Keith Epstein

Foreign Tests Don't Meet U.S. Criteria

Hype, hope and heartbreak a chronic condition

Plain Dealer – December 17, 1996

SERIES: DRUG TRIALS

Third of four articles

Trouble started on Oct. 12, 1994, when two inspectors from the Food and Drug Administration entered Dr. Geoffrey Dusheiko’s cramped office on the 10th floor of London’s Royal Free Hospital and flashed their badges like FBI men.

They got straight to the point. Did ribavirin really work?

The government had been asking the same question for two decades.

The first time, the drug’s maker hailed it as a treatment for viruses like influenza.

The FDA said it wasn’t.

In the 1980s, activists smuggled it from Mexico when scientists touted it as a therapy for AIDS. The FDA said it wasn’t.

Now, it was back – a drug in search of a disease.

The hope this time: Ribavirin could combat a deadly strain of hepatitis virus that infects almost 2 million Americans.

For the desperately ill, there finally seemed a glimmer of hope. On Wall Street, investors were tantalized; sales of the capsules might exceed $500 million a year. In Ohio, the teachers’ pension fund sank almost $14 million into the drugmaker’s stock.

Without much ado, Dusheiko defused the optimism. After four years of European tests, he privately told the FDA inspectors in his office that ribavirin had shown no sustained benefit. Despite improvements in liver function tests, Dusheiko’s research had demonstrated “little anti-viral activity.”

The manufacturer, ICN Pharmaceuticals Inc., had submitted Dusheiko’s findings as evidence that ribavirin was safe and effective. The FDA inspectors concluded he had incomplete biopsy reports, had failed to record all adverse effects and had used an inadequate consent form.

Once again, the FDA rejected ribavirin, though for four months only a handful of insiders knew. When word spread, the stock plunged – 42 percent within two weeks. Some shareholders accused insiders of selling stock before bad news deflated the price. Soon, the FBI – the real FBI – started asking questions.

Possible insider trading. Thrilling projections. Criticism from an American agency. Questions about consent. The FBI. It all left the researcher in London, who thought he had played by the rules in England, feeling bewildered.

“We did not know that the results would be submitted to the FDA,” Dusheiko said. His lawyer said the study “did not violate any legal standards in England. … FDA standards were not applicable.”

The cycle of hype, hope and heartbreak surrounding clinical trials has become a chronic condition in the increasingly global pharmaceutical industry, which now initially tests nearly two-thirds of all products for Americans overseas, 64 percent more than in 1975.

Previously undisclosed foreign records and more than 2,000 pages of internal FDA documents contain accounts of fraud, concealed side effects, improvised experiments and human rights abuses. Consent forms were incomplete or inadequate in 65 of 137 FDA inspections of foreign drug trials. In the most inspected nation, Canada, consent forms were inadequate in 21 of 36 inspections.

“Fraud and unethical conduct and sometimes mistreatment of human subjects is present everywhere,” observed Jean-Marc Husson of the French pharmaceutical firm Roussel-Uclaf, who estimates one in 10 European drug trials is fraudulent. “We need to have a better global system to detect and deal with fraud.”

But the industry’s most crippling ailment is this: More than half the foreign research submitted by pharmaceutical companies to the FDA during the last decade lacked vital documentation such as X-rays, blood tests, biopsies, lab reports and patient charts.

Verifiable scientific data was missing from 53 percent of the international research known to have been submitted to the FDA, contrasted with only 27 percent of research submitted from the United States, a Plain Dealer computer analysis shows.

Asked about The Plain Dealer’s analysis, FDA Associate Commissioner Mary Pendergast said the reason for the disparity is that overseas trials of investigational new drugs can begin without FDA permission.

Thus, she said, “there’s no expectation up front” that human research will meet U.S. regulations.

Any company with the $116,500 deposit for a New Drug Application can make an exciting claim and submit summaries of research findings. Only the details contained in humdrum, everyday medical records can separate the miracle cure from the snake oil.

Examples of missing, manufactured, altered or omitted data have been found by FDA inspectors on five continents.

Hopes for a new low-dose birth control pill for American women were dashed when doctors in Mexico City were unable to produce any records from tests on 1,000 patients. The records had been thrown away, the doctors said, because they wanted to avoid Mexican taxes on income from a U.S. drugmaker.

In Edmonton, Alberta, a few years later, the FDA found records. But they differed from summaries the British drugmaker submitted in 1986. Women on a breast cancer drug were said to have had a “partial response” when they had no response. A woman reported to have “no change” in her condition had actually gotten worse. And in a patient with a tumorous mass, doctors noted “no measurable disease.”

In Glasgow, Scotland, in 1990, cardiologists testing for an American pharmaceutical company did not disclose to some patients the risks of a heart drug and could supply no written evidence they had obtained consent from 10 other patients, an FDA inspector found. Researchers also lacked lab data and failed to mark dates of echocardiograms, and some side effects went unreported, according to the inspector.

“Nobody’s immune to this problem or its potential consequences. Missing records and faulty records always raise red flags,” said Arthur Horowitz, who prepares researchers for FDA investigations by inspecting them first himself.

Horowitz has a list of excuses he has heard. The alibis sound like “my dog ate it,” the schoolboy’s classic excuse for missed homework: They were destroyed in a fire/flood/hurricane/earthquake. They were dropped in a sewer. They were lost in a boating accident. My office was burglarized. They were lost in the mail. My father-in-law threw them out.

For Hans-Joachim Giesecke, a busy German internist in the industrial city of Mainz, the difficulty arose over quinapril capsules. During 1985 and 1986, Giesecke tested them on his elderly patients with congestive heart failure.

Like Dusheiko, he had no idea his results would be offered as evidence that the product should be approved for Americans. And how could he? Back then, even the Parke-Davis Group of pharmaceutical giant Warner-Lambert Co. had no plans to seek U.S. approval. At most, Parke-Davis anticipated the drug might be successful in Europe.

“The U.S. marketing department wasn’t interested,” recalled Hans Gunther Stelzer, who oversees Parke-Davis research in Europe. “Our goal was Europe, that was all.”

Within a few years, Parke-Davis sensed it had missed the mark – or was about to. Worldwide sales of the newest class of drugs for congestive heart failure, known as angiotensin-converting enzyme (ACE) inhibitors, by 1992 soared to $5 billion, nearly $2 billion in the United States.

Parke-Davis again compiled the paperwork given to German authorities, who had approved the drug.

By 1993, summaries of the research, by Giesecke and two other German physicians, were at FDA headquarters. All three declined to be interviewed.

It fell to Stelzer to double-check the data. As manager of clinical quality assurance, he often treks across Europe conferring with researchers and examining their records. When the FDA asks to inspect, Stelzer’s job is to try to get there first.

When he got to Giesecke’s office at 1 Erthalstrasse to check the patient records, the doctor “invited me into his basement and said he was sorry but he couldn’t find them anymore.”

Then, on May 24, 1993, a pair of FDA inspectors showed up at Giesecke’s doorstep. With Stelzer looking on, the doctor began giving them records.

“I was sitting there, and I was very surprised when [Giesecke] suddenly showed them some records that hadn’t been there before,” recalled Stelzer. “I was very nervous indeed.”

The ink appeared to be fresh, an FDA inspector noted. A study card for patient No. 11 bore erroneous dates, Feb. 4 to May 30, 1996, still three years in the future.

How could this be? the inspectors asked.

“I don’t know,” they quoted Giesecke as answering. “It was a very big mistake.”

Perhaps, he speculated, somebody spilled coffee on the original in 1986 or 1987 and the nurse made a new card with incorrect dates.

“I think he was embarrassed and, because the FDA was coming, he wanted to show he kept good records,” Stelzer speculates. “But it all looked so new.”

At the two other test sites, there wasn’t enough reliable data for FDA approval; the company substituted results from Britain.

The British results were verified and finally, in October 1993, the FDA approved quinapril for U.S. marketing – a delay caused not by excessive bureaucratic red tape, but by the drug company’s submission of questioned research.

Stelzer said the experience prompted changes at Parke-Davis. “Even though many German clinicians don’t keep their records, and neither do many doctors in private practice throughout Europe, now we insist on it.”

Quinapril has proven successful. Sales last year shot up 37 percent.

Raymond J. Lipicky, director of the FDA’s Division of Cardio-Renal Products, which reviewed Parke-Davis’ application, sees quinapril as “a perfect example of the problem of lack of source documents” in foreign research.

“We make decisions based on numbers and doing statistical tests on those numbers. If the results are not accurate … all of our conclusions are wrong. If our conclusions are wrong, it means we’ve decided something is effective when it isn’t, or safe when it isn’t.”

As for ribavirin, it continues to be used in the United States as a spray to treat infants hospitalized with severe respiratory tract infections caused by the respiratory synctal virus. Twenty-one developing countries have approved it for hepatitis.

ICN has granted Schering-Plough Corp. a license to try the promising combination of ribavirin with interferon A.

A special committee of ICN’s board of directors has exonerated the company’s top executive of insider trading. The lawsuits continue.

Meanwhile, scientists are on the trail of yet another potential breakthrough. They’ve started experimenting with a Syrian folk cure for hepatitis – a liquid extract from a plant called the salt cucumber.
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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.

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.

U.S. Medical Researchers Flout Rules Around World On nearly every continent, the U.S. government and its clinical trials partners have hidden risks and undertaken medical experiments without legally required  agreements to avoid human rights abuses.