with the drug industry: Build trust based on good science", by Scott Gottlieb, a health policy analyst at the American Enterprise Unit, in Washington, DC:

Medical treatments are becoming increasingly more individual, with respect to both disease and patient. They are also becoming more complex, and precise diagnoses and close monitoring are needed to optimise their use. In this environment, consumers and doctors need to work more closely with product developers. Yet increasing regulation of the drug industry is restricting its ability to disseminate the results of its clinical studies. This risks shrinking the opportunities patients have to improve their health. In the face of regulatory steps to restrain their scientific speech, drug makers need to take new steps in their relationship with doctors and patients and establish transparent guidelines for those interactions. They should also focus more squarely on matters of advancing science, monitoring for safety, and improving health education.

Finally, there is "Relationships with the drug industry: Focus on better information", by
Richard Tiner, medical director at the Association of the British Pharmaceutical Industry, in London:

The primary role of the research based drug industry is to discover, develop, license, and market innovative medicines to prevent, treat, or cure disease. This role has a prime benefit for patients but also helps prescribers in their role of managing disease. The UK industry is committed to a stable and pragmatic partnership with the government and the NHS on medicines—one that enshrines value for money, reward for innovation, and ensures greater availability of new medicines to patients. This should lead to the industry being seen as a trusted partner in the provision of health care by both prescribers and patients.

Certainly, these five BMJ articles give one plenty to think about concerning the issue of what is the proper relationship between doctors, patients, and drug companies.

Now it's time to let us know which of the above positions you agree with -- or present your own ideas and thoughts on this important social policy issue -- by submitting a Comment, below.

Actavis And FDA Criticized Over Their Digitek Recall Conduct In New 2009 Report

ISMP QuarterWatch: Cannot "rule out, or state definitively, whether defective digoxin tablets led to hundreds of patient deaths"

(Posted by Tom Lamb at DrugInjuryWatch.com)

On January 15, 2009 The Institute for Safe Medication Practices (ISMP) released QuarterWatch: 2008 Quarter 2, which includes an analysis of how the Digitek recall has been handled by Actavis, the drug maker, and FDA, the regulatory agency, which demonstrates how ineffectual the FDA has become when it comes it critical issues of drug safety in the U.S.

As background, the IMSP QuarterWatch Project Team consists of the following individuals:

• Thomas J. Moore, Senior Scientist, Drug Safety and Policy, ISMP;
• Michael R. Cohen RPh, MS, ScD, President, ISMP; and,
• Curt D. Furberg, MD, PhD, Professor of Public Health Sciences, Wake Forest University School of Medicine.

The Digitek recall was classified as Class I recall by the FDA, meaning there is “a reasonable probability... a violative product will cause serious adverse health consequences or death." (21 CFR 7.3 Recall Classification). 

This new ISMP QuarterWatch report, however, reveals that the FDA has seemingly taken a back seat and let Actavis determine how the Digitek recall would be done.  To start:

Although this is one of the largest Class I drug recalls we know of—affecting more than 1 million vulnerable heart patients—the FDA allowed the company to manage public notification of consumers, doctors, pharmacies and wholesalers. The public notice from the Center for Drug Evaluation and Research was a reproduction of a brief company statement.

For its Digitek recall analysis, the ISMP QuarterWatch Project Team attempted to get some new information from Actavis and the FDA about what has been learned thus far about the extent of defective Digitek (digoxin) pills that were dispensed to patients in terms of time frame and number of pills.  As can be seen by the following statements, however, both Actavis and the FDA are continuing to be vague, at best, when it comes to divulging that type of information:

• In April 2008 the Actavis Group announced the voluntary Class I, consumer level recall of 800 million digoxin tablets, the entire unexpired production of its Little Falls, NJ plant over a 26-month period, and about 60% of the entire U.S. supply of an important generic heart drug.

• The company stated that it had no evidence that any defective tablets had in fact entered commercial distribution, and that it had recalled nearly 1 billion tablets and closed its plants “out of an abundance of caution.”

• Neither the company nor the FDA will estimate how many tablets actually reached consumers; nor will either party reveal how many tablets have been recovered through the Class I recall. Neither the FDA nor the company has tested the recalled tablets to determine how many might have been defective.

In this new QuarterWatch report, at least, there is no indication by Actavis about the fate of the Digitek pills that have been collected as regards whether those pills are still available for testing in the future.  Another issue that was not addressed is whether the pills that were "returned" by patients through Stericycle are being preserved and kept separate such that any future testing would reveal which patients, if any, had been dispensed Digitek pills that had the "double-thickness" defect and up to twice the active ingredient, thereby putting them at risk for digoxin toxicity (also called digitalis poisoning).

The ISMP analysis contained in this January 2009 QuarterWatch report gives rise to well-deserved criticism of the FDA as regards the Digitek recall -- which, essentially, goes far beyond the Digitek recall:

Because of limitations in the U.S. system for post-market surveillance, the characteristics of the drug, and the nature of the system for recalling defective drugs, it is not possible to estimate how many patients might have died or become seriously injured by defective [Digitek] tablets....

Without extensive testing of distributed and recalled tablets, it is difficult to separate cases caused by defective tablets from other causes, including declining kidney function, decreasing cardiac output and failure to monitor blood levels of the medication.

Largely because of how this Digitek recall has been conducted, i.e., letting the drug company call the shots as opposed to the FDA acting in the interest of patients who took Digitek, the ISMP QuarterWatch report reached this conclusion:

The existing evidence does not permit us to either rule out, or state definitively, whether defective [Digitek] pills led to hundreds of patients deaths.

Of course, while the FDA might feel that is an acceptable endpoint, the attorneys who represent people who developed digoxin toxicity while using Digitek as well as the families of people who died due to an overdose of digitalis in product liability lawsuits will not be as easy on Actavis.

And as for the FDA, let us hope that the Obama Administration will act so as to restore the FDA to its proper role, which is protecting patients and not protecting drug makers.

In closing, a hat tip to Ed Silverman, formerly of the Pharmalot blog and now writing for The RPM Report, where we first read about this ISMP QuarterWatch Digitek analysis in his January 19, 2009 online article, "ISMP Draws Attention to Drug Safety Issues In New Report".

Stay tuned for our future reports on what is learned from Actavis in the discovery aspect of these Digitek lawsuits about the extent of defective Digitek pills dispensed to patients in terms of time frame and number of pills.

Sandoz Metoprolol Succinate ER Tablets Recall Has Been Done Rather Quietly

Many Patients Are Dissatisfied With Lack Of Information From Sandoz, FDA, Or Their Pharmacy About Why This Generic Toprol Pill Was Pulled

(Posted by Tom Lamb at DrugInjuryWatch.com)

In an August 26, 2008 Drug Injury Watch post, "FDA Warns Sandoz About Possible Quality-Control Problems At Its North Carolina Generic Drug Manufacturing Facility", I reported FDA inspectors found that Sandoz had failed to properly validate its manufacturing process for Metoprolol Succinate ER Tablets (Generic Form Of Toprol XL).

Here is the August 12, 2008 FDA Warning Letter (08-ATL-13) sent to Sandoz concerning the"Good Manufacturing Practices" (GMP) problems found at its generic drugs facility located in Wilson, North Carolina.

Returning to my earlier post, there I noted:

It is unclear as of August 26 whether Sandoz will cease distribution of its metoprolol succinate ER tablets (generic Toprol XL) and/or issue a recall of this medication.  We will be watching for these possible related developments.

Well, in the few months that followed we never saw any Metoprolol Succinate ER Tablets recall notice from the FDA nor Sandoz. 

Starting in November 2008, however, we started to get some Comments submitted to the August 26 post which indicated that, in fact, some type of recall was underway.  And elsewhere on the web, such as this Topix forum, "recall at Rite-aid -- Posted in the Metoprolol (generic), Toprol XL Forum", there were various reports coming in to this effect.

Thankfully, one of the participants in that Topix forum posted a link to this November 12, 2008 notice, "Recall: Metoprolol ER Tablets by Sandoz" published online by Pharmacy Industry News:

Sandoz is voluntarily extending the September 17, 2008, recall of Metoprolol Succinate Extended Release Tablets 25mg and 50mg, to include all strengths of distributed lots with expiration dates through August 2010. This voluntary action by Sandoz is due to deficiencies in documentation practices and in-process controls for this product. This voluntary recall is being conducted down to the retail level with the knowledge of the FDA. The affected lots were shipped approximately between November 2006 and October 2008. (Sandoz Press Release 11/3/08)

Unfortunately (but not surprisingly) I could not find the above-referenced November 3, 2008 press release on the Sandoz web site when I checked today, nor could I find there any press release about this Metoprolol Succinate ER Tablets recall from back in September 2008.

Likewise, there is nothing to be found readily on the FDA's web site about this Sandoz Metoprolol Succinate ER Tablets recall.

If you have more information about how Sandoz is carrying out this relatively "quiet" recall of its Metoprolol Succinate ER Tablets, please let us know by submitting a Comment, below, or sending me a private email.

P.S.  AstraZeneca issued a May 18, 2009 press release to announce that all wholesale ordering restrictions in place for its Toprol-XL (metoprolol succinate) extended release tablets have been removed and that supply levels of Toprol-XL are approaching near usual levels at all points in the distribution chain.  (5/21/09)

When Will We Learn The Real Extent Of Generic Drug Recalls By Actavis And ETHEX

Numerous Instances Where Out-Of-Spec Oversized Pills With Double The API Dose Are Produced: How And When Did This Happen?

(Posted by Tom Lamb at DrugInjuryWatch.com)

In late April 2008, when the Digitek recall was announced by Actavis, most were surprised to hear that so-called "double-dose" pills were being produced by a drug company here in the U.S. 

But since then we have learned about several more instances of out-of-spec, oversized pills with double the dose of their respective active pharmaceutical ingredients (API), most recently the November 2008 (third and latest) recall by ETHEX involving these generic drugs:

Propafenone HCl Tablets: 150 mg, 225 mg, and 300 mg
Isosorbide Mononitrate Extended Release Tablets: 30 mg and 60 mg
Morphine Sulfate Extended Release Tablets: 15 mg
Morphine Sulfate Immediate Release Tablets: 15 mg and 30 mg
Dextroamphetamine Sulfate Tablets: 10 mg  

Other 2008 recalls by Actavis and ETHEX involving possible double-dose pills include:

• August 2008 Actavis Recall Of All Drugs Manufactured At Its Little Falls, NJ Plant

• A New "Double-Dose" Pill Drug Recall Is Issued By ETHEX Corp.  (October 2008)

But we have had no explanation from Actavis, ETHEX, nor the FDA about what went wrong at these generic drug manufacturing plants such that we are able to know the extent to which these various defective pills were available for ingestion by unsuspecting patients.  That is, there has been little if any real information about the quantity of double-dose Digitek pills, for example, and when in time specifically those oversized pills were being produced by Actavis at its Little Falls, New Jersey facility.

In a November 10, 2008 article, "Big pills big problem for Ethex?", reporter Gareth Macdonald suggests that it may be difficult for us to learn how and when these generic pills were actually produced by ETHEX, and seemingly the same pertains to the Actavis recalls:

Details of any specific problem have not been released, making it difficult to ascertain if the oversized pills are a result of a manufacturing deficiency or simply that more out-of-spec tablets are being detected than previously as the sensitivity of analysis methods continues to improve.

Either way however, the growing safety focus following recent high-profile problems with branded products, generics and APIs is likely to result in the identification of more out-of-spec tablets as levels of regulatory scrutiny are increased.

Of course, there is always the possibility that FDA and Actavis will issue a Digitek update, for example, someday.  But with the passage of time since this FDA Class I Digitek recall was first announced in April 2008, it seems increasingly unlikely that Actavis or the FDA will be providing any clarification about the extent (in terms of quantity and time) of double-dose Digitek pills that were distributed to unsuspecting patients.

In early October 2008 Representatives John D. Dingell (D-MI) and Bart Stupak (D-MI) announced that Congress is investigating the Digitek recall to learn what the FDA knew about manufacturing problems at the Actavis facility in Little Falls, N.J.  Perhaps this investigation will yield some answers for us about the quantity and time questions.

Lastly, there will be what is called "discovery" in the Digitek litigation intended to figure out what led to the double-thickness problem at the Little Falls Actavis facility.  And, in the end, it may be this discovery process in the Digitek litigation is the only way that we will eventually learn the how and the when of what happened, there.

Pfizer Is Accused Of Withholding Or Altering Drug Study Results About Neurontin That Were Not Favorable

If Drug Companies Put Sales Above Efficacy And Safety, Should They Get Legal Immunity By Means Of Federal Preemption Doctrine?

(Posted by Tom Lamb at DrugInjuryWatch.com)

In the first part of October 2008 we learned of yet another instance where a drug company chose to put profits over people.  Yet in the near future our U.S. Supreme Court may decide that the legal doctrine of federal preemption gives legal immunity to Big Pharma for drug injury lawsuits.

An October 8, 2008 Wall Street Journal article, "Suit Alleges Pfizer Spun Unfavorable Drug Studies", explained what is new as far as bad conduct goes in the pharmaceutical sector:

Documents and emails released this week in the case in U.S. District Court in Boston suggest Pfizer's marketers influenced the drug's scientific record to boost sales at least until 2003 by declining to release or altering the conclusions of studies that found no beneficial effect from Neurontin for various off-label conditions....

According to documents in the Boston case, a European study done in the late 1990s by Warner-Lambert to measure Neurontin's use for diabetic nerve pain produced consternation at Pfizer after it failed to find a significant effect. "I think we can limit the potential downsides of the ... study by delaying the publication for as long as possible," wrote Michael Rowbothan, then Neurontin's marketing team leader, in a 2000 email sent after Pfizer bought Warner-Lambert. He added that "it will be more important to how WE write up the study."

A second October 8 article, "Experts Conclude Pfizer Manipulated Studies", published by the New York Times, added some commentary and then put this latest incident in context:

One of the experts who reviewed the documents, Dr. Kay Dickersin of the Johns Hopkins Bloomberg School of Public Health, concluded that the Pfizer documents spell out “a publication strategy meant to convince physicians of Neurontin’s effectiveness and misrepresent or suppress negative findings.” ...

The expert reports, unsealed Monday in a federal court in Boston, add to accusations that the pharmaceutical industry has controlled the flow of clinical research data, blurring the lines between science and marketing.

In April, for example, a group of academic doctors questioned the validity of drug industry research after finding that Merck had hired ghostwriters to produce scientific articles about Vioxx, then recruited prestigious doctors to serve as their official authors. Vioxx, a painkiller, was withdrawn from the market in 2004 after research indicated it could cause strokes and heart attacks.

Last winter, Merck and Schering-Plough were criticized for delaying the release of a study on their best-selling cholesterol medication Vytorin that showed the drug did not slow the growth of plaque in arteries. In the case of Pfizer’s Neurontin, the negative studies would have increased doubts about the drug’s value for several unapproved uses — treating bipolar disorder, controlling certain types of pain and preventing migraine headaches, according to the expert opinions.

What is even more remarkable, in light of this type of misconduct, is that the U.S. Supreme Court, in the Wyeth v. Levine case, may soon give these drug companies immunity to drug injury lawsuits by application of the federal preemption legal doctrine to those cases.

It seems to me that this legal immunity is a get-out-of-jail-free card that the drug companies cannot and should not be trusted with for the sake of American drug safety.