U.S. Medical Researchers Flout Rules Around World

In Zambia, Niger and other countries, experimenal risks hidden

THE PLAIN DEALER
Sunday, November 8, 1998

FIRST OF TWO ARTICLES

By KEITH EPSTEIN and BILL SLOAT
PLAIN DEALER REPORTERS

A legacy of medical exploitation, from secret Cold War radiation experiments to notorious syphilis studies on unwary blacks, has led the United States to adopt some of the world’s toughest protections for people on whom scientists test new drugs, devices and vaccines.
So firm is the underlying presumption that patients in experiments must be treated fairly and honestly that the protections of federal law apply not just to Americans but to any person, anywhere in the world, used in U.S.-financed research.

But federal and foreign records disclose that the nation with some of the world’s strictest research safeguards has flouted its own rules in dozens of countries, and has a history of “systemic deficiencies.”

On nearly every inhabited continent, the U.S. government has fashioned scientific partnerships with foreign officials and undertaken scores of medical research projects without obtaining basic agreements to avoid human rights abuses, as the law requires.

The contracts, known as “assurances,” serve as formal government-to-government accords that overseas scientists spending federal dollars are treating their patients as Americans would be treated. The contracts were missing in all 96 research projects conducted by the Centers for Disease Control and Prevention over the last decade.

The research alliances, most formed within recent years, have been sponsored by the Atlanta-based CDC, an agency with a storied reputation for protecting public health.

In these international collaborations, the United States provides money, manpower and the best available medical technology. The foreign partner provides whatever scientists it can muster and access to a vast living laboratory of human test subjects, often undereducated and desperate for medical care.
In a number of instances, drugs were given, samples taken and research completed without a written assurance of compliance with rules that patients be fully informed, monitored for safety, told of known treatments and free to refuse experimental drugs:

Altogether, the CDC “was engaged in 96 active research studies in 32 countries” where it “did not have approved assurances” from foreign collaborators they would abide by U.S. ethics laws, Marjorie A. Speers, the CDC’s deputy associate director for science, wrote in a July 1997 memorandum.

At the time, that involved every foreign research project sponsored by her agency. Some of those projects had been going on for 10 years or more, Speers said in an interview last week. Most involved tuberculosis, HIV, malaria and syphilis.

“The volume of what was out of compliance is startling,” said Gary Ellis, director of the National Institute of Health’s Office for Protection from Research Risks, to which the CDC quietly confessed last year. He said the scale of failures was unprecedented in two decades of enforcing the regulations.

J. Thomas Puglisi, director of human subjects protections at OPRR, said the amount of research that had failed to abide by the regulations “bothered me greatly,” because it demonstrated that a handful of controversial CDC experiments on foreign mothers with HIV were not isolated incidents.

“The identification of numerous international studies where all the required protections for human subjects were not in place was an indication of a need for systemic improvement at the CDC,” Puglisi said.
Speers, while acknowledging the rules were violated, said the CDC was confident no foreign research subjects had been harmed.

“What was missing was the procedural requirement to have this written assurance,” she said, “a document where an institution is saying we will follow ethical principles and abide by the rules.” Speers also said that the CDC had had to correct some overseas consent forms to make them clearly disclose to patients that they were taking part in health research.

It wasn’t the first time OPRR, the government’s main internal investigative agency on human experimentation, uncovered “systemic deficiencies” at the CDC.

Documents obtained by The Plain Dealer reveal recurrent failures, bureaucratic upheaval and broken promises of reform at the Atlanta-based public health agency.

Among the reasons: The government’s inability to police itself. A recent report to a presidential advisory commission described OPRR, the enforcer of the rules, as virtually powerless, especially when it comes to the CDC.
The human protections bureau is too “small and weak” to compel the CDC to correct problems, concluded the report by John C. Fletcher, former chief of bioethics at the National Institutes of Health.

The U.S. regulations are plain: Researchers cannot camouflage the truth. They cannot omit vital information about risks. They must offer any appropriate alternative medication. Doctors must disclose what they know and don’t know – whether in Cleveland or Cairo.

“We’re ethically bound to observe our regulations in the U.S. and overseas – because they’re based on principles we all agree on. And there’s no ethical principle I’m aware of that says we can treat other people in another country differently than ourselves,” said Dr. William Freeman, president of the Applied Research Ethics National Association, the leading U.S. membership organization of scientists and others overseeing the ethics of research.

Freeman, also director of medical research at the U.S. Indian Health Service, which oversees experiments on America’s Indian reservations, noted the grossest examples occurred when researchers treated other people differently than they would treat themselves.

Most notable, he said, was a federal study beginning in 1932 at Tuskegee, Ala., where 412 poor, black men were allowed to sicken with syphilis without being told and without being offered a known and effective treatment. The argument in Alabama, as overseas today, was that the patients probably would have received no better treatment anyway – a rationale Freeman doesn’t buy.

“The rules aren’t just rules but an expression of our morality and sense of community that you should do unto others as you would have them do unto you. If you want to be respected when you’re dependent on others, you’d better show respect to people dependent on you. If you want to be told the truth when you don’t have any way of knowing whether it’s true, then you’d better tell the truth yourself. If you want to be given a chance to say no to something, you’d better offer that chance to others.”

Said OPRR’s Puglisi: “It’s not that researchers are bad people. But sometimes they get so caught up in their immediate goals and the sense of the goodness of what they’re doing that they fail to see the larger ethical implications of their actions.”

Speers said that overseas studies supported by the CDC often operate with lower standards than in the United States.
Among the projects lacking a legally binding promise from the foreign country to follow the rules was a tuberculosis prevention study in Uganda, in which 464 Africans in a control group were given a placebo, or fake pill, instead of an established and inexpensive U.S. medication for which the CDC had long found “strong evidence and substantial clinical benefit.”

In September 1997, the CDC’s Speers confirmed that “at the time the study was done” her agency lacked an agreement with Uganda to abide by U.S. rules.
“However,” she added, “we’ve been working on getting one for the past few months.”
By then, the study was finished and results had been published by the New England Journal of Medicine.

Ethical rules challenged

CDC officials in recent months have been arguing that U.S. ethical rules ought not to apply in many of the very nations where the agency failed to adhere to the regulations.

For instance, Speers said, language differences can make it extremely difficult to follow U.S. rules for getting a patient’s informed consent.

The CDC also argues that in countries where no better care is available, scientists need not live up to U.S. standards of care.

The CDC’s sister agency, the National Institutes of Health, has more than 700 assurances in place for research in more than 110 countries.

Those assurances are generally negotiated by universities receiving NIH grants.

But Speers said the CDC had had trouble obtaining assurances because other countries strongly object to having ethics rules imposed on them by the U.S. government.

“We shouldn’t be dictating a code of ethics for other countries. Telling them how things should be done is often viewed as imperialistic,” said Speers.

The CDC has been anything but imperialistic, federal and foreign records show. Sometimes, the health agency has chosen to play by the local rules in places where there are no clear rules, according to internal e-mail traffic, memoranda, directives, compliance audits and other government documents obtained by The Plain Dealer through the Freedom of Information Act.

In Kazakhstan in 1997, nobody could be found to approve or monitor the “Central Asian Infectious Disease Project.”
Referring to a requirement for the use of ethical review committees to monitor patients’ safety, a CDC epidemiologist noted that in Kazakhstan the committees “or anything resembling them simply do not exist.”

In the Slovak Republic, a study of children with allergic diseases, launched in 1996, had to be halted.
During the study, laboratory samples were being collected for unspecified “future research” – but the children and their parents were not told what it was about, or asked for their permission.

In Egypt in 1997, a study assessing blood lead levels in children included consent forms that neglected to mention the project was “research.”

In Sierra Leone, the problem wasn’t getting a foreign government to form an alliance with the CDC, it was finding the government.

“We cannot acquire a government signature at this time due to the fighting and disturbances in Freetown,” a CDC official wrote from Africa in June 1997. “The U.S. Embassy is evacuated and we have no way to communicate at this time or know who to address.”

In Washington last fall, the National Institutes of Health was dispatching directives to CDC-affiliated researchers around the world to comply with the rules or close down.

“If your review does uncover any questionable situations we request that all further collections of biological materials be suspended until such time as the necessary [ethical] assurances are obtained,” one directive stated.

An internal chronology compiled by human protections agency and obtained by The Plain Dealer reveals ethical lapses from February 1993 through May 1997 that recurred despite attempts at reform.

CDC promised it could do better. The lapses ought not to happen again.

“CDC officials pledge their commitment to ensuring full protections for human subjects in all research conducted or supported by CDC,” the agency promised in August 1993. “They further pledge … concrete actions.”

By October 1996, ethics managers were reshuffled and CDC took the step of assigning a top official – a deputy associate director, Speers – to oversee protection of human subjects on a daily basis.

Then, in 1997, Dr. Sidney Wolfe, the Cleveland native who works for Ralph Nader, went public with his discovery that in nine government studies, including two sponsored by the CDC in Thailand and the Ivory Coast, pregnant women in control groups were not offered an expensive form of AIDS treatment available in the United States.

That aroused the curiosity of OPRR’s director, Gary Ellis, who wondered whether the CDC had obtained the necessary written contracts to abide by the rules. At the suburban Maryland office building where he works, Ellis ensconsed himself in a room of file cabinets containing copies of more than 10,000 such contracts, mostly from universities and government agencies.
He could find none for the CDC studies, so he called the agency.

Three days passed without an answer.

He called Atlanta again – and guessed. He was right. The CDC hadn’t gotten any “assurances” the AIDS studies would follow the rules. The studies were halted immediately.

A few hours later, there was another call and another confession. The problem, the CDC reported, had somewhat larger dimensions. The agency was having trouble figuring out how many international alliances it had formed. Records were in disarray.

“It takes a long time to change a culture, but there are people at the CDC now who are getting it,” said Puglisi. “They’re learning. But we’ve also learned when it comes to human subject protections, one has to be ever-vigilant.”

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Related stories:

In the Name of Healing Doctors infused a solvent also used as a gasoline additive into Laura Michalski’s abdomen. Within hours, she died. Eight years later, her family learned it had been an experiment.

“They Used Our Kids as Guinea Pigs.” Medical research records show the U.S. government is still in the business of conducting and paying for clinical trials on unsuspecting Americans.

Foreign Tests Don’t Meet U.S. Criteria The cycle of hype, hope and heartbreak surrounding clinical trials has become a chronic condition in the global pharmaceutical industry, which now initially tests two-thirds of all products for Americans overseas. The experiments often involve fraud, concealed side effects, improvised experiments and human rights abuses.

Research Standards Overseas Vary Greatly With human lives and huge investments at stake, the global pharmaceutical industry increasingly relies on research from outside the United States, where fraud and the use of unwitting test subjects is commonplace. “It’s our little secret…frightening,” acknowledges an overseer of experiments on four continents.

Overseers Operate in the Dark Institutional Review Boards, which oversee clinical trials, were supposed to wrest the monopoly on decision-making from the scientific establishment, placing it in the hands of a group that could balance the interests of medicine, human beings and the community. Average time spent reviewing each clinical trial? Two minutes.

Secrecy in Tests Led to Trouble Doctors confront a dilemma when they experiment on people: Are they healers or scientists? Should they give a patient the best treatment possible? Or do they use their patients as a means to discover better treatment for others?

Other stories in a subsequent series that took a still closer look at medical experimentation around the world:

Living Proof: U.S.-Run Study Gave Ugandans Dummy Pills Instead of Treatment American researchers let tuberculosis worsen, unchecked by an effective drug, in a control group of 500 Ugandans with HIV, as they charted its deadly progression. Some thought “placebo” was a medication that would help them. In the U.S, the practice would have been unethical.