Anglonautes > English vocabulary > Health

May 24, 2011
The New York Times
By FREDERICK C. TUCKER Jr.

Fredericksburg, Va.

LAST year the Food and Drug Administration rescinded approval of the drug Avastin for treating breast cancer patients, prompting a firestorm of criticism. The decision was denounced by some politicians as health care rationing, and by breast cancer patients who feared that they would be deprived of a drug that they felt had helped them immensely.

But these criticisms ignore the facts: Avastin was rejected simply because it didn’t work as it was supposed to, and the F.D.A. should resist the aggressive campaign by Genentech, the drug’s maker, to get that ruling reconsidered at a hearing in late June.

Avastin has been on the market for seven years, and combined with other drugs it is effective in treating, but not curing, some colon, lung, kidney and brain cancers. It inhibits the development of new blood vessels and in so doing can starve a growing tumor.

Treating a breast cancer patient with Avastin costs about $90,000 a year, and Genentech could lose $500 million to $1 billion a year in revenue if the F.D.A. upholds the ban.

A clinical trial published in 2007 demonstrated that Avastin, when paired with the chemotherapy drug Taxol, halts the growth of metastatic breast cancer for about six months longer than chemotherapy alone. Genentech then asked the F.D.A. for approval of Avastin, combined with Taxol, for use against metastatic breast cancer.

This halt in tumor growth is known as progression-free survival. But delaying the worsening of cancer does not necessarily prolong life, and Avastin was not shown to lengthen patients’ overall survival time. So Genentech argued that the drug led not to longer life, but to improved quality of life.

In 2007, an F.D.A. advisory committee rejected the application, deciding that the toxic side effects of Avastin outweighed its ability to slow tumor growth. The F.D.A., however, overrode the committee and granted what is called accelerated approval, allowing Avastin to be used pending further study. The criteria for full approval was that Avastin not worsen overall survival and that the drug provide clinically meaningful progression-free survival.

To support its case Genentech submitted data from two additional clinical trials in which Avastin was paired with chemotherapy drugs other than Taxol. Like the first trial, neither showed a survival benefit. Both showed an improvement in progression-free survival, though this outcome was much less impressive than in the original study. In addition to seeking full approval for the Avastin-Taxol combination, Genentech also asked the F.D.A. to approve the use of Avastin with the drugs used in these follow-up studies.

Genentech presented progression-free survival as a surrogate for better quality of life, but the quality-of-life data were incomplete, sketchy and, in some cases, non-existent. The best that one Genentech spokesman could say was that “health-related quality of life was not worsened when Avastin was added.” Patients didn’t live longer, and they didn’t live better.

It was this lack of demonstrated clinical benefit, combined with the potentially severe side effects of the drug, that led the F.D.A. last year to reject the use of Avastin with Taxol or with the other chemotherapies for breast cancer.

In its appeal Genentech is changing its interpretation of its own data to pursue the case. Last year Genentech argued that the decrease in progression-free survival in its supplementary studies was not due to the pairing of Avastin with drugs other than Taxol. This year, however, in its brief supporting the appeal, Genentech argues that the degree of benefit may indeed vary with “the particular chemotherapy used with Avastin.” In other words, different chemotherapies suddenly do yield different results, with Taxol being superior. The same data now generate the opposite conclusion.

Perhaps more troubling is the resort to anecdote in the brief to the F.D.A. and in the news media. Oncologists recounted their successes, and patients who were doing well on Avastin argued for its continued approval. But anecdote is not science. Such testimonials may represent the human voices behind the statistics, but the sad fact is that there are too many patients who have been treated with Avastin but are not here to tell their stories.

Avastin will not disappear because of the F.D.A. decision. It remains available for treating other cancers, and research to find its appropriate role in breast cancer treatment continues. In the meantime, the F.D.A., which is expected to make its decision in September, needs to resist Genentech’s attempt to have it ignore scientific evidence.

Serious progress in the treatment of cancer will not be the result of polemics, lobbying or marketing. Genentech’s money and efforts would be better spent on research for more meaningful treatments for breast cancer.

Frederick C. Tucker Jr. is an oncologist.

Drugs and Profits, NYT, 24.6.2011,
http://www.nytimes.com/2011/05/25/opinion/25tucker.html

F.D.A. to Restrict Avandia,

Citing Heart Risk

September 23, 2010
The New York Times
By GARDINER HARRIS

WASHINGTON — In a highly unusual coordinated announcement, drug regulators in Europe and the United States said Thursday that Avandia, the controversial diabetes medicine, would no longer be widely available.

The drug’s sales will be suspended entirely in Europe, while patients in the United States will be allowed access to the medicine only if they and their doctors attest that they have tried every other diabetes medicine and that patients have been made aware of the drug’s substantial risks to the heart. Patients now taking Avandia may continue to do so.

The Food and Drug Administration’s decision shows that the Obama administration is taking a harder line on drug safety issues, even in the face of scientific uncertainty. Along with its announcement, the agency for the first time immediately posted on its Web site internal memorandums from top staff members that in some cases offered entirely contradictory advice. Dr. Margaret Hamburg, the agency’s commissioner, said that passions within the agency had run high on the Avandia decision.

“As F.D.A. commissioner, my job would be infinitely easier if we had consensus and full scientific clarity,” she said.

Dr. Steven Nissen, a Cleveland Clinic cardiologist whose studies highlighted Avandia’s heart attack risks, said that the decision brought an end to “one of the worst drug safety tragedies in our lifetime,” adding that it was “essential to fully investigate what went wrong with the regulatory process to prevent this type of tragedy from endangering patients in the future.”

One study estimated that from 1999 to 2009, more than 47,000 people taking Avandia needlessly suffered a heart attack, stroke or heart failure, or died.

The decision on Avandia signals a new era in the treatment of diabetes, a disease that is reaching epidemic proportions in much of the industrialized world. Because of Avandia, the F.D.A. announced in 2008 that it would no longer approve medicines simply because they help diabetics control blood sugar levels — the standard for more than 80 years. Instead, the F.D.A. now insists that drugmakers conduct trials lasting at least two years to show that their medicines do not hurt the heart and that they improve the quality or length of diabetics’ lives, far tougher tests.

The Avandia story also begins a new and unsettling period for pharmaceutical companies because Avandia’s risks became known only after Dr. Nissen analyzed data from clinical trials that GlaxoSmithKline, the maker of the drug, had been forced to post on its Web site as a result of a legal settlement. Such public postings are increasingly the norm, which means that drugmakers can no longer easily hide or control scientific information about their medicines.

The agency’s decision to order restrictions on Avandia’s sales also demonstrates that the F.D.A. — given new powers over drugmakers and drug distribution in a 2007 law — intends to use those powers. The agency has now ordered that dozens of drugs be sold only with special restrictions.

In explaining why the F.D.A. decided against only adding more warnings to Avandia’s label, Dr. Janet Woodcock, director of the F.D.A.’s drug center said, “We know that labels are often not read.” It was an extraordinary acknowledgment from a veteran of an agency that for decades relied almost exclusively on label warnings to control drug use.

The suspension and restrictions all but ensure that Avandia’s sales — $1.19 billion last year and $3.2 billion as recently as 2006 — will plunge as regulatory authorities around the world are bound to follow with similar restrictions. Avandia was once the biggest-selling diabetes drug around the world, but concerns about heart attack risks have already cut sales. There are about 600,000 people currently taking Avandia in the United States, Dr. Hamburg said at a press conference. “I think the numbers will go down very, very significantly with these new requirements.”

GlaxoSmithKline responded that “the company continues to believe that Avandia is an important treatment for patients with Type 2 diabetes” and is working with the F.D.A. and European regulators “to implement the required actions.” The company promised that it would end Avandia promotions around the world.

The restrictions will take months to put in place. Patients now taking Avandia should continue to do so until they can consult their doctors, said Dr. Joshua Sharfstein, the F.D.A.’s principal deputy commissioner. But he said that doctors should now consider switching patients to other medicines.

European regulators began their own reassessment of Avandia in July after seeing a study of the drug by F.D.A. medical officers and another by Dr. Nissen in advance of a July F.D.A. advisory meeting. Once each agency learned of the other’s impending and similar decision — both were reached independently, Dr. Hamburg emphasized — they decided to coordinate their announcements.

Several consumer groups said that the F.D.A. should have removed Avandia from the market just as the Europeans did.

The F.D.A. announced that it had ordered Glaxo to end a controversial study comparing Avandia and Actos, made by Takeda. It also ordered Glaxo to conduct an independent assessment of the Record trial, a landmark study of Avandia’s heart effects that an F.D.A. medical officer found was riddled with what he said were unpardonable errors that seriously biased the trial’s conclusions.

In 2007, after a study by Dr. Nissen found that Avandia increased the risk of heart attacks, an advisory committee agreed but voted to keep it on the market.

More studies intensified the controversy, so the F.D.A. held another advisory meeting in July. This time, a majority of experts — many of whom had supported Avandia’s continued sales in 2007 — decided that the drug should either be withdrawn or its sales should be severely restricted. With Thursday’s announcements, the F.D.A. and the European Medicines Agency are following that panel’s advice.

Dr. Clifford J. Rosen, a member of the advisory panel that met in July, said he was gratified that the F.D.A. had followed the panel’s advice, and he said the new guidelines “will protect patients while at the same time allowing those few patients who have benefited from treatment to stay on the drug.”

Approved in 1999, Avandia helps control blood sugar levels in diabetics by making patients more sensitive to their own insulin. It is one of a class of three drugs, the first of which, Rezulin, was withdrawn because it caused liver damage. Actos, the last remaining drug in the class, appears safe in part because it seems to affect a different set of genes than either Rezulin or Avandia.

Senate investigators found that GlaxoSmithKline spent years hiding from regulatory authorities clear indications that Avandia increased heart risks. In July, GlaxoSmithKline took a $2.3 billion liability charge related to legal cases involving Avandia and another medicine, Paxil. At the time, investors cheered the news as the company’s attempt to set a ceiling for its liability surrounding the medicine.

But the twin announcements by European and American regulators, along with a string of troubling findings about the company’s conduct by Senate investigators, may increase the company’s legal exposure.

Senator Max Baucus, a Democrat from Montana who helped to spearhead an investigation of Avandia, said he was pleased. “The FDA’s tough new restrictions on the drug will help protect patients,” Mr. Baucus said.

F.D.A. to Restrict Avandia, Citing Heart Risk, NYT, 23.9.2010,
http://www.nytimes.com/2010/09/24/health/policy/24avandia.html

Child’s Ordeal Shows

Risks of Psychosis Drugs for Young

September 1, 2010
The New York Times
By DUFF WILSON

OPELOUSAS, La. — At 18 months, Kyle Warren started taking a daily antipsychotic drug on the orders of a pediatrician trying to quell the boy’s severe temper tantrums.

Thus began a troubled toddler’s journey from one doctor to another, from one diagnosis to another, involving even more drugs. Autism, bipolar disorder, hyperactivity, insomnia, oppositional defiant disorder. The boy’s daily pill regimen multiplied: the antipsychotic Risperdal, the antidepressant Prozac, two sleeping medicines and one for attention-deficit disorder. All by the time he was 3.

He was sedated, drooling and overweight from the side effects of the antipsychotic medicine. Although his mother, Brandy Warren, had been at her “wit’s end” when she resorted to the drug treatment, she began to worry about Kyle’s altered personality. “All I had was a medicated little boy,” Ms. Warren said. “I didn’t have my son. It’s like, you’d look into his eyes and you would just see just blankness.”

Today, 6-year-old Kyle is in his fourth week of first grade, scoring high marks on his first tests. He is rambunctious and much thinner. Weaned off the drugs through a program affiliated with Tulane University that is aimed at helping low-income families whose children have mental health problems, Kyle now laughs easily and teases his family.

Ms. Warren and Kyle’s new doctors point to his remarkable progress — and a more common diagnosis for children of attention-deficit hyperactivity disorder — as proof that he should have never been prescribed such powerful drugs in the first place.

Kyle now takes one drug, Vyvanse, for his attention deficit. His mother shared his medical records to help document a public glimpse into a trend that some psychiatric experts say they are finding increasingly worrisome: ready prescription-writing by doctors of more potent drugs to treat extremely young children, even infants, whose conditions rarely require such measures.

More than 500,000 children and adolescents in America are now taking antipsychotic drugs, according to a September 2009 report by the Food and Drug Administration. Their use is growing not only among older teenagers, when schizophrenia is believed to emerge, but also among tens of thousands of preschoolers.

A Columbia University study recently found a doubling of the rate of prescribing antipsychotic drugs for privately insured 2- to 5-year-olds from 2000 to 2007. Only 40 percent of them had received a proper mental health assessment, violating practice standards from the American Academy of Child and Adolescent Psychiatry.

“There are too many children getting on too many of these drugs too soon,” Dr. Mark Olfson, professor of clinical psychiatry and lead researcher in the government-financed study, said.

Such radical treatments are indeed needed, some doctors and experts say, to help young children with severe problems stay safe and in school or day care. In 2006, the F.D.A. did approve treating children as young as 5 with Risperdal if they had autistic disorder and aggressive behavior, self-injury tendencies, tantrums or severe mood swings. Two other drugs, Seroquel from AstraZeneca and Abilify from Bristol-Myers Squibb, are permitted for youths 10 or older with bipolar disorder.

But many doctors say prescribing them for younger and younger children may pose grave risks to development of both their fast-growing brains and their bodies. Doctors can legally prescribe them for off-label use, including in preschoolers, even though research has not shown them to be safe or effective for children. Boys are far more likely to be medicated than girls.

Dr. Ben Vitiello, chief of child and adolescent treatment and preventive research at the National Institute of Mental Health, says conditions in young children are extremely difficult to diagnose properly because of their emotional variability. “This is a recent phenomenon, in large part driven by the misperception that these agents are safe and well tolerated,” he said.

Even the most reluctant prescribers encounter a marketing juggernaut that has made antipsychotics the nation’s top-selling class of drugs by revenue, $14.6 billion last year, with prominent promotions aimed at treating children. In the waiting room of Kyle’s original child psychiatrist, children played with Legos stamped with the word Risperdal, made by Johnson & Johnson. It has since lost its patent on the drug and stopped handing out the toys.

Greg Panico, a company spokesman, said the Legos were not intended for children to play with — only as a promotional item.

Cheaper to Medicate

Dr. Lawrence L. Greenhill, president of the American Academy of Child and Adolescent Psychiatry, concerned about the lack of research, has recommended a national registry to track preschoolers on antipsychotic drugs for the next 10 years. “Psychotherapy is the key to the treatment of preschool children with severe mental disorders, and antipsychotics are adjunctive therapy — not the other way around,” he said.

But it is cheaper to medicate children than to pay for family counseling, a fact highlighted by a Rutgers University study last year that found children from low-income families, like Kyle, were four times as likely as the privately insured to receive antipsychotic medicines.

Texas Medicaid data obtained by The New York Times showed a record $96 million was spent last year on antipsychotic drugs for teenagers and children — including three unidentified infants who were given the drugs before their first birthdays.

In addition, foster care children seem to be medicated more often, prompting a Senate panel in June to ask the Government Accountability Office to investigate such practices.

In the last few years, doctors’ concerns have led some states, like Florida and California, to put in place restrictions on doctors who want to prescribe antipsychotics for young children, requiring a second opinion or prior approval, especially for those on Medicaid. Some states now report prescriptions are declining as a result.

A study released in July by 16 state Medicaid medical directors, which once had the working title “Too Many, Too Much, Too Young,” recommended that more states require second opinions, outside consultation or other methods to assure proper prescriptions. The F.D.A. has also strengthened warnings about using some of these drugs in treating children.

No Medical Reason

Kyle was rescued from his medicated state through a therapy program called Early Childhood Supports and Services, established in Louisiana through a confluence of like-minded child psychiatrists at Tulane, Louisiana State University and the state. It surrounds troubled children and their parents with social and mental health support services.

Dr. Mary Margaret Gleason, a professor of pediatrics and child psychiatry at Tulane who treated Kyle from ages 3 to 5 as he was weaned off the heavy medications, said there was no valid medical reason to give antipsychotic drugs to the boy, or virtually any other 2-year-old. “It’s disturbing,” she said.

Dr. Gleason says Kyle’s current status proves he probably never had bipolar disorder, autism or psychosis. His doctors now say Kyle’s tantrums arose from family turmoil and language delays, not any of the diagnoses used to justify antipsychotics.

“I will never, ever let my children be put on these drugs again,” said Ms. Warren, 28, choking back tears. “I didn’t realize what I was doing.”

Dr. Edgardo R. Concepcion, the first child psychiatrist to treat Kyle, said he believed the drugs could help bipolar disorder in little children. “It’s not easy to do this and prescribe this heavy medication,” he said in an interview. “But when they come to me, I have no choice. I have to help this family, this mother. I have no choice.”

Ms. Warren conceded that she resorted to medicating Kyle because she was unprepared for parenthood at age 22, living in difficult circumstances, sometimes distracted. “It was complicated,” she said. “Very tense.”

Behavior Problems

Kyle was a healthy baby physically, but he was afraid of some things. He spent hours lining up toys. When upset, he screamed, threw objects, even hit his head on the wall or floor — not uncommon for toddlers, but frightening.

“I’d bring him to the doctor and the doctor would say, ‘You just need to discipline him,’ ” Ms. Warren said. “How can you discipline a 6-month-old?”

When Kyle’s behavior worsened after his brother was born, Ms. Warren turned to a pediatrician, Dr. Martin J. deGravelle.

“Within five minutes of sitting with him, he looked at me and said, ‘He has autism, there’s no doubt about it,’ ” Ms. Warren said.

Dr. deGravelle’s clinic notes say Kyle was hyperactive, prone to tantrums, spoke only three words and “does not interact well with strangers.”

He prescribed Risperdal. At the time, Risperdal was approved by the F.D.A. only for adults with schizophrenia or acute manic episodes. The following year it was approved for certain children, 5 and older, with autism and extremely aggressive behavior. It has never been approved by the F.D.A. for use in children younger than 5, although doctors may legally prescribe it as an off-label use.

“Kyle at the time was very aggressive and easily agitated, so you try to find medication that can make him more easily controlled, because you can’t reason with an 18-month-old,” Dr. deGravelle said in a telephone interview. But Kyle was not autistic — according to several later evaluations, including one that Dr. deGravelle arranged with a neurologist. Kyle did not have the autistic child’s core deficit of social interaction, Dr. Gleason said. Instead, he craved more positive attention from his mother.

“He had trouble communicating,” Dr. Gleason said. “He didn’t have people to listen to him.”

After the neurologist review, the diagnosis changed to “oppositional defiant disorder” and the Risperdal continued.

“Yes, I did ask for it,” Ms. Warren said. “But I was at my wit’s end, and I didn’t know what else to do.”

Dr. deGravelle referred her to Dr. Concepcion, who in turn diagnosed Kyle’s condition as bipolar disorder.

“Some children, when they come to me, the parents are really so frustrated,” Dr. Concepcion said in a phone interview. “Especially the mothers are so scared or desperate in getting help. Their children are really acting psychotic.”

Dr. Concepcion also spoke with Dr. Charles H. Zeanah, a Tulane medical professor, who disagreed with both the diagnosis and the treatment. “I have never seen a preschool child with bipolar disorder in 30 years as a child psychiatrist specializing in early childhood mental health,” Dr. Zeanah said.

More Pills

“It’s a controversial diagnosis, I agree with that,” said Dr. Concepcion. “But if you will commit yourself in giving these children these medicines, you have to have a diagnosis that supports your treatment plan. You can’t just give a nondiagnosis and give them the atypical antipsychotic.”

He also prescribed four more pills.

Kyle’s third birthday photo shows a pink-cheeked boy who had ballooned to 49 pounds. Obesity and diabetes are childhood risks of antipsychotics. Kyle smiles at the camera. He is sedated.

“His shell was there, but he wasn’t there,” Ms. Warren said. “And I didn’t like that.”

Dr. Concepcion referred Kyle to the early childhood support program, which has helped about 3,000 preschoolers from low-income families at risk for mental health problems since 2002.

His speech improved. He threw fewer tantrums. “They started working with us as a family,” said Ms. Warren, who also received parenting advice. “That helps.”

Kyle’s treatment was directed by Dr. Gleason, a Columbia medical graduate who had led a team that wrote 2007 practice guidelines for psychopharmacological treatment of very young children.

“Families sometimes feel the need for a quick fix,” Dr. Gleason said. “That’s often the prescription pad. But I’m concerned that when a child sees someone who prescribes but doesn’t do therapy, they’re closing the door that can make longer-lasting change.”

Off most drugs, Kyle started losing weight and his behavior improved. Ms. Warren’s life also improved. She met a man and they moved into their own house five miles out of Opalousas, a town of 25,000. They were married last Saturday.

At their home recently, Kyle and his brother, Jade, ran and played while their baby sister watched from a playpen. Their clothes were neatly folded in a shared bedroom. They often responded “Yes, ma’am” or “Yes, sir.”

“They’re respectful, but they’re hyper kids,” Ms. Warren said. “Once he came off the medication, he’s Kyle. He’s an intelligent person. He’s loud. He’s funny. He’s smart. He’s bouncy. I mean, there’s never a dull moment. He has a few little behavior issues. But he’s like any other normal 6-year-old.”

Kyle paused to show a reading report card from the end of his kindergarten year, with an A grade.

“Awesome job, Kyle!” his kindergarten teacher wrote.

Child’s Ordeal Shows Risks of Psychosis Drugs for Young, NYT, 1.9.2010,
http://www.nytimes.com/2010/09/02/business/02kids.html

Diabetes Drug Maker

Hid Test Data on Risks,

Files Indicate

July 12, 2010
The New York Times
By GARDINER HARRIS

In the fall of 1999, the drug giant SmithKline Beecham secretly began a study to find out if its diabetes medicine, Avandia, was safer for the heart than a competing pill, Actos, made by Takeda.

Avandia’s success was crucial to SmithKline, whose labs were otherwise all but barren of new products. But the study’s results, completed that same year, were disastrous. Not only was Avandia no better than Actos, but the study also provided clear signs that it was riskier to the heart.

But instead of publishing the results, the company spent the next 11 years trying to cover them up, according to documents recently obtained by The New York Times. The company did not post the results on its Web site or submit them to federal drug regulators, as is required in most cases by law.

“This was done for the U.S. business, way under the radar,” Dr. Martin I. Freed, a SmithKline executive, wrote in an e-mail message dated March 29, 2001, about the study results that was obtained by The Times. “Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK,” the corporate successor to SmithKline.

The heart risks from Avandia first became public in May 2007, with a study from a cardiologist at the Cleveland Clinic who used data the company was forced by a lawsuit to post on its own Web site. In the ensuing months, GlaxoSmithKline officials conceded that they had known of the drug’s potential heart attack risks since at least 2005.

But the latest documents demonstrate that the company had data hinting at Avandia’s extensive heart problems almost as soon as the drug was introduced in 1999, and sought intensively to keep those risks from becoming public. In one document, the company sought to quantify the lost sales that would result if Avandia’s cardiovascular safety risk “intensifies.” The cost: $600 million from 2002 to 2004 alone, the document stated.

Mary Anne Rhyne, a GlaxoSmithKline spokeswoman, said that the company had not provided the results of its study because they “did not contribute any significant new information.”

The company said that Avandia was safe and that Dr. Freed no longer worked for GlaxoSmithKline.

A panel of experts will meet Tuesday and Wednesday to decide whether Avandia should still be sold and whether it is ethical to test Avandia directly against Actos.

Whether to withdraw Avandia is a question that has split the F.D.A., with some officials arguing that the drug is useful despite its risks and others insisting that it must be withdrawn.

According to the documents, Dr. John Jenkins, director of the agency’s office of new drugs, who has argued internally that Avandia should remain on the market, briefed the company extensively on the agency’s internal debate.

“It is clear the office of new drugs is trying to find minimal language that will satisfy the office of drug safety,” a top company official wrote in an e-mail message after he spoke with Dr. Jenkins, according to a sealed deposition obtained by The Times.

In the deposition, Dr. Rosemary Johann-Liang, a former supervisor in the drug safety office who left the F.D.A. after she was disciplined for recommending that Avandia’s heart warnings be strengthened, said of Dr. Jenkins’ conversations with GlaxoSmithKline, “This should not happen, and the fact that these kind of things happen, I mean, I think people have to make a determination about the leadership at the F.D.A.”

An F.D.A. spokeswoman said the agency would not comment on the contents of the deposition.

Members of Congress, where the Avandia case has led to legislative changes, said they were outraged at GlaxoSmithKline’s behavior.

“When drug companies withhold data regarding safety concerns about their medicines, they put patients at risk,” said Senator Max Baucus, Democrat of Montana, who is chairman of the Senate Finance Committee. Mr. Baucus and Senator Charles E. Grassley of Iowa, the committee’s ranking Republican, spent years investigating GlaxoSmithKline’s development of Avandia.

Besides the trial comparing Avandia with Actos, the company also conducted trials comparing Avandia with glyburide, a cheaper and older diabetes medicine.

When Rhona A. Berry, a company official, asked about publishing two of the trials, Dr. Freed responded in an e-mail message dated July 20, 2001, that referred to Avandia by the abbreviation of its generic name, rosiglitazone: “Rhona — Not a chance. These put Avandia in quite a negative light when folks look at the response of the RSG monotherapy arm,” the message said. “It is a difficult story to tell and we would hope that these do not see the light of day.”

Hiding the results of negative clinical trials was once widespread in the drug industry.

But after GlaxoSmithKline was found in 2004 to have hidden data that showed that its antidepressant, Paxil, led children and teenagers to have more suicidal thoughts and behaviors, the company settled a lawsuit by agreeing to publicly post data from all of its trials. In 2007, Congress mandated such disclosures. But the postings are often little more than cryptic references, so the issue is far from resolved.

With Avandia, GlaxoSmithKline has done more than hide trial data. An F.D.A. reviewer who closely examined a landmark Avandia clinical trial called “Record,” found at least a dozen instances in which patients taking Avandia suffered serious heart problems that were not counted in the trial’s tally of adverse events, mistakes that further obscured Avandia’s heart risks.

The company’s conduct of the Record trial has received sharp criticism from medical leaders for other reasons as well. To compare Avandia and Actos in 1999, researchers at SmithKline measured Actos’s effects in patients in the same way that they had conducted earlier trials of Avandia so that the results for the two drugs could be compared.

When the results of the study suggested that Avandia was more dangerous than Actos, the company decided against further comparisons.

Diabetes Drug Maker Hid Test Data on Risks, Files Indicate, NYT, 12.7.2010,
http://www.nytimes.com/2010/07/13/health/policy/13avandia.html

Pfizer Details Its Payments

to Doctors and Researchers

March 31, 2010
The New York Times
By DUFF WILSON

Pfizer, the world’s largest drug maker, said Thursday that it paid about $20 million to 4,500 doctors and other health care professionals in the United States for consulting and speaking on its behalf in the last six months of 2009, its first public accounting of payments to the people who decide which drugs to recommend.

Pfizer said it also paid $15.3 million to 250 academic medical centers and other research groups for clinical trials in the final six months of last year.

While several other pharmaceutical companies have previously disclosed payments to doctors, Pfizer is the first to disclose payments for the clinical trials where drugs are tested. The disclosure does not include payments outside the United States.

A spokeswoman for Pfizer, Kristen E. Neese, said the disclosures were required by an integrity agreement that the company signed in August to settle a federal investigation into the illegal promotion of drugs for off-label uses. Pfizer paid a $2.3 billion fine in that case, the largest criminal fine of any type in the nation’s history.

Company executives said they had long planned to be more transparent — an assertion met with skepticism by some outside experts.

“We’re proud of the relationships that we have with researchers and clinicians,” Dr. Freda C. Lewis-Hall, Pfizer’s chief medical officer, said Tuesday. She characterized the disclosure and Web site as part of “a march to disclosure” that Pfizer started in 2002.

Pfizer is the fourth major drug company to make such disclosures, following Eli Lilly, Merck and GlaxoSmithKline. All four Web sites are searchable by the names of doctors or organizations, but all are set up in ways that make it difficult to download and analyze the entire database.

“All of them are welcome, but none of them is a replacement for a single national database,” Allan Coukell, director of the Pew Prescription Project, a Boston nonprofit that seeks to protect consumers, said in a telephone interview.

Beginning in 2012, drug and medical device companies will be required to disclose payments to physicians of more than $10, with the first report available in 2013. The federal Physician Payment Sunshine Act was passed as part of health care reform and signed by President Obama last week. Some states also have disclosure laws.

Pfizer’s disclosure met with skepticism from one leading expert on conflicts of interest in medicine.

“I think it’s a good thing to do, but I put absolutely no trust in what drug companies voluntarily disclose to the public when those things are unaudited,” said Eric G. Campbell, lead author of a 2007 study of physician-industry relationships published in The New England Journal of Medicine.

The survey of 3,167 physicians in six specialties found 94 percent had some relationship with drug companies in 2003 and 2004, mostly receiving free meals, with 28 percent being paid for consulting, speaking or enrolling patients in clinical trials.

Professor Campbell, who is director of research at the Institute for Health Policy at Massachusetts General Hospital and an associate professor at Harvard Medical School, said drug companies were trying to get ahead of a rising tide of public opinion for disclosure.

“The drug companies are disclosing voluntarily now not necessarily because they believe it’s the right thing to do,” he said, “but because they want to get ahead of what is an inevitable thing in the United States.”

Pfizer executives reviewed the company’s disclosure system with the staff of Senator Charles Grassley, Republican of Iowa, who is investigating the influence of money in medicine. Senator Grassley said Wednesday in a statement: “It’s a real milestone for the transparency campaign to have one of the biggest drug makers in the world respond with an initiative like this.”

Pfizer’s clinical-trials disclosure identifies all such payments to academic medical centers from July 1, 2009 to Dec. 31, 2009, the company said, and payments for new clinical trials initiated in that time by non-academic research organizations. “These payments represent a small portion of Pfizer’s total investment in research and development,” the company said in a statement Wednesday.

The payments to doctors covered fees, travel and meals worth $25 or more and totaling $500 or more during the six-month period, Pfizer said. In all, Pfizer said, 1,500 licensed health care professionals were paid an average of $5,000 during the six-month period for consulting, and 2,800 were paid an average of $3,400 for speaking.

The company plans to post its next report on March 31, 2011, with expanded data on payments during 2010.

Pfizer Details Its Payments to Doctors and Researchers, NYT, 31.3.2010,
http://www.nytimes.com/2010/04/01/business/01payments.html

Research Ties Diabetes Drug to Heart Woes

February 20, 2010
The New York Times
By GARDINER HARRIS

Hundreds of people taking Avandia, a controversial diabetes medicine, needlessly suffer heart attacks and heart failure each month, according to confidential government reports that recommend the drug be removed from the market.

The reports, obtained by The New York Times, say that if every diabetic now taking Avandia were instead given a similar pill named Actos, about 500 heart attacks and 300 cases of heart failure would be averted every month because Avandia can hurt the heart. Avandia, intended to treat Type 2 diabetes, is known as rosiglitazone and was linked to 304 deaths during the third quarter of 2009.

“Rosiglitazone should be removed from the market,” one report, by Dr. David Graham and Dr. Kate Gelperin of the Food and Drug Administration, concludes. Both authors recommended that Avandia be withdrawn.

The internal F.D.A. reports are part of a fierce debate within the agency over what to do about Avandia, manufactured by GlaxoSmithKline. Some agency officials want the drug withdrawn because they believe there is a safer alternative; others insist that studies of the drug provide contradictory information and that Avandia should continue to be an option for doctors and patients. GlaxoSmithKline said that it had studied Avandia extensively and that “scientific evidence simply does not establish that Avandia increases” the risk of heart attacks.

The battle has been brewing for years but has been brought to a head by disagreement over a new clinical trial and a Senate investigation that concluded that GlaxoSmithKline should have warned patients earlier of the drug’s potential risks.

Avandia was once one of the biggest-selling drugs in the world. Driven in part by a multimillion-dollar advertising campaign, sales were $3.2 billion in 2006. But a 2007 study by a Cleveland Clinic cardiologist suggesting that the drug harmed the heart prompted the F.D.A. to issue a warning, and sales plunged. A committee of independent experts found in 2007 that Avandia might increase the risk of heart attack but recommended that it remain on the market, and an F.D.A. oversight board voted 8 to 7 to accept that advice.

Hundreds of thousands still take the medicine, although some top endocrinologists say they have sworn off the drug.

Since 2007, more studies have been done. In a December 2009 internal memorandum, Dr. Janet Woodcock, director of the F.D.A.’s drug center, wrote that “there are multiple conflicting opinions” about Avandia within the agency, and she ordered officials to assemble another advisory committee, expected this summer, to reconsider whether the drug should be sold.

“I await the recommendations of the advisory committee,” the agency’s commissioner, Dr. Margaret Hamburg, said Friday night. “Meanwhile, I am reviewing the inquiry made by Senators Baucus and Grassley and I am reaching out to ensure that I have a complete understanding and awareness of all of the data and issues involved.”

The bipartisan multiyear Senate investigation — whose results are expected to be released publicly on Monday but which were also obtained by The Times — sharply criticizes GlaxoSmithKline, saying it failed to warn patients years earlier that Avandia was potentially deadly.

“Instead, G.S.K. executives attempted to intimidate independent physicians, focused on strategies to minimize or misrepresent findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that a competing drug might reduce cardiovascular risk,” concludes the report, which was overseen by Senator Max Baucus, a Montana Democrat, and Senator Charles E. Grassley, an Iowa Republican.

Mr. Baucus said of the report, “Patients trust drug companies with their health and their lives, and GlaxoSmithKline abused that trust.”

In response, GlaxoSmithKline said that it disagreed with the Senate investigation’s conclusions. The company said that it could not comment on internal F.D.A. documents but that “the official ruling from F.D.A. is that Avandia remain on the market.”

In the wake of the controversy, agency officials ordered GlaxoSmithKline to undertake a study comparing how many heart attacks, strokes and heart-related deaths occur among patients given either Avandia, Actos or a placebo. Studies suggest that Actos, made by Takeda, lowers blood sugar as well as Avandia but without hurting the heart as much.

But Dr. Graham and Dr. Gelperin, working in the F.D.A.’s office of surveillance and epidemiology, argued in two separate internal reports that the new GlaxoSmithKline study, called TIDE, is “unethical and exploitative” because patients given Avandia face far greater risks than those given Actos, with no promise of any additional benefit. The trial may include patients who have had heart attacks or chest pains even though some foreign drug authorities have warned against Avandia’s use by precisely such patients, the reports note.

“Although the proposed TIDE trial is motivated by a desire for definitive answers regarding the cardiovascular safety of the drug rosiglitazone, the safety of the study itself cannot be assured and is not acceptable,” one of the reports concludes.

These concerns, in internal reports dated October 2008 but not made public until now, were later overruled by other agency officials, and GlaxoSmithKline is currently enrolling patients in the TIDE trial. The trial is not expected to be completed until 2020, although the company is hoping to report some results to the F.D.A. by 2014. The company’s patent on Avandia expires in 2012, and generic versions will probably swallow most remaining profits.

In a letter sent Thursday to Dr. Hamburg, the Food and Drug Administration commissioner, Mr. Baucus and Mr. Grassley asked “what steps the F.D.A. has taken to protect patients in the TIDE trial” and said the trial’s patients had never been told about the concerns raised by the agency’s own safety officers.

Mr. Grassley said the internal agency battle showed that the agency needed to be restructured to give more power to safety officials like Dr. Graham and Dr. Gelperin over their counterparts who approve medicines and deal more directly with drug makers.

“It doesn’t make any sense to have these experts who study drugs after they have been on the market for several years under the thumb of the officials who approved the drug in the first place and have a natural interest in defending that decision,” Mr. Grassley said. “The Avandia case may be the most alarming example of the problem with this setup.”

The question of when and how to communicate possible drug risks has long bedeviled drug makers and regulators. Hints are common that drugs may cause injuries; thousands of drug injury reports pour into the Food and Drug Administration every week. For example, Avandia ranked first among all prescribed drugs in the number of serious, disabling and fatal problems — including 304 deaths — reported to the agency in the third quarter of 2009, according to an analysis done by the Institute for Safe Medication Practice, a drug safety oversight group.

But companies say that such reports do not offer proof of a problem and that highlighting them can scare patients away from needed treatment, so they often argue that more certainty is needed before alarms are raised. GlaxoSmithKline said a “vast majority” of the recent reports regarding Avandia was related to litigation.

The Senate investigation — the result of years of digging through more than 250,000 internal company documents — concludes that GlaxoSmithKline and by extension the F.D.A. delayed far too long in this process.

In November 2003, for instance, the company completed a study in which diabetics given Avandia had far more heart problems than those given placebos. Two months later, the World Health Organization sent the company an alert linking Avandia to heart ailments. In a June 2004 meeting, the company’s Global Safety Board said a hard look should be taken at all Avandia clinical trials for more signs of heart problems, documents show.

European regulators had earlier ordered GlaxoSmithKline to conduct a study — called the Record trial — to examine Avandia’s heart risks because hints of these problems appeared in the company’s earliest trials.. But the Senate report shows that by at least 2004, company executives were aware that the Record trial was going so poorly that it would never answer the heart question with any kind of certainty.

So company executives gathered dozens of Avandia studies and sifted their combined data. Called a meta-analysis, this combined look found first in 2005 and in an updated look in 2006 that Avandia increased the risks of serious heart problems by nearly a third, the Senate investigation shows. Because two-thirds of diabetics die of heart problems, this was hugely worrying.

In 2005, executives revealed the results of their meta-analysis to the F.D.A., and in 2006 they provided the agency with the underlying data.

Two large company-sponsored trials — called Dream and Adopt — were published near the end of 2006, and each provided more hints that Avandia hurts the heart, the documents show. In a March 2007 meeting of the company’s Diabetes Franchise Cardiology Advisory Board, advisers called the safety worries found in these many studies “disquieting.” Negotiations with agency officials about how and whether to alert the public continued.

Meanwhile, the company continued to market and advertise Avandia aggressively. The Senate inquiry concludes that the company threatened doctors who suggested in public that Avandia might have serious risks.

In 1999, for instance, Dr. John Buse, a professor of medicine at the University of North Carolina, gave presentations at scientific meetings suggesting that Avandia had heart risks. GlaxoSmithKline executives complained to his supervisor and hinted of legal action against him, according to the Senate inquiry. Dr. Buse eventually signed a document provided by GlaxoSmithKline agreeing not to discuss his worries about Avandia publicly. The report cites a separate episode of intimidation of investigators at the University of Pennsylvania.

GlaxoSmithKline said that it “does not condone any effort to silence” scientific debate, and that it disagrees with allegations that it tried to silence Dr. Buse. Still, it said the situation “could have been handled differently.”

Research Ties Diabetes Drug to Heart Woes, NYT, 20.2.2010,
http://www.nytimes.com/2010/02/20/health/policy/20avandia.html

Popular Drugs

May Help Only Severe Depression

January 6, 2010
The New York Times
By BENEDICT CAREY

Some widely prescribed drugs for depression provide relief in extreme cases but are no more effective than placebo pills for most patients, according to a new analysis released Tuesday.

The findings could help settle a longstanding debate about antidepressants. While the study does not imply that the drugs are worthless for anyone with moderate to serious depression — many such people do seem to benefit — it does provide one likely explanation for the sharp disagreement among experts about the drugs’ overall effectiveness.

Taken together, previous studies have painted a confusing picture. On one hand, industry-supported trials have generally found that the drugs sharply reduce symptoms. On the other, many studies that were not initially published, or were buried, showed no significant benefits compared with placebos.

The new report, appearing in The Journal of the American Medical Association, reviews data from previous trials on two types of drugs and finds that their effectiveness varies according to the severity of the depression being treated.

Previous analyses had found a similar pattern. But the new study is the first to analyze responses from hundreds of people being treated for more moderate symptoms, as are most people who seek care.

“I think the study could dampen enthusiasm for antidepressant medications a bit, and that may be a good thing,” said Dr. Erick H. Turner, a psychiatrist at Oregon Health and Science University. “People’s expectations for the drugs won’t be so high, and doctors won’t be surprised if they’re not curing every patient they see with medications.”

But Dr. Turner added, “The findings shouldn’t dampen expectations so much that people refuse to even try medication.”

A team of researchers, including psychologists who favor talk therapy and doctors who consult widely with drug makers, performed the new analysis, using government grants. The group evaluated six large drug trials, including 728 men and women, about half of them with severe depression and half with more moderate symptoms.

Three of the trials were of Paxil, from GlaxoSmithKline, a so-called S.S.R.I., and the other three were of imipramine, an older generic drug from the class known as tricyclics. The team, led by Jay C. Fournier and Robert J. DeRubeis of the University of Pennsylvania, found that compared with placebos, the drugs caused a much steeper reduction in symptoms of severe depression (cases scoring 25 or higher on a standard scale of severity, putting them in the top quarter of the sample). Patients with scores of less than 25 got little or no added benefit from the medications.

“We were able to give an overall estimate of effectiveness for the first time in this more moderate severity range, from 14 to 20 on the scale, in which there’s no question that doctors would likely consider prescribing medication,” Dr. DeRubeis said.

His co-authors included Steven D. Hollon and Dr. Richard C. Shelton of Vanderbilt University, Sona Dimidjian of the University of Colorado, Dr. Jan Fawcett of the University of New Mexico and Dr. Jay D. Amsterdam of Penn.

The effects of other popular S.S.R.I.’s like Lexapro and Prozac are not likely to be much different than those of Paxil, experts said.

Dr. DeRubeis and others said antidepressants’ inability to outperform placebos against moderate symptoms stemmed partly from the sustained attention that patients in drug trials received from top doctors — which itself can help relieve symptoms, drug or no drug. For some people, too, the drugs’ side effects may cancel any benefit.

“The message for patients with mild to moderate depression,” Dr. DeRubeis said, “is, ‘Look, medications are always an option, but there’s little evidence that they add to other efforts to shake the depression — whether it’s exercise, seeing the doctor, reading about the disorder or going for psychotherapy.’ ”

Popular Drugs May Help Only Severe Depression, NYT, 6.1.2010,
http://www.nytimes.com/2010/01/06/health/views/06depress.html

Rising Prices of Drugs

Lead to Call for Inquiry

November 19, 2009
The New York Times
By DUFF WILSON

Democrats in Congress asked for two separate investigations of drug industry pricing Wednesday as they continue working on legislation to overhaul the nation’s health care system.

Responding to news reports of unusually high wholesale price increases in brand-name prescription drugs, four House leaders and one senator asked for government reviews of the pricing practices.

Although drug makers challenge the theory, some experts say the run-up in wholesale prices may be partly related to the industry’s concerns about future cost containment under any health care legislation.

“Recent studies have indicated that the industry may be artificially raising prices for certain pharmaceutical products in expectation of new reforms,” the House Democrats wrote in a letter to the Government Accountability Office, a nonpartisan investigative arm of Congress. “Any price gouging is unacceptable, but anticipatory price gouging is especially offensive,” the letter added, asking the G.A.O. to conduct an expedited review of the price increases.

The House letter was signed by four representatives who have been active in the health care legislation: Charles B. Rangel of New York, chairman of the Ways and Means Committee; Henry A. Waxman of California, chairman of the Energy and Commerce Committee; and Pete Stark of California, and John Lewis of Georgia, chairmen of two Ways and Means subcommittees.

Separately, Senator Bill Nelson of Florida, a Democrat who has led efforts in the Senate to seek more concessions from drug makers, wrote to the inspector general of the Department of Health and Human Services asking for “an immediate and thorough investigation into drug industry pricing and recent increases, and the extent to which these increases may affect the Medicare and Medicaid programs.”

Both letters cited a New York Times article on Monday reporting that wholesale prices of brand-name drugs rose about 9 percent in the 12 months that ended Sept. 30, the highest increase in years — even as the Consumer Price Index was declining during the same 12-month period.

The Times article cited a Wall Street analyst’s calculations; a study sponsored by the AARP, the advocacy group for older Americans; and a report by IMS Health, a consulting firm to the drug industry.

The price increases could add more than $10 billion to the nation’s drug bill, which is on track to exceed $300 billion this year.

At that rate, the increases would more than offset at least the first year of savings that the drug industry has agreed to make under a provision of the health care bill that was approved by the Senate Finance Committee and has been incorporated into the full Senate bill introduced on Wednesday. That measure calls for the industry to come up with discounts and rebates that would save Medicare recipients and the government $8 billion a year for 10 years.

“I want to know if there’s a back-door move under way by the drug makers to recover some of the concessions they’ve promised for health care reform,” Senator Nelson said in a statement Wednesday.

Drug companies do not deny having raised wholesale prices at the highest rate in years. But they say it has nothing to do with the impending health care legislation. They say the price increases are necessary to maintain profits for research and employment in the face of a difficult business environment, which includes a slowdown in sales of many brand-name products, expiring patents and increasing competition from generic drugs.

The wholesale prices of brand-name drugs most commonly used by Medicare recipients rose in the latest 12-month period at the fastest rate since at least 1992, according to Stephen W. Schondelmeyer, a pricing expert working with AARP.

Separately, a study by the investment bank Credit Suisse found that prices for all drugs from the eight largest United States pharmaceutical companies had risen, on average, at the highest rate in at least five years.

And IMS Health said there were higher-than-expected price increases this year.

Mr. Schondelmeyer, professor of pharmaceutical economics at the University of Minnesota, and Catherine J. Arnold, a senior drug industry analyst for Credit Suisse, have said they believe that part of the reason for the price increases was to get ahead of possible cost containment measures in health care reform.

Professor Schondelmeyer and Joseph P. Newhouse, a Harvard health economist, said there were precedents for drug price increases before government actions affecting the industry.

The House Democrats also said the G.A.O. had previously found unusual price increases in some prescription drugs in the year before Congress added drug benefits to Medicare.

The House letter on Wednesday said that the G.A.O. could build on that work.

The House members are also asking the G.A.O. to submit a proposal to continuously monitor prescription drug prices. The House health care bill already includes a provision authorizing Medicare to negotiate directly with manufacturers — a proposal hotly opposed by the industry.

Ken Johnson, an official with the drug industry’s trade association, said in a statement that calls for an investigation were “based on misleading use of statistics and sensationalized media reports.”

Mr. Johnson, senior vice president for the Pharmaceutical Manufacturers and Research Association, did not deny any of the specific findings of AARP, Credit Suisse and IMS Health reports, which were based on data supplied by manufacturers and wholesalers. But he said other measurements of drug price increases show they have risen substantially less than 9 percent.

Mr. Johnson accused AARP of “trying to muddy the waters for its own political gain as we enter the homestretch of the health care reform debate.”

An AARP executive vice president, John Rother, said in a statement: “This isn’t about politics. It’s about affordable health care.”

Rising Prices of Drugs Lead to Call for Inquiry, NYT, 19.11.2009,
http://www.nytimes.com/2009/11/19/health/policy/19drugs.html

The Work-Up

Costly Drugs Known as Biologics

Prompt Exclusivity Debate

July 22, 2009
The New York Times
By ANDREW POLLACK

A bitter Congressional fight over the cost of superexpensive biotechnology drugs has come down to a single, hotly debated number: How many years should makers of those drugs be exempt from generic competition?

But what few people in Washington seem to recognize — or publicly acknowledge, anyway — is that this magic number may ultimately not matter as much as the most vitriolic debaters insist.

At issue are such drugs as Biogen Idec’s Avonex, for multiple sclerosis, which can cost more than $20,000 a year; Genentech’s Avastin for cancer, which can cost more than $50,000; and several Genzyme drugs for rare diseases that can cost $200,000 a year or more. Typically, such drugs are given by injection or intravenous infusions.

These drugs, known as biologics, are complex proteins made in vats of living cells. Because they are hard to copy exactly, they have not been subject to the generic competition that eventually knocks down the price of drugs like Lipitor and Prozac. Pills like Lipitor, known in the industry as small-molecule drugs, are made from simple chemicals whose recipes are easy to reproduce.

But now Congress, as a cost-cutting piece of the overall health care effort, is preparing legislation to enable the Food and Drug Administration to approve copycat versions of biologic drugs. That could save consumers, insurers and the government billions of dollars in the coming years.

The trick is to allow competition without undermining the financial incentives the pharmaceutical industry needs to undertake the risky job of developing the next drugs for cancer and other diseases. That is where the magic year number comes in. Trade groups for the big pharmaceutical and biotechnology companies say that to recoup their investments, they need an exclusivity period free of generic competition that would last 12 to 14 years from the time the F.D.A. approves a drug for sale.

But consumer groups, insurers, employers and generic drug companies say anything more than five years — the exclusivity period now given to small-molecule drugs like Lipitor — would eviscerate any potential savings from the new competition.

So far, the biotechnology industry appears to be winning. The Senate’s health committee, for example, has agreed to 12 years of exclusivity. In the House, a bill that provides at least 12 years of exclusivity has many more co-sponsors than one that would provide five years. The Obama administration has said that seven years would be a “generous compromise.”

But in reality, neither the threats to innovation nor the potential savings from generic competition are as great as claimed.

For starters, whatever the exclusivity period, biologic drugs would also continue to be protected from copycats by patents. And in many cases, the patent protection would last longer than the exclusivity period, making the Congressionally mandated exclusivity a moot point.

Genentech’s Avastin, for instance, has patent protection until 2019 — 15 years after the drug’s 2004 approval by the F.D.A. The company’s breast cancer drug, Herceptin, has patents that extend 21 years from its 1998 approval.

Where the exclusivity period might matter most would be in the cases of drugs whose patents were nearing expiration by the time the developer succeeded in winning F.D.A. approval. But that seldom happens.

“I can’t think of a biotech drug that’s been on the market that doesn’t have more than 7 to 14 years of patent protection,” said Eric Schmidt, biotechnology analyst at Cowen & Company.

Still, it is probably not true, as the other side claims, that the legislation would be virtually worthless if it granted a long exclusivity period. There are plenty of blockbuster biologics, like Epogen and Neupogen from Amgen, that have been on the market more than 12 or 14 years and thus would get no extra protection from even an exclusivity period at the long end of the ranges now being discussed.

As for cost savings, the Congressional Budget Office has estimated that generic biologics might save the government only about $10 billion in the next 10 years. That is a relative drop in the bucket when it comes to paying for health care reform, which is expected to cost about $1 trillion over 10 years.

One reason for limited savings in the first decade is that it would probably take a few years for copycat biologics to reach the market after the law was enacted. Another factor is that biologics accounted for only 16 percent — about $46 billion — of total prescription drug spending last year, according to the market researchers IMS Health. And pharmaceuticals represent only about 10 percent of the nation’s overall health care spending.

The real savings might come more than 10 years out, as new biologic drugs appeared and as biologics represented an increasingly greater part of overall spending on drugs. That ramp-up is already evident: Express Scripts, a pharmacy benefits manager, says its spending on biologics grew 10 percent last year, compared with 2.5 percent for other drugs.

But anyone expecting the price wars that ensue when generic pills come on the market — when prices often drop by more than 60 percent — might be disappointed by the way competition plays out in biologic drugs.

Because it is harder and costlier to make biologic drugs than it is to copy pills, fewer generic competitors are likely to enter the fray. Many experts, including the Federal Trade Commission, expect price declines of more like 10 to 40 percent in biologics.

Even that would be a substantial savings for the overall health care system. But for many individuals, a $35,000 copycat version of a $50,000 cancer drug would still be unaffordable.

Another factor is that generic biologics are likely to undergo greater regulatory scrutiny than generic pills require.

It is difficult or impossible to verify that a copy of a biologic is exactly the same as the original — which is why the drugs are often called “biosimilars” rather than generic biologics. Because even small changes might affect the drug’s safety or activity, it is likely that makers of biosimilars will have to conduct at least some clinical trials to win F.D.A. approval of their drugs, which makers of generic small-molecule pills are not required to do. Such trials can cost a lot of money.

Since biosimilars will not be exact replicas, generic makers will probably need sales forces to persuade doctors to prescribe their drugs and pharmacists to dispense them. All of that costs money, too.

In Europe, which has approved biosimilar versions of three biologic drugs, companies generally price their biosimilar drugs about 20 to 30 percent lower than the originals. The impact in Europe has been limited so far, but in Germany the biosimilars have captured about 30 percent of the market for anemia drugs and forced the brand-name manufacturers to lower their prices.

The likelihood that biosimilar competition might be somewhat muted means that sales and profits of the originals may not necessarily dry up.

Kevin W. Sharer, Amgen’s chief executive, told investors in May that he hoped biotechnology companies would retain 30 to 50 percent of the cash flow from their drugs even after biosimilars reached the market. That, he said, “is a dramatically different outcome than we see in the small-molecule companies.” That is also one reason the Federal Trade Commission, in a report last month, said that no exclusivity period at all was needed. At the very least, because biologic drugs do not require appreciably more time or money to bring to market than small-molecule drugs, it is reasonable to ask why they should deserve longer protection from competition than the five years that small-molecule drugs now receive.

The reason, biotechnology executives say, is that patents may offer less protection for biologics than for small-molecule drugs. Because a biosimilar is not an exact knock-off of the original, a competitor might persuasively claim that it is not infringing the patents on the original drug.

So far biologic patents have held up well in court cases. Amgen, for example, has won legal victories preventing competitors from introducing anemia drugs that are slightly different from its own Epogen.

But generic makers and their supporters, sensing that many of the biologic patents may not withstand court challenges, are lobbying for the shortest possible exclusivity period.

“If your patents are strong, let your patents stand for themselves,” said Katie Huffard, executive director of the Coalition for a Competitive Pharmaceutical Market, a group of employers, insurers, pharmacies and generic makers lobbying for easier access to biosimilars. “That’s what every other industry has to do.”

Costly Drugs Known as Biologics Prompt Exclusivity Debate, NYT, 22.7.2009,
http://www.nytimes.com/2009/07/22/business/22biogenerics.html

Editorial

When Drug Costs Soar Beyond Reach

April 15, 2008
The New York Times

It doesn’t take a health policy expert to recognize that something has gone terribly wrong when patients have to pay thousands of dollars a month for drugs that they need to maintain their health — and possibly save their lives. Congress needs to determine why this is happening and what can be done about it.

The plight of patients who have recently been hit with a huge increase in their insurance co-payments for high-priced prescription drugs was laid out in The Times on Monday by Gina Kolata. Instead of paying a modest $10 to $30 co-payment, as is usually the case for cheaper drugs, patients who need especially costly medicines are being forced to pay 20 percent to 33 percent of the bill (up to an annual maximum) for drugs that can cost tens of thousands of dollars, or even hundreds of thousands of dollars, a year.

These drugs — what insurers call Tier 4 medicines — are used to treat such serious illnesses as multiple sclerosis, hemophilia, certain cancers and rheumatoid arthritis. And since there are usually no cheaper alternatives, patients must either pay or do without, unless they can get their medicines through some charitable plan.

There is little doubt that the so-called tiered formularies, in which co-payments rise along with the cost of the drugs, are a sensible approach for encouraging consumers to use the cheapest drug suitable for their condition. But the system seems to break down when it moves to Tier 4 drugs where co-payments can be huge and suitable alternatives don’t exist.

The insurers say that forcing patients to pay more for unusually high-priced drugs allows them to keep down the premiums charged to everyone else. That turns the ordinary notion of insurance on its head. Instead of spreading the risks and costs across a wide pool of people to protect a smaller number of very sick patients from financial ruin, insurers are gouging the sickest patients to keep premiums down for healthier people.

The health insurance system is so complex that it is hard to parse the blame for this injustice. The drug companies, especially the biotechnology companies, are at the root of the problem; they often charge exorbitant prices for monopoly drugs that were developed with heavy government assistance. Washington needs to rein them in by encouraging generic competition for biological drugs and allowing government programs to negotiate lower prices.

Employers, including the federal government, also bear responsibility. They have been pressing to reduce their prescription drug expenditures, and all health care expenditures, by shifting more of the burden to patients. One patient who had been paying only $20 for a month’s supply of a multiple sclerosis drug was shocked when the charge rose to $325 per month. (It has since been suspended.) Another patient found that his co-payment for a newly prescribed leukemia drug would exceed $4,000 for a 90-day supply, so he has deferred buying it.

If patients do without medicines or put off taking them, the likely result will be sicker patients, and higher costs, down the road.

What is not clear is whether insurers are primarily reacting to pressure from employers or are exploiting the situation to increase their profits. Congress needs to probe hard to find out how many patients are facing enormous drug bills and how best to protect them from medical and financial disaster.

When Drug Costs Soar Beyond Reach, NYT, 15.4.2008,
http://www.nytimes.com/2008/04/15/opinion/15tues1.html

27 January 1926

New vaccines for tetanus and diptheria

From The Guardian Archive

[ Diptheria, nicknamed "the strangler",
was until the mid-1920s
the prime cause of death among children
up to their mid-teens.

Immunity Claimed for Infants. "Vaccines" against diphtheria and tetanus, comparable as prophylactics with Jenner's vaccine against smallpox, have been discovered at the Pasteur Institute here by a French chemist, M. G. Ramon. They are harmless, do not cause the slightest reaction, and confer an immunity even more lasting than that of calf-lymph against small-pox. It is suggested that all infants over twelve months' old should henceforth go through a second vaccination for diphtheria, and that all soldiers on active service should be vaccinated against tetanus, as they are now against typhus.

A generation ago Dr. Roux, the friend and successor of Pasteur, discovered specific serums against diphtheria and tetanus, but the immunising effect of injections in both cases has been extremely ephemeral, lasting only a few days. M. Ramon set himself to find something that would be as good, if not better, than Jenner's vaccine.

It is, of course, known that the microbes of diphtheria and of tetanus develop in the blood, or in a serum, extremely harmless specific poisons, the diphtheria toxin and the tetanus toxin. By subjecting these toxins to about blood temperature, 38 degrees centigrade, for about a month and utilising certain chemicals, as, for example, formol, M. Ramon has succeeded in obtaining new products that he calls anatoxins, an anti-diphtheria anatoxin and an anti-tetanus anatoxin.

Two years ago experiments began with anatoxins upon human beings at the Pasteur hospital and the military hospital in Paris. Some scores of thousands of patients, chiefly babies, have been innoculated against diphtheria, and the results are such that it is claimed that if infants are vaccinated against it, this dread disease of early life would disappear.

At the Pasteur Institute it has been equally shown that human beings – and domestic animals too – can be immunised against tetanus. Over a hundred human subjects have been treated, with a consequent immunity that is remarkably high.

Soldiers on campaign are a class especially exposed to tetanus infections. They are already subjected to anti-typhoid inoculation. M. Ramon has formed a mixture of "vaccines" which dispenses with a second injection and enables young soldiers to be immunised simultaneously against typhoid fever and tetanus, the twin scourges of armies in the field.

    New vaccines for tetanus and diptheria, G, 27 January 1926, republished 27.1.2009, p. 32,
    http://digital.guardian.co.uk/guardian/2009/01/27/pages/ber32.shtml ,
    http://www.guardian.co.uk/theguardian/2009/jan/27/tetanus-diptheria-vaccines-discovery

March 6, 1844

Cure your worms, teeth and giddiness

From The Guardian Archive

Wednesday March 6, 1844
Guardian

Worms Destroyed

Medicine never witnessed a more important discovery than in Pritchett's Vegetable Vermifuge, a remedy that neither purges, vomits, nor otherwise affects the constitution; requires no confinement, has neither taste nor smell, and is so harmless that it may be taken by an infant of an hour old; yet never, in one instance, failed destroying every worm in the body.

It contains not a particle of calomel, scammony, gamboge, or other drastic article. Large packets 2s.9d.

Apoplexy prevented

Determination of blood to the head effectually prevented by the occasional use of Frampton's Pill of Health, which, by strengthening the action of the stomach, prevents alarming giddiness, oppression of the brain, singing noise in the ears, headache. They are an excellent aperient, without griping or prostration of strength. Price 1 1/2d. and 2s.9d. a box.

For stopping decayed teeth

Patronised by her Majesty the Queen, his Royal Higness Prince Albert, her Royal Highness the Duchess of Kent, his Majesty the King of the Belgians, his Majesty the King of Prussia, his Grace the Archbishop of Canterbury, and nearly all the nobility, the bishops, and the clergy. Mr Thomas's Succedaneum, for filling decayed teeth, however large the cavity.

It is superior to anything ever before used, as it is placed in the tooth in a soft state, without any pressure or pain, and in a short time becomes as hard as the enamel, and will remain firm in the tooth for many years, rendering extraction unnecessary.

It arrests all further progress of decay, and renders them again useful in mastication. All persons can use Mr Thomas's Succedaneum themselves with else, without the aid of a dentist. Prepared only by Mr. Thomas, surgeon-dentist, 8, Berners-street, Oxford-street, London ; price 4s. 6d. Mr Thomas will send it free by post.

General debility

To these who are suffering from nervous complaints, rheumatism, scurvy, sorbutic eruptions and all diseases arising from impurity of the blood. The Cordial Balm of Syriacum is a gentle stimulant and enovator of the impaired functions of life, and is, therefore, calculated to afford decided relief to those who have fallen into a state of most chronic debility. It possesses wonderful efficacy in fits, headache, weakness, heaviness, dimness of sight, confused thoughts, wandering of the mind, and all kinds of hysteric complaints. Price 11s.

    From The Guardian Archive > Cure your worms, teeth and giddiness, 6.3.1844,
    G, Republished 6.3.2006,
    http://www.guardian.co.uk/fromthearchive/story/0,,1724515,00.html

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