Merck troubles mount

Merck & Co., in the middle of $41.1 (US) billion merger talks with Schering-Plough Corp., is facing more troubles as the Food and Drug Administration in the United States demands that warnings of dangerous side effects from its top-selling asthma drug be boosted following growing evidence of problems.

AstraZeneca and Cornerstone Therapeutics are facing similar orders.

After 15 months of investigation, the Food and Drug Administration said Merck & Co. Inc., AstraZeneca and Cornerstone Therapeutics will have to raise label warnings about psychiatric problems reported by a handful of patients taking their drugs.

"Patients and healthcare professionals should be aware of the potential for neuropsychiatric events with these medications," the FDA said in a posting to its Web site.

A spokeswoman for Merck said the language already appears in Singulair's label, but will be raised to the "precautions" section. It's now listed in a section about various side effects reported by patients.

"We've been working with the FDA since Singulair came to market and every time we update the label it's in cooperation with them," said Merck spokeswoman Pamela Eisele. ...

The exact language of the labeling updates has not been released, but the FDA said it could mention a slew of psychiatric problems, including: "agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior — including suicide — and tremors."

The move comes just weeks after a former research subinvestigator at Vivra Asthma & Allergy, an asthma research and treatment centre, went public with allegations that its Singular trails were knowingly skewed and falsified.

Trials of Singular, Serevent, Foradil, Flovent, Xolair, Accolate, and Xopenex conducted at the Tucson, Ariz., facility of Vivra Asthma & Allergy were corrupted by protocol violations and outright falsifications, says Robert Davidson, M.D., a former clinical research subinvestigator (SI) at the facility. ...

Davidson charges that during aggressive recruitment schemes in the late 1990s, patients with abnormal EKGs, multiple risk factors for coronary artery disease, arrhythmias, pulmonary embolisms, rheumatic fever histories, acute illnesses, and even pituitary tumors were enrolled with impunity in trials that earned investigators as much as $10,000 per patient.

Patients were “prescreened” for asthma drug trials with medically unnecessary pulmonary function tests (PFTs) without their knowledge or consent and had medication dosages reduced in apparent efforts to qualify them for the lucrative trials.

Staff could be seen entering rooms where placebos and real drugs were mixed and unblended, invalidating entire studies sent to the FDA as data for new drug applications.

The brazen “study buddy” and “crossover” arrangements, as staff referred to them, included churning or serially enrolling patients into clinical trials despite risks to their health and early terminations, coercing unwilling patients to participate, and directly falsifying patient study diaries, say documents filed by Davidson in a federal complaint.

Merck stands by its drug.

"For the millions of people suffering from either asthma or allergic rhinitis, SINGULAIR is an important treatment option for appropriate patients," said Scott Korn, M.D., vice president, Clinical Risk Management and Safety Surveillance, Merck Research Laboratories.

Merck held a conference call with drug reps late Friday to talk about the FDA order, but according to BNET Pharma and CafePharma.com, things didn't go well.

Naturally, Merck management scheduled a conference call for drug reps who tout Singulair at 6p.m. on Friday (an hour guaranteed to please reps hoping for a stress-free weekend). Unfortunately, many reps only received the note scheduling the meeting at 7 p.m. — one hour after the call started. From CafePharma:

I found out about a 6PM teleconference after 7PM. Gotta love management.

Other reps had difficulty navigating Merck’s dial in system:

First, they give vague directions about the teleconference (you had to go on to Comm. Central to get the dial-in number). Then they start 15 min late trying to get their s$%t together. Then TC says that this is a great opportunity to show our customers how committed we are to patients. When is the last time these people were in the field? Completely out of touch. Another Monday am to dread.

Those who did dial-in on time were kept on hold, just as they had been at an earlier conference call at 8 a.m. which apparently only got started at 8.20 a.m.:

This morning the the other S teleconference scheduled for 8 AM starts after 8:20 AM. What is going on inside? Half the country is on hold listening to music. I got work to do guys. I have to move and make calls.

All this comes amid allegations that Merck used fake academic journals and suppressed negative drug trail results.

In a final note, the American Journal of Bioethics blog, blog.bioethics.net, has congratulated this blog on its coverage of Merck and other drug companies of late.

I couldn't be more pleased that [insert gratuitous but sincere praise:] outstanding Toronto Star writer Stuart Laidlaw has been rigorously following the Merck/Elsevier scandal. It's practically flattering that he's listening to bioethics' and in particular bioethics' publishing voices, and he's quoted The American Journal of Bioethics Editor's Blog [that'd be the fancy-pants name for blog.bioethics.net] on his own Toronto Star Medical Ethics blog. However...the old adage that "the enemy of my enemy is my friend" may not apply to taking on the admittedly incredible ethical missteps by Merck ... and its publishing mules, comprising a whole fleet of bogus journals made to fool academics and clinicians.

You'd think that Merck would have learned from Vioxx and their New England Journal mistake (oops, forgot to send that data...) where publishing is concerned. You'd think ANY publishing company would learn that presenting the appearance of peer review for sale, then refusing to be transparent about just how much it COSTS to buy a peer reviewed journal. But you'd be wrong.

The thing is ... Stuart ... these guys are not, well, did you see the movie The Insider? [note to pharma lawyers and publishers of all kinds: I live on a small island in the Pacific...really...]

Summer Johnson, PhD

Let's hope she's wrong.

Ghostwriters used by Lily to promote drugs in journals

Eli Lily & Co. employees acted as ghostwriters, preparing favourable scientific papers on the company's top-selling anti-psychotic drug that later appeared in medical journals under the names of real doctors and researchers claiming to have written them.

Later non-ghostwritten articles found the drug, Zyprexa, causes added risk of developing diabetes.

Eli Lilly & Co. officials wrote medical journal studies about the anti-psychotic Zyprexa and then asked doctors to put their names on the articles, a practice called “ghostwriting,” according to unsealed company files.

Lilly employees also compiled a guide to hiring scientists to write favorable articles, complained to journal editors when publication was delayed and submitted rejected articles to other outlets, according to documents filed in drug-overpricing suits against the Indianapolis-based company, the largest manufacturer of psychiatric medicines.

Drugmakers’ use of ghostwriters has created “a huge body of medical literature that society can’t trust,” said Carl Elliott, a University of Minnesota bioethicist who has written about the practice.

Lilly sought to make Zyprexa “the number one selling psychotropic in history,” according to a 2000 plan distributed to its product team. The memo was among more than 10,000 pages of internal documents unsealed last month in lawsuits by insurers and pension funds seeking to recoup money spent on the drug. They allege Lilly exaggerated Zyprexa’s effectiveness.

“Plaintiffs are releasing one-sided, cherry-picked documents obtained in discovery to selected news media in an effort to try their cases” there, said Lilly spokeswoman Marni Lemons. “Lilly remains prepared to defend ourselves against all of these allegations in the appropriate venue, a court of law.”

Lily joins other top drug makers involved in revelations about questionable scientific studies -- and even fake scientific journals -- published as little more than marketing tools for medications that later turned out to have dangerous side effects, including Merck & Co., and Pfizer Inc.

Medical ethicists quoted in the Bloomberg story about Lily said it was akin to plagiarism for doctors and researchers allowing their names to appear on ghostwritten articles. Barton Moffatt, a Mississippi State University bioethicist, called it "academic misconduct" and predicted that as the scandal grows researchers could find themselves fired over the practice.

John Buse, a former president of the American Diabetes Association who was listed as lead author of an article prepared with a Lily staffer in the Journal of Clinical Epidemiology, said researchers can develop a "stockholm Syndrome" with the drug companies they're are dealing with.

“I’m not saying that the pharmaceutical industry captures me,” Buse said. “But to the extent that the relationship has something above and beyond medicine, science, you know, it could cloud one’s judgement.”

Buse added that many researchers develop emotional attachments to drugs they’ve discovered or studied extensively.

“There’s this natural tendency for people to fall in love with your drug: it’s like your child,” Buse said. “So you have a hard time accepting criticism.”

Also this week, Zyprexa was approved in the U.S. for use by teenagers.

Altruistic vaccines

I wrote an article in today's Toronto Star about a novel way to fight Dengue Fever -- or potentially any other disease passed on by mosquitoes.

The idea is an "altruistic vaccine" that does nothing to help the person actually getting the shot. Instead, the person's blood is rendered poisonous to any mosquitoes who bite the vaccinated person -- making the little critters unable to spread the disease.

The vaccine is being developed at Queensland University, in a part of Australia with a fast-growing Dengue problem. Global warming is being blamed for its rapid spread. The Bill and Melinda Gate Foundation is funding the work.

All vaccines have some altruist qualities to them, ethicist Angus Dawson told me, in that governments fund vaccination programs to prevent the spread of disease. Altruistic drugs take that one step further by giving no direct benefit to the person getting the shot.

That much is in the story.

What I couldn't fit in was Dawson's observation that the research is an example of society continuing to look for technological solutions to problems with wider causes.

It would perhaps be more ethical, says Dawson, founding director of the Centre for Professional Ethics at Keele University in Britain and now a visiting ethicist at the University of Toronto's Joint Centre for Bioethics, to address the long-term, underlying causes of disease spreading in general -- such as poverty, lack of access to proper care and global warming.

 He's right, of course, but I won't hold my breath.

Swine flu on Facebook

The American Journal of Bioethics has set up a Facebook group to provide up-to-the-minute information on the current swine flu outbreak.

Launched today, pandemic.bioethics.net is your leading source for bioethics news, commentary and scholarship related to swine flu (H1N1), vaccine research, public health policy and more.

Whether you want up-to-the minute news updates, to comment on what we are writing here at bioethics.net, or to post your own news stories and to write your own comments via Twitter or Facebook, pandemic.bioethics.net is the primary source on the Internet for ethics and pandemics.

Available starting today also via our website, AJOB and Taylor and Francis have made available all pandemic-related publications for a six-month period. Links to those publications are available at blog.bioethics.net and pandemic.bioethics.net.

To learn more and to join in on the dialogue, visit us on Facebook, bookmark our URL, or select any of the links above.

Summer Johnson, PhD

The group already has links to several articles related to pandemic planning, including one on mandating vaccinations, another on ensuring people live up to their responsibilities during a pandemic and one on rationing vaccine.

It's an open group, so anyone can join and invite others to join.

Preparing for a swine flu pandemic

Margaret R. McLean, director of bioethics at the Markkula Center for Applied Ethics at Santa Clara University, says preparing for a swine flu pandemic must be about far more than stockpiling vaccines or freeing up hospital beds.

It must also go hand-in-hand with ethics, she says.

In a video  posted to YouTube, McLean discusses the issue, drawing on research she did two years ago looking into response to a possible bird flu pandemic.

In pandemic planning, as in medicine in general, the allocation of these scarce medical resources is the most difficult ethical issue confronting the current health care system. No one wants to speak of rationing, but it occurs daily and necessarily escalates during a disaster. In a time of pandemic, rationing is inevitable and must be done in a manner that is transparent, respectful of persons, inclusive, accountable, proportional, fair, and minimizes harm.

Drawing on the Canadian experience with the 2003 SARS outbreak, the authors of “SARS and Hospital Priority Setting” (Jennifer AH Bell, et al) argue that a public health crisis demands heightened attention to fairness: “In the midst of a crisis such as SARS where guidance is incomplete, consequences uncertain, and information constantly changing, where hour-by-hour decisions involve life and death, fairness is more important rather than less.”

The World Health Organization, meanwhile, has a 33-page document outlining the ethics of pandemic planning, looking at such issues as access to treatment, quarantine, the role of health care workers, the importance of international co-operation, etc.

Swine flu ethics

Hong Kong says it will detain in hospital anyone arriving there who has a fever, at least until it can be proven that they don't have swine flu.

Hardly a surprising reaction by a place that was the epicentre of the SARS outbreak six years ago, but it raises interesting ethical questions about the needs of the many versus the rights of individuals.

Is it ethical to effectively jail someone merely on the suspicion of illness? On the other hand, with thousands, perhaps millions, of lives at stake if this thing becomes a pandemic, would it unethical not to detain people?

Tough questions, to be sure, but ones that I suspect we'll be hearing more about in the coming days as swine flu continues scaring people around the world.

Detention sounds like an easy answer, but it raises some practical problems. For one, will people avoid getting treatment for fear that doing so will get them detained? If even a handful of people react that way, the results could be catastrophic. On the other hand, can we count on people to do the right thing and get tested -- and stay indoors if diagnosed -- without strict controls?

Local health authorities are meeting around the world to discuss theses issues.

Another practical concern is deciding who will get vaccinated against this new flu. Health care workers will almost certainly be top of the list, but even the details of that could be up for debate. I wrote in the Toronto Star last fall about a study that argued that not all medical staff should get the flu shot during a pandemic. Why would a foot doctor be needed. it asked.

Better, it said to direct some of the vaccine to truckers and public works staff to ensure that food, water and electricity remain available through any health crisis.

"It takes a lot of people to keep society going," says Nancy Kass, a professor at the Johns Hopkins Berman Institute of Bioethics and lead author of the study in the most recent edition of the journal Biosecurity and Bioterrorism.

Traditional pandemic planning calls for giving first priority for medical treatment to hospital staff and "first responders" to a crisis, such as firefighters and ambulance workers, so that the immediate health crisis can be dealt with effectively.

But as Hurricane Katrina showed three years ago, the study argues, "the after-effects of a disaster can be as damaging as the precipitating event," as electricity and heat are cut off, clean water becomes scarce and sewage starts to back up.

"There could be widespread social chaos, significant outbreaks of other infectious diseases, and severe anxiety, with the possibility of social degeneration, looting, or even violence as people try to secure needed supplies," the study says.

Even people whose homes were not damaged by the hurricane had trouble getting food, electricity and gasoline, Kass says in an interview.

Up to 40 per cent of the workers whose job it is to keep the lights on and the water flowing could be absent from work after a pandemic, the study says. That's enough to cause a breakdown of such services.

I will be watching to see how the many ethical issues play themselves out with the swine flu story.

Meanwhile, blogger Janet D. Stemwedel (aka Dr. Free-Ride) has been keeping track of how various airlines and others are responding. From a Canadian perspective, both Air Canada and WestJet are waiving fees for changing Mexican travel plans.

Tortured ethics

In the wake of new revelations about Bush-era torture of terrorism suspects, the American Medical Association has written a letter to US President Barack Obama telling him that the use of doctors in torture violates basic medical ethics.

Any involvement by physicians in torture is fundamentally incompatible with the physician’s role as a healer. Such involvement would violate core ethical obligations of the medical profession to “first, do no harm” and to respect human dignity and rights.

These core principles are enshrined in the Code of Medical Ethics of the American Medical Association (AMA) and the codes of other professional medical organizations throughout the world. Our AMA Code forcefully states medicine’s opposition to torture or coercive interrogation and prohibits physician participation in such activities. Our Code calls on physicians to support victims of torture, to report the use of torture, and to strive to change situations in which torture is practiced. At stake are the rights and well-being of individuals, the integrity of medicine, and society’s trust in the profession.

The group says it is ready and willing to work with the new president "to ensure that these core principles guide our nation’s physicians."

Last Saturday, the Washington Post outlined the role of medical professionals in the torture.

The CIA dispatched personnel from its office of medical services to each secret prison and evaluated medical professionals involved in interrogations "to make sure they could stand up, psychologically handle it," according to a former CIA official.

The alleged actions of medical professionals in the secret prisons are viewed as particularly troubling by an array of groups, including the American Medical Association and the International Committee of the Red Cross.

AMA policies state that physicians "must not be present when torture is used or threatened." The guidelines allow doctors to treat detainees only "if doing so is in their [detainees'] best interest" and not merely to monitor their health "so that torture can begin or continue."

The various justifications used by the CIA for using medical professionals are outlined on the Mic Check blog, along with other justifications, as contained in a declassified CIA memo.

Rights complaint against hospital

The parents of a baby girl who died at Toronto's Hospital for Sick Children have filed a complaint with the Ontario Human Rights Commission, saying their daughter received inadequate care and that a do not resuscitate order was filed without their consent.

The Star's Emily Mathieu writes about the case in today's Toronto Star.

The parents of Annie Farlow – a 2-month-old who died at the Hospital for Sick Children in 2005 after receiving what her parents allege was inadequate care because of a genetic condition – are attempting to take their case to the Human Rights Tribunal of Ontario.

"I think every child regardless of their disabilities deserves a chance at life and if the treatment or surgery is not in their best interest, then they deserve a dignified, comfortable and peaceful death," said Annie's mother, Barb Farlow, yesterday outside a meeting to determine if their application for a hearing will go forward.

Annie had Trisomy 13, a genetic condition associated with severe developmental and physical disabilities. The Farlows raised concerns that the hospital has a policy to provide children with genetic conditions only supportive care, keeping them comfortable until they die rather than attempt extraordinary life-saving measures.

The Farlows also said the hospital has been reluctant to release crucial records related to Annie's care – including an audit detailing the period of time close to her death.

The hospital said allegations that any child with a genetic condition or disability receives lesser care are untrue.

The rest of the story is here.

The Star's Helen Henderson also wrote about Annie last summer.

Annie's mother, Barbara, told her daughter's story at the University of Toronto's Joint Centre for Bioethics last June. Her lecture is archived here. The Farlows have also set up a web site to tell Annie's story.

The ethics of baby Kaylee's life

  With the chance of little Kaylee Wallace donating her heart to Lillian O'Conner, as had been hoped earlier this week, now seemingly passed, the ethical debate has taken off in earnest.

In a story in today's Toronto Star, I look at the ethics of transplants, and why donors and recipients are generally not known to one another.

"The death of one person needs to be separated from the need of an organ in another person," Bowman says. "Our system is going to be an ethical mess if we allow one to pull the other."

Linda Wright, director of bioethics at University Health Network, says allowing the families of dying patients to decide where organs will go would mean that some deserving patients may be left out.

"Because organs are so scarce and so valuable, the argument has been that we should give them to the person who needs them the most," says Wright, who stressed she is not talking about any case in particular.

Wright warns, however, that allowing donor families to decide who gets an organ is open to abuse, since we can never know the motivations of those involved.

Organs could end up distributed on the basis of race, religion or economic class, rather than need, says Michael Millis, director of the transplant centre at the University of Chicago Medical Center.

In a worst-case scenario, it could lead to organs being bought and sold, says Margaret Somerville, director of the McGill Centre for Medicine, Ethics and Law.

"You worry about some sort of scheme that might come up, some sort of payment for organs."

My colleague at the Star, Theresa Boyle, looks at the question of donation after cardiac death, or DCD.

"This case is really exceptional because heart transplants after (cardiac death) are extremely rare. There's really only minimal experience worldwide," Dr. Sam Shemie, medical director of organ and tissue donations at Canadian Blood Services, said yesterday.

The New England Journal of Medicine last year reported on three cardiac-death transplants involving infants at Denver Children's Hospital, touching off a debate about medical ethics. In each case, the heart was removed from a newborn suffering from severe brain damage less than two minutes after they were taken off life support. While the hearts saved terminally ill babies, questions were raised about whether the donors were really dead.

The Denver cases stirred debate about how long after cardiac functioning ceased should a retrieval team wait to ensure the baby's heart would not restart without intervention. While the chances of a successful transplantation improve the faster the heart is harvested, acting too soon can make retrieval seem like death by organ donation.

In a Canadian Press piece, Margaret Somerville and the University of Toronto's Trudo Lemmens reflected on the role of the media in the wrenching case.

The saga was being played out in real time on TV networks, news websites and in the pages of newspapers, with the names of all the players attached. The very public nature of the case concerns many medical ethicists who feel a deep sense of unease as they watch it unfold.

"These are not the kinds of decisions that have to be taken in the newspapers," says Trudo Lemmens, a professor of health law and bioethics at the University of Toronto.

"I guess one of the things you could ask is: Is having this media frenzy around this (case), is it a sufficient respect for that baby’s life and death?" wonders ethicist Margaret Somerville.

Their words seemed to bear themselves out this morning, when Kaylee's father Jason Wallace lashed out at the media.

Speaking to TV cameras in front of the Hospital for Sick Children, Jason Wallace lashed out at recent media coverage and hospital staff.

"The public's judging us, that we want our daughter to die in some way," Wallace said. "We're going through this.

"And now having the public now judge us that we're doing something wrong?"

In an interview with Sun this morning, the father vowed he wants his daughter to live.

"Forget people that think we're trying to euthanize our child," he said.

"This is BS!" He alleged Sick Kids staff told him to stop going public, saying one person told him, "you should keep your mouth shut and let your daughter die with dignity."

"Comments from this hospital saying things like we'll have to consider at some point in time how much money we're spending caring for your daughter," he said. "There is no issue whatsoever, I want my daughter to live."

Toronto Star reporter Emily Mathieu, who has led coverage of this story all week, gave us all a sense of the difficult week with a front-page story today looking at Kaylee's life and her parents' anguish.

They had nine months to prepare for the life of their daughter.

But, instead of sharing hopes and dreams for the baby's future, the parents have had less than two months to accept the fact their daughter was gravely ill and likely to die.

"We thought we were going to be able to have a normal life, take her home, do what a normal family would do," said her mother, Crystal Vitelli, 20. Kaylee's short life has been anything but normal.

She has spent her entire life in hospital and, on Tuesday, with the entire city watching, was taken off a respirator and was expected to die. In a nearby operating room, another critically ill baby was waiting for a heart transplant from Kaylee.

But Kaylee lived and last night, in a dramatic and emotional turn of events, her parents revealed that they were planning to take their daughter home to Bradford for the first time.

 

 

Picking who gets your baby's heart

Lillian O’Connor is one month old, and won't survive without a new heart. Kaylee Wallace is two months old, and due to a brain condition, won't survive once she is taken off a ventilator.

Their story has raised a number of ethical concerns.

They are in the same hospital, Toronto's Hospital for Sick Children. Their parents heard each others' story, and Kaylee's parents offered their girl's heart to Lillian.

Kerry Bowman, an ethicist with the Joint Centre for Bioethics, called that a wonderful human gesture, but can't be done.

Bowman, quoted frequently on this case in the media, worries that such promises put us on a slippery slope, by connecting the death of one person to the survival of another. It's a small step from there, he warns, to saying that since the donor will die anyway, why not allow euthanasia to speed up the process?

The other fear is that allowing people to pick who gets a family member's organs might mean that the most deserving (as in, the sickest) patient might not get the life-saving transplant. People might want to give the organs to someone who is like them, socially or culturally.

They might even try to sell them, ethicists warn.

It seems there is no shortage of slippery slopes in this story.