Two years ago on Christmas Eve, the Food and Drug Administration approved a new prescription drug mainly for mild to moderate pain. A few weeks later, Suprol entered the already crowded market for pain relievers.

But within a few months, a disturbing syndrome of acute kidney damage began to show up, nearly always in healthy, relatively young men who had taken only one or two capsules.

By early 1987, more than 300 cases had been reported to the FDA in an estimated half-million users. In May, the manufacturer, McNeil Pharmaceutical, a subsidiary of Johnson & Johnson, announced it was stopping worldwide sales of the painkiller.

In explaining that decision, McNeil president Thomas H. Odiorne wrote in a letter to 730,000 U.S. physicians: "The company continues to believe the product to be efficacious with an acceptable overall safety profile for patients not adequately controlled by other drugs. However, controversy over the flank pain syndrome {acute kidney damage} has diminished sales to the point where the product is no longer economically viable."

No deaths have been associated with the drug, and all of the people who suffered kidney pain have reportedly recovered.

For most of the public, Suprol's short career on pharmacists' shelves is all but forgotten. But the controversy lingers. To critics of the drug industry, the way Suprol won approval -- and remained on the market -- illustrates how tangled the relationship between drug companies and the FDA can be. The Suprol story also raises questions about whether the public is being adequately protected from potentially harmful drugs in a climate of deregulation.

Did Johnson & Johnson, for example, know -- before FDA approval -- that kidney damage could occur? If so, did J&J withhold the evidence from the agency despite a regulation requiring swift reporting of significant adverse reactions? Finally, were both J&J and the FDA slow in reacting to reports of kidney damage in connection with the painkiller?

The final answers will not be known until the FDA completes an investigation of possible law violations in the Suprol affair. But to Rep. Ted Weiss (D-N.Y.), Capitol Hill's leading overseer of the FDA, the episode reinforces concerns about the drug approval process.

After a months-long investigation by the staff of his House Government Operations subcommittee, the congressman held a little-noted hearing on the Suprol episode on May 27 of this year.

Although the company didn't testify at the hearing, it did reply at length in writing to questions submitted by The Washington Post, saying it had "complied with the spirit and letter of all regulations and scrupulously made all required reports of adverse effects."

In addition, the FDA in September sent a 20-page reply to detailed inquiries that Weiss had sent in February to Commisisoner Frank E. Young.

Dr. Robert J. Temple, director of FDA's Office of Drug Research and Review, who testified at the hearing, said that the Suprol case "illustrates, in many ways, how the drug-review system and its post-marketing component are supposed to work."

But to Weiss, the episode is "one more manifestation of misdirected policies, especially those based on the enduring assumption that the dangers of a new drug should be tolerated because it is new." ::

Suprol -- a trade name for suprofen -- was invented in Belgium in 1972. It is one of a class of drugs called non-steroidal anti-inflammatory drugs (NSAID), a group of pain relievers that also includes ibuprofen. J&J subsidiaries introduced it in 1982 in Europe, where it was cleared for sale by eight of 12 European Community countries. In all, it was approved by 24 countries around the world. One exception was Canada, which never approved it.

In the U.S. the company's Ortho Pharmaceutical subsidiary was the first to handle Suprol, and it filed for approval in 1978 -- but it got off to a rocky start. FDA investigators spotted what Temple in his testimony at the hearing called "suspiciously consistent" results and "wholesale fraud" in several of the pivotal studies. The incident resulted in criminal charges against two physician-testers who had contracts with Ortho and several drug companies, and the two men were later convicted of falsifying data.

Ortho repeated the studies and performed new ones. The new data indicated Suprol "to be an effective NSAID analgesic not markedly different from other members of its class," said FDA's Temple.

Ortho filed a revised application in August 1981 but, still, there were problems. Nearly four years later -- six months before the drug was approved -- the FDA's Dr. John F. Harter, who had primary responsibility for Suprol, said in an internal memo that the application "has been plagued from beginning to end with 'bad data,' " much of it "the result of poor 'workmanship' . . ."

Harter also wrote in the memo that his review team was left "with an uneasy lack of confidence that we have found 'everything' and can expect 'no surprises.' We communicated this lack of confidence to J&J's top management, but as far as we can tell it has had little effect on tying up the loose ends in this application." Hints of Trouble

During the drug approval process, FDA regulations require the sponsor of an experimental medicine -- one for which marketing approval is sought -- to "promptly report any findings associated with the use of the drug that may suggest significant hazards, contraindications, side effects . . ."

In 1982 and again in 1983, Ortho sponsored so-called "phase one" studies in which human volunteers are given a drug usually to see if it is safe, but also to assess such matters as dosage forms and amounts. Results of this study showed that some volunteers who were treated with Suprol experienced acute renal toxicity, particularly what would become a hallmark symptom in men usually in their mid-thirties: a rare "flank pain syndrome" -- severe pain in both sides between the ribs and the hip that often radiated to the groin or abdomen, accompanied by blood in the urine. Some users had decreased function of the kidneys -- impairment of their ability to cleanse chemicals from the blood.

Also in the pre-approval era, Ortho had reports of acute renal toxicity from foreign phase one studies -- one in 1982, two in 1984 and four in the first half of 1985.

Ortho's parent company J&J said that it reported the results of two of these studies to the FDA. It did not report the remainder because the researchers were examining manufacturing processes and dosages never intended for use in the U.S. -- and therefore it was not neccessary to report results under FDA regulations.

Moreover, the company said, the kidney effects did not become apparent until a review of the studies after the drug was approved.

But, in the final two months of 1985, two more critically important studies were performed by the Institute for Clinical Pharmacology in West Germany (IPHAR) that clearly signaled kidney problems associated with the drug. These tests were commissioned by Cilag AG, the J&J subsidiary in Switzerland.

The final data showed that nine of 24 healthy young male volunteers -- 37.5 percent -- "suffered either mild or moderate flank pain," according to FDA files made public at the Weiss hearing. Three others manifested signs of Suprol-related renal toxicity.

Whether Cilag -- and, in effect, parent company Johnson & Johnson -- were told these findings before the Dec. 24 FDA approval remains unclear. The FDA, in a Sept. 3, 1987, letter to Weiss responding to questions from the congressman, said it is "at least theoretically" possible Cilag was told.

Johnson & Johnson told The Post that the two IPHAR studies were not reported to Cilag until February and March 1986 -- months after approval -- and were not passed on to McNeil, the U.S. manufacturer, until March and May 1986.

Still more time passed before McNeil reported the IPHAR-detected kidney problems to the FDA. In its September response to Weiss, the FDA said that McNeil didn't send the reports to the regulatory agency until July 30, 1986.

What is clear is that neither J&J nor the FDA considered the IPHAR study results to be very significant.

In answer to The Post's questions, J&J stated that "the IPHAR cases were non-serious reactions, none of the subjects died, required hospitalization, required prescription drug therapy or suffered a permanent disability. Consequently, under the regulations, they did not need to be reported at all."

Similarly, according to Weiss' letter to the FDA commissioner, McNeil told the FDA in July 1986 that the IPHAR men "did not require hospitalization . . . or discontinuation in the study." Eight weeks later, however, McNeil amended its report and told the agency that three "required institutionalization," while three others required "discontinuation from the study."

Still, the FDA was not overly concerned. It was not until the following year -- when Weiss wrote Feb. 26, 1987, to FDA Commissioner Young -- that the agency took a closer look at Suprol. In the letter, Weiss cited seven studies done before the IPHAR studies that showed that 24 of 107 healthy male volunteers had flank or loin pain. "All these studies were reported well before Suprol's U.S. approval," Weiss said in the letter.

As Temple testified before Weiss at the May 1987 hearing: "Your letter, which went through the cases and enumerated possible instances of the flank-pain syndrome, did cause us to again look at them and realize that further investigation was needed."

Yet six months earlier, in September 1986, the Public Citizen Health Research Group, founded by Ralph Nader, had already urged the FDA to ban Suprol "as quickly as possible." HRG director Dr. Sidney M. Wolfe said in a letter to the FDA commissioner that the drug had inflicted kidney damage on many more users than the 270 cases that had been officially reported. The consumer group drew up a petition to ban the drug, which the FDA rejected. HRG then brought a lawsuit, which became moot when Suprol was finally taken off the market.

Clear 'Danger Sign'

What's more, in March 1986 -- nearly a year before Weiss alerted the FDA to growing reports of kidney damage connected to Suprol -- McNeil had asked Dr. Michael Dunn, a Case Western Reserve University kidney expert, to review adverse reactions to the drug in Americans.

Dunn, however, said he was not told of the critical IPHAR studies. His first knowledge of the IPHAR data came more than a year later, when, in preparation for the May 1987 subcommittee hearing, the staff sent the studies to him for review.

"I don't know how you could look at these data and not see a danger sign," Dunn testified. "You would literally either not have to look or have a severe visual problem."

Dunn also testified that in another pre-approval study, a male volunteer who had "acute kidney failure was dismissed from the study because of his need for hospitalization, and quite unaccountably, this was not reported as a significant effect of the drug, but rather was attributed to either . . . his fragility or his emotional content. I mean, it was extraordinary that this was overlooked."

Weiss, noting that the FDA was unaware of the "unusual renal toxicity when it approved the drug," asked Dunn whether the IPHAR and other studies would "have alerted competent medical reviewers to the drug's unusual renal toxicity when it approved the drug."

"Absolutely yes," Dunn replied.

"I agree with that wholeheartedly," Weiss was later told by Dr. William F. Keane, a University of Minnesota expert on assessing the renal toxicity of new drugs.

Still, throughout 1986, the FDA showed no major concern over Suprol. The FDA arthritis advisory panel -- which reviews drugs of this type -- met on Dec. 2 to consider what action to take regarding Suprol. The agency had no kidney experts present. In fact, the only kidney specialist was Keane, who was representing J&J's McNeil Co. Even so, as Keane testified before Weiss, no one at the FDA panel meeting asked his opinion of the pain reliever .

That "was probably the most surprising point of the session," Keane told the subcommittee. Yet at that point, he viewed Suprol as so toxic that it clearly was not a drug "that one would want to use for the alleviation of pain."

He said the next biggest surprise was the "somewhat anecdotal" deliberations "that there might be a patient somewhere in the country" who might benefit from Suprol. In the end, the consultants to the FDA panel recommended that the drug remain on sale as an alternative analgesic.

'Lax Regulation'

The FDA investigation of Suprol is now under way. J&J's position has remained unchanged. The company told The Post:

"We were not aware of the existence of the . . . syndrome at the time of approval. Rather our understanding of this phenomenon began after the drug had been marketed in the U.S. and evolved through our intensive research progam."

But beyond the specific details of the controversy over Surprol, Weiss saw in the case a larger problem, that of "lax regulation under the drug law, which requires FDA to assure that drugs are safe and effective in the uses for which they are recommended, and misuse of advisory panels of outside experts."

This was, after all, the third time in five years that the subcommittee staff had found evidence -- in the FDA's own files -- of serious and, in other drugs, even fatal adverse reactions that a drug company had reported late or not at all.

The earlier cases involved numerous unreported deaths and injuries in users of another pain reliever, Oraflex, an arthritis medicine, and of Merital, an anti-depressant. Eli Lilly, which made Oraflex, pleaded guilty to 25 criminal misdemeanors in 1985, and Hoechst-Roussel, which sold Merital, is under FDA investigation.

Finally, new questions are being raised about NSAIDs pain relievers as a class. As recently at Sept. 26, a report in Lancet, a leading British medical journal, cited studies showing that "nearly three quarters of patients on long-term treatment with {NSAIDs} have small-intestinal inflammation, the consequences of which are unknown." The studies showed that the inflammation was "associated with blood and protein loss, both of which may contribute to the general ill health of rheumatic patients," the article said.

And still the story of Suprol won't go away. On May 15 -- the same day worldwide sales were halted -- the company also told U.S. doctors "existing supplies . . . can be dispensed to patients and taken in accordance with the current prescribing information." The company told the FDA: "There is no health hazard involved."

Dr. Carl C. Peck, who recently became director of the FDA's new Center for Drug Evaluation and Research, wrote on Nov. 18 to HRG's Wolfe:

"I understand that the decision regarding recall was a close one in which there was some disagreement within FDA and the advisory committee staff.

"Like you, I am concerned about the residual suprofen that is 'out there.' I am told that we will receive an estimate of the quantity within a few weeks from the company."