[From the Washington Post]

ABBOTT LABORATORIES PROBED-FDA'S METHODS "QUESTIONABLE," HOUSE UNIT SAYS

(By Morton Mintz, Washington Post staff writer)

On the morning of September 1, 1964, Inspector Jerome Bressler, of the Food and Drug Administration, got a phone call from the agency's Chicago district office.

"Bail out," he was told. "Get out before noon."

The call was made while Bressler and two colleagues were in the third day of an inspection at the huge plant of Abbott Laboratories in North Chicago, Ill.

Up to that point, the Bressler team had observed 25 questionable manufacturing practices and listed 14 specific recommendations for improvement. But they bailed out. The time: 11:56 a.m.

The bail-out order originated in Washington with Allen E. Rayfield, Head of FDA's Bureau of Regulatory Compliance.

He phoned Clifford G. Shane, chief inspector in Chicago, and said, "I want them out by noon," Shane testified.

Rayfield gave no explanation, Shane told the House Intergovernmental Relations Subcommittee. He "hung up and that's the end of the conversation."

Rayfield's testimony was that he thought he had given his reasons: The team had been in the plant long enough, had discovered nothing new, and was making production personnel nervous, increasing the possibility of error. He also believed Abbott needed more time to initiate new control procedures, he testified.

The inspectors and Rayfield who began his FDA career as a seafood inspector 30 years ago, were among the agency witnesses heard by the subcommittee during five executive sessions held from July through September.

The 673-page transcript of the hearings, which used the Abbott matter to provide a case history of FDA's performance, now has been made public.

Representative L. H. Fountain, Democrat, of North Carolina, chairman of the subcommittee, said yesterday that "the hearings clearly demonstrated some highly questionable actions and procedures on the part of FDA in administering the 'good manufacturing practices' provisions of the Drug Amendments of 1962.' He said he expects the full House Government Operations Committee to make recommendations intended "to strengthen generally this important phase of FDA's drug safety activities."

The transcript shows that the day before Rayfield ordered the inspectors out he conferred here with Elmer O. Krueger, director of quality control for Abbott.

But Rayfield denied under oath that the drug company executive had asked for a halt to the investigation.

Subcommittee investigators, however, produced a memorandum from Abbott's files in which Krueger said that at the August 31 meeting he had asked Rayfield to "give serious consideration to my request" that the inspection be delayed on the ground that this would better serve the public interest. The memorandum added that Rayfield "indicated that he would."

Questioned by Representative Fountain about "this conflict," Rayfield insisted he had no recollection of Krueger's requests, although the executive "may well have" made it.

"I do not know any other explanation I can make, sir,” he said.

The circumstances of the bail-out order figured in a charge by Fountain that "much conflicting testimony" and "lapses of memory"-most of them Rayfield's prevented the subcommittee from getting all the facts from FDA witnesses. The provisions of the law with which the legislators were concerned classify drugs not produced in accord with current good manufacturing practices as adulterated and provide criminal penalties. They do not take a manufacturer's intent into account.

FDA Commissioner George P. Larrick, in an open session preceding the closed hearings, restated to the subcommittee the position he took in a 1960 speech. "Drug manufacturers who do not have adequate scientific control facilities," he said, "are toying with the health of the American public.”

At the same session the subcommittee inserted in the record another speech, made here a year ago, in which an Assistant Commissioner, Winton B. Rankin, said there had been 243 recalls of drug lots in the 21⁄2 years ended June 30, 1964many more than in any comparable period in the past.

Rankin attributed the 243 recalls "in part to a breakdown in control in a significant number of pharmaceutical manufacturing plants."

In the closed hearings that followed, the subcommittee investigated how FDA, in 1964 and 1965, handled a series of recalls of injectable solutions. In the case of Abbott Laboratories, the quantitites of the commonly used solutions involved in the recalls were among the largest in the agency's 59-year history. Although reports of one death and numerous adverse reactions were received, the subcommittee said, it found no clear-cut evidence that these were attributable to the mixups.

In a statement yesterday, Abbott said that "contrary to" a summary prepared by the subcommittee "no serious medical difficulties were reported to Abbott *** nor to our knowledge *** to the FDA.”

Abbott officials were interviewed in Chicago by subcommittee investigators but did not testify. The subcommittee staff said the company was aware of the hearings and would have been granted an opportunity to testify had it requested it.

Defending the FDA's role in the Abbott case, Acting Commissioner Rankin said, "We believe the public interest has been fully protected throughout."

The first phase began on April 30, 1964, when Abbott notified FDA that it was recalling 11,430 bottles of intravenous solutions after 500 incorrect labels accidentally went into a labeling machine. A total of 11,215 were recovered and destroyed including 483 out of 500 that had been accidentally mislabeled. Patients had received 151.

Involved in the mislabeling were dextrose (sugar) and sodium chloride (salt) solutions. FDA medical personnel saw a hazard, especially to diabetics.

In this and later recalls, Abbott said yesterday, the possibility of harm was "extremely remote." Among seven independent medical experts it had consulted on this question, Abbott said, six agreed and one did not express an opinion.

CHANGES PUT INTO EFFECT

FDA sent inspectors to the Abbott plant. They found 27 objectionable practices, many relating to labeling in manufacturing processes. Within about 2 weeks, FDA said, its "major recommendations" had been effected. On July 1, 1964, the case was placed in permanent abeyance.

The second phase began on August 13, 1964, when Abbott learned that a second batch of solutions-made before the recommendations had been effectedhad label mixups.

Abbott employees recovered 10,461 out of the 11,256 bottles involved. They also launched a check of each of the 7 million bottles of all Abbott injectable solutions in distribution channels throughout the Nation. This check was audited

by FDA inspectors who looked at 900,000 bottles.

The results were in on August 28: 69 bottles in 54 different manufacturing lots were found mislabeled. On that date, a second plant inspection, the one which lead to the "bail out" instruction to FDA inspectors, was started.

In a very few instances, the subcommittee said, FDA inspectors found that Abbott personnel had violated company orders by saying they had checked bottles when they had not.

USERS WARNED BY TELEGRAM

Six days earlier, at a meeting here between FDA and Abbott officials, the company agreed to send telegrams-400,000 of them-to all potential users. The telegrams warned against use of any bottle with a cap and label giving conflicting information.

In his statement yesterday, FDA's Rankin noted that the wires cost Abbott $385,000. The cost to the firm of the 1964 phases as a whole was indicated by Rayfield's testimony to be about $1 million.

Last year, the firm earned $22.5 million after taxes on sales of $212.6 million. The warning telegrams, Rayfield testified, were considered adequate action by Dr. Arthur Ruskin, deputy director of FDA's Division of New Drugs.

But Dr. Ruskin said otherwise in a memo that the subcommittee found in FDA files. The memo was dated August 25, 1964, 3 days after the meeting between FDA and Abbott officials.

Because of the large number of mixups, he wrote, and because of "the impossibility of determining if bottle contents may not be labeled properly by either bottle cap or bottle label, we recommend that all Abbott injectables be removed from the market ***"

Dr. Ruskin cited eight afflictions, including heart, kidney, and liver disease, in which a mixup "might prove fatal."

The subcommittee wanted to know why this recommendation-which Rayfield estimated would have cost Abbott $5 million-had been dropped in favor of a less costly, less drastic action.

Rayfield testified that the memo had been prepared for the files and had not been shown to anyone with regulatory responsibility.

The memo, typed on yellow paper, was in fact not addressed to anyone.

STILL ANOTHER MEMO FOUND

Subcommittee investigators found another memo in FDA files that bore the same date as Dr. Ruskin's. This one was written by Julius Hauser, then assistant to Dr. Joseph F. Sadusk, the medical director.

Hauser, wrote that the 45 batches known as of August 25, 1964, to have label mixups "are more than sufficient to establish that all parenteral (injectable) drugs produced by the firm by the same methods and using the same facilities and controls are adulterated within the meaning of" the 1962 amendments to the drug law.

Hauser, who, like Dr. Ruskin, was not called to testify, recommended removal from the market of all questioned Abbott injectable solutions "as promptly as possible."

"I have no explanation" for the Hauser-Ruskin memos, Rayfield testified. He added that the adequacy of the telegram warnings was concurred in by Commissioner Larrick and Dr. Sadusk.

Larrick has been widely reported to be planning to retire (and his Deputy, John L. Harvey, has confirmed that he does plan to retire). Dr. Sadusk's decisions in the drug-safety area have been sharply criticized by Fountain in earlier hearings.

NEEDS OUTWEIGHED RISKS

In the Abbott statement yesterday, the firm said that recall of all of its injectables would have created a "health hazard vastly greater than the remote risks of a few mislabeled bottles," because of "the need of the majority of hospitals *** for Abbott's huge production."

Also explored by the Fountain subcommittee with the role played by Deputy Commissioner Harvey, one of whose brothers is an Abbott sales executive.

"I have not consulted with him," Rayfield testified in his initial subcommittee appearance. "I have deliberately avoided him on this matter."

He went on to say that although he had kept FDA's second-raking official "on board" (informed of developments), Harvey, who also plans to retire, had told him:

"Allen, I am not going to get involved in the decisionmaking process. I have a brother connected with Abbott."

But in a second round of questioning Rayfield was confronted with a memo prepared by James Nakada, the FDA headquarters employee with primary responsibility for monitoring the Abbott recalls.

The memo told of a meeting at FDA on September 1, 1964-the day Rayfield phoned the out-by-noon order to Chicago.

Nakada wrote that Rayfield discussed the situation with Harvey who had, recommended a tough choice be given Abbott:

Either "recall all lots where mixups were found," which Abbott was reluctant to do, or else "issue a complete information letter" to everyone who might have stocks of the drugs in question.

Nakada testified that he attended the meeting.

Representative Fountain then asked Rayfield why-having told the subcommittee earlier that the Deputy Commissioner was not making decisions in the Abbott matter-he went to Harvey for a decision.

Rayfield rummaged among possibilities, then suggested one-for which he had no documentation-that it was not Harvey who made the decision, but Commissioner Larrick.

On the day the inspectors left, Abbott elected to recall every batch in which there was mislabeling. The firm retrieved 131,510 bottles.

Fourteen days later, the situation apparently changed. The subcommittee found still another memo, this one dated September 15, in which Krueger, the Abbott executive, said he had met with Rayfield (no one else was present) and reached an agreement.

With certain exceptions, Kreuger wrote, he had been given authority to decide whether to recall additional lots of injectable solutions if discrepancies were discovered between bottle label and bottle cap information.

The subcommittee brought out:

(1) That Rayfield's office calendar showed an appointment with Kreuger on September 15, 1964-the date on the memo.

(2) That Chief Inspector Shane testified that Krueger had cited the agreement to him in refusing certain lots of solutions with label mixups.

Shane phoned Washington to find out if the agreement existed. Rayfield, who was out of town, was phoned by his deputy, Franklin D. Clark. Shane and Nakada testified that Clark told them Rayfield had verified the agreement. Clark's testimony was that he couldn't remember the incident.

While minimizing the importance of the agreement, the Abbott statement implicitly acknowledged its existence.

Yet, Rayfield swore that he could not recollect having met with Krueger on the day in question, or of having reached the agreement.

Fountain found this "a little unusual." Rayfield replied, "I am afraid I must agree with you." If in fact he had made the agreement, he added, "it was a bad decision * * *."

The final phase of the Abbott plant last June. tered by the inspector.' (1) The inspector had

new cap liner.

THIRD INSPECTION MADE

Abbott episode involved a third inspection made at the
Rayfield testified that "there was no problem encoun-
But the subcommittee brought out that:

found a significant problem involving trouble with a

(2) A finding by a supervisor that there were "inadequate manufacturing control procedures" had been deleted after another phone call by Rayfield to FDA's Chicago office.

Last September 22, Commissioner Larric, wrote Fountain that Abbott was recalling 310 lots (3.4 million bottles) of bulk solutions made between October 1964 and April 1965. The reason: The cap line problem cited by the inspector in June.

Rayfield then conceded that he had knowledge of the problem when he had testified earlier.

Why hadn't he mentioned it? Because, he testified FDA had not concluded that the problem represented a deficiency in manufacturing methods.

Abbott said in its statement that the factsheet and summary released by the subcommittee "do not fairly reflect" the 673-page transcript. The quotations in this story were taken from a 2-day reading of the transcript.

The company also said that the factsheet and summary "cast unjustified doubts on standards and practices" of Abbott, FDA "and on the quality of drugs produced in the United States."

Mr. FOGARTY. Will you give us an answer to this? Your name is in here.

(The statement requested follows:)

FOOD AND DRUG ADMINISTRATION STATEMENT ON ABBOTT LABORATORIES Drug RECALL

The Food and Drug Administration believes the public interest has been fully protected on the matter of the recall of certain batches of parenteral solutions manufactured by Abbott Laboratories. The facts are as follows:

1. THE LABEL MIXUP

On April 30, 1964, FDA learned from Abbott that a customer had reported a bottle with the right cap but the wrong label.

Immediate inspection established that in preparing a 11,430-bottle batch, 500 wrong labels had been used.

Recall was instituted at once and 11,215 bottles were recovered.

We told Abbott that we had noted deficiencies in its control and manufacturing operations, and our major recommendations for improvement were placed into effect by May 15, 1964.

Later, in August 1964, Abbott learned that another batch produced in April, before it improved its procedures, had been mislabeled. Out of 11,256 bottles, 10,461 were recovered.

This precipitated a bottle-by-bottle examination of Abbott's entire stock in the channels of distribution, amounting to approximately 10 million bottles at points all over the United States. Abbott examined all of this stock; we checked 900,000 bottles. This turned up a total of 69 bottles with the wrong cap or label.

Since these 69 bottles came from 54 different lots, Abbott was required at a cost of $385,000 to send telegrams to all doctors, nursing homes, sanitariums and clinics, telling them not to use any bottle on which cap and label did not match.

Abbott also was required on September 1, 1964, to recall every batch in which even one bottle had been found with the wrong label. Forty-nine batches, totaling 131,510 bottles, were recalled.

FDA has continued to check on the situation. A total of 122,000 Abbott bottles in hospitals throughout the country have been examined in a survey conducted without finding a mislabeled or miscapped bottle.

2. MOLD IN PARENTERAL SOLUTIONS

FDA's Boston district on October 5, 1964, in connection with the mislabeling survey, reported finding two lots of Abbott products at a Windsor, Vt., hospital, that contained mold.

This hospital had 12 bottles, but it had had them for almost 4 years.

FDA's 1964 survey of 900,000 bottles discovered only one other unopened bottle with mold. It too was almost 4 years old.

Parenteral solutions are subject to deterioration because of conditions of storage or age.

The label states:

"Do not use if not sparkling clear or if the seal is broken or damaged."

3. FAILURE OF CAP LINERS

Late in 1964 Abbott changed to a new plastic cap liner because of inability to obtain the kind it had previously used.

This new liner was discontinued in April 1965, because of complaints by customers of leaks.

When Abbott advised us of this, a further nationwide investigation was conducted.

A recall was initiated by Abbott of all stocks using the new liner. As of January 28, 1966, 489,277 bottles had been returned. We found one sample to be nonsterile and recommended seizure, but it was brought back to Abbott by the recall before the seizure could be effected.

FDA STATEMENT ON ORAL CONTRACEPTIVES

Mr. FOGARTY. The same writer had an article, reprinted in my local paper back home, which I cut out some time ago. The headline was "How Safe Is the Pill? Millions of Women and Their Doctors Trust It. How Well Was It Tested?"

[From the Providence Journal-Bulletin, Dec. 19, 1965]

HOW SAFE IS "THE PILL"? MILLIONS OF WOMEN AND THEIR DOCTORS TRUST IT HOW WELL WAS IT TESTED?

(Millions of women in the United States and abroad are now using "The Pill"— the familiar name given to one or another of the numerous oral contraceptivesto avoid unwanted pregnancies. So far as can readily be determined, most of them, and most of their doctors, have every confidence that the pills are effective, reliable, and safe. Yet, during the last year or two, a number of physicians and researchers have openly expressed doubts about the quality of the testing upon which approval-and hence the presumed certain safety-of "The Pill" rests.

(The following story is an account of those doubts and reservations and the opinions of the men holding them. It is based on exhaustive interviews with medical specialists, examination of testing procedures and the study of testimony before congressional committees. The writer is Morton Mintz, a reporter for the Washington Post who first wrote the story of how Dr. Frances O. Kelsey of the Food and Drug Administration prevented the marketing of the drug thalidomide. Mr. Mintz has been a Post reporter since 1958 and was a Nieman Fellow at Harvard in 1963-64. He is the author of new book, "The Therapeutic Nightmare," which is critical of the roles of the FDA, the American Medical Association, and drug manufacturers in drug testing and marketing.