Why not? In last month’s Journal of General Internal Medicine, a University of Michigan team pointed to some systemic problems. Analyzing more than 100 studies published during 2007 in prestigious medical journals, the researchers found that more than 20 percent excluded participants above a particular age. That actually represented considerable progress; a previous study of trials published from 1994 to 2006 found that 39 percent had excluded people over age 65.

More disturbingly, even when older people aren’t barred by age, they get left out for other reasons. More than 45 percent of the trials that didn’t have age limits excluded people for having other illnesses or cognitive impairment, for having a reduced life expectancy or physical disabilities or functional limitations, even for living in a nursing home or senior residence – all restrictions that tend to remove the elderly from the mix. Simply requiring study participants to show up at an office or clinic for regular monitoring may prevent frail elders or those who lack transportation from participating.

Dr. Donna Zulman, an internist and the study’s lead author (she’s now teaching at Stanford University), empathizes with her fellow researchers. “It’s really hard to do clinical trials, and when patients are complicated, with multiple health problems, it can be even more difficult,” she told me in an interview. “It makes for a cleaner trial if certain patients are excluded.”Nevertheless, “the study population should reflect the population that will be treated in the real world,” she said, “particularly if it’s studying a drug that will be used by older and frailer adults.”

Locating a group of perfectly healthy 85-year-olds for a drug trial — people who have no “co-morbidities” (doctorspeak for other illnesses) that might confound the experiment — is tough, agrees Dr. John Sloan, a family physician in Vancouver, British Columbia, whose book “A Bitter Pill” criticizes the prevailing treatment of older patients. But even if investigators manage to find enough of those sturdy subjects, the trial’s results won’t be very useful in his practice. Most of Dr. Sloan’s elderly patients aren’t perfectly healthy; they have multiple chronic diseases, often including dementia; they take lots of drugs and are physically fragile.

So the study’s authors call on regulators and investigators to include older adults in clinical trials and to analyze whether treatments affect them differently from younger participants. “Huge amounts of money flow into these trials,” Dr. Zulman said. “If we’re not getting results that help us take care of these most complex and expensive patients, we’re not getting much value from them.”

It has happened a few times in the U.S., and the opinion piece in Wednesday’s Journal of the American Medical Association says putting children temporarily in foster care is in some cases more ethical than obesity surgery.

Dr. David Ludwig, an obesity specialist at Harvard-affiliated Children’s Hospital Boston, said the point isn’t to blame parents, but rather to act in children’s best interest and get them help that for whatever reason their parents can’t provide.

State intervention “ideally will support not just the child but the whole family, with the goal of reuniting child and family as soon as possible. That may require instruction on parenting,” said Ludwig, who wrote the article with Lindsey Murtagh, a lawyer and a researcher at Harvard’s School of Public Health.

“Despite the discomfort posed by state intervention, it may sometimes be necessary to protect a child,” Murtagh said.

But University of Pennsylvania bioethicist Art Caplan said he worries that the debate risks putting too much blame on parents. Obese children are victims of advertising, marketing, peer pressure and bullying — things a parent can’t control, he said.

“If you’re going to change a child’s weight, you’re going to have to change all of them,” Caplan said.

Roughly 2 million U.S. children are extremely obese. Most are not in imminent danger, Ludwig said. But some have obesity-related conditions such as Type 2 diabetes, breathing difficulties and liver problems that could kill them by age 30. It is these kids for whom state intervention, including education, parent training, and temporary protective custody in the most extreme cases, should be considered, Ludwig said.

While some doctors promote weight-loss surgery for severely obese teens, Ludwig said it hasn’t been used for very long in adolescents and can have serious, sometimes life-threatening complications.

“We don’t know the long-term safety and effectiveness of these procedures done at an early age,” he said.

Ludwig said he starting thinking about the issue after a 90-pound 3-year-old girl came to his obesity clinic several years ago. Her parents had physical disabilities, little money and difficulty controlling her weight. Last year, at age 12, she weighed 400 pounds and had developed diabetes, cholesterol problems, high blood pressure and sleep apnea.

“Out of medical concern, the state placed this girl in foster care, where she simply received three balanced meals a day and a snack or two and moderate physical activity,” he said. After a year, she lost 130 pounds. Though she is still obese, her diabetes and apnea disappeared; she remains in foster care, he said.

In a commentary in the medical journal BMJ last year, London pediatrician Dr. Russell Viner and colleagues said obesity was a factor in several child protection cases in Britain. They argued that child protection services should be considered if parents are neglectful or actively reject efforts to control an extremely obese child’s weight.

A 2009 opinion article in Pediatrics made similar arguments. Its authors said temporary removal from the home would be warranted “when all reasonable alternative options have been exhausted.”

That piece discussed a 440-pound 16-year-old girl who developed breathing problems from excess weight and nearly died at a University of Wisconsin hospital. Doctors discussed whether to report her family for neglect. But they didn’t need to, because her medical crisis “was a wake-up call” for her family, and the girl ended up losing about 100 pounds, said co-author Dr. Norman Fost, a medical ethicist at the university’s Madison campus.

State intervention in obesity “doesn’t necessarily involve new legal requirements,” Ludwig said. Health care providers are required to report children who are at immediate risk, and that can be for a variety of reasons, including neglect, abuse and what doctors call “failure to thrive.” That’s when children are severely underweight.

Jerri Gray, a Greenville, S.C., single mother who lost custody of her 555-pound 14-year-old son two years ago, said authorities don’t understand the challenges families may face in trying to control their kids’ weight.

“I was always working two jobs so we wouldn’t end up living in ghettos,” Gray said. She said she often didn’t have time to cook, so she would buy her son fast food. She said she asked doctors for help for her son’s big appetite but was accused of neglect.

Her sister has custody of the boy, now 16. The sister has the money to help him with a special diet and exercise, and the boy has lost more than 200 pounds, Gray said.

“Even though good has come out of this as far as him losing weight, he told me just last week, ‘Mommy, I want to be back with you so bad.’ They’ve done damage by pulling us apart,” Gray said.

Stormy Bradley, an Atlanta mother whose overweight 14-year-old daughter is participating in a Georgia advocacy group’s “Stop Childhood Obesity” campaign, said she sympathizes with families facing legal action because of their kids’ weight.

Healthier food often costs more, and trying to monitor kids’ weight can be difficult, especially when they reach their teens and shun parental control, Bradley said. But taking youngsters away from their parents “definitely seems too extreme,” she said.

Dr. Lainie Ross, a medical ethicist at the University of Chicago, said: “There’s a stigma with state intervention. We just have to do it with caution and humility and make sure we really can say that our interventions are going to do more good than harm.”

This could be changing, however. The pharmaceutical industry has persuaded several governments to stiffen regulations against fake drugs and to conduct more aggressive raids (see chart). Companies are also devising novel technologies to outfox the criminals. Even the Catholic church is joining the cause, issuing a stern statement in August that it is in “the best interest of all concerned that smuggling of counterfeit drugs be fought against”.

The pope’s concern is justified. Counterfeit drugs can kill. Many are shoddily made, containing the wrong dose of the active ingredient. Taking them instead of the real thing can turn a treatable disease into a fatal one. It can also foster drug resistance among germs. This has been a big problem for a long time in developing countries. Studies of anti-infective treatments in Africa and South-East Asia have found that perhaps 15-30% are fakes. The UN estimates that roughly half of the anti-malarial drugs sold in Africa—worth some $438m a year—are counterfeits.

Roger Bate of the American Enterprise Institute, a think-tank in Washington, DC, cautions that any such estimates should be treated with care. The countries with the most fakes may not be cracking down, so official figures will look rosy; in contrast, countries with a smaller counterfeit trade that are vigilant may end up with more seizures. The World Health Organisation agrees, and has recently taken its estimates off its website. Even so, Mr Bate says his field work has convinced him that counterfeits kill at least 100,000 people a year, mostly in the poor world.

Now it appears that fakes are taking off in the rich world too. Yes, Viagra still tops the list of knock-offs seen by Pfizer, says John Clark, the American drug firm’s global head of security; but fake versions of at least 20 of its products (including Lipitor, a blockbuster cholesterol drug) have been detected in the legitimate supply chains of at least 44 countries. Mr Clark’s intelligence comes from Pfizer’s global network of informants, consumer tip-offs and in-store inspections. He sees worrying trends.

Counterfeiters used to operate chiefly in developing countries, says Mr Clark, but now his firm sees fakes coming from such rich and well-regulated places as Canada and Britain. And the crooks are growing more technologically sophisticated: some can even counterfeit the holograms on packets that are meant to reassure customers that pills are genuine.

A consumer study funded by Pfizer recently found that nearly a fifth of Europeans polled in 14 countries had obtained medicines through illicit channels. That, the firm reckons, makes for a grey market in the EU of over €10 billion ($12.8 billion). Terry Hisey of Deloitte, a consultancy, thinks the global market for fakes could be worth between $75 billion and $200 billion a year. Those staggering sums, he argues, help explain the emergence of a flurry of new technologies and companies hoping to help the drugs industry “secure its global supply chain”.

In July Oracle, an American software giant, unveiled Pedigree, a programme that helps drugs firms “track and trace” pills all the way from the factory to your fingers. IBM has a rival offering, as well as one using radio-frequency identification (RfID) chips, which are embedded in packaging to detect tampering and allow precise tracking. 3M, a materials company, and Abbott Laboratories, an American medical firm, are also rolling out an RfID-based product. A division of Johnson & Johnson, a drugs giant, has developed web-based software to help customs officials quickly verify whether drugs are fake or real.

Poor countries find it hard to take advantage of such technologies. Sophisticated radio tags and database software are not much use in places where street hawkers peddle fakes with impunity. Still, even in such difficult circumstances, a combination of political will and business ingenuity can make a difference.

Bottom-up battle

A Ghanaian start-up firm, mPedigree, has come up with a clever way to use mobile phones in this fight. Participating drugs companies emboss a special code onto packages, which customers find by scratching off a coating. By sending a free text with that code, they can find out instantly if the package is genuine or a fake.

Bright Simons, the firm’s boss, argues that technologies like his can be a useful bottom-up complement to top-down enforcement. Having successfully completed initial trials, he says, mPedigree is ready to expand its service in the region. The government of Nigeria, where fakery is rife, recently declared its intention to adopt such a text-based validation system.

Thomas Kubic of the Pharmaceutical Security Institute, an industry-funded outfit, gives warning that this war will be hard to win. After more than 30 years as an investigator, he is sure that crooks will eventually find a way around any defence.

Even so, he thinks novel approaches such as mobile-based validation may “harden the target”, just as a burglar alarm makes your home somewhat trickier to rob. If the cost and complexity of faking drugs goes up, crooks may choose to fake Gucci handbags instead. This would still be theft, not to mention a crime against fashion. But it will not kill anyone.

The Denver Democrat used Craig Hospital, which is internationally acclaimed for its rehab facilities for people with spinal- cord and brain injuries, as the backdrop to introduce the Stem Cell Research Advancement Act of 2011, which she is co-sponsoring with Rep. Charlie Dent, R-Pa.

The bill would codify the National Institutes of Health’s guidelines for carrying out all stem-cell research and require the NIH to review its guidelines every three years and make updates as science warrants.

“What it will do once and for all is ensure that this lifesaving research will be conducted and be uninterrupted and unimpeded by political interference,” said DeGette, who has been actively working on this bill since 1999.

“There are tens of millions of Americans who could be positively affected by this research,” she said. “I talk to people all the time who have a spinal-cord injury, Alzheimer’s or Parkinson’s and who could receive a new outlook on their future with this science.”

Among them is Chris Chappell, a former Craig patient who has been a quadriplegic since breaking his neck in a mountain-bike accident 11 years ago.

“When you have your health, you don’t give it a second thought,” said Chappell, who works at the hospital as a graduate relations coordinator. “And when you don’t have your health, it’s your only thought.”

DeGette got legislation passed in the House and Senate in 2006 and 2007 that was similar to the Research Advancement Act of 2011. Both bills were vetoed by President George W. Bush.

Her legislation served as the framework for President Barack Obama’s 2009 executive order that overturned the Bush administration’s ban on funding for stem-cell research.

Rep. Doug Lamborn, a Colorado Springs Republican, has been among those opposed to embryonic-stem-cell research on the grounds that it’s unethical and immoral to use human embryos for scientific research.

His office was unavailable for comment Wednesday.

The 2011 act has been presented to Congress, and DeGette is “cautiously optimistic” that Congress can pass the legislation for a third time and get it to Obama’s desk for approval.

“Legislation is progress, and progress is good for all of us,” Chappell said. “Stem-cell research could be used as a way to restore function for patients. And if they’re functional, they become a part of society in a more progressive and positive way.”

In an article published online for the June 16 issue of The American Journal of Public Health, scientists calculated the number of deaths attributable to each of six social factors, including low income.

To estimate the number of deaths caused by each factor, the scientists reviewed 47 earlier studies on the subject, combining the data in a meta-analysis. The studies were generally based on large national surveys like the National Health and Nutrition Examination Survey, a continuing study by the Centers for Disease Control and Prevention.

Then, using the pooled data, the researchers calculated the “population-attributable fraction” of deaths — that is, the number of deaths caused by living with a given social disadvantage.

Finally, they multiplied that fraction by the total number of deaths in the year 2000 to come up with a number of deaths caused by each of the six social conditions. The researchers then separated the contribution of each social factor.

“The methods we’re using are limited,” Dr. Sandro Galea, the lead author, acknowledged. “Any time you try to say that death is attributable to a single cause, there’s a problem — all deaths are attributable to many causes. But what we did is just as valid as what was done to establish smoking as a cause of death.”

“This is a very interesting paper,” said Roger T. Anderson, a professor of public health sciences at Pennsylvania State College of Medicine who was not involved in the study. “It’s simple and elegant, a very straightforward approach to looking at these kinds of data.

“It brings to the surface what the impact of social disadvantage is in terms of numbers of deaths, and the authors have done a very nice job of laying out the argument.”

The researchers used various criteria to define an adverse social condition. Low education, for example, was defined as not having graduated from high school. Poverty was defined as a household income of less than $10,000. A population in which more than 25 percent of people reported their race or ethnicity as non-Hispanic black was considered racially segregated.

The study also calculated the effect of an area’s overall poverty level, income differential and low social support.

For 2000, the study attributed 176,000 deaths to racial segregation and 133,000 to individual poverty. The numbers are substantial. For example, looking at direct causes of death, 119,000 people in the United States die from accidents each year, and 156,000 from lung cancer.

Social factors are not the same as diseases or accidents, but Dr. Galea argues that they are equivalent to a behaviors like smoking, and that, as with smoking, there is evidence of the mechanism involved. He said that the causal chain between, for example, poverty and death from heart disease has many well-established links.

Dr. Galea also said that poverty results in poor access to health screening, poor access to quality care for those who actually have heart disease, greater vulnerability to stresses associated with heart disease and a greater likelihood of engaging in unhealthy behavior.

“In some ways,” Dr. Galea added, “the question is not ‘Why should we think of poverty as a cause of death?’ but rather ‘Why should we not think of poverty as a cause of death?’ ”

If they had not smoked, 400,000 people each year would not have died, Dr. Galea said. Similarly, he said, if they had graduated from high school, the 245,000 people whose cause of death he attributes to low education would still be alive.

“This might be a useful lens to help focus our minds,” said Dr. Galea, who is the chairman of the department of epidemiology at the Mailman School of Public Health at Columbia University. “If you say that 193,000 deaths are due to heart attack, then heart attack matters. If you say 300,000 deaths are due to obesity, then obesity matters.

“Well, if 291,000 deaths are due to poverty and income inequality, then those things matter too.”

]]> http://www.bioethicsinternational.org/blog/2011/07/05/researchers-link-deaths-to-social-ills/feed/ 0 http://www.bioethicsinternational.org/blog/2011/07/03/could-another-guatemala-case-happen/ http://www.bioethicsinternational.org/blog/2011/07/03/could-another-guatemala-case-happen/#comments Sun, 03 Jul 2011 16:48:33 +0000 Yara Tercero-Parker, BEI Intern http://www.bioethicsinternational.org/blog/?p=2453 [Blog.Bioethics.gov]- The question was simple, the answers not.

At the Presidential Commission for the Study of Bioethical Issues today, Commission Chair Dr. Amy Gutmann, president of the University of Pennsylvania, asked a panel of international experts on bioethics whether the so-called Guatemala incident could happen again. In Guatemala, from 1946 to 1948, a U.S.-funded research experiment deliberately infected people in a trial with sexually transmitted diseases and in some cases did not treat them.

“Of the many things that happened there, no, it could not happen again because of informed consent,” said Dafna Feinholz, chief of the Bioethics Section, Division of Ethics and Science and Technology, Sector for Social and Human Sciences, United Nations Educational, Scientific and Cultural Organization.

But she said there was great room for improvement in the current sets of regulations guiding clinical trials. She specifically mentioned the area of “how to enter negotiations about research projects, about what is relevant, and why is it being conducted.”

Others on the panel agreed that human subjects in clinical trials remained vulnerable today.

Francis P. Crawley, executive director of the Good Clinical Practice Alliance in Europe, championed the need for more transparency around clinical trials. First, he thanked the panel and Susan Reverby, the Wellesley College professor whose research uncovered the Guatemala experiments last year, leading President Obama to ask the Commission to investigate that study as well as whether federal funded research adequately protected human subjects in trials.

“I think this work by Dr. Reverby was done in an exemplary way as a historian, ethicist, and a human being,” Crawley said. “One of the things Dr. Reverby has done is to bring something out of darkness. And that is really, really important to us.”

He continued: “We need to consider carefully what we do as ethicists. Are we protecting human subjects? Is that what we are about? Are we justifying research of subjects? Are we advancing health? How are we advancing health? What are our roles and what should be our principle objective here? I think our primary objective should be health.”

Crawley said now there was a “trust deficit” between researchers and possible subjects of trials. He said that the U.S government, European governments and the World Health Organization have all moved quickly to promote more transparency of the clinical research.

But Commission member Anita L. Allen, professor of law and philosophy at the University of Pennsylvania, questioned whether transparency was the main problem.

“It’s often said that African Americans’ distrust of clinical medicine is due to a belief if a group is low enough in social status, (abuses) can happen in broad daylight,” she said. “Slavery and the Holocaust happened in broad daylight. So is transparency the key? Or is human rights and equality really the key?”

“I agree with you entirely,” Crawley said. “ … Trust is really the key issue here. It’s very important we maintain trust in research. … Transparency is in and of itself insufficient. It will never be sufficient. It is a necessary condition, but it is not sufficient.”

Commission member Christine Grady, deputy chief of the Department of Bioethics at the National Institutes of Health Clinical Center, raised another thorny issue: Do the interests of people participating in a clinical trial trump everything else?

Gutmann asked Grady to answer her own question.

“Sometimes the interest, the immediate interest, especially the medical interest of the individual at hand are not the primary focus of what is going on,” Grady said. “… The sort of struggle that has occupied many people for many years is what level of risk do we allow people to take if they are able to make autonomous decisions in the interest of science, in the interest of developing new knowledge that will help other people. That is really a very tough question.”

Johannes J.M. van Delden, president of the Council for International Organizations of Medical Sciences, said that in many cases “clinical research cannot be beneficial for the participants. … Usually there will be procedures that are harmful, or certainly not beneficial.”

MASSDEVICE ON CALL — Medtronic Inc. (NYSE:MDT) faces new heat over the Infuse bone growth product, this time for allegations that the therapy caused excess bone growth in the spinal canal of 70 percent of patients in an independent clinical trial.

In what has become a familiar cry against the Infuse product, doctors on the company’s payroll were accused of concealing vital information from published studies.

A 2004 paper written about a clinical trial conducted by MDT’s paid consultants maintained that no harm was done to patients and that any excess bone growth, known as ectopic bone, didn’t cause any ill effects.

Just a few months ago, a clinical trial found that nearly three quarters of patients had unwanted bone growth in their spinal canals, and the trial was cut off after only 34 of hundreds of enrolled patients had received the implant, the Milwaukee Journal Sentinel reported.

The allegations continue to stack the deck against the Infuse implant, which has been widely used to fuse spinal vertebrae during surgeries since 2002.

A study published last month accused the Fridley, Minn.-based company of concealing that the bio-engineered bone growth protein can increase the risk of infertility in men. Last week two U.S. Senators demanded that the medical device giant turn over documents relating to internal correspondence with paid consultants and researchers who worked on product trials, expanding the investigation into whether physicians on the company’s payroll concealed the infertility risk.

A critical review of Infuse’s complications will be published in the Spine Journal this week.

The National Assembly voted to uphold the curbs in the second reading of the new bioethics law. Conservative legislators and the Roman Catholic Church had protested after an initial Senate vote to authorize this research.

The Senate holds its second reading of the bill in early June. If it votes again to allow embryonic stem cell research, the bill will go to a parliamentary conference committee where the National Assembly version of the bill would take precedence.

France has one of the stricter laws on embryonic stem cell research in Europe, banning it except for research with imported embryos not used for in vitro fertilization in other countries.

Opponents of embryonic stem cell research argue it is morally wrong because it manipulates or destroys human embryos. Supporters see it as a possible avenue toward new treatments for many medical conditions.

Paris Cardinal Andre Vingt-Trois, head of the Catholic Church in France, urged legislators this week not to liberalize the law, saying that would amount to “a regression in civilization” and open the door to “state-sponsored eugenics.”

The New York company added that the death rate associated with the drug, across several studies, “is within the range of rates reported for biologic therapies” for rheumatoid arthritis.

The drug, tofacitinib, is an oral pill that Pfizer hopes can be an alternative to injectible and infused rheumatoid-arthritis drugs, including Abbott Laboratories’ Humira. It is viewed as an especially promising drug in Pfizer’s research pipeline, with analysts predicting annual sales approaching $2 billion if it reaches market.

The company needs successful new drugs to help offset an anticipated big revenue decline when its best-selling drug, cholesterol-lowering Lipitor, loses patent protection in November and becomes exposed to generic competition.

Pfizer shares fell 3% to $19.79 in 4 p.m. composite trading Thursday on the New York Stock Exchange.

A report of the deaths first appeared in a summary of the study, called ORAL Sync, that was posted online by the European League Against Rheumatism, or Eular, ahead its annual scientific conference in London.

The full results are scheduled to be presented at the meeting on May 27. The summary said four patients who received tofacitinib in a one-year, 792-patient trial had died and four contracted opportunistic infections.

Two deaths occurred during the study, one from acute heart failure and one from respiratory failure. Only the respiratory failure death was reported as “study drug-related,” Pfizer said.

After treatment was discontinued at the end of the trial, two other patients died, one from traumatic brain injury and one from rheumatoid arthritis, the study summary said. Pfizer said the brain injury death occurred 22 days after the participant stopped taking the drug while the rheumatoid arthritis patient died 42 days after discontinuing the drug.

Pfizer also said that under the design of the study, 80% of the patients got tofacitinib, while 20% got a placebo, one reason why “the majority of adverse events would be expected to occur in patients on active treatment.”

When the company recently announced preliminary findings of the study, it said tofacitinib was superior to a placebo in improving symptoms of rheumatoid arthritis among patients with active disease who hadn’t responded well to certain other drugs for the condition. The company didn’t mention any deaths and said at the time there weren’t any new safety flags found in the study.

Some analysts have voiced concern about a possible link to risk of heart failure with the drug. J.P. Morgan analyst Chris Schott said in a research note that some other rheumatoid-arthritis treatments on the market also are associated with risk of heart failure.

“While this signal clearly warrants attention, we believe Pfizer’s product would still be approvable even if a modest [heart failure] signal were present,” Mr. Schott said.

Batten disease, also known as neuronal ceroid lipfuscinosis or NCL, is a fatal neurodegenerative disorder in children.

Palo Alto-based StemCells in 2009 completed a Phase I safety trial in six patients with advances stages of Batten and in October 2010 started a Phase Ib trial at Oregon Health & Science University to evaluate the cells in six additional patients in earlier stages of the disease. But no eligible patients were identified or enrolled, the company said, despite “diligent efforts” by investigators.

The company said it would shelve its NCL program for now.

Out of 22 initial prospects, not one met the entry criteria, said Dr. Stephen Huhn, StemCells vice president and head of its NCL program.

“This experience has also highlighted the significant challenges the company would face in completing, within a reasonable period of time, the much larger studies in the target patient population that would ultimately be required for marketing approval,” Huhn said in a press release.