Drug Injury Watch

Some Drug Studies On ClinicalTrials.gov Not Completely Transparent

Study In NEJM Details How Drug Companies "Hide" Critical Information

A study published in the December 29, 2005 New England Journal of Medicine (NEJM), "Trial Registration at ClinicalTrials.gov between May and October 2005",  discusses how some major drug companies are continuing to withhold important information about their clinical drug trials.

The NEJM-published study is written by National Institutes of Health staffers (Deborah A. Zarin, M.D., Tony Tse, Ph.D., and Nicholas C. Ide, M.S.) associated with the federal web site, www.ClinicalTrials.gov . The authors assert that some drug companies -- such as Merck & Co., Pfizer Inc., and GlaxoSmithKline PLC -- are not disclosing or obscuring critical information about their clinical trials that have been registered on this federal site.  Examples mentioned in the study include the omission of the most basic type of information, like the very names of some drugs which are the subject of these clinical trials.

As background, some drug companies have routinely kept secret the results of clinical studies that reflected badly on their drugs, but published widely those studies which attained positive results for their drugs.  The federal ClinicalTrials.com site for reporting on clinical trials was created in 2002 to be a publicly accessible registry of clinical trials of prescription drugs and medical devices designed to treat serious or life-threatening diseases and conditions. As mandated by Congress, the drug and device companies are allowed to register trials on this federal web site only if the companies provide certain required information.

This December 2005 NEJM article includes assertions that several large companies are providing information that is incomplete or vague.  As mentioned above, some drug companies do not disclose the name of the drug which is the subject of their registered clinical study.  Instead, when completing a data field for the drug name, a company will use an obscure phrase such as "investigational drug."

In a December 29, 2005 Wall Street Journal article, Jeffrey M. Drazen, editor in chief of NEJM, commented that the current federal requirements had a critical "loophole" by not requiring companies to specifically name the drugs being tested.  Further, Dr. Drazen observed, by obscuring such basic information these drug companies "are meeting the letter but not the spirit of the law".

An editorial by Dr. Drazin in the December 29, 2005 edition of the NEJM called for medical researchers and potential patient-subjects to avoid participating in clinical trials where the drug company takes such a secretive approach.  Dr. Drazen wrote that it "makes moral sense" to provide complete trial information, adding:

"When patients put themselves at risk to participate in clinical trials, they do so with tacit understanding that their risk is part of the public record, not merely the secret record of the sponsor."

Note: The full text of the December 29, 2005 NEJM article about this ClinicalTrials.gov study is being made available for free by the medical journal to non-subscribers as a public service.

(Posted by: Tom Lamb)

Do Erectile Dysfunction Drugs Cause Blindness, Or Not, That Is The Issue

Public Citizen Compares Viagra And Cialis Against Lipitor To Find Out The Answer

Sidney M. Wolfe, MD, Director of Public Citizen's Health Research Group, recently alleged that there have been inadequate warnings that erectile dysfunction drugs can cause blindness.  Relatedly, he announced the results of a comparison test intended to make the point that the FDA and the drug companies responsible for the erectile dysfunction (ED) drugs Viagra, Cialis, and Levitra are, perhaps, misleading the public about the alleged link between these drugs and ischemic optic neuropathy (ION).

Dr. Wolfe sets the stage by drawing attention to the standard position asserted by the FDA and the drug companies, that the men using the ED drugs who have been stricken with ION are patients with cardiovascular risk factors, and it is those factors, not the Viagra, Cialis, nor Levitra, which caused the blindness.   To determine the validity of this position, Dr. Wolfe designed a comparison test using the cholesterol drug Lipitor as the control -- the idea being that people using Lipitor were another patient population with cardiovascular risk factors.  Dr. Wolfe wanted to find out whether Lipitor users were experiencing this blindness at the same rate as men who had developed ION after taking Viagra or Cialis.

For the sake of precision, we let Dr. Wolfe set forth the findings of that Viagra and Cialis v. Lipitor comparison test:

"For Viagra, there were 18 times more reports of ION per million prescriptions than for Lipitor and, for Cialis, 25 times more reports. Thus, it is very likely that the drugs can actually cause blindness in some people. Further evidence of causation can be seen in a case report in which one patient using Cialis suffered reversible visual field defects each time within 2 hours after taking 4 sequential doses of Cialis and suffered permanent partial loss of vision shortly after the fifth dose."

Based on these findings and other research, the consumer advocacy group Public Citizen has petitioned the FDA to immediately require the respective drug companies to add a "black-box" warning on the package insert labels for Viagra, Cialis, and Levitra.  In addition, the Public Citizen petition calls for the institution of a registry of all reported cases of blindness, specifically ischemic optic neuropathy or ION, following one's use of an ED drug.

(Posted by: Tom Lamb)

FDA Consumer Magazine: Prescription Drug News and Information, And More

Offers Broad Coverage, Including Reports On Current FDA Regulatory Activites

FDA Consumer magazine is available online at no cost, while the traditional paper version of this federal government publication has a $14 annual subscription rate for six bimonthly issues.  Moreover, by going to the FDA Consumer web site, one can read the entire contents of recent issues.  In addition, there is the online archive which goes back to 1989, although the contents of the entire magazine are not available for earlier years.

Intended for consumers and patients who want to stay healthy and safe, as well as individuals with a general interest in FDA regulatory activity, the FDA Consumer magazine is both well-written and informative.  According to the magazine's web site, the FDA Consumer "reports on current FDA activities to ensure that the products the agency regulates -- food, human and animal drugs, medical devices, cosmetics, radiation-emitting products, biologics -- are fit to use."

Each issue of the FDA Consumer magazine features a consumer quiz, commentary on recent regulatory activities, and a column from the magazine's editor. 

Insofar that it's free to view online, there is nothing to lose and plenty to gain, here.

(Posted by: Tom Lamb)

Many "Canadian" Online Drugs Are, In Fact, Not From Canada

FDA Says These Are "Drugs Of Dubious Origin, Safety, And Efficacy"

In mid-December 2005 the FDA reported that the majority of Web sites believed to be Canadian pharmacies selling prescription drugs manufactured in Canada are actually "fronts" for drugs that were not manufactured in Canada and, in fact, came from 27 different countries.

In August 2005 the FDA conducted an inspection of packages containing prescription drugs ordered online by U.S. patients that were shipped through John F. Kennedy International Airport in New York, Miami International Airport, and Los Angeles International Airport. 

According to a December 20, 2005 article in The Wall Street Journal:

"Out of nearly 4,000 parcels examined, almost 1,700, or 43%, had been ordered from 'Canadian' Internet pharmacies and were represented as being of Canadian origin. Of the 1,700 packages, 85% of the drugs weren't manufactured in Canada and came from 27 different countries."

In more detail, the agency identified India, Israel, Costa Rica, and Vanuatu as the four countries which appeared to be the primary sources of those drugs that were ordered online from pharmacies alleged to be Canadian in origin.

In a December 16, 2005 statement Andrew von Eschenbach, the FDA's acting commissioner, commented:

• "This operation suggests that drugs ordered from so-called Canadian Internet sites are not drugs of known safety and efficacy."
• "These results make clear there are Internet sites that claim to be 'Canadian' that, in fact, are peddling drugs of dubious origin, safety and efficacy."

As is well-known by now, many consumers order prescription drugs from Canada because they usually cost less than those sold in the U.S. The FDA, however, has long warned patients in the U.S. not to order prescription drugs online from Canada or other foreign countries for the very reasons stated by Dr. von Eschenbach.

In addition to having been falsely promoted as being of Canadian origin, the FDA found that some of the prescription drug products were counterfeit -- an even more alarming problem for patients.

The FDA said it is working with Canadian drug regulators and law-enforcement authorities on the matter.

(Posted by: Tom Lamb)

WHI Study Was Perhaps Flawed And Subsequent HRT Advice May Be Wrong

Cyclical Hormones, But Not Prempro, May Be Protective Against Heart Disease

Many people will recall that in July 2002 women were told to talk to their doctor about perhaps stopping their hormone replacement therapy (HRT) after the Women's Health Initiative (WHI) said a trial of Wyeth's Prempro showed that the drug raised the risk of heart attack, stroke, and breast cancer.

A recent study, which was published on December 16, 2005 in the medical journal Fertility and Sterility, now suggests that the broad-brush notion that hormone replacement therapy raises the risk of heart disease and breast cancer -- causing many women to stop using the HRT drugs -- was fundamentally flawed.

Accordingly, Dr. Edward Klaiber, a Worcester, Massachusetts endocrinologist and lead author of the new study, asserts "Women are now being told not to take hormones for heart disease prevention, and that may be totally wrong".

Prior to the 2002 WHI study results, hormone replacement therapy was routinely prescribed to women as they reached menopause for the purpose of not only relieving unpleasant symptoms like hot flashes but, also, because it was thought to protect against heart disease and osteoporosis. 

Based on the alleged problems he found with the WHI study, Dr. Klaiber believes that earlier medical research which showed that cyclical hormones are protective against heart disease is probably still valid, today.

According to Dr. Klaiber, the first problem with the WHI study results is that when the WHI trial was initially designed, hormone replacement therapy usually involved cyclical progesterone, meaning that it was taken just 10 or 12 days a month.  Then came Prempro, which combined estrogen and progestin in a daily pill -- a regimen that had never been associated with heart protection, Klaiber said.

Given this difference between the earlier approach to HRT and Prempro, Dr. Klaiber maintains: "The [WHI study] results might have been different if they had used a different form of estrogen that resembled a normal cycle."

Dr. Klaiber states that the WHI study's other major flaw was that the clinical trial participants were older, with a mean age of 62.7 years.  This population was already at a greater risk of cardiovascular problems. "The incidence of heart disease is 12 times higher for women in their 80s than it is in the 50s," Dr. Klaiber said.  Put otherwise, the WHI study began HRT for the first time in women who might have had pre-existing heart disease.

To determine the strength of his theory, Dr. Klaiber will be following a multi-center trial launched last year by the Phoenix-based Kronos Longevity Research Institute. In the Kronos study women aged 40 to 55 with be treated with hormone pills, hormones delivered through a skin patch, or a placebo.  Dr. Klaiber anticipates that the Kronos study will eventually show that hormone replacement therapy is not risky in women who are just beginning to go through menopause.  The Kronos study results, however, will not be available until 2010, according to Dr. Klaiber.   

Dr. Klaiber does allow that, regardless of its alleged flaws, the WHI study made a very significant contribution to the medical world because it showed that "Prempro was a mistake".

(Posted by: Tom Lamb)

Bextra Will Not Return In Canada As Safety Risks Outweigh Benefits

Health Canada Safety Panel Cites Heart Attacks, Strokes, and Severe Skin Reactions

Bextra, Pfizer's anti-inflammatory drug for arthritis patients, will not be returned to the Canadian market according to a Health Canada announcement in mid-December 2005.  Bextra was withdrawn voluntarily from the Canadian market in April 2005 by Pfizer after severe skin reactions affected seven people in Canada.

Citing the findings and recommendations of its expert safety panel, Health Canada said that the safety risks of Bextra outweighed its benefits.  In particular, Health Canada pointed out the serious cardiovascular risks associated with Bextra, including heart attack and stroke, and said that Bextra causes rare but severe and potentially fatal skin reactions more often than other drugs in its class.  Specifically, the severe skin reactions are erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).

A Health Canada spokesman, Jirina Vlk, was quoted in a December 17, 2005 Toronto Star article: "We concluded that there is insufficient evidence to establish the safety of the drug for its recommended use."

Bextra is a COX-2 inhibitor.  This class of drugs includes Vioxx and Celebrex.  In September 2004 Vioxx, once the most popular painkiller in Canada, was pulled from the worldwide market.  Subsequent to the the Vioxx recall, new warnings about serious cardiovascular risks have been added to the package insert, or label, for Celebrex.

According to the Toronto Star article, in a written release, Pfizer Canada said "Bextra is an important treatment option ... (and) it should continue to be available for those patients who could benefit from it."

More information about this action as well as earlier actions by Health Canada concernng Bextra can be found in its December 16, 2005 Advisory, posted on the Health Canada web site.

(Posted by: Tom Lamb)

FDA's David Graham Says U.S. Drug Safety System No Better in 2005

Graham Criticizes Agency's Performance During The Year Since Vioxx Recall 

In November 2004 David Graham, associate director for science and medicine at the FDA's Office of Drug Safety, criticized the FDA's drug oversight practices during a Senate Finance Committee hearing.  During his testimony, Graham made the now well-known remark that the FDA is "virtually defenseless" against another "terrible tragedy and a profound regulatory failure," such as Merck's withdrawn arthritis drug Vioxx.

In a November 2005 interview with Rita Rubin, a reporter for USA TODAY, Graham said that not much has changed at the FDA in the year since the Vioxx recall.  Graham told US TODAY that, "Today the United States of America is worse off when it comes to drug safety than it was a year ago when I testified."  In addition, this November USA TODAY article by Ms. Rubin included these comments by Graham:

• The FDA's new drug safety initiatives operate only as a diversion without real solutions.
• The Office of Drug Safety should be independent from FDA.
• The Drug Safety Oversight Board is a "a kangaroo court" because many of the board's 15 members are FDA employees that help review and approve new drugs.
• The ongoing Institute of Medicine study requested by FDA to examine drug safety will not have a great impact, because it is based heavily on FDA-supplied information.
   

Ms. Rubin wrote an accompanying piece for USA TODAY, also, which listed the several unsafe drugs which David Graham is especially concerned about, now.  As some may recall, when Graham gave his November 2004 Senate testimony he named five prescription drugs that he believed had an undue propensity for serious side effects.  That 2004 list consisted of Accutane, Bextra, Crestor, Meridia, and Serevent.

Graham's 2005 list of unsafe drugs included the following:

Natrecor (nesiritide): an intravenous heart-failure treatment approved by the FDA to treat hospitalized patients with acutely decompensated congestive heart failure.  As pointed out by esteemed cardiologist Eric Topol, of the Cleveland Clinic, in a July 2005 New England Journal of Medicine article, no clinical trial has yet proved that Natrecor reduces the risk of death or repeated hospitalization from heart failure.  As such, Dr. Topol questioned whether Natrecor should stay on the market.

Risperdal (risperidone): an atypical anti-psychotic which has been approved by the FDA to treat schizophrenia but is widely prescribed "off-label" for behavioral problems in elderly patients with dementia.  After ignoring reports of serious side effects from Risperdal in this population of patients, in April 2005 the FDA finally mandated that the drug's maker, Jansen, put a "black-box" warning on the Risperdal package insert to remind prescribing doctors that treating behavioral problems in dementia patients is not an FDA-approved use of Risperdal, and that such off-label prescribing of Risperdal has been linked to a higher death risk in these elderly patients.

Senate Finance Committee chair Charles Grassley, a Republican from Iowa, told USA TODAY that "Dr. Graham and people like him make a big difference."

We concur with Senator Grassley that David Graham should be commended for his good work on the cause of drug safety.  We are discouraged, however, that much of Dr. Graham's advice about how the FDA should perform its drug safety oversight role is still being ignored in Washington.

(Posted by: Tom Lamb)

Large Study to Investigate Heart Risks Of Celebrex, Ibuprofen, and Naproxen

Cleveland Clinic's Dr. Nissen To Lead 20,000 Patient "Precision" Clinical Trial

In mid-December 2005 the drug company Pfizer Inc. announced that Dr. Steven E. Nissen, medical director of the Cleveland Clinic's cardiovascular coordinating center, will lead a large-scale clinical trial to compare three of the most commonly used painkillers -- Pfizer's Celebrex, and prescription-strength doses of ibuprofen and naproxen -- among arthritis patients who also have pre-existing cardiovascular disease or who are otherwise at high risk of heart problems.

In laymen's terms, the "end point" of this massive study will be to answer this simple question: What is the safest medicine for these patients to control their pain?

Earlier in 2005, the FDA mandated that increased warnings be added to the package insert labels of Celebrex, a COX-2 inhibitor, as well as ibuprofen and naproxen, which are non-steroidal anti-inflammatory drugs (NSAIDs). The reason behind this FDA action was that some clinical studies had raised concerns that Celebrex and the two NSAIDs, like the recalled painkiller Vioxx, may increase a patient's risk of having a heart attack, stroke, or other serious cardiovascular event. The problem for the FDA, not to mention doctors and their patients, was that these previous studies were not definitive on the cardiovascular safety issue.  In part, that "uncertainty" problem was the result of the fact that there had not yet been any large-scale clinical studies of Celebrex, or the two NSAIDs, which focused on patients who had one or more pre-existing risk factors for cardiovascular disease.

The aim of this new Pfizer-sponsored clinical study -- which will be called "Precision", according to Forbes reporter Matthew Herper -- is to track incidents of cardiovascular deaths as well as non-fatal heart attacks and strokes in order to determine whether Celebrex, ibuprofen, and/or naproxen are safe for use by patients already at risk for serious cardiovasucular side effects. 

To this end, the Pfizer study will enroll 20,000 patients "worldwide" (actually just Australia, the U.S., Eastern Europe, and Switzerland, according to a December 13, 2005 Forbes online article by Matthew Herper) over an eighteen-month period.  Those patients will be followed for an average of two years, at a cost to Pfizer in the range of $100 million.  The results of this "Precision" study are expected to be available in no less than four years.

In a December 13, 2005 article in The Wall Street Journal, Dr. Nissen commented:

• "The public and the medical community are confused.... The relative safety of these three drugs is simply not known.  We're going to answer the question are they the same or are they not."
• "There has been an erosion of public confidence in this class of drugs.... We need to get an answer that is done in a way that is completely transparent."

Not all medical researchers, however, believe this Pfizer-sponsored study is a good thing.  For example, Garret FitzGerald, a renowned pharmacologist at the University of Pennsylvania, thinks giving Celebrex or the two NSAIDs to patients already at a high risk of having a heart attack or a stroke may be "ethically questionable", according to the December 13 Forbes article.  That article by Mr. Herper states, also, that Dr. FitzGerald "expressed concerns that the study could be just a way to buy Pfizer some more time."

According to news reports, the first patient will not be enrolled in the "Precision" clinical trial until some time in 2006.

(Posted by: Tom Lamb)

December 2005 FDA "Patient Safety News" Videos For Doctors Online

Edition Covers Paxil, Strattera, Menactra Meningococcal Vaccine, and More

The FDA's Patient Safety News (PSN) is a series of monthly video news shows intended primarily for doctors and other health care professionals.  Generally, this series covers significant approvals, recalls, and safety alerts for prescription drugs and medical devices.  Some of the FDA PSN videos contain footage and demonstrations relevant to protecting patients from serious side effects and other unwanted consequences.

Subjects covered in the December 2005 edition of the FDA Patient Safety News include the following:

Risk of Suicidality in Children Treated with Strattera

Recall of Enteryx Injections for Gastroesophageal Reflux Disease

Possible Connection between Menactra Meningococcal Vaccine and Guillain-Barre Syndrome

New Caution on Using Paxil During Pregnancy

Preventing Errors with Neuromuscular Blocking Agents

Luer Lock Misconnections can be Deadly

Drug Name Confusion: Toprol - XL, Topamax, Tegretol and Tegretol - XR

One can find more information about this December 2005 PSN edition and the series in general on the PSN section of the FDA's web site.   

(Posted by: Tom Lamb)

Judge Fallon Declares Mistrial In Irvin / Plunkett Vioxx Case

Merck's Vioxx Trial Record to Date: One Victory, One Loss, One Draw

The Reuters news service reported at 10:00 a.m. EST Monday, December 12, 2005 that Judge Eldon Fallon declared a mistrial in Irvin / Plunkett v. Merck, the first federal lawsuit involving the painkiller Vioxx, after jurors said they remained deadlocked.

A nine-member jury had been deliberating since last Thursday, and had continued its work during a rare Saturday court session.  After about 18 hours of deliberations over these three days, the jurors could not reach an unanimous verdict, as is required in a federal court lawsuit.  This situation is commonly referred to as a "hung jury".

An online news alert issued by The Wall Street Journal (WSJ) later in the morning reported:

The jury resumed what was to be its fourth day of deliberations Monday, but within about 20 minutes, U.S. District Judge Eldon Fallon called the jurors in and reminded them they had agreed to reach a verdict in a "reasonable time."

"It has now been a reasonable time. We cannot get a verdict," Judge Fallon said, declaring a mistrial.

The WSJ news alert also reported that Judge Fallon would schedule the Irvin / Plunkett case for a new trial, which will be heard in New Orleans.

(Posted by: Tom Lamb)