Director of The Hastings Center Poses Ethical ? about Synthentic Biology

Serendipity: A prominent ethicist is also thinking about synthetic biology at this moment.

Thomas Murray: Dir., The Hastings Center

Risk, Reward, Regulation and Synthetic Biology: The Ethical Questions
Environmental clean-up, medications with fewer side effects, improved food supplies-do the theoretical benefits of synthetic biology suggest we forge ahead on the basis of promise?

Or, do we focus on risks, such as unintended contamination or intentional weaponization, and hold back in the face of uncertainty?

And how do we navigate regulation between these different perspectives and mind-sets?

Is there a moral line to draw in the world of synthetic biology: ethically acceptable and unethical?

The Rea[ Promise of Synthetic Biotogy
Scientists are closing in on the abilityto make life from scratch, with potential consequences both good and bad
BY LAWRENCE M. KRAUSS
I have seen the future, and it is now.
Those words came to mind again as I recently
listened to Craig Venter, one of those leading
the new areas of synthetic genomics and synthetic
biology. Every time I hear a talk on this
subject, it seems a new rhreshold in the artificial
manipulation and, ultimately, creation of life l-ras been passed.
Consider just some of the progress associated rvith the J. Craig
Venter Institute. In 2003 its researchers cleated a synthetic version
of the bacteriophage phiX174. ln 2007 they successfully
transformed one species of bacteria to another by genome transplantation.
Most recently, they deveioped methods for the coinplete
synthetic assembly of tl.re genome of the bacterium
My c op I a s m a ge n it a Ii um.
The techniques now developed make the feat of
sequencing the human genome in 2001 seem
prehistoric. Not only have rhe cost and speed - of sequencing evolved faster than those of fcomputer
chips, but the ability to use both '' I -)
chemistry and biology to synthesize new
complex organisms has undergone a revolution
in the past five years. Instructions
embedded in synthetic gene sequences
can now be implanted in foreign cells
and thereby cause those cells to express
proteins; those proteins, in turn, build
nerv functioning copies of the life-forms
whose instruction manual is in the embedded
sequences. Venter calls this cycle "softrvare that creates its own
hardware." I expect to hear news soon of the successful creation
of the first completelv artificial life-form, built from scratch and
not alive until the scientists assembled it.
Semiconductor nanotechnologv has been heralded for more
than a decade, but I believe it ri'iil pale beside the ability of biotechnology
to transform life and society. Imagine the impact of
piggybacking on nature's majesty and designing living systems
that can perform tasks not found in nature, from microbes that
make gasoline or eat carbon dioxide to create nonbiodegradable
plastic building materials to organisms designed to surgically and
strategically operate on cancer cells. I expect that within 50 vears
the world's economy will be driven not by computer-generated information
but by biologically generated softrvare.
Of course, as Spiderman would sa,v, rvith great power comes
great responsibility. Hackers now create software viruses that periodically
disable huge computer networks. \7ith the ability to
make DNA sequences to order has risen the specter of garagebased
DNA hackers who might terrorize the world-intentionally
or accidentally-by re-creating the Ebola virus or the 1918 fl:.
Each of those disease organisms has a genetic code far smaller
than that of the recently s.'nthesized M. genitaliunu. One could
also imagine producing, again perhaps r"rnwittingly, viruses that
are immune to existing vaccines.
Some may fear the existence of new life-forms that might attack
a11 life on earth or at least human life. This fear is probably
misplaced. Life has sr-rrvived for more than three billion years because
it is robust, and almost no mutations can easill'outrvit the
defense mechanisms built up through eons of exposure to
potential pathogens. Venter's argument that new naturally
emerging diseases are a far greater threat than new artifi
cial diseases seems relatively compelling.
Nevertheless, there have been, until fairly recently,
few checks on the unfettered reproduction
of generic information. As the abilitl'to
' synthesize more complex biological systems
has increased, however, the research
community has put in place a voluntary system
of restrictions, for example, on the fulfillment
of commercial orders for genetic sequences
that correspond to portions of potentially
lethal organisms. At present, the
technological know-how associated with developing
synthetic biolcQy laboratories with
malice aforetl.rought is probably beyond the means of even sophisticated
terrorist networks. Moreover, it is important not to let misplaced
t-ears of Armageddon unduly restrict scientific work with
great potential to benefit humankind.
I have alrvays felt that, aside from research that violates universal
human mores, when it comes to technological applications,
that which can be done will be done. What we need to do is rigorouslv
attempt to anticipate what may be possible so that rve can
minimize the risks and maximize rhe benefits. 'We need to walk
into the future, no matter how unnerving, with open eyes if society
is to keep pace with technology. r
Lawrence M. Krauss; a theoretical physicist, commentLttor
and book awtbor, is Foundation Professor and director
of the Origins Initiatiue at Arizon;t State Uniuersity
( h ttp : // kraLt s s.faculty. a su. e du).
-
I
=
Ii
32 scteHrtnc AMERTcAN February 2010

2nd of 2 articles on doctors and drug company payments

Drug firms' payments to doctors raise ethical concerns for many
By Colleen O'Connor
The Denver Post
Posted: 10/31/2010 01:00:00 AM
Following the money from seven pharmaceutical companies to Colorado's medical experts — payments for things such as lectures, consulting, travel, meals and patient-education programs — shows that over the past two years, nearly $4.9 million has been disbursed around the state.
It's gone to doctors at National Jewish Health, the Rocky Mountain Cancer Center and the Heart Center of the Rockies; to a family dermatology practice in Westminster, a nurse practitioner in Fruita; and a bone-research center in Lakewood.
A database compiled by the national investigative news service ProPublica analyzed the financial ties between doctors and the seven drug companies in the U.S. that currently disclose the figures. The seven make up 36 percent of the sales market.
These payments are legal, but controversial, and there is a national effort by state lawmakers, Congress and academic medical institutions to shine light on the financial relationships between doctors and the pharmaceutical industry.
Proponents say that these paid speeches fill an educational gap, especially in rural places where primary-care doctors have a hard time keeping up with the latest treatments.
But critics say that travel, meals and other expenses paid by drug companies add to the cost of medications for everyone. They also say paid lectures amount to bribery by the drug companies, because the doctors talking about how to better recognize a condition may also recommend medications to treat it.
Patients uneasy about pay
Patients also are critical, according to the second annual prescription drug survey released this summer by Consumer Reports.
Fifty-eight percent said they were concerned by drug companies' buying meals for doctors and their staffs, while 72 percent were not happy with payments made by pharmaceutical companies to doctors for testimonials or for serving as a company spokesperson for a given drug.
"These financial relationships present a conflict of interest in which the physicians might be tempted to put their own interests ahead of their patients," said Catherine DeAngelis, editor in chief of the Journal of the American Medical Association, in an e-mail interview with The Denver Post.
In Colorado, two of the top earners of payments from the seven drug firms work for National Jewish Health.
Ronald Balkissoon, a pulmonologist, received more than $220,000 for speaking and consulting, while Joseph Spahn, a pediatric allergist, received more than $155,000.
Education vs. appearances
National Jewish Health has a conflict-of-interest policy that requires doctors each year to report if they received more than $10,000 from any private company in the past year. The department chair and chief compliance officer then decide whether there is a potential conflict of interest, said spokesman William Alstetter.
None was found in either case, he said.
Most of these doctors' talks were given to other doctors, especially in rural outposts, educating them about diseases and the companies' drug treatments, he said.
Alstetter declined to make either Balkissoon or Spahn available for interview.
Although both doctors commonly prescribe medications by GlaxoSmithKline and AstraZeneca, which paid their speaking fees, "we like to believe that education is the dominant part of the talks, understanding better how to manage and diagnose the disease," Alstetter said. "There are diseases that are poorly managed, or not even diagnosed, and this can do a lot in getting doctors to understand and recognize them."
John Tucker Hardy, a child and adolescent psychiatrist based in Pueblo, is another top earner in Colorado, receiving more than $167,000 from the seven companies.
He declined requests to speak about his fees.
The national movement for increased transparency also affected the health care reform bill, which requires that by 2013, all pharmaceutical companies must disclose payments to physicians to the federal government, which will post the information on a website. More than 70 drug companies operate in the U.S.
On the state level, Gov. Bill Ritter this summer signed legislation that will require the Colorado Department of Regulatory Agencies to post this information on its website.
"Right now, this is an area of intense discussion across the board, at institutions and at the government level," said Heather Pierce , senior director of science policy and regulatory counsel at the Association for American Medical Colleges. "There have been a lot of specific incidents that brought this to the forefront."
A central incident was the 2008 congressional investigation into how a renowned child psychiatrist at Harvard failed to disclose to the school that he received $1.6 million in consulting fees over a two-year period from a drug company that made the anti-psychotic that he'd been prescribing.
"The interest is exponentially more now than it was five years ago, which was exponentially more than it was five years before that," said Richard Krugman, who has served as dean of the University of Colorado School of Medicine for 20 years.
"Overall, there's a lot more public scrutiny of physicians and public employees in a world where money is now tight, and people want to know what their money is being spent on," he said, especially in "the health care industry, which is 16 percent of the gross domestic product — trillions of dollars."
It's a delicate balance, especially for medical schools.
Walking a fine line of trust
Pharmaceutical companies frequently collaborate with physician investigators and scientists at these institutions to create medical breakthroughs and perform clinical trials to determine the safety of promising new therapies.
"To maintain the public trust, it is imperative that these relationships not be or appear to be influenced by factors other than the pursuit of knowledge or the best interests of the patient," according to the disclosure policy of the Feinberg School of Medicine at Northwestern University, which requires its faculty to report all externally compensated professional activities, no matter how small the amount. The disclosures are then posted on the school's public website.
Institutions such as the Stanford University School of Medicine and Harvard Medical School have banned their doctors from participating as paid consultants and lecturers in the drug companies' speakers' bureau.
CU med school guidelines
In Colorado, physicians at the CU School of Medicine are allowed to participate in speakers' bureaus, but industry representatives are not allowed to select speakers or topics and cannot preapprove the content of educational programs.
Physicians are not allowed to accept meals or other hospitality from drug companies.
"We have a lot of national and international experts in their fields, and pharmaceutical companies are one of many different groups that may be interested in their opinion," Krugman said. "There's nothing inherently wrong with having a contract with a company. It depends on what the work is for and whether it fits into place with our policies."
As with most medical schools in the country, the main watchdog of enforcement is a physician's integrity.
"The guidelines and professional behavior assumes that you will act professionally, and it's on the honor system," Krugman said. "Generally speaking, that works. There are times when information comes to us that suggests there may be a problem, and then we look into it."
Colleen O'Connor: 303-954-1083 or coconnor@denverpost.com


Read more: Drug firms' payments to doctors raise ethical concerns for many - The Denver Post http://www.denverpost.com/news/ci_16480972#ixzz14KHw0ik6

Is there an ethical problem with doctors receiving $ from drug companies? first of two articles

Genentech Offers Secret Rebates for Eye Drug

Genentech has begun offering secret rebates to eye doctors as an apparent inducement to get them to use more of the company’s expensive drug Lucentis rather than a less costly alternative.
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Madalyn Ruggiero for The New York Times
Dr. Greg Rosenthal, a retina specialist, said the rebates on Lucentis amounted to bribery.
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Madalyn Ruggiero for The New York Times
Barbara Glassner gets an injection of Avastin, another drug made by Genentech.
Under the program, which started on Oct. 1, medical practices can earn up to tens of thousands of dollars in rebates each quarter if they use a lot of Lucentis and if their usage increases from the previous quarter, according to a confidential document outlining the program that was obtained by The New York Times.
Lucentis, approved in 2006, is mainly used to treat age-related macular degeneration, the leading cause of blindness in the elderly. It costs about $2,000 for each injection, with an injection into the eye needed as often as once a month.
The competition comes from Avastin, another Genentech drug that has the same mode of action. While Avastin is approved only to treat cancer, many retina specialists say it works just as well in the eye as Lucentis. So they are using it off-label because each injection costs only $20 to $50.
Using Avastin instead of Lucentis saves Medicare — and costs Genentech — hundreds of millions of dollars a year.
The rebates are considered a form of volume discount, and have been offered for some other drugs. They are legal if they adhere to certain guidelines.
Still, some doctors said they had ethical concerns about the arrangement.
“There’s no way to look at that without calling it bribery,” said Dr. Greg Rosenthal, a retina specialist in Toledo, Ohio, who has been critical of attempts by Genentech to get doctors to use Lucentis. He is not a participant in the rebate program.
Genentech, which is owned by the Swiss company Roche, said in a statement, “Rebate and discount programs are a common business practice across the industry, including in the field of ophthalmology.” The company said it had such programs for other drugs and that they “help reduce the cost of our medicines for hospitals, pharmacies and doctors.”
Senator Herb Kohl, chairman of the Special Committee on Aging, who has investigated efforts to curtail the use of Avastin in the past, criticized the Lucentis incentives.
“This rebate program appears to be an attempt to reverse the trend of significantly reduced reimbursements that Genentech has been receiving from Medicare for Lucentis,” Mr. Kohl, a Democrat from Wisconsin, said in a statement. “I am highly doubtful that Medicare will benefit in any way from the rebates being offered to doctors.”
Since both Lucentis and Avastin are administered in the doctor’s office, doctors buy the drugs and are then reimbursed by Medicare or private insurers.
Medicare reimburses at 6 percent above the average selling price of a drug, so that doctors can profit from use of a drug. For Lucentis, that 6 percent would translate to roughly $120 a dose. That potential profit increases if the doctors get a bigger discount when they purchase the drug, or a rebate later. Rebates are counted by Medicare in calculating the average selling price of a drug, so the new Lucentis rebates might help slightly lower the amount Medicare pays per injection in future quarters.
The issue of doctors profiting from drugs is fairly new to ophthalmology. Cancer doctors, however, have long made money on the chemotherapy drugs they administer in their offices, though such profits have been sharply reduced in recent years because they were perceived to be giving doctors an incentive to overtreat.
In 2008, Amgen stopped offering rebates to oncologists using its anemia drug Aranesp. Critics, including Senator Charles E. Grassley, Republican of Iowa, said the rebates might have been increasing usage even as studies were showing that high doses of the drug might be harmful.
Genentech suggested that it started the Lucentis rebate program now to spur doctors to try the drug to treat retinal vein occlusion. Lucentis was recently approved to treat that condition.
Some doctors said they thought the company might be worried about the results, expected next spring, of a clinical trial comparing Avastin and Lucentis in treating macular degeneration. If the drugs are proven equivalent, the rebates might help slow the defection to the cheaper alternative.
The rebates might also encourage doctors to give Lucentis off-label for other eye diseases or give more frequent injections.
Many doctors inject the drug less frequently than once every four weeks, the interval specified in the drug’s label.
Several retina specialists who were contacted did not know about the rebate program because it is being offered only to practices that use a certain amount of Lucentis. And doctors who have signed up for the rebates are not allowed to acknowledge even the existence of the program, let alone to talk about the specific terms.
“The existence of this agreement is confidential,” says the contract that medical practices are asked to sign.
(Page 2 of 2)
One retina specialist who is not in the program but heard about it from a colleague said that his Genentech sales representative declined to talk about it, instead handing him a slip of paper containing a number to call at Genentech.
This doctor, who spoke on condition of anonymity because he did not want to offend the company, said he was told when he called the number that the rebates were being offered only to the top 300 Lucentis-using practices. But he said that might still represent most use of Lucentis.
The program offers rebates based both on volume and on increases in use. For the volume part, the rebates range from 0.25 percent to 1.5 percent of the wholesale cost. One example provided in the document was that a practice using 600 vials a quarter would get a rebate of $8,775.
The rebate based on increased usage ranges from 1 percent to 1.5 percent. Growth in usage of only 0.01 percent qualifies for the 1 percent rebate, while growth of 10 percent or more qualifies for the top rebate. The example provided in the document was of a rebate of $9,652.50.
A practice meeting the minimum requirements for the largest rebates in both categories would receive more than $58,000 in the quarter, according to a calculation done by The New York Times.
Dr. David W. Parke II, chief executive of the American Academy of Ophthalmology, said the society was looking into the new program. “The issue is really does this constitute a financial inducement that in some way alters delivery of care in a way that is not in the patient’s best interest?” he said.
Dr. Parke said that Genentech obviously believed the rebates would sway physician practice. But he said he doubted a rebate of $20 or $30 an injection would be that influential.
“The dollars involved for the average practice are not likely to massively change a physician’s prescribing practices,” he said. Dr. Susan Malinowksi, a retina specialist in Southfield, Mich., disagreed, saying that with doctors’ income already facing cuts because of health care reform, the rebates would be welcome. Just on Wednesday, Medicare proposed cutting the separate fee, apart from the drug cost, that it pays doctors for giving injections into the eye. “$18,000 a quarter, $19,000, why would that not incentivize you?” said Dr. Malinowski, who was not offered the rebates.
The clinical trial that will directly compare Avastin and Lucentis is being sponsored by the National Eye Institute and will be closely watched.
“If Avastin is as good as or better than Lucentis, it’s obviously going to win,” said Dr. Lawrence J. Singerman, a retina specialist in Cleveland. He said the trial results would have more influence on doctors than the rebate.
Practices seem split now, with some using mostly Lucentis and others mostly Avastin, and some using Lucentis for well-insured patients and Avastin for others.
In 2008, Medicare paid for about 480,000 injections of Avastin to treat macular degeneration, compared with only 337,000 injections of Lucentis, according to Dr. Philip J. Rosenfeld of the University of Miami, who studied the records with Medicare officials. Yet the fewer Lucentis injections cost Medicare $537 million while the Avastin injections cost only $20 million.
Sales of Lucentis in the United States rose 29 percent in the first nine months of this year, to 1.08 billion Swiss francs, or about $1.1 billion, according to Roche’s financial report.
http://www.nytimes.com/2010/11/04/business/04eye.html?pagewanted=1&_r=3&hp

what is the ethical dilemma here? what principles are in conflict?

Losing Touch With the Patient
By PAULINE W. CHEN, M.D.
Published: October 21, 2010

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Several years ago I helped care for a man who had been hospitalized with a severe infection of the abdominal wall. When his primary doctors discovered that the bacteria responsible was resistant to most antibiotics, they quickly isolated him, moving him into a single room with a sign on the door proclaiming “Contact Precautions” and directing visitors to put on gloves, mask and gown before entering.
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But garbing up in all those items was not a straightforward exercise. The gowns, vast swaths of baby-yellow polyester, added an insulating and sweat-inducing layer. The masks were either so flimsy they fell off easily or so unyielding they muffled voices and steamed up eyeglasses. And the gloves had such generous finger pockets that the excess latex inevitably got tangled in the loops and ties of the gowns and masks or in the dressing materials and bedding of the patient.

None of these precautions made it easy to examine or even visit him. Most of us were loath to go through the process of gearing up more than we had to; and even his wife of more than 20 years occasionally groaned as she dutifully swathed herself in the protective coverings each day. As the weeks wore on, we clinicians found ourselves minimizing our interactions, designating one team member to suit up and complete the work needed or shouting out updates and questions to the patient from the sterile safety of the doorway.

Increasingly isolated in these ways, he began to withdraw from everyone except his wife. His once daily declarations that he was going to “beat this infection” became less vocal, dimming to whispers, then disappearing altogether. He stopped turning to face us when we called out to him, choosing instead to continue staring blankly at the ceiling.

As his lungs, heart and then kidneys began to fail, his room became crammed with life-support machines and metal poles and pumps metering out intravenous medications. The small space in which he was confined eventually became a space-age pastiche of beeping machines, plastic tubes and wires, and shrouded, faceless, hovering yellow figures.

When he finally died, from cardiac arrest, more than two months later, it was hard not to remember the weeks leading up to his death and to wonder about one thing. In trying so hard to contain the infection, had we lost sight of the person?

For nearly half a century, infectious disease experts and hospital epidemiologists have relied on various methods of contact precautions to contain increasingly widespread and often virulent multi-drug-resistant bacteria. These methods of infection control — hand washing, alcohol foams, physical isolation, gowns, gloves and sometimes masks and eye protection — are now a routine part of clinical life in hospitals across the country; up to a quarter of all hospitalized patients at any time are placed under such restrictions. But while contact precautions are generally not just accepted but expected by doctors and patients alike, what has not been acknowledged until more recently are the unintended consequences of such strict limitations.

In the current issue of The Annals of Family Medicine, Dr. Leif Hass, a family practice physician working as a hospitalist at the Alta Bates Summit Medical Center in Oakland, Calif., eloquently describes some of these repercussions. After he and his daughter recuperate from mysterious arm and leg infections caused by the drug-resistant MRSA bacteria, Dr. Hass suddenly finds himself reaching for gloves every time he sees a patient in the hospital. He is torn between his sense of duty to reach out, gloveless, to “the people most in need of touch” and a gripping and not entirely irrational fear that “hospital wards that had been so familiar now seemed like uncontrollable pools of pathogens.”

Such fear of contagion among physicians, studies have shown, can compromise the quality of care delivered. When compared with patients not in isolation, those individuals on contact precautions have fewer interactions with clinicians, more delays in care, decreased satisfaction and greater incidences of depression and anxiety. These differences translate into more noninfectious complications like falls and pressure ulcers and an increase of as much at 100 percent in the overall incidence of adverse events.

“There is a misperception that infections are the single worst adverse event that can happen in a hospital,” said Dr. Daniel J. Morgan, lead author of a recent review of these studies and an assistant professor of epidemiology and public health at the University of Maryland in Baltimore. “In getting overly focused on preventing one type of infection, we fail to see the overall picture for patients.”

What may help clinicians remain focused on the larger picture while still safeguarding patients and themselves from multi-drug-resistant bacteria are less restrictive but equally efficacious precautions. In two separate studies, researchers at the Medical College of Virginia in Richmond found that the rate of infection was identical whether health care workers wore gowns and gloves with only the patients in isolation or whether they wore only gloves with all patients.

“Wearing gloves when examining all patients may become the reality of clinical medicine,” said Dr. Gonzalo Bearman, lead author of both studies and the associate hospital epidemiologist at the Virginia Commonwealth University Medical Center in Richmond.

All of this research points to one eventuality: that some type of contact barrier is in our future as doctors and patients, even though, as Dr. Hass noted when I spoke to him this week, “there are times when an I.C.U. looks like an assembly plant in Silicon Valley.” And while physicians will be forced to rely less on touch and more on other communication skills like listening and acknowledging, the risk remains that the presence of these physical — and technological — barriers will further eclipse some of the most effective ways in which doctors can alleviate the suffering of their patients.

“We just have to make sure,” Dr. Hass said, “that in the age of technology and rapid reforms, some of our best tools for healing — simple things like touching people and telling them you care and making them feel you are there for them — don’t get lost.”

Health Care Reform Spending Rules: Are they Fair? Why? or Why not?

Acne Cream? Tax-Sheltered. Breast Pump? No.
By DAVID KOCIENIEWSKI
Published: October 26, 2010 NYTIMES



Denture wearers will get a tax break on the cost of adhesives to keep their false teeth in place. So will acne sufferers who buy pimple creams.
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A breast pump and various accessories can run about $500 to $1,000 for most mothers a year.

People whose children have severe allergies might even be allowed the break for replacing grass with artificial turf since it could be considered a medical expense.

But nursing mothers will not be allowed to use their tax-sheltered health care accounts to pay for breast pumps and other supplies.

That is because the Internal Revenue Service has ruled that breast-feeding does not have enough health benefits to quality as a form of medical care.

With all the changes the health care overhaul will bring in the coming years, it nonetheless will leave those regulations intact when new rules for flexible spending accounts go into effect in January. Those allow millions of Americans to set aside part of their pretax earnings to pay for unreimbursed medical expenses.

While breast-feeding supplies weren’t allowed under the old regulations either, one major goal of the health care overhaul was to control medical costs by encouraging preventive procedures like immunizations and screenings.

Despite a growing body of research indicating that the antibodies passed from mother to child in breast milk could reduce disease among infants — including one recent study that found it could prevent the premature death of 900 babies a year — the I.R.S. has denied a request from the American Academy of Pediatrics to reclassify breast-feeding costs as a medical care expense.

In some respects, the biggest roadblock for mothers’ groups and advocates of breast-feeding is one of their central arguments: nursing a child is beneficial because it is natural.

I.R.S. officials say they consider breast milk a food that can promote good health, the same way that eating citrus fruit can prevent scurvy. But because the I.R.S. code considers nutrition a necessity rather than a medical condition, the agency’s analysts view the cost of breast pumps, bottles and pads as no more deserving of a tax break than an orange juicer.

Many mothers’ groups and medical experts say that breast milk provides nutrition and natural supplements that prevent disease, and would like to see its use expanded. Hospital accreditation groups have been prodding maternity wards to encourage parents to feed only breast milk until a child is 6 months old.

The new health law does include one breakthrough for nursing mothers, a mandate that they be permitted unpaid breaks to use breast pumps. Spurned by tax authorities, breast-feeding advocates say they will return to Congress to get a tax break, too.

“There’s been a lot of progress in the past few years making the public, the medical establishment and even Congress recognize the health benefits of breast-feeding,” said Melissa Bonghi, a lactation consultant in Bainbridge Island, Wash. “But I guess the I.R.S. will just take a little longer.”

With the new regulations set to take effect in two months, millions of American workers now in the open enrollment period at their employers have to determine whether, and how much, to set aside for 2011. More than 20 million people have flexible spending or other tax-exempt health care savings accounts, and the programs are projected to cost the federal Treasury about $3.8 billion this year and $68 billion over the next decade.

The most far-reaching change involves over-the-counter medicines. Since 2003, most of them have been eligible expenses, making flexible spending accounts so popular that some plans issued debit cards that allowed users to make purchases without having to file for reimbursement later.

As of Jan. 1, however, over-the-counter medications — including allergy remedies, cough suppressants or even pain relievers like aspirin or ibuprofen — will be eligible only if they are prescribed by a doctor. That change is so drastic that the National Association of Chain Drug Stores, which represents 37,000 pharmacies, last week asked the I.R.S. for a two-year delay in that regulation, to allow merchants to recalibrate the computer systems that determine which products are eligible for purchase with flexible spending account debit cards.

Many factors, including the length of maternity leave, affect how long a woman breast-feeds.

According to a survey by the Centers for Disease Control and Prevention, about 75 percent of the 4.3 million mothers who gave birth in 2007 started breast-feeding. By the time the baby was 6 months old, the portion dropped to 43 percent, and on the child’s first birthday, to 22 percent.

A study released this year by Harvard Medical School concluded that if 90 percent of mothers followed the standard medical advice of feeding infants only breast milk for their first six months, the United States could save $13 billion a year in health care costs and prevent the premature deaths of 900 infants each year from respiratory illness and other infections.

“The old adage that breast-feeding is a child’s first immunization really is true,” said Dr. Robert W. Block, president-elect of the American Academy of Pediatrics. “So we need to do everything we can to remove the barriers that make it difficult.”

To continue breast-feeding once they return to work, many mothers need to use pumps to extract milk, which can be chilled and bottle-fed to the child later. The cost of buying or renting a breast pump and the various accessories needed to store milk runs about $500 to $1,000 for most mothers over the course of a year, according to the United States Breastfeeding Committee, a nonprofit advocacy group. Lactation consultants, who can cost several hundred dollars, also would not be an eligible expense.

Roy Ramthun, a former Treasury Department official, said that tax officials’ reluctance to classify those costs as medical expenses stemmed from a fear that the program might be abused.

“They get very uneasy about anything that smacks of food because they fear it will open up all sorts of exceptions,” said Mr. Ramthun, who runs a consulting company that specializes in health savings accounts. “It’s a matter of cost and of protecting the integrity of the tax code.”

Bills introduced last year by Representative Carolyn B. Maloney, Democrat of New York, and Senator Jeff Merkley, Democrat of Oregon, would have allowed nursing mothers to claim the tax break. But breast-feeding advocates say that effort, like many before, was undone by economic and cultural factors.

“Everyone says they support breast-feeding, but getting businesses and Congress to act on it has been surprisingly difficult,” said Barbara Emanuel, executive director of the breast-feeding advocacy group La Leche League International. “We get resistance from the formula companies and cultural resistance, so it can be hard to get nursing mothers the support that everyone agrees they deserve.”

Unless the law changes, some mothers may ask their pediatricians for a note that breast-feeding is medically necessary. Jody L. Dietel, who works for a company that processes claims from flexible spending accounts, says that many patients who receive orthodontic procedures have used such a tactic.

“Orthodontia is really so you have nice, straight teeth,” said Ms. Dietel, chief compliance officer for WageWorks. “But the doctors write notes warning that the patient’s jaw might be damaged without treatment or their overbite could cause health problems, and it becomes an eligible expense. For breast-feeding there are two components, too: nutritional and preventative medicine.”

If Medical Research is Flawed, Are Too Our Ethical Decision Making Processes?

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Lies, Damned Lies, and Medical Science by David Freeman.

Much of what medical researchers conclude in their studies is misleading, exaggerated, or flat-out wrong. So why are doctors—to a striking extent—still drawing upon misinformation in their everyday practice? Dr. John Ioannidis has spent his career challenging his peers by exposing their bad science.
By David H. Freedman

IMAGE CREDIT: ROBYN TWOMEY/REDUX
IN 2001, RUMORS were circulating in Greek hospitals that surgery residents, eager to rack up scalpel time, were falsely diagnosing hapless Albanian immigrants with appendicitis. At the University of Ioannina medical school’s teaching hospital, a newly minted doctor named Athina Tatsioni was discussing the rumors with colleagues when a professor who had overheard asked her if she’d like to try to prove whether they were true—he seemed to be almost daring her. She accepted the challenge and, with the professor’s and other colleagues’ help, eventually produced a formal study showing that, for whatever reason, the appendices removed from patients with Albanian names in six Greek hospitals were more than three times as likely to be perfectly healthy as those removed from patients with Greek names. “It was hard to find a journal willing to publish it, but we did,” recalls Tatsioni. “I also discovered that I really liked research.” Good thing, because the study had actually been a sort of audition. The professor, it turned out, had been putting together a team of exceptionally brash and curious young clinicians and Ph.D.s to join him in tackling an unusual and controversial agenda.
Last spring, I sat in on one of the team’s weekly meetings on the medical school’s campus, which is plunked crazily across a series of sharp hills. The building in which we met, like most at the school, had the look of a barracks and was festooned with political graffiti. But the group convened in a spacious conference room that would have been at home at a Silicon Valley start-up. Sprawled around a large table were Tatsioni and eight other youngish Greek researchers and physicians who, in contrast to the pasty younger staff frequently seen in U.S. hospitals, looked like the casually glamorous cast of a television medical drama. The professor, a dapper and soft-spoken man named John Ioannidis, loosely presided.
One of the researchers, a biostatistician named Georgia Salanti, fired up a laptop and projector and started to take the group through a study she and a few colleagues were completing that asked this question: were drug companies manipulating published research to make their drugs look good? Salanti ticked off data that seemed to indicate they were, but the other team members almost immediately started interrupting. One noted that Salanti’s study didn’t address the fact that drug-company research wasn’t measuring critically important “hard” outcomes for patients, such as survival versus death, and instead tended to measure “softer” outcomes, such as self-reported symptoms (“my chest doesn’t hurt as much today”). Another pointed out that Salanti’s study ignored the fact that when drug-company data seemed to show patients’ health improving, the data often failed to show that the drug was responsible, or that the improvement was more than marginal.
Salanti remained poised, as if the grilling were par for the course, and gamely acknowledged that the suggestions were all good—but a single study can’t prove everything, she said. Just as I was getting the sense that the data in drug studies were endlessly malleable, Ioannidis, who had mostly been listening, delivered what felt like a coup de grâce: wasn’t it possible, he asked, that drug companies were carefully selecting the topics of their studies—for example, comparing their new drugs against those already known to be inferior to others on the market—so that they were ahead of the game even before the data juggling began? “Maybe sometimes it’s the questions that are biased, not the answers,” he said, flashing a friendly smile. Everyone nodded. Though the results of drug studies often make newspaper headlines, you have to wonder whether they prove anything at all. Indeed, given the breadth of the potential problems raised at the meeting, can any medical-research studies be trusted?
That question has been central to Ioannidis’s career. He’s what’s known as a meta-researcher, and he’s become one of the world’s foremost experts on the credibility of medical research. He and his team have shown, again and again, and in many different ways, that much of what biomedical researchers conclude in published studies—conclusions that doctors keep in mind when they prescribe antibiotics or blood-pressure medication, or when they advise us to consume more fiber or less meat, or when they recommend surgery for heart disease or back pain—is misleading, exaggerated, and often flat-out wrong. He charges that as much as 90 percent of the published medical information that doctors rely on is flawed. His work has been widely accepted by the medical community; it has been published in the field’s top journals, where it is heavily cited; and he is a big draw at conferences. Given this exposure, and the fact that his work broadly targets everyone else’s work in medicine, as well as everything that physicians do and all the health advice we get, Ioannidis may be one of the most influential scientists alive. Yet for all his influence, he worries that the field of medical research is so pervasively flawed, and so riddled with conflicts of interest, that it might be chronically resistant to change—or even to publicly admitting that there’s a problem.
THE CITY OF IOANNINA is a big college town a short drive from the ruins of a 20,000-seat amphitheater and a Zeusian sanctuary built at the site of the Dodona oracle. The oracle was said to have issued pronouncements to priests through the rustling of a sacred oak tree. Today, a different oak tree at the site provides visitors with a chance to try their own hands at extracting a prophecy. “I take all the researchers who visit me here, and almost every single one of them asks the tree the same question,” Ioannidis tells me, as we contemplate the tree the day after the team’s meeting. “‘Will my research grant be approved?’” He chuckles, but Ioannidis (pronounced yo-NEE-dees) tends to laugh not so much in mirth as to soften the sting of his attack. And sure enough, he goes on to suggest that an obsession with winning funding has gone a long way toward weakening the reliability of medical research.
He first stumbled on the sorts of problems plaguing the field, he explains, as a young physician-researcher in the early 1990s at Harvard. At the time, he was interested in diagnosing rare diseases, for which a lack of case data can leave doctors with little to go on other than intuition and rules of thumb. But he noticed that doctors seemed to proceed in much the same manner even when it came to cancer, heart disease, and other common ailments. Where were the hard data that would back up their treatment decisions? There was plenty of published research, but much of it was remarkably unscientific, based largely on observations of a small number of cases. A new “evidence-based medicine” movement was just starting to gather force, and Ioannidis decided to throw himself into it, working first with prominent researchers at Tufts University and then taking positions at Johns Hopkins University and the National Institutes of Health. He was unusually well armed: he had been a math prodigy of near-celebrity status in high school in Greece, and had followed his parents, who were both physician-researchers, into medicine. Now he’d have a chance to combine math and medicine by applying rigorous statistical analysis to what seemed a surprisingly sloppy field. “I assumed that everything we physicians did was basically right, but now I was going to help verify it,” he says. “All we’d have to do was systematically review the evidence, trust what it told us, and then everything would be perfect.”
It didn’t turn out that way. In poring over medical journals, he was struck by how many findings of all types were refuted by later findings. Of course, medical-science “never minds” are hardly secret. And they sometimes make headlines, as when in recent years large studies or growing consensuses of researchers concluded that mammograms, colonoscopies, and PSA tests are far less useful cancer-detection tools than we had been told; or when widely prescribed antidepressants such as Prozac, Zoloft, and Paxil were revealed to be no more effective than a placebo for most cases of depression; or when we learned that staying out of the sun entirely can actually increase cancer risks; or when we were told that the advice to drink lots of water during intense exercise was potentially fatal; or when, last April, we were informed that taking fish oil, exercising, and doing puzzles doesn’t really help fend off Alzheimer’s disease, as long claimed. Peer-reviewed studies have come to opposite conclusions on whether using cell phones can cause brain cancer, whether sleeping more than eight hours a night is healthful or dangerous, whether taking aspirin every day is more likely to save your life or cut it short, and whether routine angioplasty works better than pills to unclog heart arteries.
But beyond the headlines, Ioannidis was shocked at the range and reach of the reversals he was seeing in everyday medical research. “Randomized controlled trials,” which compare how one group responds to a treatment against how an identical group fares without the treatment, had long been considered nearly unshakable evidence, but they, too, ended up being wrong some of the time. “I realized even our gold-standard research had a lot of problems,” he says. Baffled, he started looking for the specific ways in which studies were going wrong. And before long he discovered that the range of errors being committed was astonishing: from what questions researchers posed, to how they set up the studies, to which patients they recruited for the studies, to which measurements they took, to how they analyzed the data, to how they presented their results, to how particular studies came to be published in medical journals.
This array suggested a bigger, underlying dysfunction, and Ioannidis thought he knew what it was. “The studies were biased,” he says. “Sometimes they were overtly biased. Sometimes it was difficult to see the bias, but it was there.” Researchers headed into their studies wanting certain results—and, lo and behold, they were getting them. We think of the scientific process as being objective, rigorous, and even ruthless in separating out what is true from what we merely wish to be true, but in fact it’s easy to manipulate results, even unintentionally or unconsciously. “At every step in the process, there is room to distort results, a way to make a stronger claim or to select what is going to be concluded,” says Ioannidis. “There is an intellectual conflict of interest that pressures researchers to find whatever it is that is most likely to get them funded.”
Perhaps only a minority of researchers were succumbing to this bias, but their distorted findings were having an outsize effect on published research. To get funding and tenured positions, and often merely to stay afloat, researchers have to get their work published in well-regarded journals, where rejection rates can climb above 90 percent. Not surprisingly, the studies that tend to make the grade are those with eye-catching findings. But while coming up with eye-catching theories is relatively easy, getting reality to bear them out is another matter. The great majority collapse under the weight of contradictory data when studied rigorously. Imagine, though, that five different research teams test an interesting theory that’s making the rounds, and four of the groups correctly prove the idea false, while the one less cautious group incorrectly “proves” it true through some combination of error, fluke, and clever selection of data. Guess whose findings your doctor ends up reading about in the journal, and you end up hearing about on the evening news? Researchers can sometimes win attention by refuting a prominent finding, which can help to at least raise doubts about results, but in general it is far more rewarding to add a new insight or exciting-sounding twist to existing research than to retest its basic premises—after all, simply re-proving someone else’s results is unlikely to get you published, and attempting to undermine the work of respected colleagues can have ugly professional repercussions.
In the late 1990s, Ioannidis set up a base at the University of Ioannina. He pulled together his team, which remains largely intact today, and started chipping away at the problem in a series of papers that pointed out specific ways certain studies were getting misleading results. Other meta-researchers were also starting to spotlight disturbingly high rates of error in the medical literature. But Ioannidis wanted to get the big picture across, and to do so with solid data, clear reasoning, and good statistical analysis. The project dragged on, until finally he retreated to the tiny island of Sikinos in the Aegean Sea, where he drew inspiration from the relatively primitive surroundings and the intellectual traditions they recalled. “A pervasive theme of ancient Greek literature is that you need to pursue the truth, no matter what the truth might be,” he says. In 2005, he unleashed two papers that challenged the foundations of medical research.
He chose to publish one paper, fittingly, in the online journal PLoS Medicine, which is committed to running any methodologically sound article without regard to how “interesting” the results may be. In the paper, Ioannidis laid out a detailed mathematical proof that, assuming modest levels of researcher bias, typically imperfect research techniques, and the well-known tendency to focus on exciting rather than highly plausible theories, researchers will come up with wrong findings most of the time. Simply put, if you’re attracted to ideas that have a good chance of being wrong, and if you’re motivated to prove them right, and if you have a little wiggle room in how you assemble the evidence, you’ll probably succeed in proving wrong theories right. His model predicted, in different fields of medical research, rates of wrongness roughly corresponding to the observed rates at which findings were later convincingly refuted: 80 percent of non-randomized studies (by far the most common type) turn out to be wrong, as do 25 percent of supposedly gold-standard randomized trials, and as much as 10 percent of the platinum-standard large randomized trials. The article spelled out his belief that researchers were frequently manipulating data analyses, chasing career-advancing findings rather than good science, and even using the peer-review process—in which journals ask researchers to help decide which studies to publish—to suppress opposing views. “You can question some of the details of John’s calculations, but it’s hard to argue that the essential ideas aren’t absolutely correct,” says Doug Altman, an Oxford University researcher who directs the Centre for Statistics in Medicine.
Still, Ioannidis anticipated that the community might shrug off his findings: sure, a lot of dubious research makes it into journals, but we researchers and physicians know to ignore it and focus on the good stuff, so what’s the big deal? The other paper headed off that claim. He zoomed in on 49 of the most highly regarded research findings in medicine over the previous 13 years, as judged by the science community’s two standard measures: the papers had appeared in the journals most widely cited in research articles, and the 49 articles themselves were the most widely cited articles in these journals. These were articles that helped lead to the widespread popularity of treatments such as the use of hormone-replacement therapy for menopausal women, vitamin E to reduce the risk of heart disease, coronary stents to ward off heart attacks, and daily low-dose aspirin to control blood pressure and prevent heart attacks and strokes. Ioannidis was putting his contentions to the test not against run-of-the-mill research, or even merely well-accepted research, but against the absolute tip of the research pyramid. Of the 49 articles, 45 claimed to have uncovered effective interventions. Thirty-four of these claims had been retested, and 14 of these, or 41 percent, had been convincingly shown to be wrong or significantly exaggerated. If between a third and a half of the most acclaimed research in medicine was proving untrustworthy, the scope and impact of the problem were undeniable. That article was published in the Journal of the American Medical Association.
DRIVING ME BACK to campus in his smallish SUV—after insisting, as he apparently does with all his visitors, on showing me a nearby lake and the six monasteries situated on an islet within it—Ioannidis apologized profusely for running a yellow light, explaining with a laugh that he didn’t trust the truck behind him to stop. Considering his willingness, even eagerness, to slap the face of the medical-research community, Ioannidis comes off as thoughtful, upbeat, and deeply civil. He’s a careful listener, and his frequent grin and semi-apologetic chuckle can make the sharp prodding of his arguments seem almost good-natured. He is as quick, if not quicker, to question his own motives and competence as anyone else’s. A neat and compact 45-year-old with a trim mustache, he presents as a sort of dashing nerd—Giancarlo Giannini with a bit of Mr. Bean.
The humility and graciousness seem to serve him well in getting across a message that is not easy to digest or, for that matter, believe: that even highly regarded researchers at prestigious institutions sometimes churn out attention-grabbing findings rather than findings likely to be right. But Ioannidis points out that obviously questionable findings cram the pages of top medical journals, not to mention the morning headlines. Consider, he says, the endless stream of results from nutritional studies in which researchers follow thousands of people for some number of years, tracking what they eat and what supplements they take, and how their health changes over the course of the study. “Then the researchers start asking, ‘What did vitamin E do? What did vitamin C or D or A do? What changed with calorie intake, or protein or fat intake? What happened to cholesterol levels? Who got what type of cancer?’” he says. “They run everything through the mill, one at a time, and they start finding associations, and eventually conclude that vitamin X lowers the risk of cancer Y, or this food helps with the risk of that disease.” In a single week this fall, Google’s news page offered these headlines: “More Omega-3 Fats Didn’t Aid Heart Patients”; “Fruits, Vegetables Cut Cancer Risk for Smokers”; “Soy May Ease Sleep Problems in Older Women”; and dozens of similar stories.
By David H. Freedman
When a five-year study of 10,000 people finds that those who take more vitamin X are less likely to get cancer Y, you’d think you have pretty good reason to take more vitamin X, and physicians routinely pass these recommendations on to patients. But these studies often sharply conflict with one another. Studies have gone back and forth on the cancer-preventing powers of vitamins A, D, and E; on the heart-health benefits of eating fat and carbs; and even on the question of whether being overweight is more likely to extend or shorten your life. How should we choose among these dueling, high-profile nutritional findings? Ioannidis suggests a simple approach: ignore them all.
For starters, he explains, the odds are that in any large database of many nutritional and health factors, there will be a few apparent connections that are in fact merely flukes, not real health effects—it’s a bit like combing through long, random strings of letters and claiming there’s an important message in any words that happen to turn up. But even if a study managed to highlight a genuine health connection to some nutrient, you’re unlikely to benefit much from taking more of it, because we consume thousands of nutrients that act together as a sort of network, and changing intake of just one of them is bound to cause ripples throughout the network that are far too complex for these studies to detect, and that may be as likely to harm you as help you. Even if changing that one factor does bring on the claimed improvement, there’s still a good chance that it won’t do you much good in the long run, because these studies rarely go on long enough to track the decades-long course of disease and ultimately death. Instead, they track easily measurable health “markers” such as cholesterol levels, blood pressure, and blood-sugar levels, and meta-experts have shown that changes in these markers often don’t correlate as well with long-term health as we have been led to believe.
On the relatively rare occasions when a study does go on long enough to track mortality, the findings frequently upend those of the shorter studies. (For example, though the vast majority of studies of overweight individuals link excess weight to ill health, the longest of them haven’t convincingly shown that overweight people are likely to die sooner, and a few of them have seemingly demonstrated that moderately overweight people are likely to live longer.) And these problems are aside from ubiquitous measurement errors (for example, people habitually misreport their diets in studies), routine misanalysis (researchers rely on complex software capable of juggling results in ways they don’t always understand), and the less common, but serious, problem of outright fraud (which has been revealed, in confidential surveys, to be much more widespread than scientists like to acknowledge).
If a study somehow avoids every one of these problems and finds a real connection to long-term changes in health, you’re still not guaranteed to benefit, because studies report average results that typically represent a vast range of individual outcomes. Should you be among the lucky minority that stands to benefit, don’t expect a noticeable improvement in your health, because studies usually detect only modest effects that merely tend to whittle your chances of succumbing to a particular disease from small to somewhat smaller. “The odds that anything useful will survive from any of these studies are poor,” says Ioannidis—dismissing in a breath a good chunk of the research into which we sink about $100 billion a year in the United States alone.
And so it goes for all medical studies, he says. Indeed, nutritional studies aren’t the worst. Drug studies have the added corruptive force of financial conflict of interest. The exciting links between genes and various diseases and traits that are relentlessly hyped in the press for heralding miraculous around-the-corner treatments for everything from colon cancer to schizophrenia have in the past proved so vulnerable to error and distortion, Ioannidis has found, that in some cases you’d have done about as well by throwing darts at a chart of the genome. (These studies seem to have improved somewhat in recent years, but whether they will hold up or be useful in treatment are still open questions.) Vioxx, Zelnorm, and Baycol were among the widely prescribed drugs found to be safe and effective in large randomized controlled trials before the drugs were yanked from the market as unsafe or not so effective, or both.
“Often the claims made by studies are so extravagant that you can immediately cross them out without needing to know much about the specific problems with the studies,” Ioannidis says. But of course it’s that very extravagance of claim (one large randomized controlled trial even proved that secret prayer by unknown parties can save the lives of heart-surgery patients, while another proved that secret prayer can harm them) that helps gets these findings into journals and then into our treatments and lifestyles, especially when the claim builds on impressive-sounding evidence. “Even when the evidence shows that a particular research idea is wrong, if you have thousands of scientists who have invested their careers in it, they’ll continue to publish papers on it,” he says. “It’s like an epidemic, in the sense that they’re infected with these wrong ideas, and they’re spreading it to other researchers through journals.”
THOUGH SCIENTISTS AND science journalists are constantly talking up the value of the peer-review process, researchers admit among themselves that biased, erroneous, and even blatantly fraudulent studies easily slip through it. Nature, the grande dame of science journals, stated in a 2006 editorial, “Scientists understand that peer review per se provides only a minimal assurance of quality, and that the public conception of peer review as a stamp of authentication is far from the truth.” What’s more, the peer-review process often pressures researchers to shy away from striking out in genuinely new directions, and instead to build on the findings of their colleagues (that is, their potential reviewers) in ways that only seem like breakthroughs—as with the exciting-sounding gene linkages (autism genes identified!) and nutritional findings (olive oil lowers blood pressure!) that are really just dubious and conflicting variations on a theme.
Most journal editors don’t even claim to protect against the problems that plague these studies. University and government research overseers rarely step in to directly enforce research quality, and when they do, the science community goes ballistic over the outside interference. The ultimate protection against research error and bias is supposed to come from the way scientists constantly retest each other’s results—except they don’t. Only the most prominent findings are likely to be put to the test, because there’s likely to be publication payoff in firming up the proof, or contradicting it.
But even for medicine’s most influential studies, the evidence sometimes remains surprisingly narrow. Of those 45 super-cited studies that Ioannidis focused on, 11 had never been retested. Perhaps worse, Ioannidis found that even when a research error is outed, it typically persists for years or even decades. He looked at three prominent health studies from the 1980s and 1990s that were each later soundly refuted, and discovered that researchers continued to cite the original results as correct more often than as flawed—in one case for at least 12 years after the results were discredited.
Doctors may notice that their patients don’t seem to fare as well with certain treatments as the literature would lead them to expect, but the field is appropriately conditioned to subjugate such anecdotal evidence to study findings. Yet much, perhaps even most, of what doctors do has never been formally put to the test in credible studies, given that the need to do so became obvious to the field only in the 1990s, leaving it playing catch-up with a century or more of non-evidence-based medicine, and contributing to Ioannidis’s shockingly high estimate of the degree to which medical knowledge is flawed. That we’re not routinely made seriously ill by this shortfall, he argues, is due largely to the fact that most medical interventions and advice don’t address life-and-death situations, but rather aim to leave us marginally healthier or less unhealthy, so we usually neither gain nor risk all that much.
Medical research is not especially plagued with wrongness. Other meta-research experts have confirmed that similar issues distort research in all fields of science, from physics to economics (where the highly regarded economists J. Bradford DeLong and Kevin Lang once showed how a remarkably consistent paucity of strong evidence in published economics studies made it unlikely that any of them were right). And needless to say, things only get worse when it comes to the pop expertise that endlessly spews at us from diet, relationship, investment, and parenting gurus and pundits. But we expect more of scientists, and especially of medical scientists, given that we believe we are staking our lives on their results. The public hardly recognizes how bad a bet this is. The medical community itself might still be largely oblivious to the scope of the problem, if Ioannidis hadn’t forced a confrontation when he published his studies in 2005.
Ioannidis initially thought the community might come out fighting. Instead, it seemed relieved, as if it had been guiltily waiting for someone to blow the whistle, and eager to hear more. David Gorski, a surgeon and researcher at Detroit’s Barbara Ann Karmanos Cancer Institute, noted in his prominent medical blog that when he presented Ioannidis’s paper on highly cited research at a professional meeting, “not a single one of my surgical colleagues was the least bit surprised or disturbed by its findings.” Ioannidis offers a theory for the relatively calm reception. “I think that people didn’t feel I was only trying to provoke them, because I showed that it was a community problem, instead of pointing fingers at individual examples of bad research,” he says. In a sense, he gave scientists an opportunity to cluck about the wrongness without having to acknowledge that they themselves succumb to it—it was something everyone else did.
To say that Ioannidis’s work has been embraced would be an understatement. His PLoS Medicine paper is the most downloaded in the journal’s history, and it’s not even Ioannidis’s most-cited work—that would be a paper he published in Nature Genetics on the problems with gene-link studies. Other researchers are eager to work with him: he has published papers with 1,328 different co-authors at 538 institutions in 43 countries, he says. Last year he received, by his estimate, invitations to speak at 1,000 conferences and institutions around the world, and he was accepting an average of about five invitations a month until a case last year of excessive-travel-induced vertigo led him to cut back. Even so, in the weeks before I visited him he had addressed an AIDS conference in San Francisco, the European Society for Clinical Investigation, Harvard’s School of Public Health, and the medical schools at Stanford and Tufts.
The irony of his having achieved this sort of success by accusing the medical-research community of chasing after success is not lost on him, and he notes that it ought to raise the question of whether he himself might be pumping up his findings. “If I did a study and the results showed that in fact there wasn’t really much bias in research, would I be willing to publish it?” he asks. “That would create a real psychological conflict for me.” But his bigger worry, he says, is that while his fellow researchers seem to be getting the message, he hasn’t necessarily forced anyone to do a better job. He fears he won’t in the end have done much to improve anyone’s health. “There may not be fierce objections to what I’m saying,” he explains. “But it’s difficult to change the way that everyday doctors, patients, and healthy people think and behave.”
AS HELTER-SKELTER as the University of Ioannina Medical School campus looks, the hospital abutting it looks reassuringly stolid. Athina Tatsioni has offered to take me on a tour of the facility, but we make it only as far as the entrance when she is greeted—accosted, really—by a worried-looking older woman. Tatsioni, normally a bit reserved, is warm and animated with the woman, and the two have a brief but intense conversation before embracing and saying goodbye. Tatsioni explains to me that the woman and her husband were patients of hers years ago; now the husband has been admitted to the hospital with abdominal pains, and Tatsioni has promised she’ll stop by his room later to say hello. Recalling the appendicitis story, I prod a bit, and she confesses she plans to do her own exam. She needs to be circumspect, though, so she won’t appear to be second-guessing the other doctors.
Tatsioni doesn’t so much fear that someone will carve out the man’s healthy appendix. Rather, she’s concerned that, like many patients, he’ll end up with prescriptions for multiple drugs that will do little to help him, and may well harm him. “Usually what happens is that the doctor will ask for a suite of biochemical tests—liver fat, pancreas function, and so on,” she tells me. “The tests could turn up something, but they’re probably irrelevant. Just having a good talk with the patient and getting a close history is much more likely to tell me what’s wrong.” Of course, the doctors have all been trained to order these tests, she notes, and doing so is a lot quicker than a long bedside chat. They’re also trained to ply the patient with whatever drugs might help whack any errant test numbers back into line. What they’re not trained to do is to go back and look at the research papers that helped make these drugs the standard of care. “When you look the papers up, you often find the drugs didn’t even work better than a placebo. And no one tested how they worked in combination with the other drugs,” she says. “Just taking the patient off everything can improve their health right away.” But not only is checking out the research another time-consuming task, patients often don’t even like it when they’re taken off their drugs, she explains; they find their prescriptions reassuring.
Later, Ioannidis tells me he makes a point of having several clinicians on his team. “Researchers and physicians often don’t understand each other; they speak different languages,” he says. Knowing that some of his researchers are spending more than half their time seeing patients makes him feel the team is better positioned to bridge that gap; their experience informs the team’s research with firsthand knowledge, and helps the team shape its papers in a way more likely to hit home with physicians. It’s not that he envisions doctors making all their decisions based solely on solid evidence—there’s simply too much complexity in patient treatment to pin down every situation with a great study. “Doctors need to rely on instinct and judgment to make choices,” he says. “But these choices should be as informed as possible by the evidence. And if the evidence isn’t good, doctors should know that, too. And so should patients.”
In fact, the question of whether the problems with medical research should be broadcast to the public is a sticky one in the meta-research community. Already feeling that they’re fighting to keep patients from turning to alternative medical treatments such as homeopathy, or misdiagnosing themselves on the Internet, or simply neglecting medical treatment altogether, many researchers and physicians aren’t eager to provide even more reason to be skeptical of what doctors do—not to mention how public disenchantment with medicine could affect research funding. Ioannidis dismisses these concerns. “If we don’t tell the public about these problems, then we’re no better than nonscientists who falsely claim they can heal,” he says. “If the drugs don’t work and we’re not sure how to treat something, why should we claim differently? Some fear that there may be less funding because we stop claiming we can prove we have miraculous treatments. But if we can’t really provide those miracles, how long will we be able to fool the public anyway? The scientific enterprise is probably the most fantastic achievement in human history, but that doesn’t mean we have a right to overstate what we’re accomplishing.”
We could solve much of the wrongness problem, Ioannidis says, if the world simply stopped expecting scientists to be right. That’s because being wrong in science is fine, and even necessary—as long as scientists recognize that they blew it, report their mistake openly instead of disguising it as a success, and then move on to the next thing, until they come up with the very occasional genuine breakthrough. But as long as careers remain contingent on producing a stream of research that’s dressed up to seem more right than it is, scientists will keep delivering exactly that.
“Science is a noble endeavor, but it’s also a low-yield endeavor,” he says. “I’m not sure that more than a very small percentage of medical research is ever likely to lead to major improvements in clinical outcomes and quality of life. We should be very comfortable with that fact.”