May 11, 2006– Vol. 41, No. 39

Research lab accused of racism in clinical trials

George E. Jordan

KENILWORTH, N.J. — Cecil Pickett is a scientist at the top of his game.

As the head of research at Schering-Plough, he lives in a world of enzymes, viruses and proteins — the building blocks of life and disease.

So, by his own admission, he was taken aback last month when an advocacy group accused his laboratory of racism.

Schering-Plough is on the verge of a breakthrough in the treatment of hepatitis C — a virus that infects 4 million in the United States and 200 million worldwide. But hepatitis patient advocates allege the Kenilworth company excluded blacks from early human testing to skew the data and accelerate regulatory approval. It was the first time a drugmaker was accused of racial bias for the design of a clinical trial.

It’s always tough to separate politics from the drug industry, but this time it was personal. Pickett, who grew up as one of nine children in a rural Illinois town, is black in an industry where few African Americans reach the top.

“That’s absurd,” said Pickett of the allegations, as he stood behind his desk recently, hands fanned outward for emphasis. “It makes no sense at all.”

The dispute highlights a collision of scientific research and social realities in the development of life-saving medicines. It also illustrates conflicting principles of risk vs. benefit in the ethical guidelines that have governed all human experimentation since the Nazi era Nuremberg Trials and the notorious Tuskegee Syphilis Study.

In the Schering-Plough case, the issue is not whether to experiment on people — but who to include.

African Americans don’t respond well to existing hepatitis therapies, Pickett said. They were kept out of the early trial in case the drug wasn’t safe, he said. There were always plans to include blacks in the final Phase III trials, he said.

“The point is we didn’t want to expose a population we know are poor responders to existing therapies to an investigational new drug,” he said.

Bioethicists warn the dust-up is certain to play out again as pharmaceutical companies that employ tens of thousands in people in New Jersey deliver drugs that target diseases suffered by racial and ethnic groups.

“It’s going to put the FDA, drug companies, ethicists and everybody in an interesting boat sailing in the genetic sea,” said Arthur Caplan, chairman of the department of medical ethics at the University of Pennsylvania and director of its Center for Bioethics.

What if, for example, pharmaceutical researchers discovered a promising cure for HIV2, the strain of the AIDS virus in Sub-Saharan Africa? Despite a legitimate scientific rationale, Caplan said the scientists “could look like the world’s greatest racist” for limiting human testing to poor African villagers.

Schering-Plough faces a similar problem now, he said.

“Somebody better wake up in Washington to come up with the next generation of rules that tells how to go forward with testing drugs,” he said.

A spokesman for the FDA did not return telephone messages seeking comment.

A Big Market

Hepatitis, an inflammation of the liver, infects about two of every five HIV sufferers in the United States, mainly because both viruses are transmitted by contact with blood. It is a leading cause of chronic liver disease. Infection typically happens during sex, childbirth or the sharing hypodermic needles by drug addicts.

About half of people infected with the most common strain of hepatitis C in the United States do not respond well to the existing treatment, a combination of the protein interferon and anti-viral agent ribavirin. The injections are so physically demanding that often patients qualify for temporary disability.

For reasons unknown to science, blacks have even a lower response rate to interferon-based drugs, if they work at all.

That’s why Schering-Plough’s hepatitis drug, designed specifically to treat “non-responders,” is being watched so closely by both the pharmaceutical industry and HIV/AIDS activists. It also has the eye of Wall Street as a potentially important source of revenue for the company. The worldwide market for hepatitis C drugs is expected to reach nearly $4 billion next year.

Schering-Plough’s drug is a protease inhibitor, a genetically engineered agent designed to switch off the hepatitis virus’s ability to copy itself and spread. Stop its ability to spread, the thinking goes, and halt the disease.

Code-named SCH 503034, the tablet has been granted fast track status by the FDA, which means the agency is closely monitoring Schering-Plough’s testing program. Phase III trials that involve thousands of patients could get under way next year.

Clinical trials occur in four phases that play out over several years. Generally, Phase I tests for toxicity and Phase II establishes efficacy over ranges of dosages. Phase III is the definitive assessment, double-blind randomized controlled trials with up to 5,000 patients. Phase IV involves surveillance for side effects after the drug receives FDA approval for sale.

Only one of 10 drug candidates win final FDA approval, so the stakes are high.

Science or Business?

Dr. William Gray, a family physician in Spokane, Wash., and an official of the Association of Clinical Research Professionals, said Schering-Plough must be guided by science.

“They don’t they have any obligation to fulfill any social obligation very early in the testing of a new drug,” he said. “The research team has to come up with a development plan that is purely scientific and does not have to follow social conscious.”

But Dr. Jacob Lalezari, an assistant clinical professor at University of California, San Francisco, denounced the hepatitis drug’s Phase II trial design as “bad science.” He said it was a missed opportunity to add to the medical literature about a little-documented new medicine.

“This is a business decision,” said Lalezari, who is a supporter of the hepatitis activist movement and director of Quest Clinical Research, which develops antiviral treatments. “If black patients responded well or better they would want them in their study.”

Schering-Plough said Phase II trials will attempt to find the compound’s optimal doses and determine if it makes interferon and ribavirin treatments work better. All the Phase II volunteers had failed to respond to existing treatments.

Patients who defined themselves as African Americans, Pickett said, were excluded for fear the low dosage of interferon in combination with the new drug could “generate mutations in the virus” that made them resistant to future treatments. Black patients, he said, were enrolled in another branch of the Phase II trial that uses a high dosage of the new drug researchers believed had a better chance of working.

“If they develop resistance to this therapy,” he said, “there is no other therapy available.”

Defining Race

Schering-Plough’s clinical trial design caught the attention of Karama Neal, who has a doctorate in genetics from Emory University and has written extensively about the use of race in biomedical research.

She took part in a conference call this month with Pickett and other Schering-Plough scientists. Neal voiced opposition to volunteers “self-definition” of their race “because it’s not possible to define this concept and group at a biological level.” The University of Pennsylvania’s Caplan also panned “the crude characterization” of race in the trial design.

James Learned of the national Hepatitis C Action & Advocacy Coalition said the group wrote a letter to the FDA protesting the clinical trial design. He called Schering-Plough’s claim of safety concerns “a smoke screen” and that “we would have had the same reaction if women were excluded or any race were excluded, where we found no safety issue.”

Felix Khin-Maung-Gyi, a bioethicist at Chesapeake Research Review, which evaluates clinical trials, said the controversy is an example of the tough choices between ethical principles in the Belmont Report, which guides human medical research in the United States.

According to Khin-Maung-Gyi, the hepatitis advocates are calling for justice — the inclusion of African Americans to ensure they are afforded the benefits of the research.

The drugmaker, he said, is exercising beneficence — a risk-benefit analysis to minimize possible harm to clinical trail volunteers.

“If people died because they were not responding and we entered them in the study anyway, you could appreciate the conflict,” he said. “We should not just be all inclusive and disregard all the other principles in Belmont.”

Schering-Plough’s Pickett and Learned, the activist, meanwhile, both concede the controversy could have been defused with more extensive disclosure of the clinical trial’s goals.

“It would have made a difference,” Learned said.

Even so, Pickett was stung by the suggestion the company was biased against the very people who stand to benefit most of its new drug.

“It can have an impact on people of color who are infected by these diseases. Yeah, I’m interested,” he said. “Yeah, I was irritated. There are very few political things that catch my attention. This one caught my attention.”

(Associated Press/The Star-Ledger)




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