4 posts tagged “drugs”

By GARDINER HARRIS
The New York Times
Published: April 28, 2008

Drug and medical device companies should be banned from offering free food, gifts, travel and ghost-writing services to doctors, staff members and students in all 129 of the nation’s medical colleges, an influential college association has concluded.

The proposed ban is the result of a two-year effort by the group, the Association of American Medical Colleges, to create a model policy governing interactions between the schools and industry. While schools can ignore the association’s advice, most follow its recommendations.

Rob Restuccia, executive director of the Prescription Project, a nonprofit group dedicated to eliminating conflicts of interest in medicine, said the report would transform medical education.

“Most medical schools do not have strong conflict-of-interest policies, and this report will change that,” Mr. Restuccia said.

The rules would apply only to medical schools, but they could have enormous influence across medicine, said Dr. David Rothman, president of the Institute on Medicine as a Profession at Columbia University.

“We’re hoping the example set by academic medical colleges will be contagious,” Dr. Rothman said.

Drug companies spend billions wooing doctors — more than they spend on research or consumer advertising. Medical schools, packed with prominent professors and impressionable trainees, are particularly attractive marketing targets.

So companies have for decades provided faculty and students free food and gifts, offered lucrative consulting arrangements to top-notch teachers and even ghost-wrote research papers for busy professors.

“Such forms of industry involvement tend to establish reciprocal relationships that can inject bias, distort decision-making and create the perception among colleagues, students, trainees and the public that practitioners are being ‘bought’ or ‘bribed’ by industry,” the report said.

A group of influential doctors decried these practices in a 2006 article in The Journal of the American Medical Association, and said that medical schools should ban them. In the article’s wake, the medical college association created a task force.

With Dr. Roy Vagelos, a former Merck chief executive, serving as the task force’s chairman and the chief executives of Pfizer, Eli Lilly, Amgen and Medtronic on the roster, some who advocate for greater restrictions on industry influence in medicine predicted that the report would be weak.

They were wrong.

In addition to the gift, food and travel bans, the report recommended that medical schools should “strongly discourage participation by their faculty in industry-sponsored speakers’ bureaus,” in which doctors are paid to promote drug and device benefits.

It recommended that schools set up centralized systems for accepting free drug samples or “alternative ways to manage pharmaceutical sample distribution that do not carry the risks to professionalism with which current practices are associated.” It suggested that schools audit independently accredited medical education seminars given by faculty “for the presence of inappropriate influence.” And it said the rules should apply to faculty even when off-duty or away from school.

Speakers’ bureaus and drug samples are pillars of the industry’s marketing operations, and many medical school professors have resisted efforts to restrict them. Only a handful of medical schools presently bar faculty members from serving on speakers’ bureaus, so if this recommendation is widely adopted, it could transform the relationship between medical school faculty and industry, and it could change substantially the way medical education is routinely delivered.

Indeed, the chief executives of Pfizer and Eli Lilly dissented from the report’s recommendation regarding speakers’ bureaus.

“We continue to believe that these types of programs, which are subject to clear regulations regarding their content, can be worthwhile educational activities,” wrote Jeffrey B. Kindler of Pfizer and Sidney Taurel of Lilly.

David Beier, an Amgen senior vice president, wrote a letter that endorsed the report’s recommendations but disagreed with some of its text “because we have a different view about the accuracy concerning representations about the motives of the participants in industry-academic interactions.”

Ken Johnson of the Pharmaceutical Research and Manufacturers of America, said his group would review the report.

“Providing physicians — and medical students — with timely, accurate information about the medicines they prescribe clearly benefits patients and advances healthcare throughout the United States,” Mr. Johnson said.

Dr. Robert J. Alpern, dean of the Yale School of Medicine, said that the university presently had no limits on participation in company speakers’ bureaus, but that because of the medical college association’s report he was thinking of taking them on.

“I don’t have a problem with doctors making $3,000 or $5,000 a year on the side,” he said, “but it’s a totally different thing when it’s $80,000.” Even more distasteful, Dr. Alpern said, is that the slides used in many of these presentations are created by drug makers, not the speakers.

“That’s like ghost-talking,” Dr. Alpern said.

Dr. Arthur S. Levine, dean of the University of Pittsburgh School of Medicine, said that when he graduated from medical school in 1964, Eli Lilly gave him his first doctor’s bag, and Roche gave him an Omega watch for being valedictorian. He still has the watch.

But this year’s graduating class of doctors at Pittsburgh will not be allowed to accept any of these gifts, and the daily pizza lunches brought by drug companies are gone, he said.

Julie Gottlieb, assistant dean of policy coordination for Johns Hopkins University School of Medicine, said Hopkins had adopted some of the association’s recommendations and was considering others.

“This report is bound to influence our deliberations,” she said.

Dr. Vagelos, formerly of Merck, said that the report’s recommendations were certain to face resistance among faculty who liked the present system.

“The outcome of this for the industry is that those companies that are strong in science will always be welcome at medical colleges and others won’t,” Dr. Vagelos said.

U.S. Identifies Tainted Heparin in 11 Countries
By GARDINER HARRIS
The New York Times
Published: April 22, 2008

WASHINGTON — A contaminated blood thinner from China has been found in drug supplies in 11 countries, and federal officials said Monday they had discovered a clear link between the contaminant and severe reactions now associated with 81 deaths in the United States.

a Chinese official disputed the assertion that the contaminant found in the drug, heparin, caused any deaths and insisted that his country’s inspectors be allowed to inspect the American plant where the finished heparin vials were made. He said any future agreement to allow American inspections of Chinese firms should be reciprocal.

“We don’t have a strong evidence to show that it is heparin or its contaminant that caused the problem,” said the official, Ning Chen, second secretary at the Chinese Embassy.

Mr. Chen said that illnesses associated with contaminated heparin had occurred only in the United States, which he said suggested that the problem arose in this country.

Dr. Janet Woodcock, director of the Food and Drug Administration’s drug center, said that German regulators uncovered a cluster of illnesses among dialysis patients who took contaminated heparin. She said Chinese officials had conceded that heparin produced in their country contained a contaminant, though they say it was not connected to the illnesses.

“Heparin should not be contaminated, regardless of whether or not that contamination caused acute adverse events,” Dr. Woodcock said. “We are fairly confident based on the biological information that we have had that this contaminant is capable of triggering these adverse reactions.”

The dispute is a sign of growing tensions between China and the United States over the safety of Chinese imports. China has in recent years exported poisonous toothpaste, lead-painted toys, toxic pet food, tainted fish and now, contaminated medicine.

Bills to require far more aggressive inspections of Chinese products and companies are being proposed by members of Congress. Hearings are scheduled for Tuesday in the House and Thursday in the Senate.

China has lurched between defensiveness and cooperation on issues of product safety. Last year, it initially blocked the F.D.A. from investigating tainted pet food and accused foreign forces of exaggerating the issue. Then in July, China said that it had executed its former top food and drug regulator for taking bribes and promised reforms.

The F.D.A. sent a warning letter on Monday to Changzhou SPL, the Chinese plant identified as the source of contaminated heparin made by Baxter International in the United States. It warned that the plant used unclean tanks to make heparin, that it accepted raw materials from an unacceptable vendor and that it had no adequate way to remove impurities.

Heparin is made from the mucous membranes of the intestines of slaughtered pigs that, in China, are often cooked in unregulated family workshops. The contaminant, identified as oversulfated chondroitin sulfate, a cheaper substance, slipped through the usual testing and was recognized only after more sophisticated tests were used.

The F.D.A. has identified 12 Chinese companies that have supplied contaminated heparin to 11 countries — Australia, Canada, China, Denmark, France, Germany, Italy, Japan, the Netherlands, New Zealand and the United States. Deborah Autor, director of compliance at the F.D.A.’s drug center, said the agency did not know the original source of all the contamination or the points in the supply chain at which it was added.

Officials have discovered heparin lots that included the cheap fake additive manufactured as early as early as 2006, although a spike in illnesses associated with contaminated heparin began in November and persisted through February, officials said.

Separately, the Government Accountability Office will release a report on Tuesday showing that the F.D.A. would need to spend at least $56 million more next year to begin full inspections of foreign plants. It would need to spend at least $15 million annually to inspect China’s drug plants every two years, which is the domestic standard.

Bush administration officials have acknowledged problems associated with poor inspection of overseas plants and have plans to improve the situation. But President Bush’s budget does not provide the F.D.A. with funds to hire more inspectors.

At its present inspection pace, the F.D.A. would need at least 27 years to inspect every foreign medical device plant that exports to the United States, 13 years to check every foreign drug plant and 1,900 years to examine every foreign food plant.  [Emphasis mine, profound evil theirs.]

Proposals circulating on Capitol Hill would increase the agency’s financing and charge domestic and foreign manufacturers fees to pay for inspections.

“Even the Bush administration seems to understand the potential peril that these foreign firms pose, but they offer only vague plans to address the problems and they refuse to spend more than a fraction of the money needed to protect the public,” said Representative John D. Dingell, a Michigan Democrat who leads the House Committee on Energy and Commerce.

The F.D.A. has announced plans to open inspection offices in three Chinese cities, but the agency has yet to get permission from the Chinese government. Mr. Chen said any inspection agreement should be reciprocal. “Will the U.S. government accept the Chinese F.D.A. to set up in the United States?” he said.

Dr. Woodcock said the Chinese had agreed to test heparin lots before allowing them to be exported. But Dr. Moheb Nasr, director of the drug agency’s office of new drug quality assessment, said that the Chinese test might not be sensitive enough to identify the contaminant.

Dr. Woodcock assured patients, however, that all heparin supplies in the United States had been tested with the most sensitive assays and had been found to be uncontaminated.

Scientific Protein Laboratories and Changzhou SPL said the company regretted the agency’s decision to send a warning letter that, it said, did not reflect the company’s current safety practices. The company said it had no way of detecting a contaminant present in heparin supplies throughout China.

Baxter International, which bought heparin ingredients from SPL and sold the finished drug in the United States, said that its tests confirmed that the contaminant could cause illness. It disputed the F.D.A.’s analysis that its product was linked with 81 deaths, saying it had identified only 5 in which its product “may have contributed to the adverse outcome, though there is not yet enough medical data available to draw a firm conclusion that the reaction caused the death.”

Deaths linked to the drug may have been concentrated in the United States because American doctors may be more likely to use large, quickly infused amounts of the drug, said drug officials. Also, the F.D.A. may track serious side effects better than its counterparts abroad.

By MICHAEL MELIA
The Associated Press
Tuesday, February 5, 2008

SAN JUAN, Puerto Rico -- The first warning sign came when a sharp-eyed worker sorting pills noticed that the odd blue flecks dotting the finished drug capsules matched the paint on the factory doors.

After the flecks were spotted again on the capsules, a blood-pressure medication called Diltiazem, the plant began placing covers over drugs in carts in its manufacturing areas.

But the factory owner, Canadian drug maker Biovail Corp., never tried to find out whether past shipments of the drug were contaminated - or prevent future contamination, according to U.S. regulators.

Thirteen of the 20 best-selling drugs in the United States come from plants on this island. But an investigation by The Associated Press has found dozens of examples over four years of lapses in quality control in the Puerto Rican pharmaceutical industry, which churns out $35 billion of drugs each year, most of it for sale as part of the $300 billion market in the U.S.

An AP review of 100 pages of Food and Drug Administration reports shows even modern drug plants here under the watch of U.S. regulators have failed to keep laboratories sterile and have exported tainted pills.

"People would be shocked to find this whole variety of contamination," said Dr. Sidney Wolfe of the Washington watchdog group Public Citizen. "The common denominator of all these is there's really poor quality control."

FDA officials say the problems in Puerto Rico are proportionate with the large number of pharmaceutical plants here and generally no worse than those on the U.S. mainland.  

Consumer advocates say they demonstrate the regulatory agency does not sufficiently monitor the industry across Puerto Rico and in the mainland.

The FDA issued a warning letter to Wyeth in May 2006, after consumers reported finding machinery pins inside bottles of Effexor, a leading depression treatment, and the heartburn drug Protonix. The letter expressed concern that the plant was not "able to detect that the affected equipment was missing some of its parts." The Madison, N.J.-based company faulted mistakes by workers who packaged the drugs.

In another case cited in a June 2006 FDA inspection report, a plant owned by Teva Pharmaceutical Industries exported drugs - including the diabetes treatment Metformin - even though they were known to contain small amounts of metal particles. The company had also received at least six consumer complaints of dark residue inside bottles or foreign material embedded in tablets, according to the report.

Teva's quality-control unit said the presence of some metallic material was to be expected because the manufacturing equipment is made of metal, according to the report.

Teva recalled 21 different drugs as a result of the inspection, according to FDA officials, and the Israeli drugmaker announced two months later it was closing the plant, citing a restructuring.

Denise Bradley, a Teva spokeswoman, insisted the medicine from the now-closed plant was safe and effective despite the contamination.

The reports obtained by AP were produced by FDA inspections from 2003 to 2007 of 13 pharmaceutical plants - roughly half the total in this U.S. territory, a Caribbean island with one of the world's highest concentrations of drug makers.

Several are closing or downsizing as the expense of updating decades-old plants to meet regulations adds to struggles with rising energy costs and tightening tax breaks.

The FDA often hesitates to crack down at the first sign of problems because manufacturers can chalk them up to isolated mishaps, said John Scharmann, a former FDA administrator for the Denver district now associated with a watchdog group.

That appeared to be the case at the Biovail-owned factory in the San Juan suburb of Carolina where the sharp-eyed worker noticed the foreign specks of blue.

"Incident was considered an isolated event ... even when the employee reported having observed the same particles before," the report said.

David Elder, director of enforcement in FDA's regulatory affairs office, said pharmaceutical companies generally fix problems on their own and issue recalls if necessary once notified.

"They're making products that save or support lives, so it's not in their interest to make products that are unsafe or ineffective," he said. "I think they're good corporate citizens by and large and want to do right by their patients."

Four of the plants described in the reports closed or announced plans to do so after the discovery of significant quality-control problems, but none of them cited the discoveries as a reason for closing.

One of those four, GlaxoSmithKline PLC, produced tablets of the popular antidepressant Paxil CR that split apart, potentially causing patients to take incorrect dosages.

When the company would not recall all the affected pills, U.S. marshals raided the plant in March 2005 in the largest drug seizure in FDA history and also collected tablets of the diabetes treatment Avandamet after some were found not to have accurate doses of the active ingredient.

Some plants in Puerto Rico are three decades old, built when the territory's pharmaceutical industry took off thanks to tax incentives aimed at developing more high-tech manufacturing.

The industry here has faded somewhat. Companies have shed more than 3,000 jobs in the last 18 months and closed several plants for a variety of reasons, including the loss of federal tax breaks and cost-cutting.

Still, this island turns out some top-selling drugs on the U.S. market, including cholesterol drugs Lipitor and Zocor, the blood-thinner Plavix, anemia drugs Aranesp and Epogen and the antidepressant Zoloft.

The FDA's San Juan office has 22 inspectors who devote about a quarter of their time to pharmaceutical plants. They typically visit the factories once every two years, more often if there are consumer complaints or the company has repeated infractions.

Factories confronted with violations often make extensive changes. The Biovail plant invested $5 million in equipment upgrades and addressed problems including errant metal particles from cleaning spatulas. A follow-up FDA inspection found no problems, said Gilbert Godin, executive vice president of the Ontario-based company.

Scharmann, a consulting editor for the watchdog publication Dickinson's FDA Review, said the FDA is concerned by anything that affects drug quality but considers the likelihood that the companies may file legal challenges to enforcement actions.

"There's a fairly broad latitude that is allowed," Scharmann said.

Elder contends inspections are rigorous.

"The folks doing this work aren't just regulators. That's our job, but we're also consumers of these products," he said. "It's personal to us to make sure these products are in compliance."

New York Times
By GARDINER HARRIS
Published: January 24, 2008

After decades of inattention to the possible psychiatric side effects of experimental medicines, the Food and Drug Administration is now requiring drug makers to study closely whether patients become suicidal during clinical trials.

The new rules represent one of the most profound changes of the past 16 years to regulations governing drug development. But since the F.D.A.’s oversight of experimental medicines is done in secret, the agency’s shift has not been announced publicly.

The drug industry, however, is keenly aware of the change. Makers of drugs to treat obesity, urinary incontinence, epilepsy, smoking cessation, depression and many other conditions are being asked for the first time by the drug agency to put a comprehensive suicide assessment into their clinical trials.

In recent months, the agency has sent letters — it would not say how many — to drug makers requiring that they use such a scale. Merck, Sanofi-Aventis and Eli Lilly are all using a detailed suicide assessment in clinical trials being conducted now.

The seeds for the new federal effort were planted four years ago with the discovery that antidepressants may cause some children and teenagers to become suicidal. Top agency officials at first discounted the finding but commissioned researchers from Columbia University’s department of psychiatry, led by Kelly L. Posner, to reanalyze the drugs’ clinical trials. This work caused the drug agency and its experts to view the risk as real.

Then it received an application for rimonabant, a much-heralded obesity drug developed by the French drug giant, Sanofi-Aventis. As agency medical reviewers pored over the drug’s clinical trial data, they discovered hints that it could cause psychiatric problems, too.

Unsettled by their experience with antidepressants, agency reviewers again mandated the use of Dr. Posner’s system. The assessment found that the drug doubled the risks of suicidal symptoms. In June, an F.D.A. advisory committee voted unanimously that the agency reject rimonabant because of its psychiatric effects, and Sanofi-Aventis withdrew the application although the drug is sold in Europe.

Just this month, the results of a trial of Merck’s obesity drug, taranabant, were published showing similar psychiatric problems. Meanwhile, fears have grown that drugs used to treat epilepsy, seizures and mood disorders may have similar effects. An extensive examination of these medicines by the drug agency should be completed this year.

Suddenly, agency officials realized that multiple classes of medicines might cause dangerous psychiatric problems.

“Clearly we were somewhat surprised when this signal emerged in the pediatric antidepressant data,” said Dr. Thomas P. Laughren, director of the drug agency’s division of psychiatry products. “So various groups within F.D.A. are now looking at suicidality more broadly as a possible adverse event.”

The drug agency’s concerns are consistent with a growing body of research confirming that behavior is heavily influenced not only by genes but also by seemingly innocuous changes in body chemistry. Drugs not reaching the brain were once thought to be largely free of mental effects.

“One lesson from pharmacology is that you can see effects on emotion and cognition without the drug entering the brain if a drug leads to peripheral changes in” other chemicals that enter the brain, said Dr. Thomas R. Insel, director of the National Institute of Mental Health.

Some critics say that the agency’s new-found focus on psychiatric side effects is long overdue.

“The list of drugs that causes psychiatric problems is a very long one,” said Dr. Sidney M. Wolfe, director of Public Citizen’s health research group.

Medicines to treat acne, hypertension, high cholesterol, swelling, heartburn, pain, bacterial infections and insomnia can all cause psychiatric problems, effects that were discovered in most cases after the drugs were approved and used in millions of patients.

Some drugs cause depression so often that doctors prescribe antidepressants prophylactically with them.

Among medicines still for sale, the F.D.A. has determined that the drugs’ benefits outweigh their psychiatric risks. Still, the agency now wants to uncover such problems more reliably and before approval.

There are two reasons that the F.D.A. for years was inattentive to the psychiatric effects of new medicines. First, distinguishing between mental problems that spring from a disease and those that result from its treatment is often difficult. For antidepressants, many researchers suggested that suicidal behaviors resulted because, as patients’ depression lifted, they suddenly had the energy to carry out previous suicidal thoughts.

Second, drug side effects are often first identified in clinical trials when multiple doctors treating hundreds of patients record similar problems in trial notes. But terms to describe depression or suicidal thoughts can vary widely, making them hard to discern.

“The whole spectrum of suicidal thoughts, ideation and attempts is much more difficult to define and study than” other drug problems, said Dr. Eric Colman, deputy director of the drug agency’s division of metabolic and endocrine products.

Indeed, the agency’s initial review of the effects of antidepressants in children was plagued by inconsistent and erroneous observations by investigators. A 10-year-old boy who tried to hang himself was listed only as having a “personality disorder,” an overdose of 11 tablets was called a “medication error” and a girl who slapped herself in the face was labeled as having attempted suicide.

Dr. Posner’s team spent months reclassifying these events as either a suicidal symptom or not. The team created a detailed questionnaire called the Columbia Suicide Severity Rating Scale, now adopted by the drug agency as an often mandatory test to be used in clinical trials.

The last time one medicine’s side effect led the F.D.A. to broadly re-examine its drug approval process was in 1992, when it discovered that Seldane, a popular antihistamine, could cause dangerous heart arrhythmias. Tests revealed other drugs that could affect heart rhythms, and the agency soon mandated that nearly all experimental medicines be tested for heart rhythm effects.

Unlike the Seldane example, however, not every experimental drug program must use the new suicidal symptoms scale. Drug officials said that they looked at a drug’s molecular structure and its effects in animals before deciding whether to insist on the new test.

“That’s where it gets tricky,” said Dr. Colman. “It’s difficult to say where you draw the line.”

But Dr. Posner said in an interview that so many companies and academic research programs were adopting the suicide questionnaire that she was having trouble keeping up with the demand for its use. The questionnaire has been translated into 80 languages, and Dr. Posner has trained scores of teams of investigators from around the world on how to use it. On Jan. 4 she lectured a group of investigators at Yale.

Benjamin A. Toll, an assistant professor in the university’s department of psychiatry, was in the audience and said he planned to use the Columbia questionnaire in a trial almost immediately.

“It’s much more detailed than what we were doing before,” Dr. Toll said. “We used to ask, ‘Are you feeling down? Are you feeling sad?’ ”

Dr. Colman said that the new questionnaire, while important, would not end the uncertainty around suicidal symptoms.

“If a drug makes people depressed but doesn’t make them suicidal, what do you conclude?” he asked. “There will always be some degree of uncertainty.”