【疑问旧事】先灵葆雅曾因产品质量问题被罚5亿美元

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Drug Maker to Pay $500 Million Fine ForFactory Lapses

By MELODY PETERSENMAY 18, 2002

The Schering-Plough Corporation announcedyesterday that it had agreed to pay $500 million to the federal governmentbecause of its repeated failure over the years to fix problems in manufacturingdozens of drugs at four of its factories.

If approved by the United States DistrictCourt in Newark, the agreement would impose by far the highest financialpenalty on a pharmaceutical company for failing to comply with federalmanufacturing guidelines. In 1999, Abbott Laboratories paid $100 million tosettle accusations about manufacturing problems.

The agreement with Schering-Plough coversviolations, dating back as far as 1998, that government inspectors found in thecompany's factories in New Jersey and Puerto Rico. Some of the problems relateto the lack of controls that would identify faulty medicines, while others stemfrom outdated equipment. They involve some 200 medicines, including Claritin,the allergy medicine that is Schering's top-selling product. The manufacturingproblems have caused shortages of several drugs, including Celestone, which isused to speed the development of the lungs of premature infants.

In March 2000, Schering-Plough recalledmillions of asthma inhalers, saying there was a remote possibility that somedid not contain a key ingredient. Many of those inhalers were manufactured andshipped long before the recall.

Under the proposed agreement,Schering-Plough must submit a plan to the Food and Drug Administration forbringing its factories into compliance with federal rules. The company mustalso station specially trained personnel at each factory to oversee operations,and hire outside consultants to conduct annual inspections. Federal regulatorswill also inspect the factories.

''This action is another clear sign thatF.D.A. will continue to enforce the rules and regulations requiring companiesto carefully control and monitor their processes,'' said Dr. Lester M.Crawford, the F.D.A.'s deputy commissioner, in a statement. ''Manufacturers whochoose to wait until F.D.A. investigators find violations rather than policingthemselves will find that they have made a poor and costly decision.''

In addition to Schering-Plough and Abbott,several other large drug makers have recently been criticized by federalregulators, who have found numerous problems with how they make prescriptiondrugs and other medical products. The reasons for the growing number ofproblems are hotly debated. The industry has tended to attribute the rise towhat executives describe as overly aggressive regulators, while the F.D.A. hassaid that drug companies have failed to keep their factories up to date.

If Schering-Plough fails to meet the termsof the agreement, which is known as a consent decree, the government couldimpose even greater financial penalties.

In a statement yesterday, Richard JayKogan, the chairman and chief executive, said the company believed that all ofits pharmaceutical products were safe and effective.

''We are confident of our ability to moveforward under the agreement and complete our improvement programssuccessfully,'' he said.

But Schering-Plough also said the proposedagreement did not resolve a continuing investigation by the F.D.A.'s Office of CriminalInvestigation in Puerto Rico, where the company has two factories.

The company has said it does not know whatproducts may be involved in that investigation, which is at a preliminarystage, and the F.D.A. has declined to comment on the inquiry.

There has been speculation on Wall Streetthat the inquiry might center on whether products were manufactured withinsufficient amounts of active drug ingredients.

In the 2000 recall, the company was forcedto take millions of inhalers off the shelf after determining that some of themmight not have been properly filled with albuterol, a drug that helps asthmasufferers breathe. Those inhalers were made in New Jersey.

Government inspectors found similarproblems last year at the company's factory in Manati, P.R., according toinspection reports. For example, hundreds of consumers have complained that thecompany's Nasonex nasal spray, which is made at that factory, did not work, thereports said.

Last year, Public Citizen, theWashington-based consumer group, called for a criminal investigation ofSchering-Plough after finding that some asthma patients had died while usinginhalers that were later recalled.

Dr. Sidney Wolfe, the director of PublicCitizen's health research group, said that a lawyer from the United Statesattorney's office in New Jersey and an official from the F.D.A.'s Office ofCriminal Investigation had interviewed him last fall about the information hehad obtained about the inhalers and the patients who died.

Robert J. Consalvo, a spokesman forSchering-Plough, said yesterday that the company had no indication that theinvestigation might center on the asthma inhalers.

Under the consent decree announcedyesterday, Schering-Plough agreed to recall two drugs used to treat asthma --Proventil Repetabs and theophylline -- because tests showed they mightdeteriorate before their expiration date.

The company said it had also decided thatit would no longer manufacture dozens of other older products. AndSchering-Plough said it was temporarily suspending production of certain animalhealth products -- including Nuflor, a medicine for foot rot in cattle -- thatare made at the plant in Manati.

Schering-Plough said late last year that itmight have to pay as much as $500 million to the government. The company hasalready reserved for such a payment in its financial statements.Schering-Plough said yesterday that it was lowering its expected earningsgrowth rate for this year to a ''mid-single-digit'' percentage from the ''lowdouble-digit'' figure it had projected previously.

Despite that change, the stock price roseyesterday by more than 5 percent, or $1.37, to $26.12, although it is down 27percent for the year.

Timothy M. Anderson, an analyst withPrudential Securities, said the company's announcement of the agreement hadhelped clear up some of Wall Street's uncertainty about Schering-Plough.

syhorchid

先灵葆雅是一家全球性的跨国制药公司

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多个工厂存在生产问题，并且多年没有解决持续的生产质量问题，导致其新的重要产品批准延迟，同时公司主席 Mr. Cesan以及CEO Mr. Kogan相继辞职。

Public Citizen asked for the inquiry after receiving a copy of an internal consultant's report on the factory problems and a recent F.D.A. inspection report. The two reports were sent by a person who also included a letter mentioning Mr. Cesan. In the letter, the person refused to be identified out of fear of dismissal.

''Under the present C.O.O., Raul Cesan,'' it said, ''this company has changed from a quality drug manufacturer to one that is now profit-driven.'' The letter added: ''Within the past two years, many quality directors and upper management were driven out and replaced with unqualified people. The result, as the F.D.A. report indicates, is a product that is not within the level of quality, purity or safety that the company purports it to be.''

A spokesman for Schering-Plough refused to comment on the letter.

选自:Factory Problems Unresolved, Schering-Plough President Is Out

        Schering Chief Executive Is Stepping Down

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Table 1. - Warning Letters Issued toSchering-Plough by the Food and Drug Administration for Good ManufacturingPractice Guideline Deficiencies for the Production of Human Drugs Since June1998

Date	Facility	Drug(s)  Involved	Examples of  Problems Noted in Warning Letters
6/29/98 [5]	Las Piedras,  Puerto Rico	Theo-Dur,   Claritin 10 mg	Extension of  expiration period for Theo-Dur, an asthma drug.   Failure to investigate variability in Claritin 10 mg tablets, an  antihistamine.
10/23/98 [6]	Kenilworth and  Union, New Jersey	Proventil  Inhaler, Claritin D,   Diprolene Oint., Nasonex Nasal Spray	Proventil  Inhaler, an important asthma drug, failing pressure results.   Claritin D, a combination antihistamine-decongestant, dissolution rate  problems.   Diprolene Ointment, a topical steroid, out of specification assay results.   Nasonex Nasal Spray, used for allergy, failed to conform to all specifications.
11/23/98 [7]	Innishannon,  County Cork, Ireland	Intron A	Intron A is an  injectable used to treat a variety of disorders including some cancers and  chronic hepatitis C. Failure to establish appropriate procedures to insure  that Intron A is sterile.
7/21/99[8]	Kenilworth and  Union, New Jersey	Vanceril DS  Inhaler, Proventil Inhaler	Vanceril  Inhaler, used to treat chronic asthma, failure to follow test procedures and  failure to meet specifications.   Proventil Inhaler, also for asthma, there was failure to properly test the  content of canisters.
5/8/00 [9]	Manati, Puerto  Rico	Garamycin  Ophthalmic Solution,   Vancenase AQ, Nasonex Nasal	Garamycin is  an antibiotic used to treat eye infections. There was failure to perform  adequate investigation into the cause of out of specifications results for  stability testing for some batches of the drug.   Vancenase AQ and Nasonex Nasal suspension are used for allergy treatment.  There were deviations from protocol for the Uniformity of Spray Content  Assays for these products.

Appendix 1.- Chronological Sequence ofEvents

Date	Action	Drugs  Mentioned	Documentation
5/7/98	Inspection -  Las Piedras, PR		From the 6/29/98 Warning Letter
6/29/98	Warning Letter  - Las Piedras, PR	Theo-Dur  Claritin 10 mg	www.fda.gov/foi/warning_letters/d1423b.pdfaccessed  2/19/01
7/30/98	Inspection -  Kenilworth and Union, NJ		From 10/23/98 Warning Letter
10/23/98	Warning Letter  - Kenilworth and Union, NJ   "Current regulations specify that drug products failing to meet  standards or specifications and any other relevant quality control criteria  shall be rejected. Reprocessing may be performed, provided certain criteria  are met according to written procedures. The practice of partial releases, no  matter how stringent the re-sampling, raises doubt as to the safety and  efficacy of the product being released. It is not acceptable to substitute  testing over adequate control of a process."	Claritin-D,  Diprolene Oint, Proventil Inhaler, Nasonex Nasal Spray	www.fda.gov/foi/warning_letters/m2366n.pdfaccessed  2/19/01
11/23/98	Warning Letter  - County Cork, Ireland	Intron A	www.fda.gov/foi/warning_letters/m2327n.pdfaccessed  2/19/01
5/28/99	Inspection  Union and Kenilworth, NJ		From 7/21/99 Warning Letter
6/7/99	Teleconference  in NJ between S-P and CDER concerning Proventil and Vanceril inhalers.		From 7/21/99 Warning Letter
6/17/99	Meeting at FDA  between S-P and CDER to discuss conditions under which S-P may resume  shipment of Proventil Inhalers.		From 7/21/99 Warning Letter
6/25/99	CDER letter to  Dr. Alexander Giaquinto, Sr. VP, Worldwide Regulatory Affairs detailing a  four-phase proposal for the release of Proventil Aerosol. S-P must strictly  adhere to the proposal to continue distributing Proventil Inhalers. This  amounts to "prior approval" by the FDA.		From 7/21/99 Warning Letter
7/21/99	Warning Letter  - Union and Kenilworth, NJ   The 6/15/99 response to the 10/23/98 Warning Letter was not satisfactory.  Drug products failing to meet established standards or specifications and any  other relevant quality control criteria shall be rejected. Retesting later is  not an acceptable practice.	Vanceril   Proventil	www.fda.gov/foi/warning_letters/m2818n.pdfaccessed  12/19/01
9/9/99	Class I Recall -  Warrick Pharmaceuticals Albuterol Aerosol. 190, 679. AL, CT, FL, GA, KY, MD,  MA, NJ, NY, NC, OH, PA, RI, TN, VA, WV. Some units fail to contain active  ingredient.   The recall affects a lot that was distributed between late April and early  May 1999.		Schering-Plough  Press Release 9/9/99
12/2/99	Class II  Recall - Vanceril Double Strength Aerosol. 82,029 units nationwide. Some  units may not contain active drug. Drug was distributed in November 1999.   "The cause of the problem has been identified as inadequate batch  start-up practices that occurred for a short period during filling of the  subject lots. The company has taken corrective actions to prevent a  recurrence."		Schering-Plough  Press Release 12/2/99
3/28/00	Inspection -  Manati, PR		5/8/00 - Warning Letter

选自：Letter Encouraging Investigatation of Schering-Plough for Shipping Defective Asthma Inhalers