The Honorable Jane Henney, M.D.
Food and Drug Administration
Room 14-71 (HF-1)
5600 Fishers Lane
Rockville, Maryland 20857
Dear Dr. Henney:
On October 27, 2000, the FDA provided documents in partial response to my letter of October 18th concerning the manufacturer of mifepristone and requesting certain documents. On October 30, 2000, the FDA provided a briefing to the Committee staff to respond further to the October 18th letter and Committee concerns regarding counterfeit bulk drug imports.
Based on the documents and what the Committee staff has reported to me, I am concerned about evidence suggesting a pattern of wrongful acts by the manufacturer of mifepristone that may call into question the integrity of the approval process of mifepristone. Moreover, I am astonished by FDA's inability, failure, and disinterest in investigating certain information about the manufacturer of mifepristone.
Documents show that the manufacturer of mifepristone was previously known as Shanghai Pharmaceutical Factory #12. In September 1990, FDA. inspected this firm as a bulk supplier of fluorouracil for Quad Pharmaceuticals. (See attached inspection report). FDA identified objectionable conditions that the firm either corrected or promised to correct. As a result, the FDA recommended the firm as an acceptable supplier. However, FDA's data does not show that Shanghai Pharmaceutical Factory #12 ever shipped product to the United States. On January 25, 1996, the U.S. agent sent a written statement to the FDA declaring that Shanghai Pharmaceutical Factory #12 was no longer actively manufacturing product intended for the United States. (See attached). In 1998, the California Health Department published an analysis of 260 imported traditional Chinese medicines and found truly alarming levels of contaminants in almost half of them. The article listed the brand, manufacturer, and contaminant. The California Health Department identified Shanghai Pharmaceutical Factory #12 as a firm that imported a traditional Chinese medicine called Compositae Tegafuri Capsulae contaminated with 2,4 (1H, 3H)-pyrimidinedione, florouracil (D). It is not clear from the article when this product was shipped to the United States. However, there is a reasonable possibility that after January 25, 1996 and in conflict with the U.S. agent's statement, Shanghai Pharmaceutical Factory #12 shipped a health product to the U.S. contaminated with an unapproved drug (fluorouracil). In addition, irrespective of the date of shipment, this firm shipped a health product to the U.S. contaminated with a hidden unapproved drug. At the briefing, the FDA indicated that it did not consider this past record of the firm relevant to the safety of mifepristone and therefore would not look at this issue any further. I disagree. Possible false statements, the threat to public health posed by the shipment of contaminated medicines, and other violations of the Food, Drug, and Cosmetic Act is a pattern of conduct that reflects on the honesty and integrity of the management of Shanghai Hualian Pharmaceutical and thus its submissions to the FDA. I do not believe FDA's position is acceptable for a public health agency.
As noted in my October 18th letter, the FDA's import records indicate that Shanghai Hualian imported "betamethasone sodium phosphase (sic) USP raw material for compounding" that was detained by FDA's Cincinnati office on July 17, 2000 for false or misleading labeling and misbranding. FDA documents show the detention was related to a discrepancy concerning the drug listing number provided and the product description. At the briefing, FDA admitted that Shanghai Hualian was not an FDA-approved source for betamethasone sodium phosphate, although it was possible that the firm could legally ship such unapproved product to U.S. pharmacies compounding human drugs. FDA further admitted that the product was returned to the Chinese manufacturer or the Canadian distributor and that FDA never checked or analyzed the material to determine if it was actually betamethasone sodium phosphate. According to the FDA, the import detention was not known to the FDA inspectors who conducted the July 2000 re-inspection of Shanghai Hualian. Although FDA has asserted that the approval of mifepristone was the result of adhering strictly to FDA's legal mandate and mission, such a claim is belied by the FDA's wilful ignorance about the full nature of Shanghai Hualian's conduct in the shipment of a falsely labeled, unapproved drug into the United States.
In addition to betamethasone sodium phosphate, the FDA provided import records showing that Shanghai Hualian Pharmaceutical shipped mifepristone to the United States on May 14, 1999, December 3, 1999, and February 8, 2000. (See attached records). However, FDA did not approve mifepristone until September 28, 2000. Moreover, mifepristone has no other FDA-approved use. During the briefing the FDA could not determine whether these shipments of mifepristone were legal, what kind of mifepristone was shipped, the destination of these shipments, and the reason for these shipments. Moreover, the deficiencies in FDA's import controls leaves open the possibility that even purportedly legal shipments of mifepristone could be diverted to a black market. Once again, none of this information was known by the inspectors who conducted the July 2000 re-inspection of Shanghai Hualian. Given FDA's claim of adhering strictly to FDA's legal mandate and mission, I am astounded that FDA did not have readily available information to provide to the Committee to explain the nature of these shipments. Such a lack of information suggests that FDA did not fully explore the background and conduct of the manufacturer of mifepristone.
Despite records showing shipments of drug product to the U.S. in 1999 and 2000, the attached FDA inspection reports of Shanghai Hualian Pharmaceutical do not indicate whether the firm is shipping other pharmaceutical products to the United States. Moreover, neither of the inspection reports indicate that the firm under its previous name of Shanghai Pharmaceutical Factory #12 had been inspected by the FDA in 1990. As a matter of standard procedure, these are items that FDA inspectors would request from the firm at an entry conference. That such information is lacking in the reports may reflect material information withheld by the firm.
FDA also mentioned at the briefing that the Commissioner and other senior officials at the FDA met to discuss the issue of ongoing investigation of allegations that may be related to the approval of mifepristone. The FDA maintained that an internal memorandum and the draft of the memorandum analyzing the allegations were the subject of discussions at these meetings. None of these meetings were documented. I note that the date of the internal memorandum was September 26, 2000 -- one day after my letter dated September 25th requesting documents relating to Shanghai Hualian Pharmaceutical. Moreover, the internal memorandum only addressed the fact that a certain individual or entity under investigation identified by the informant as connected to the mifepristone approval was not in fact connected. However, the confidential informant made allegations against another individual or entity that was in fact connected to the mifepristone approval. The internal memorandum did not address these allegations or its implications on the approval of the mifepristone application. Thus, it appears the FDA did not completely and diligently review all relevant allegations connected to the approval of mifepristone.
Finally, I remain alarmed about the overall failure of FDA's data systems regarding imported drugs. FDA admitted at the briefing that it still does not know how many foreign firms are exporting pharmaceutical products to the United States and are subject to inspection. FDA further admitted none of its data systems are designed to answer such a question, but that information in its drug listing database suggested there were at least 1500 uninspected foreign API manufacturers that were subject to inspection. On October 3, 2000, you testified that there were 242 foreign API manufacturers that appear to have exported to the U.S. in 1999, but have not been inspected. This statistic was derived from using two data bases that at the October 30 staff briefing the FDA admitted were incomplete. The GAO in March 1998 reported that by April 1998, "FDA should have a comprehensive inventory of all foreign manufacturers hipping pharmaceutical products to the United States. This information could then be used to improve FDA's planning and scheduling of foreign pharmaceutical inspections." It is apparent that FDA lacks this comprehensive inventory and is unable to effectively plan and schedule foreign drug inspections. It is most troubling that FDA continues to peddle the notion to this Committee that it actually knows the total universe of firms to be inspected when it cites numbers of Tier III and Tier IV firms to be inspected.
Pursuant to Rules X and XI of the U.S. House of Representatives and in light of the issues raised, please provide records and written responses by November 13, 2000 relating to the following:
1. All investigations since November 1, 1995 that FDA has conducted to identify all instances of wrongful acts and to determine the extent to which the wrongful acts may have affected approved or pending applications.
2. All validity assessments since November 1, 1995 that FDA has conducted to resolve questions regarding reliability of data in an application.
3. How many uninspected foreign firms are shipping pharmaceutical products to the United States and are subject to FDA inspection? How many products do these firms in question ship to the U.S.? What are these products?
4. The FDA indicated at the briefing that foreign manufacturers of over-the-counter (OTC) drug products are required to comply with GMPs (good manufacturing practices). How many foreign manufacturers of OTC drug ingredients or products ship to the United States? How many products from these foreign manufacturers are shipped to the United States? What are these products? How many foreign manufacturers of OTC drug ingredients or products are in compliance with GMPs? Please list those firms not in compliance with GMPs and what actions FDA has taken against these firms.
5. All assessments by FDA of countries that are most problematic in manufacturing or distributing counterfeit bulk drugs, counterfeit finished drugs, and counterfeit over-the-counter drugs.
6. Dr. Murray Lumpkin recently resigned his position from FDA's Center of Drug Evaluation and Research Office of Review Management for personal reasons. It has been rumored in the trade press that his resignation "had to do with a conflict of conscience over the recent approval of the abortion drug mifepristone." Please explain what is the Agency's understanding of exactly why Dr. Lumpkin resigned his position.
In addition, please make arrangements for Deborah Ralston of the Office of Regulatory Affairs to brief Committee staff with respect to Questions 3, 4, and 5.
Please note that, for the purpose of responding to these requests, the terms "records" and "relating" should be interpreted in accordance with the Attachment to this letter.
Thank you for your assistance. If you have any questions, please contact Alan Slobodin of the Committee staff at (202) 225-2927.
cc: The Honorable John D. Dingell, Ranking Member
1. The term "records" is to be construed in the broadest sense and shall mean any written or graphic material, however produced or reproduced, of any kind or description, consisting of the original and any non-identical copy (whether different from the original because of notes made on or attached to such copy or otherwise) and drafts and both sides thereof, whether printed or recorded electronically or magnetically or stored in any type of data bank, including, but not limited to, the following: correspondence, memoranda, records, summaries of personal conversations or interviews, minutes or records of meetings or conferences, opinions or reports of consultants, projections, statistical statements, drafts, contracts, agreements, purchase orders, invoices, confirmations, telegraphs, telexes, agendas, books, notes, pamphlets, periodicals, reports, studies, evaluations, opinions, logs, diaries, desk calendars, appointment books, tape recordings, video recordings, e-mails, voice mails, computer tapes, or other computer stored matter, magnetic tapes, microfilm, microfiche, punch cards, all other records kept by electronic, photographic, or mechanical means, charts, photographs, notebooks, drawings, plans, inter-office communications, intra-office and intra-departmental communications, transcripts, checks and canceled checks, bank statements, ledgers, books, records or statements of accounts, and papers and things similar to any of the foregoing, however denominated.
2. The terms "relating," "relate," or "regarding" as to any given subject means anything that constitutes, contains, embodies, identifies, deals with, or is in any manner whatsoever pertinent to that subject, including but not limited to records concerning the preparation of other records.