The Food and Drug Administration said on Tuesday two 2010 inspections, an internal company investigation and a third-party audit uncovered “significant instances of misconduct and violations” at a Cetero facility in Houston.

The Cary, North Carolina-based firm does early-phase clinical research and bioanalytics for a number of drugmakers. The pharmaceutical companies can then use those studies as supporting evidence in drug approval applications to the FDA.

“The pattern of misconduct was serious enough to raise concerns about the integrity of the data Cetero generated during the five-year time frame,” the FDA said, warning drugmakers they might have to repeat or confirm any studies Cetero did in support of their applications between April 2005 and June 2010.

It remains unclear which drugmakers have used Cetero’s services to apply for regulatory approvals and the FDA is asking companies to identify such instances. The regulators said the measure is precautionary and the safety and efficacy of drugs already on the market are unlikely to be affected.

The FDA inspected Cetero in May and December last year and found falsified records about studies.

Specifically, in at least 1,900 instances between April 2005 and June 2009, laboratory technicians identified as conducting certain studies were not actually present at Cetero facilities at that time, the FDA said in its May report.

The FDA also said at the time that Cetero might have “fixed” studies to get the desired result, or did not include failed results in their report.

“Cetero’s May 2010 and December 2010 responses are inadequate because the scope of their internal investigation was far too narrow to identify and adequately address the root cause of these systemic failures,” the regulators said.

Cetero was not immediately available for comment.

(Reporting by Alina Selyukh and Anna Yukhananov; editing by Andre Grenon)

When they asked how much it would cost, “nobody knew,” Corcoran said. “No one would tell me.”

They called around, and found that the price of an MRI varied from $350 to $1,200.

That experience was a driving force behind the health care price transparency bill that the New Port Richey Republican introduced this year. It was approved overwhelmingly and takes effect on Friday.

Urgent care clinics across the state will be required to post on 15-square-foot signs the prices of their 50 most frequently provided services. Those that don’t face fines of up to $1,000 a day until they comply.

Corcoran sees the law as a first step toward making the often-mysterious and varied prices of health care services more available to patients. It comes at a time when patients are paying a greater share of their health costs, either because they are uninsured or are covered by high-deductible plans. That’s the kind of insurance Corcoran had as the owner of a small business, before he was elected to the state House last fall.

“When you’re paying the first $10,000 out of pocket, the first thing you ask is, what’s the cost?” he said.

Many doctors, however, say that health care pricing is too complex for fast-food-style pricing. With thousands of billing codes and so many ways to pay, including cash, private insurance and government programs such as Medicare and Medicaid, posting a single price could be more misleading than helpful.

“It’s very well-intentioned,” said Rep. Ronald Renuart, R-Ponte Vedra Beach, who’s a physician. “But the law isn’t as straightforward as it seems.”

Corcoran argues that such price transparency already exists in the state, at private urgent-care clinics like Solantic, a chain previously owned by Florida Gov. Rick Scott, and MedExpress, which has several locations in the Tampa Bay area. So he crafted legislation based largely on what those clinics have been doing.

The posted prices will apply only to patients who are paying cash for services, not those using insurance. The law applies to urgent-care clinics, but not facilities such as hospital emergency rooms. Individual primary care physicians aren’t required to post prices, but if they do so voluntarily, they don’t have to pay license fees and fulfill continuing medical education requirements for a period of time.

• • •

The law has drawn a mixed reaction. Consumer and business groups such as Florida Public Interest Research Group and Associated Industries of Florida supported the legislation.

But doctors have been less enthusiastic. When details were presented at a recent meeting of the Pinellas County Medical Association, the news was greeted with a collective groan. Doctors wanted to know more about the requirements and which types of practices they applied to.

Renuart says there are good reasons for their concern.

It’s still unclear exactly which clinics must comply. Besides urgent care centers, there’s still a question of whether any clinic that accepts walk-in patients must post prices as well. Corcoran said the state Agency for Health Care Administration is in the process of determining that.

Renuart said that the prices could create confusion because they only apply to patients who pay by cash or debit or credit cards. He said the majority of patients at many clinics are covered by some type of insurance.

He also offered this possibility: that seeing the prices might give some patients sticker shock. “You don’t want to drive away patients who need care,” Renuart said.

Further, he said waiving continuing medical education requirements could be no incentive at all, since many physicians need to meet them to remain board certified. These courses help physicians stay on top of new information about medications and treatments that benefit patients, he noted.

Both Renuart and Corcoran expect that the number of primary care physicians who post their prices voluntarily will be low. Renuart, who works for Baptist Primary Care, a large physician network covering northeast Florida and Southern Georgia, said he isn’t likely to do so.

• • •

Urgent care clinic operators around Tampa Bay have been working to meet the Friday deadline. Among them are Morton Plant Mease, which has clinics in Trinity and Largo, and Bayfront Medical Center, which has six clinics in Pinellas County.

Morton Plant’s clinics will include prices for a standard office visit, X-rays, vaccines, school physicals and laboratory tests, said Kevin Corrigan, chief operating officer of Morton Plant Mease Primary Care. He said the list may change quarterly, based on the most frequently provided services.

Bayfront clinics will go beyond the required 50 services and list about 90 of them, said Phil Powell, executive director of the clinics. He said part of the reason is that Bayfront officials believe their prices are competitive with what other clinics charge.

“I think any time consumers get more information, it’s going to be a good thing,” he said.

Among the prices patients are likely to see at Bayfront’s clinics: school physicals ($30); routine office visit ($75); chest X-ray ($130).

The clinic also has a flat rate of $17 for any medication it dispenses. “Patients may be able to get it for less or more elsewhere, but we make it simple,” Powell said.

Corcoran would like to expand the pricing requirement to more physicians and clinics in the future. He added that lawmakers in Oklahoma have contacted him, interested in passing a similar bill there.

“I see it as a first step toward creating a real free market in health care, where you have the greatest quality of care at the lowest cost to the consumer,” he said.

The CIA organised a fake vaccination programme in the town where it believed Osama bin Laden was hiding in an elaborate attempt to obtain DNA from the fugitive al-Qaida leader’s family, a Guardian investigation has found.

As part of extensive preparations for the raid that killed Bin Laden in May, CIA agents recruited a senior Pakistani doctor to organise the vaccine drive in Abbottabad, even starting the “project” in a poorer part of town to make it look more authentic, according to Pakistani and US officials and local residents.

The doctor, Shakil Afridi, has since been arrested by the Inter-Services Intelligence agency (ISI) for co-operating with American intelligence agents.

Relations between Washington and Islamabad, already severely strained by the Bin Laden operation, have deteriorated considerably since then. The doctor’s arrest has exacerbated these tensions. The US is understood to be concerned for the doctor’s safety, and is thought to have intervened on his behalf.

The vaccination plan was conceived after American intelligence officers tracked an al-Qaida courier, known as Abu Ahmad al-Kuwaiti, to what turned out to be Bin Laden’s Abbottabad compound last summer. The agency monitored the compound by satellite and surveillance from a local CIA safe house in Abbottabad, but wanted confirmation that Bin Laden was there before mounting a risky operation inside another country.

DNA from any of the Bin Laden children in the compound could be compared with a sample from his sister, who died in Boston in 2010, to provide evidence that the family was present.

So agents approached Afridi, the health official in charge of Khyber, part of the tribal area that runs along the Afghan border.

The doctor went to Abbottabad in March, saying he had procured funds to give free vaccinations for hepatitis B. Bypassing the management of the Abbottabad health services, he paid generous sums to low-ranking local government health workers, who took part in the operation without knowing about the connection to Bin Laden. Health visitors in the area were among the few people who had gained access to the Bin Laden compound in the past, administering polio drops to some of the children.

Afridi had posters for the vaccination programme put up around Abbottabad, featuring a vaccine made by Amson, a medicine manufacturer based on the outskirts of Islamabad.

In March health workers administered the vaccine in a poor neighbourhood on the edge of Abbottabad called Nawa Sher. The hepatitis B vaccine is usually given in three doses, the second a month after the first. But in April, instead of administering the second dose in Nawa Sher, the doctor returned to Abbottabad and moved the nurses on to Bilal Town, the suburb where Bin Laden lived.

It is not known exactly how the doctor hoped to get DNA from the vaccinations, although nurses could have been trained to withdraw some blood in the needle after administrating the drug.

“The whole thing was totally irregular,” said one Pakistani official. “Bilal Town is a well-to-do area. Why would you choose that place to give free vaccines? And what is the official surgeon of Khyber doing working in Abbottabad?”

A nurse known as Bakhto, whose full name is Mukhtar Bibi, managed to gain entry to the Bin Laden compound to administer the vaccines. According to several sources, the doctor, who waited outside, told her to take in a handbag that was fitted with an electronic device. It is not clear what the device was, or whether she left it behind. It is also not known whether the CIA managed to obtain any Bin Laden DNA, although one source suggested the operation did not succeed.

Mukhtar Bibi, who was unaware of the real purpose of the vaccination campaign, would not comment on the programme.

Pakistani intelligence became aware of the doctor’s activities during the investigation into the US raid in which Bin Laden was killed on the top floor of the Abbottabad house. Islamabad refused to comment officially on Afridi’s arrest, but one senior official said: “Wouldn’t any country detain people for working for a foreign spy service?”

The doctor is one of several people suspected of helping the CIA to have been arrested by the ISI, but he is thought to be the only one still in custody.

Pakistan is furious over being kept in the dark about the raid, and the US is angry that the Pakistani investigation appears more focused on finding out how the CIA was able to track down the al-Qaida leader than on how Bin Laden was able to live in Abbottabad for five years.

Over the weekend, relations were pummelled further when the US announced that it would cut $800m (£500m) worth of military aid as punishment for Pakistan’s perceived lack of co-operation in the anti-terror fight. William Daley, the White House chief of staff, went on US television on Sunday to say: “Obviously, there’s still a lot of pain that the political system in Pakistan is feeling by virtue of the raid that we did to get Osama bin Laden, something the president felt strongly about and we have no regrets over.”

The CIA refused to comment on the vaccination plot.

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.

Doctors would assess her tumor cells, looking for gene patterns that would determine which drugs would best attack her particular cancer. She would not waste precious time with ineffective drugs or trial-and-error treatment. The Duke program — considered a breakthrough at the time — was the first fruit of the new genomics, a way of letting a cancer cell’s own genes reveal the cancer’s weaknesses.

But the research at Duke turned out to be wrong. Its gene-based tests proved worthless, and the research behind them was discredited. Ms. Jacobs died a few months after treatment, and her husband and other patients’ relatives are suing Duke.

The episode is a stark illustration of serious problems in a field in which the medical community has placed great hope: using patterns from large groups of genes or other molecules to improve the detection and treatment of cancer. Companies have been formed and products have been introduced that claim to use genetics in this way, but assertions have turned out to be unfounded. While researchers agree there is great promise in this science, it has yet to yield many reliable methods for diagnosing cancer or identifying the best treatment.

Instead, as patients and their doctors try to make critical decisions about serious illnesses, they may be getting worthless information that is based on bad science. The scientific world is concerned enough that two prominent groups, the National Cancer Institute and the Institute of Medicine, have begun examining the Duke case; they hope to find new ways to evaluate claims based on emerging and complex analyses of patterns of genes and other molecules.

So far, the Food and Drug Administration “has generally not enforced” its regulation of tests created by individual labs because, until recently, such tests were relatively simple and relied heavily on the expertise of a particular doctor, said Erica Jefferson, a spokeswoman for the agency. But now, with labs offering more complex tests on a large scale, the F.D.A. is taking a new look at enforcement.

Dr. Scott Ramsey, director of cancer outcomes research at the Fred Hutchison Cancer Center in Seattle, says there is already “a mini-gold rush” of companies trying to market tests based on the new techniques, at a time when good science has not caught up with the financial push. “That’s the scariest part of all,” Dr. Ramsey said.

Doctors say the heart of the problem is the intricacy of the analyses in this emerging field and the difficulty in finding errors. Even well-respected scientists often “oversee a machine they do not understand and cannot supervise directly” because each segment of the research requires different areas of expertise, said Dr. Lajos Pusztai, a breast cancer researcher at M. D. Anderson Cancer Center at the University of Texas. As a senior scientist, he added, “It’s true for me, too.”

The Duke case came right after two other claims that gave medical researchers pause. Like the Duke case, they used complex analyses to detect patterns of genes or cell proteins. But these were tests that were supposed to find ovarian cancer in patients’ blood. One, OvaSure, was developed by a Yale scientist, Dr. Gil G. Mor, licensed by the university and sold to patients before it was found to be useless.

The other, OvaCheck, was developed by a company, Correlogic, with contributions from scientists from the National Cancer Institute and the Food and Drug Administration. Major commercial labs licensed it and were about to start using it before two statisticians from M. D. Anderson discovered and publicized its faults.

The Duke saga began when a prestigious journal, Nature Medicine, published a paper on Nov. 6, 2006, by Dr. Anil Potti, a cancer researcher at Duke University Medical Center; Joseph R. Nevins, a senior scientist there; and their colleagues. They wrote about genomic tests they developed that looked at the molecular traits of a cancerous tumor and figured out which chemotherapy would work best.

Other groups of cancer researchers had been trying to do the same thing.

“Our group was despondent to get beaten out,” said Dr. John Minna, a lung cancer researcher at the University of Texas Southwestern Medical Center. But Dr. Minna rallied; at the very least, he thought, he would make use of this incredible discovery to select drugs for lung cancer patients.

First, though, he asked two statisticians at M. D. Anderson, Keith Baggerly and Kevin Coombes, to check the work. Several other doctors approached them with the same request.

Dr. Baggerly and Dr. Coombes found errors almost immediately. Some seemed careless — moving a row or a column over by one in a giant spreadsheet — while others seemed inexplicable. The Duke team shrugged them off as “clerical errors.”

And the Duke researchers continued to publish papers on their genomic signatures in prestigious journals. Meanwhile, they started three trials using the work to decide which drugs to give patients.

Dr. Baggerly and Dr. Coombes tried to sound an alarm. They got the attention of the National Cancer Institute, whose own investigators wanted to use the Duke system in a clinical trial but were dissuaded by the criticisms. Finally, they published their analysis in The Annals of Applied Statistics, a journal that medical scientists rarely read.

The situation finally grabbed the cancer world’s attention last July, not because of the efforts of Dr. Baggerly and Dr. Coombes, but because a trade publication, The Cancer Letter, reported that the lead researcher, Dr. Potti, had falsified parts of his résumé. He claimed, among other things, that he had been a Rhodes scholar.

“It took that to make people sit up and take notice,” said Dr. Steven Goodman, professor of oncology, pediatrics, epidemiology and biostatistics at Johns Hopkins University.

In the end, four gene signature papers were retracted. Duke shut down three trials using the results. Dr. Potti resigned from Duke. He declined to be interviewed for this article. His collaborator and mentor, Dr. Nevins, no longer directs one of Duke’s genomics centers.

The cancer world is reeling.

The Duke researchers had even set up a company — now disbanded — and planned to sell their test to determine cancer treatments. Duke cancer patients and their families, including Mrs. Jacobs’s husband, Walter Jacobs, say they feel angry and betrayed. And medical researchers see the story as a call to action. With such huge data sets and complicated analyses, researchers can no longer trust their hunches that a result does — or does not — make sense.

“Our intuition is pretty darn poor,” Dr. Baggerly said.

This article has been revised to reflect the following correction:

Correction: July 7, 2011

An earlier version of this post misstated Dr. Steven Goodman’s affiliation at Johns Hopkins University. He is a professor of oncology, pediatrics, epidemiology and biostatistics, not the director of oncology biostatistics.

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.

Much of this occurred 40 to 80 years ago, but it is the backdrop for this week’s meeting in Washington of a presidential bioethics commission. It was triggered by the government’s apology last fall for federal doctors infecting prisoners and mental patients in Guatemala with syphilis 65 years ago.

U.S. officials also acknowledged there had been dozens of similar experiments in the U.S. — studies that often made healthy people sick.

An Associated Press review of medical journal reports and decades-old press clippings found more than 40 such studies. Some searched for lifesaving treatments; others hurt people but provided no useful results.

They will be compared to the well-known Tuskegee syphilis study in which U.S. health officials tracked 600 black men in Alabama who had syphilis but didn’t give them adequate treatment even after penicillin became available.

Attitudes about medical research were different when the studies were done. Infectious diseases killed more people, and doctors worked urgently to invent and test cures. Many researchers felt it was OK to experiment on people who did not have full rights in society — prisoners, mental patients, poor blacks.

“There was definitely a sense — that we don’t have today — that sacrifice for the nation was important,” said Laura Stark, a Wesleyan University assistant professor of science in society who is writing a book about past federal medical experiments.

The AP review found:

A federally funded study begun in 1942 injected experimental flu vaccine in male patients at a state insane asylum in Ypsilanti, Mich., then exposed them to flu several months later. It was co-authored by Dr. Jonas Salk, who later invented the polio vaccine.

Some men weren’t able to describe their symptoms, raising serious questions about how well they understood what was being done.

In federally funded studies in the 1940s, Dr. W. Paul Havens Jr. exposed men to hepatitis in experiments, including one using patients from mental institutions in Middletown and Norwich, Conn. Havens, a World Health Organization expert on viral diseases, was one of the first scientists to differentiate types of hepatitis and their causes.

In the mid-1940s, researchers studied the transmission of a deadly stomach bug by having young men at the New York State Vocational Institution, a reformatory in West Coxsackie, swallow unfiltered stool suspension. The point was to compare that way of spreading the disease with having test subjects breathe sprayed germs. Swallowing it was more effective, researchers concluded.

Government researchers in the 1950s tried to infect about two dozen volunteer prison inmates with gonorrhea using two methods in an experiment at a federal penitentiary in Atlanta.

Around World War II, prisoners were enlisted to take part in studies that could help the troops. For example, malaria studies at Stateville Penitentiary in Illinois and two other prisons were designed to test antimalarial drugs that could help soldiers in the Pacific.

About this time, the prosecution of Nazi doctors in 1947 led to the “Nuremberg Code,” a set of international rules to protect human test subjects. Many U.S. doctors essentially ignored them, arguing that they applied to Nazi atrocities — not to American medicine.

The late 1940s and 1950s saw huge growth in the U.S. pharmaceutical and health care industries, and a boom in prisoner experiments funded by the government and corporations. By the 1960s, at least half the states allowed prisoners to be used as medical guinea pigs.

But two studies in the 1960s changed the public’s attitude toward the way test subjects were treated.

The first came to light in 1963. Researchers injected cancer cells into 19 old and debilitated patients at a Jewish Chronic Disease Hospital in Brooklyn, N.Y., to see if they would be rejected.

The hospital director said the patients were not told they were being injected with cancer cells as the cells were deemed harmless. But the experiment upset lawyer William Hyman, who sat on the hospital’s board of directors. The state investigated, and the hospital ultimately said any such experiments would require the patient’s written consent.

In Staten Island, from 1963 to 1966, a medical study was conducted at the Willowbrook State School for children with mental retardation. The children were intentionally given hepatitis orally and by injection to see if they could then be cured with gamma globulin.

Those two studies — along with the Tuskegee experiment revealed in 1972 — proved to be a “holy trinity” that sparked extensive and critical media coverage and public disgust, said Susan Reverby, the Wellesley College historian who first discovered records of the syphilis study in Guatemala.

By the 1970s, even experiments involving prisoners were thought scandalous. In widely covered congressional hearings in 1973, pharmaceutical industry officials agreed they were using prisoners for testing because they were cheaper than chimpanzees.

The government initiated reforms. In the mid-1970s, the U.S. Bureau of Prisons effectively excluded all research by drug companies and other outside agencies within federal prisons.

So researchers looked to other countries. Clinical trials could be done more cheaply and with fewer rules there. And it was easy to find patients who were taking no medication, a factor that can complicate drug tests.

Other ethical guidelines have been enacted, and few believe another Guatemala study could happen today

Still, in the last 15 years, two international studies sparked outrage.

U.S.-funded doctors failed to give the AIDS drug AZT to all the HIV-infected pregnant women in a Uganda study even though it would have protected their newborns. U.S. health officials argued the study would answer questions about AZT’s use in developing countries.

A Pfizer Inc. study gave the antibiotic Trovan to children with meningitis in Nigeria, though there were doubts about its effectiveness. Critics blamed the study for the deaths of 11 children and the disabling of others. Pfizer settled a lawsuit with Nigerian officials for $75 million but admitted no wrongdoing.

Last year, the U.S. Department of Health and Human Services’ inspector general reported between 40 percent and 65 percent of clinical studies of federally regulated medical products were done in other countries in 2008. It was also noted U.S. regulators inspected fewer than 1 percent of these sites.

Last October, the Guatemala study came to light.

In the 1946-48 study, U.S. scientists infected prisoners and patients in a mental hospital in Guatemala with syphilis, apparently to see if penicillin could prevent the sexually transmitted disease. The study came up with no useful information.

It nauseated ethicists on many levels. Beyond infecting patients with a terrible illness, it was clear people did not understand what was being done to them or could not give their consent.

That it occurred overseas was an opening for the Obama administration to have the bioethics panel seek a new evaluation of international medical studies.

To focus on federally funded international studies, the bioethics commission has formed an international panel of about a dozen experts. Regarding the Guatemala study, it has hired 15 staff investigators and is working with more historians and consulting experts.

The panel is to send a report to President Barack Obama by September. Any further steps would be up to the administration.

Their only access was through a clinical trial testing whether risky prenatal surgery was better than standard surgery after birth. Participating meant being randomly assigned to one surgery or the other.

“They take you to a room and a paper tells you what part of the trial you were randomized to,” said Jessica Thomas, 26, of Stansbury Park, Utah, assigned to prenatal surgery when pregnant with her son Tyson. “It was my only sense of hope to try to give him a better life.”

Amy Shapiro, 40, of Leander, Tex., was assigned to postnatal surgery, performed on her son Zachary the day after he was born.

“It was one of the hardest decisions I had to make to be in the study,” said Ms. Shapiro, who knew how disabling spina bifida was because her sister-in-law has it. “It was a big disappointment that we didn’t get the prenatal surgery because I knew that that was the surgery that was most likely going to help him the most, because otherwise why would they be doing the study? But at the same time, he could have died or been born prematurely from prenatal surgery. When they explained everything to us, I wanted to be in it regardless.”

Now, results are in: Fetal surgery, while increasing premature births and causing tearing at some mother’s incisions, made babies more likely to walk and less likely to have neurological problems or need shunts to drain brain fluid.

Besides the groundbreaking results, the seven-year study spotlights ethical dilemmas in research.

The surgery was becoming popular in the 1990s, even appearing on a Time magazine cover, and some experts believed that it might eventually eliminate most symptoms. But given the risks, others wanted proof that it was better than postnatal surgery.

“There were no systematic data regarding safety and efficacy,” said Dr. Jeremy Sugarman, a bioethicist at Johns Hopkins University who participated in early discussions. “Many things we believe to be true and right and appropriate ultimately are shown to be harmful and ineffective.” Spina bifida researchers believed that few women would participate if the surgery were available elsewhere, so they persuaded all but the three hospitals in the trial to stop doing the procedure, an unusual agreement.

“I frankly have a lot of problems when a group of physicians get together and in effect shut down everything so they can have a trial,” said Baruch A. Brody, director of the Center for Medical Ethics and Health Policy at Baylor College of Medicine. “For physicians who believe in it, why should they be pressured into stopping? For families who believe they should have the surgery, why should they be told they can’t?”

But several ethicists praised the pause. “It’s impressive to see that kind of collaboration,” said Dr. Jeffrey R. Botkin, a pediatric ethicist at the University of Utah. “The sophistication surgeons need to do this is so high, it makes sense to answer research questions by allowing it only at a few centers.”

The surgery proved beneficial enough that an independent monitoring board stopped the trial, not wanting to deny more women the opportunity for prenatal surgery. But stopping trials early sometimes limits the information researchers can collect that might benefit future patients.

Monitoring boards “walk a very fine line,” said Dr. Steven Goodman, an epidemiologist at Johns Hopkins and editor of the journal Clinical Trials. “At what point is the benefit of getting more information outweighed by the consequences of not releasing results and continuing to randomize patients?”

In some trials, if one treatment proves superior, other participants can then receive that treatment. But with prenatal surgery, that isn’t possible, said Jeffrey Kahn, director of the University of Minnesota’s bioethics center. “Some people are accepting risk for the benefit of those who will come after them.”

Still, regardless of therapy, “people who enroll in clinical trials, for the most part, do better than people who don’t, because care is controlled and monitored,” Dr. Goodman said. “You simply can’t go back and say, ‘In every trial people who didn’t get the winning therapy were deprived.’ ”

Tyson Thomas emerged from prenatal surgery with no need for a shunt and, at 22 months old, uses a walker but is almost walking independently. Zachary Shapiro, 6, has a shunt, walks with braces, and has some attention problems. Both boys, who received their surgery at the University of California, San Francisco, need catheters.

Ms. Shapiro, a kindergarten teacher, said of her son, “I do feel like he benefited, even though he didn’t benefit from the actual surgery.”

She added, “He benefited from the research that has happened about his disability.”

As absolute and correct as those aphorisms may be, they can be hard for doctors to apply in the complex world of modern medicine.

A recent Medscape medical ethics survey of over 10,000 physicians found that when it comes to patient treatment, a significant number of physicians struggle when it comes to topics relating to honest, straight-forward communication, and even pain management. Physicians from a broad range of specialties answered 3 questions pertaining to patient treatment:

-     Would you ever hide information from a patient about a terminal or preterminal diagnosis, because you believe that it will bolster their spirit or attitude?
-      Would you ever prescribe a treatment that’s a placebo, simply because the patient wanted treatment?
-      Would you ever undertreat a patient’s pain, because of a fear of repercussions or because you are concerned that a patient — even a terminal patient — might become addicted?

Open Communication Is Often Difficult

When it comes to delivering bad news, 59.8% of physicians indicate they “tell it exactly as I see it,” while 14.6% indicate that they soften the news and “give hope even if there is little chance.” Two percent indicate that unless a patient is going to die imminently, they don’t tell him or her how bad the situation is and nearly one quarter (23.8%) say “it depends.”

“The kind of compassion that brings people into medicine is the type of compassion that is needed for delivering bad news,” says Kenneth Goodman, PhD, Director of the Bioethics Program at the University of Miami and author of Ethics and Evidence-Based Medicine: Fallibility and Responsibility in Clinical Medicine. But that compassion should never compromise the truth, he cautions.

Many of the physicians surveyed augmented their responses noting that, while they are honest, they try hard to deliver bad news in the most gentle, humane, and supportive way possible. That’s exactly what patients should expect from their doctors, Goodman advises. But in “softening” the truth, he believes that doctors don’t need to deviate from it.

“If there is something positive you can say, by all means say it. But only tell the truth: ‘I will be there with you. I will help you manage your pain. I will see to it that you can arrange your affairs.’ Those are truthful things,” Goodman says.

When doctors withhold information, they make it more difficult for patients to chart their course and undermine their own credibility.

From the patient’s point of view, “If I don’t know my time is limited I can’t put my affairs in order. I can’t say, ‘I’m sorry,’” he says. What’s more, “it’s not like patients are asking Dr. Kildare, ‘What are my chances, Doc?’ Patients are increasingly educated. If you don’t tell them, they’re going to be looking it up on the internet the next day, so you should probably be the source of the data, because you’re a human and you care about them.”

Goodman advises that the same rationale applies to the use of placebos. Nearly one quarter (23.5%) of respondents said they would prescribe a treatment that was essentially a placebo to a patient simply because he or she wanted treatment. Another 18.2% said, “It depends.”

Physicians who were willing to provide “placebo” treatment generally fell into 2 camps. Some said they would do it to appease a patient but only after telling them it wouldn’t do them any good. One doctor noted that he’d prescribe vitamins and supplements, “but I’d tell them I thought it was worthless”; while another would prescribe a cream for hemorrhoids, “but they are also forewarned” that the treatment wouldn’t do any good.

Still another noted, “In this day and age, many patients will not accept that the best treatment is tincture of time and they have no hesitation about reporting you to the state board or hospital administrator. So, I figure out something that will do the least potential harm and try that.”

Others say they’d be willing to prescribe a benign but ineffectual treatment in hopes of achieving a positive placebo effect. “Placebo works up to 50% of the time,” said one. “Placebos ARE a form of treatment!” noted another and, “Placebo can be psychologically beneficial and I don’t see that as placebo,” wrote a third.

Physicians in the first group need to be able to stand their ground in the face of insistent patients, Goodman advises. After all, they are the medical experts.

“Doctors need to be able to say, ‘I’m sorry, there is nothing I can do,’ No physician is going to provide drugs for a recreational purpose. Why, if a patient asks for an antibiotic for a virus or a prescription that won’t work, should he get it?” Goodman asks. As for those hoping to achieve a placebo effect he notes, if a patient finds out he or she has been prescribed a placebo, it will cause irrevocable damage to the physician-patient relationship.

Pain Management Quandaries

While the first 2 patient treatment questions in the survey pertained to communication, the last addressed pain management. While the overwhelming majority (84.1%) of physicians said they would never undertreat pain, a handful (5.6%) said they would, and about 1 in 10 (10.3%) said they would have to evaluate the situation before making a decision.

After filtering out responses from physicians – many of them emergency department doctors – noting that they routinely deny drug-seeking “frequent fliers” prescriptions for pharmaceuticals, the theme frequently voiced by doctors was that they would undertreat pain due to fear of lawsuits. A number of respondents augmented their answers with frustrated, emotional responses about state medical boards, government intrusion, and litigious patients.

Comments included: “I undertreat not due to concerns about addiction but concerns about Drug Enforcement.” “We live in a real world. I would like to think I would answer ‘no’ if real tort reform took place.” “I bet we all would in today’s drug-abusing, litigious society.” And “The state boards can wreck a doctor without appeal.”

Despite those concerns, others remained steadfast. “I have only the patient to believe as to how much pain they are experiencing. I have been lied to at times over the years, but I would rather try to believe people than to deny everyone because of some bad actors,” wrote one.

When Treatment Denial Causes Suffering

Another noted that physicians’ fears of repercussions have “caused patients to suffer needless pain. If a physician does not feel competent or comfortable handling pain issues, (s)he should refer that patient to a reputable pain specialist. Pain is a legitimate medical condition, which we took an oath to alleviate when possible. If the treatment is appropriate and well documented with the current safeguards in place, there should be no fear.”

Most respondents who elaborated on their answers, however, drew a sharp distinction between patients with chronic conditions and the terminally ill. Many noted that they do not prescribe narcotics to patients with chronic conditions, refer them to pain management specialists, and are vigilant when it comes to chronically ill patients who tend to “lose” prescriptions too often. When it comes to treating the terminally ill, however, respondents spoke in a single voice: treat their pain.

“Terminal patients should be able to get whatever they need whenever they need it,” wrote one. “Terminal patients get whatever they need,” said another. A third noted, “Terminal patients should never be allowed to suffer with pain because of inadequate treatment, especially fear of addiction: what difference does it make if they are going to die addicted to narcotics?”

Or, as one physician summed it up, “Palliative care is humane.”