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Center for Drug Evaluation and Research 2003

Bioresearch Monitoring Program

Warning Letter Issued to Clinical Researcher

Failure to Follow Protocol Results in Inaccurate Data in Clinical Study

On May 27, 2003, the Center for Drug Evaluation and Research (CDER) issued a Warning Letter to William N. Sokol, M.D., Newport Beach, California. FDA investigators conducted an inspection of clinical studies in which Dr. Sokol participated. The inspection was performed as part of FDA’s Bioresearch Monitoring Program. Based on an evaluation of information obtained during the inspection, CDER determined that Dr. Sokol violated FDA regulations governing the proper conduct of clinical studies involving an investigational new drug and the protection of human subjects.

The Warning Letter listed the following violations:

  • Failure to conduct studies in accordance with the approved protocol;
  • Failure to maintain adequate and accurate records; failure to obtain informed consent from study subjects; and
  • Failure to inform the Institutional Review Board of changes to the protocol.

The Warning Letter advised Dr. Sokol as follows, “Your violations of FDA regulations outlined above, particularly the protocol violations, resulted in the submission of inaccurate data to the sponsors of the referenced clinical studies, and the submission of unacceptable data to FDA. You must address these deficiencies and establish procedures to ensure that any on-going or future studies be conducted in compliance with FDA regulations. We plan to monitor your research activities to ensure that you have indeed implemented appropriate corrective actions and that your revised clinical investigation procedures comply with federal regulations.”

CDER Issues Warning For Numerous and Serious Violations of FDA Regulations

Clinical Investigator Fails to Submit IND for Clinical Study

On March 31, 2003, the FDA’s Division of Scientific Investigations, Center for Drug Evaluation and Research (CDER), issued a Warning Letter to Alkis Togias, M.D., Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland. CDER conducted an inspection on June 18 and 28, 2001, into the death of a healthy volunteer who had received the drug, hexamethonium bromide, in a study. Dr. Togias participated in the study as a sponsor and an investigator.

Based on FDA’s evaluation of the inspectional findings, Dr. Togias’ written response to the Form FDA 483 dated July 16, 2001, and an informal meeting with FDA, CDER concluded that Dr. Togias violated the Federal Food, Drug, and Cosmetic Act (the Act) and FDA regulations governing the use of investigational new drugs by initiating a clinical investigation subject to 21 CFR Part 312 without submitting an investigational new drug application (IND). CDER also concluded that Dr. Togias failed to meet the obligations of a sponsor and an investigator under applicable regulations as noted below.

The Warning Letter stated, “Specifically, you caused the shipment in interstate commerce of hexamethonium bromide for use in a clinical investigation performed in Baltimore, Maryland without an approved application.” Other serious violations identified and documented in the Warning Letter included the following:

  • Failure to submit an IND for the conduct of a clinical investigation with an investigational new drug;
  • Failure to provide technical information related to the investigational drug, including source and purity of the drug substance, and [redacted] of the investigational drug;
  • Failure to submit a summary of previous human studies with hexamethonium salts administered by oral and intravenous routes;
  • Failure to summarize previous human experience with the administration of a hyperosmolar solution (such as hexamethonium bromide) to the human lung by aerosol inhalation;
  • Failure to provide a dosing rationale and specific information on dosing conditions, including nebulizer use, in the protocol;
  • Failure to conduct the investigation in accordance with the protocol; and,
  • Failure to obtain proper informed consent in that the following essential elements of informed consent were not included in the consent form that was provided to the healthy volunteers.

The Warning Letter advised Dr. Togias, “Within fifteen (15) working days of receipt of this letter, you must notify this office in writing of the specific corrective actions you have taken or will be taking to address these deficiencies and to achieve compliance with FDA regulations. We [FDA] will review your response and determine whether the actions are adequate. As one way to achieve compliance, we recommend that you consider entering into the attached restricted agreement with the agency regarding your future use of investigational new drugs.”

Clinical Investigator Sentenced

Doctor Sentenced for Fabricating Data and Records for Patients in Investigational Study

United States v. Allyn Norman (W.D.N.Y.). On January 27, 2003, Magistrate Judge Hugh B. Scott sentenced Allyn Norman, M.D., to a $5000 fine and a $25 special assessment fee for violating the Federal Food, Drug, and Cosmetic Act. While conducting clinical testing of the drug Rofecoxib pursuant to an investigational new drug application, Dr. Norman fabricated the data and records relating to six patients as well as information about the disposition of the drug.

Dr. Norman submitted the falsified data to the study monitor who noticed the discrepancies and questioned him. Dr. Norman then admitted that he had fabricated the information. Dr. Norman pled guilty in October 2002.

Pursuant to the plea agreement, Dr. Norman entered into a separate disqualification agreement with FDA which provides, among other things, that he is not entitled to receive investigational drugs, animal drugs, biologics, devices, or food additives, or to conduct further studies of FDA-regulated investigational products.

Good Manufacturing Practices

Manufacturers of Finished Pharmaceuticals

Warning Letter for CGMP Deviations

The FDA’s New Orleans District Office issued a Warning Letter on February 28, 2003, to Crown Laboratories, Inc., Johnson City, Tennessee, as a result of an inspection on January 7 - 14, 2003. The inspection disclosed that the firm was manufacturing drug products; but was not in compliance with FDA’s current good manufacturing practice (CGMP) regulations. Deviations observed during the inspection included: no cleaning validation for drug products or equipment; inadequate sampling and testing of components; inadequate product process validation; inadequate finished product testing; and inadequate stability testing.

Firm Voluntarily Ceases Distribution and Production

The FDA’s Cincinnati District Office conducted an inspection of Ondeo Nalco Company, Chagrin Falls, Ohio, on August 19 - 22, 2003. The inspection found significant drug CGMP deviations for the firm's drug product, Germ-B-Gon, a medicated hand cleaner. The CGMP deviations included the lack of production validation; no final product testing; no stability data; and incomplete master/batch records. The firm voluntarily ceased distribution and production of drug products.

Despite Significant Problems With Process Validation Firm Continues Manufacturing Unapproved Drug

The FDA’s Cincinnati District Office conducted a drug CGMP inspection at Forest Pharmaceuticals, Cincinnati, Ohio, which ended on February 20, 2003. The inspection revealed significant problems involving process validation and the firm’s stability program. The FDA issued a Warning Letter to Forest Pharmaceuticals, on August 7, 2003. The Warning Letter stated that the firm continued to market Levothroid (levothyroxine sodium tablets, USP) without an approved application.

Previously, on August 14, 1997, FDA announced in the Federal Register (62 FR 43535) that orally administered levothyroxine sodium drug products are new drugs. However, the notice stated that levothyroxine sodium drug products are used to treat hypothyroidism, and that no alternative drug is relied on by the medical community as an adequate substitute. Because of this, the FDA announced it would exercise enforcement discretion, permitting unapproved orally administered levothyroxine sodium drug products to remain on the market until August 14, 2000.

At the February 2003 inspection, FDA investigators determined that the firm failed to obtain an approved application and had made a deliberate decision not to follow the agency’s gradual phase-out plan. The Warning Letter advised the firm that it no longer was entitled to the enforcement discretion granted by the agency, and was on notice that the distribution of the firm’s unapproved product, Levothroid, was in violation of Section 505 of the Federal Food, Drug, and Cosmetic Act.

During this same inspection, FDA investigators also documented deviations from CGMP regulations for the following drugs: Levothroid (levothyroxine sodium tablets, USP); Armour Thyroid (thyroid tablets, USP); and Thyrolar (liotrix tablets, USP) drug products. The deviations included the following:

  • Laboratory controls did not include the establishment of scientifically sound and appropriate specifications designed to assure that components, in-process materials, and drug products conform to appropriate standards of identity, strength, quality and purity;
  • Lack of adequate written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess;
  • Results of stability testing were not used in determining appropriate storage conditions and expiration dates;
  • Acceptance criteria for the sampling and testing conducted by the quality control unit was not adequate to assure that batches of drug products met each appropriate specification as a condition for their approval and release; and,
  • Packaging facilities are not inspected immediately before use to assure all drug products had been removed from previous operations.

The Warning Letter advised that failure to achieve prompt correction may result in regulatory action without further notice. The Act provides for seizure of illegal products and/or injunction against the manufacturer and/or distributor of illegal products.

FDA Announces Recall of Contraceptive

Packaging Errors Could Result in Increased Pregnancy Risk

On July 11, 2003, FDA announced that Barr Laboratories was voluntarily recalling three lots of its Nortrel 7/7/7 (28 day norethindrone and ethinyl estradiol tablets, USP) oral contraceptive due to packaging errors that could lead to an increased pregnancy risk. The recall was effective immediately and involved Lot Numbers 290122001, 290122002, and 290122003 only. The company provided the following information to consumers.

Nortrel 7/7/7 (28 day is packaged in a blister card containing four horizontal rows of seven tablets each, with each row representing one week of tablets. The first (i.e. top) row should contain yellow tablets. The second row should contain blue tablets. The third row should contain peach tablets. The fourth (i.e. bottom) row should contain white tablets. The colored tablets contain the active hormonal ingredients. The white tablets are placebos that contain no active ingredient.

Any woman who received a Nortrel 7/7/7 (28 day blister card with tablets in the wrong color) sequence could be at an increased risk of pregnancy. In addition, changes to the menstrual cycle, including delayed bleeding, irregular bleeding or spotting, may occur. Women taking Nortrel 7/7/728 day should carefully check their blister cards.

The Company said that out of approximately 470,000 packages of marketed Nortrel 7/7/7 28 day that are subject to the recall, it has received two reports in which the tablets in the blister were reversed, causing the white placebo row to be in the first row labeled “start” (i.e., week one) rather than in the last row labeled “Week 4.” Additionally, the lot number and expiration date were not visible on the back of these two cards. Nortrel, an oral contraceptive that is a generic form of Ortho-Novum 7/7/7, is sold in pharmacies. The recalled lots were distributed between January and April 2003. Any adverse reactions experienced with the use of this product should be reported to FDA's MedWatch program.

Consent Decree of Permanent Injunction Against Phyne Pharmaceuticals

Long History of Violations and Distribution of Super-Potent Drug Results in Permanent Injunction

United States v. Phyne Pharmaceuticals, Inc.(D. Ariz.). FDA filed this action for injunctive relief in October 2002, based on the continued failure of Phyne Pharmaceuticals, Inc. (Phyne) to assure that the drugs it distributed were approved, free from pyrogens, and not misbranded. Phyne primarily distributed small volume parenteral drugs and naturopathic remedies made to its specifications by contract manufacturers. Phyne's decades-long history of violations includes a 1983 injunction in Florida, and a May 2000 felony criminal conviction in Arizonafor distributing unapproved, adulterated, and misbranded drugs. In December 2002, a super-potent drug distributed by Phyne caused serious illness in three people.

An inspection of Phyne's contract manufacturer for the drug (since voluntarily shut down) revealed severe Current Good Manufacturing Practice (CGMP) violations. In addition, an inspection of Phyne's principal place of business showed that Phyne continued to distribute unapproved and misbranded products.

On January 17, 2003, a Chief District Judge entered a Consent Decree of Permanent Injunction against Phyne and Donna I. Critchlow, Phyne's sole corporate officer. Under the decree, the defendants are permanently enjoined from manufacturing, processing, mixing, packaging, labeling, selling, distributing, shipping, promoting, advertising, offering for sale, holding for sale, receiving, importing, or exporting any product regulated by FDA. The decree requires defendants to pay, in addition to other civil and criminal remedies that may be sought under the Act, liquidated damages of $500,000 for the corporation and $150,000 for the individual should the Court find a material violation of the decree's provisions. In addition, the decree provides FDA with recall authority, the arbitrary and capricious standard of review, and costs.

Consent Decree of Permanent Injunction Against M.E. Pharmaceuticals, Inc.

Poor CGMPs Result in Permanent Injunction – Consent Decree Requires Firm to Destroy Inventory

United States v. M.E. Pharmaceuticals, Inc.(S.D. Ind.). On January 8, 2003, District Court Judge John D. Tinder entered a Consent Decree of Permanent Injunction in this case involving drugs manufactured in violation of Current Good Manufacturing Practice (CGMP). The defendants are enjoined from manufacturing, processing, packing, labeling, holding, or distributing any article of drug until an expert certifies that they are in compliance with CGMPs and FDA inspects defendants' facilities and notifies them in writing that they appear to be in compliance.

After defendants resume manufacturing drug products, the decree requires audits of their operations (once every six months for the first year, then once every 12 months for the next three years). In addition, defendants must destroy their entire inventory of in-process and finished drug products. The decree also provides for letter shutdown authority, recall authority, inspection costs, and the arbitrary and capricious standard of review.

Contract Testing Laboratories

Consent Decree of Permanent Injunction Against Bio-Science Research Institute and Tae W. Kang

Consent Decree Requires Firm to Shut Down Until Independent Expert Certifies Compliance with CGMPs

United States v. Bio-Science Research Institute and Tae W. Kang, (C.D. Cal.). On December 23, 2002, District Judge Robert J. Timlin entered a Consent Decree of Permanent Injunction against the defendants in this case. Defendant Bio-Science is a contract testing laboratory that is paid by various drug manufacturers and compounding pharmacies to perform a variety of quality control tests on drug products for compliance with specifications established by the drug manufacturers and the U.S. Pharmacopeia, as required by the current good manufacturing practice (CGMP) regulations for drugs.

Defendant Tae W. Tang is the owner and President of Bio-Science and has responsibility for all its operations. The decree requires an up-front shutdown of defendants’ operations until the defendants retain an independent expert, the expert certifies to FDA that the defendants’ facility is in compliance with CGMPs, FDA inspects and is satisfied that the facility appears to be in compliance, and the defendants reimburse FDA for its inspection.

The decree also requires the independent expert to conduct semi-annual inspections for a period of not less than three years after FDA permits operations to resume. The decree further requires defendants to provide a copy of the decree to all companies and persons with whom defendants are under contract to perform tests and prior to entering future contracts to perform such testing. The decree requires that the defendants pay for all inspections conducted under the Decree and upon receipt of a written order by FDA, to immediately stop testing operations and notify customers of any tests that were not conducted in compliance with CGMPs. The decree provides that any judicial review be decided under the arbitrary and capricious standard.

Medical Gases

FDA Inspection Discloses Numerous CGMP Deviations

The FDA’s New Orleans District Office issued a Warning Letter to Dennis Welding Supply, Inc., Montgomery, Alabama, on February 28, 2003. The firm manufactures Oxygen USP, in high pressure cylinders and cryogenic vessels. An inspection of the facility conducted from January 7 - 13, 2003, revealed significant CGMP deviations, including failure of the quality control unit to review and approve oxygen production and control records; failure to establish adequate batch production and control records for each batch of drug product produced; failure to maintain complete records of the periodic calibration of the oxygen analyzer. In addition, the labeling procedure was inadequate and was not being followed, and the firm failed to document routine calibration and equipment checks, at suitable intervals.

Seizure at Helget's Medical Gas Facility

FDA Inspections Reveal Continuing CGMP Violations Despite FDA Warnings

On July 15, 2003, FDA investigators accompanied the U.S.Marshals Service in a seizure of medical oxygen located at Helget's Medical Gas, North Kansas City, Missouri. Previously, in December 1998, FDA issued a Warning Letter to the firm identifying numerous significant CGMP violations found during a November 1998 inspection. The Warning Letter requested that the violations be corrected and stated that failure to correct the violations may result in regulatory action, including seizure and/or injunction.

In December 1998, the firm responded, stating that it had corrected the violations. However, FDA inspections conducted in May 1999, and October/November 2001, found continuing CGMP violations, some of which dated back to the earlier inspections. In May 1999, the firm stated that the CGMP violations would be corrected. The firm did not respond to FDA's October/November 2001 inspection. The firm was inspected in December 2002, and the firm's January 2003 response to that inspection again promised correction.

A subsequent FDA inspection on April 3-4, 2003, revealed continuing numerous and significant CGMP violations, including the following:

  • Failure to adequately test each batch of drug product prior to release for conformance to final specifications;
  • Failure to establish an adequate quality control unit having the responsibility and authority to approve or reject all components, drug product containers, closures, labeling, written procedures, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated;
  • Failure to assure that each person engaged in the manufacture, processing, packing, or holding of medical gases has the education, training, or experience to enable that person to perform the assigned functions;
  • Failure to have all drug product production and control records reviewed and approved by the quality control unit prior to release of the drug product;
  • Failure to establish and follow adequate written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess;
  • Failure to establish adequate batch production and control records, including documentation that each significant step in the manufacturing, processing, packing, or holding of the batch was accomplished;
  • Failure to establish written procedures designed to assure that correct label, labeling, and packaging materials are used for drug products; and
  • Failure to establish adequate written procedures describing the handling of all written and oral complaints regarding a drug product.

Warning Letter Issued for CGMP Deviations

On February 28, 2003, the FDA’s New Orleans District Office issued a Warning Letter to Pediatric Services, Inc., Norcross, Georgia, for deviations noted during an inspection of their Lafayette, Louisianafacility. The firm distributes liquid oxygen in cryogenic vessels. An inspection of the facility, conducted January 8 - 10, 2003, revealed significant CGMP deviations:

  • Failure to witness the testing of at least 31 lots of incoming liquid Oxygen USP for purity and strength prior to filling the cryogenic home units;
  • Failure to retain production and testing records for liquid Oxygen USP distributed from your facility prior to August 14, 2002; and,
  • Failed to review all testing and batch records for liquid Oxygen USP distributed from your facility since August 14, 2002.

Repackers of Pharmaceutical Products

FDA Initiates Seizure of Potentially Dangerous Drugs From Repacker

Drugs Manufactured In Violation of CGMPS Are Seized To Prevent Entry into Commerce

On September 15, 2003, FDA announced the seizure of all drug products labeled in a foreign language and/or labeled as repacked by Alliance Wholesale Distributors and/or Local Repack, Inc., Richton Park, Illinois.

FDA acted to prevent these drug products from entering the U.S.drug distribution system because there was no assurance that they were/are safe or effective. Many of the products received and repackaged at Local Repack were of unknown origin, and their storage and handling was unverifiable.

Local Repack repeatedly failed to comply with FDA’s current good manufacturing practice (CGMP) requirements. Many drugs at Local Repack's facility were misbranded. These drugs also posed a serious or even life-threatening risk to patients using them.

FDA inspections after an August 1999 Warning Letter to Local Repack revealed significant and continuing violations. The most recent inspections, conducted from February 20 through March 20, 2003, and June 16, 2003, as well as other recent information available to FDA, revealed numerous deficiencies, including:

  • Local Repack failed to reveal customer complaints to FDA during inspections, including complaints where the label of the repackaged product did not match the actual contents of the package (e.g., the company failed to report its recall of product labeled 2mg Coumadin even though the product was actually 6mg Coumadin);
  • Repeated instances where repackaging records were purportedly signed by a quality control employee on dates he had indicated to FDA personnel were his regular days off;
  • Quality control records indicating review and approval of repackaging operations were signed before the operations were even completed;
  • Incomplete or missing repackaging records, i.e., the company did not document repackaging operations for approximately 25% of its orders;
  • Duplicate and inconsistent repackaging records for the same batch;
  • Lack of accounting for both labels and product used in repackaging (e.g., in one instance there was no record as to the disposition of more than 5,000 Celebrex 200mg capsules received by Local Repack);
  • Unreliable receiving and distribution records for drug products;
  • Lot numbers on raw goods not matching lot numbers on records for final repackaged products;
  • Failure to document lot numbers shipped, making it impossible to conduct a recall for specific lots of product;
  • Numerous empty plastic 5,000 count containers labeled as Lipitor 10mg tablets (in Portuguese) and Lipitor 20mg tablets (in Spanish). None of the bottles or labels were the authentic manufacturer's packaging or labeling for U.S. or foreign markets;
  • Numerous empty boxes of blister-packs of Lipitor, Celebra (Brazilian version of Pfizer’s Celebrex) and Zyprexa labeled in Portuguese; and
  • Inadequate label control -- loose labels for various products lying around the product area where other drugs were being repackaged, creating the danger that mislabeled products would be shipped.

This seizure action followed a July 9, 2003, seizure of more than 4,500 bottles of prescription drugs that were being repackaged by Local Repack stemming from an investigation of counterfeit Lipitor.

The bottles ranged in size from 5,000 and 10,000 count bottles of bulk product with foreign language labels to 90 count bottles of foreign product that had been repacked and labeled in English for sale to pharmacies across the U.S.

Many of the products seized in July were marked with expiration dates that would have allowed them to be sold after similar U.S.-approved drugs would have already expired. For example, Portuguese-labeled product that Local Repack labeled as Lipitor had expiration dates well beyond the two-year limit that is based on stability studies performed as part of the New Drug Application (NDA) approved in the U.S.for Lipitor. None of these products had been shipped to Local Repack in authentic, original manufacturer’s packaging or labeling.

Recall of Ancom Anti-Hypertensive Compound Tablets

  • On March 17, 2003, Tai Chien, Inc., announced that the firm was recalling all 100-tablet bottles of Ancom Anti-Hypertensive Compound Tablets, an unapproved new drug labeled to contain several prescription drug ingredients, including reserpine, diazepam, promethiazine, and hydrochlorothiazide. The sale of a product with this combination of ingredients poses possible serious health risks including sedation, depression, and potentially life-threatening abnormalities of the blood.

    This recall included all lot codes of the product remaining on the market. Ancom Tablets were sold without prescriptions to consumers at Tai Chien's retail establishment in New York City. Product was also sold to a distributor in Puerto Rico.

  • On January 17, 2003, Herbsland, Inc., announced a recall of all 100 tablet bottles of Ancom Anti-Hypertensive Compound Tablets, an unapproved new drug labeled to contain several prescription drug ingredients, including reserpine, diazepam, promethiazine, and hydrochlorothiazide. The sale of a product with this combination of ingredients poses possible serious health risks including sedation, depression, and potentially life-threatening abnormalities of the blood. This recall included all lot codes of the product remaining on the market.

    Ancom Tablets are labeled for anti-hypertensive use and are packaged in white plastic bottles of 100 tablets bearing blue and white lettered labeling. Each bottle is sold in an outer cardboard holding carton. Both the carton and immediate container label bear the product name as Ancom tablets, Anti-hypertensive Compound, and display the manufacture's name as Shanghai Pharmaceutical Industry Corp., Shanghai, China. The labeling also bore Chinese markings, which appeared to be dual declarations. The holding carton is white with a pink and blue vertical stripe bearing blue and white lettering. The product carton also included a pre-printed insert labeled with an ingredient statement and directions for use.

    Ancom Tablets were sold without prescriptions to consumers through distributors and retail stores located in the New York Citymetropolitan area, specifically Manhattan, Brooklyn, and Queens. Nationwide sales are also possible as this product was sold via the Internet.

Counterfeit Drugs

New Initiative to Halt Counterfeiting of Drugs

FDA Commissioner Establishes Counterfeit Drugs Task Force

On July 2003, the Commissioner of Food and Drugs, Mark B. McClellan M.D., Ph.D., established a task force as part of FDA's heightened battle against counterfeit drugs. Commissioner McClellan specifically charged the task force with developing recommendations for achieving four fundamental goals: (1) preventing the introduction of counterfeit drugs into the U.S. market, (2) facilitating the identification of counterfeit drugs, (3) minimizing the risk and exposure of consumers to counterfeit drugs, and (4) avoiding the addition of unnecessary costs on the prescription drug distribution system, or unnecessary restrictions on lower-cost sources of drugs.

On October 2, 2003, FDA’s Counterfeit Drug Task Force issued an interim report containing potential options for a multi-pronged approach to combat counterfeit drugs. In recent years, the FDA has seen an increase in the number and sophistication of efforts to introduce counterfeit drugs (i.e., drugs which, or the container or labeling of which, is purported to be something that it isn’t).

“FDA’s task force is developing innovative approaches as never before on the significant and growing problem of counterfeit drugs,” said Mark B. McClellan, M.D., Ph.D., Commissioner of Food and Drugs. “The potential options we are announcing today start us on the path to a 21st century system that can better protect consumers against this emerging public health threat. As we develop these new approaches, FDA will continue to work hard to prevent counterfeit drugs from entering our drug supply, and to use the full force of the law against counterfeiters who would risk the health of the public for profit.”

With these goals in mind, the interim report contained a series of potential options for consideration in each of the following areas:

  • Technology;
  • Regulatory requirements and secure business practices;
  • Rapid alert and response systems;
  • Education and public awareness; and
  • International collaboration.

Moreover, the potential options discussed in the interim report were based on reports the task force reviewed and what the task force heard from other governmental agencies, individual private stakeholders and consumers, including the U.S. Secret Service, the Bureau of Engraving and Printing, state governments, drug manufacturers, wholesale distributors, pharmacy associations, academics, independent consultants and manufacturers of anti-counterfeiting technology. The interim report emphasized that the potential options outlined were designed to address the specific problem of keeping America’s drug supply secure against counterfeit drugs.

This is not the same problem as the distinct risks posed by unapproved drugs and potentially unsafe drugs that are being imported via the Internet and other unregulated international channels. Under current law those drugs are purchased outside of U.S. and foreign consumer protection systems, so they are “buyer beware” products that have traveled outside of the regulatory protections of the legal U.S. drug distribution system.

Two Distributors Recall All Lipitor Repacked by MED-PRO

On June 17, 2003, FDA announced that its continuing investigation of counterfeit Lipitor had resulted in Albers Medical Distributors, Inc., of Kansas City, Missouri, expanding their recall to include all Lipitor products repacked by MED-PRO, Inc., of Lexington, Nebraska. In addition, H.D. Smith Wholesale Drug Co., of Springfield, Illinois, recalled all Lipitor products repacked by MED-PRO.

FDA also announced that its Forensic ChemistryCenterin Cincinnati, Ohio, had determined that the counterfeit tablets that had been tested contained atorvastatin, the active ingredient of Lipitor. The FDA’s ForensicChemistryCenter’s analysis to date has not identified any known harmful substances in the counterfeit tablets, although analytical testing continues.

Despite these results, FDA could not assure that the counterfeit products were safe and effective. Individual tablets of this counterfeit medicine may vary significantly, even within individual lots, because the source of the atorvastatin is unknown and because there is no evidence that the tablets have been produced according to good manufacturing practices that are meant to ensure consistency from batch to batch.

Consequently, FDA’s advice to healthcare providers and consumers remains the same as when the agency issued its original alert on counterfeit Lipitor on May 23, 2003. Consumers should check the packaging very carefully before using Lipitor. Patients who have any of the product labeled as “Repackaged by: MED-PRO, Inc.; Lexington, NE 68850” should not take it, and they should return the product to their pharmacy. Patients who are not sure whether they have the recalled product should check with their pharmacist.

FDA continues to work closely with the individual states and with health professionals, especially with pharmacists and pharmacy associations, to alert them to this counterfeit product and the recall. FDA’s MedWatch Safety Information and Adverse Event Reporting system has alerted health professionals and others to Albers’ expanded recall.

Previously, on May 23, 2003, FDA announced that Albers Medical Distributors, Inc., had voluntarily recalled three lots of 90-count bottles of the cholesterol-lowering drug Lipitor and warned healthcare providers and others that these three lots of counterfeit Lipitor represent a potentially significant risk to consumers. The product was repackaged by Med-Pro, Inc., of Lexington, Neb., and the labels say "Repackaged by: MED-PRO, Inc. Lexington, Neb." in the lower left-hand corner.

The following lots were involved in this recall:

20722V - 90-tablet bottles, Expiration 09-2004
04132V - 90-tablet bottles, Expiration 01-2004
16942V - 90-tablet bottles, Expiration 09-2004

Counterfeit Procrit

FDA’s ongoing efforts to investigate and address unscrupulous counterfeiting activities uncovered the existence of contaminated counterfeit Procrit, also known as epoetin alfa. Procrit is used to stimulate the production of red blood cells in humans to treat severe anemia.

As a result of investigative review and laboratory testing performed by FDA, and in cooperation with Ortho Biotech Products, L.P., Bridgewater, New Jersey, healthcare providers and consumers were alerted to the existence of three lots of counterfeit product labeled as Procrit (epoetin alfa):

P007645 - 40,000 units/mL, Expiration 10-2004
P004677 - 40,000 units/mL, Expiration 02-2004
P004839 - 40,000 units/mL, Expiration 02-2004

The firm issued the warning to healthcare providers and others letter (also posted on its website) because counterfeit Procrit has been found to be contaminated with bacteria and therefore represents a significant potential hazard to consumers. In addition, FDA testing had demonstrated that some counterfeit product contained no active ingredient.

FDA urged health care providers and patients alike to check the packaging and vials very carefully before using this product. Anyone finding counterfeit product should not use it, should quarantine it, and should immediately contact FDA.

FDA/U.S. Customs’ Import Exams Reveal Hundreds of Potentially Dangerous Imported Drug Shipments

FDA/Customs Import Exams Reveal 88% of Products Examined Contained Unapproved Drugs

On September 29, 2003, FDA announced a series of spot examinations of mail shipments of foreign drugs to U.S.consumers conducted by the FDA and U.S. Customs and Border Protection (CBP or Customs). These examinations revealed that these shipments often contained dangerous unapproved or counterfeit drugs that pose potentially serious safety problems. This joint operation was carried out to help FDA and CBP target, identify, and stop counterfeit and potentially unsafe drugs from entering the United Statesfrom foreign countries via mail and common carriers. It was also designed to help FDA and CBP assess the extent of this problem.

These “blitz” exams were conducted in the Miamiand New York (JFK) mail facilities from July 29-31, 2003, and the San Francisco, and Carson, California, mail facilities from August 5-7 2003, to obtain a representative picture of products entering the United States. In each location, packages shipped by international mail through U.S. Postal Service facilities over a 3-day time span were examined.

For the purposes of these blitzes FDA and CBP identified, through review of historical data and experience, those packages likely to contain drug products. For example, packages were considered if they were from countries from which drugs are known to be exported via the mail. Due to the speed at which parcels are automatically processed and transported through the mail facilities, country of origin was the only specific criterion that could be consistently applied to all parcels.

Approximately 100 parcels (each of which may have contained multiple drug products) per day per facility were selected based upon their country of origin and historical experience. They were subsequently opened by CBP and jointly examined by both agencies. Those in violation of CBP provisions were held by CBP. Those in violation of FDA regulations were detained by FDA.

Although many drugs obtained from foreign sources purport, and may even appear to be, the same as FDA-approved medications, these examinations showed that many of these products were of unknown quality or origin. Of the 1,153 imported drug products examined, the overwhelming majority, 1,019 (88%), were violative because they contained unapproved drugs. Many of these imported drugs could pose clear safety problems.

These drugs arrived from many countries. For example, 15.8% (161) entered the U.S.from Canada; 14.3% (146) from India; 13.8% (141) from Thailand; and 8.0% (82) from the Philippines. The remaining entries came from other countries.

The potentially hazardous products found in these blitz exams revealed:

  • Drugs different from those approved by FDA -- Drugs that FDA has never approved are being imported. For example, Roaccutane (an unapproved version of Accutane) is being imported from Thailand. In the United States, prescribers of Accutane (a drug to treat a severe form of acne) are required to monitor patients to avoid certain serious risks such as birth defects that may occur following use of the drug. Taro-warfarin (an apparently unapproved version of Warfarin) from Canadais also being imported. Warfarin is used to prevent blood clotting and its potency may vary depending on how it is manufactured. Because it can cause serious, life-threatening bleeding if not administered appropriately, it requires careful monitoring by a health care provider of a patient’s blood count during treatment.
  • Drugs requiring careful dosing -- Drugs such as unapproved versions of Dilantin (from Philippines); unapproved versions of Synthroid (from Canada); and unapproved versions of Glucophage (from Canada and Philippines) that require individual titration and very careful dosing to avoid serious life-threatening side effects are being imported.
  • Drugs with inadequate labeling -- Moreover, most of these drugs came without adequate labeling or instructions for proper, safe use. Some of the drug labeling was not in English and important information about matters such as proper dosage was often missing.
  • Drugs inappropriately packaged -- In some cases, these drugs were inappropriately packaged in baggies, tissue paper, or letter envelopes. In other instances, the imported drugs arrived crushed and broken.
  • Drugs withdrawn from the market -- Consumers are importing drugs that FDA has withdrawn from the market for safety reasons. For example, one unapproved drug that came from Mexico, Buscapina, appears to be the drug Dipyrone that was removed from the U.S.market in 1977 because of several reports of the development of severe blood disorders following the drug’s administration, some of which resulted in fatalities.
  • Animal drugs not approved for human use -- Animal drugs that FDA has not approved for humans use are being imported. For example, Clenbuterol, a drug approved for the treatment of airway disease in horses but that has not been approved for human use and has been banned by the International Olympic Committee as a performance enhancing drug, came from Costa Ricaand China.
  • Drugs with dangerous interactions -- Drugs such as ketoconazole (from Thailand) unapproved versions of Viagra (from United Kingdom, India, Philippines and Japan); and unapproved versions of Zocor (from Canada) are being illegally imported and have the potential to cause clinically significant interactions with other drugs which consumers may be taking.
  • Drugs that carry risks requiring initial screening and/or periodic patient monitoring -- Drugs such as unapproved versions of Lipitor (from Ireland, Thailand, Japan, Philippines, Canada, Argentina, New Zealand, Englandand Brazil); and unapproved versions of Pravachol (from Canada) are being illegally imported. Initial screening and periodic patient monitoring by a medical professional (e.g. monitoring liver function) are recommended in FDA’s approved labeling for these drugs to help assure their safe use.
  • Controlled substances -- Over 25 different controlled substances were offered for import including Diazepam (from Canada, Thailand, Philippines, Costa Rica, Malaysia, New Zealand, and India); Xanax (from Philippines); Codeine (from Canada, Philippines, Costa Rica, United Kingdom, New Zealand, Thailand, Guatemala, China, Peru, and Taiwan); Valium (from Philippinesand Thailand); and anabolic steroids (from Costa Rica). These drugs were referred to the Drug Enforcement Administration. Controlled substances pose serious safety issues for consumers because they are dangerous narcotics that have abuse potential for patients who take them inappropriately or without the proper physician supervision.

The “blitz” was helpful in understanding trends in the illegal importation of unsafe drugs. In 2001, FDA conducted a similar analysis that prompted the same concerns about the risk of these imported drugs. Compared to the 2001 results at the Carsonmail facility, this blitz uncovered a somewhat larger number of imports, including a larger number of unapproved drugs and drugs that appeared to be counterfeits.

The blitz FDA conducted at the Carsonmail facility in 2001, as well as the most recent blitz conducted by FDA in coordination with Customs, illustrate the type of regular surveillance activities involving imported drug products that FDA undertakes. As a result of the current blitz, FDA is re-evaluating the enforcement strategies and objectives the Agency uses to target the entry of unapproved and/or counterfeit drug products through international mail facilities.

The blitz results will assist the Agency in its efforts to:

  • Utilize its investigatory and regulatory resources more strategically to focus on the foreign sources of illegal, unsafe imported drugs;
  • Identify shipping patterns specific to identified sources of unsafe drugs so that it can target future shipments and sources of such drugs; and
  • Seek out partnerships with other federal and state agencies to combat this problem.

In addition, FDA continues its efforts to educate the public about the dangers of drugs through illegal, poorly-regulated, and potentially unsafe foreign channels.

Illegal Importation of Prescription Drugs

Order for Preliminary Injunction Entered Against Rx Depot

Court Enters Preliminary Injunction To Halt Illegal Importation of Rx Drugs from Canada

United States v. Rx Depot, Inc. and Rx of Canada, LLC, corporations, and Carl Moore and David Peoples, individuals, (N.D. Okla.). On November 6, 2003, U.S. District Court Judge Claire V. Eagan entered an Order of Preliminary Injunction against the defendants, who ran a business that forwarded prescriptions to Canadian pharmacies, which would fill the prescriptions and send the drugs to individuals in the United States.

Judge Eagan found that there is a substantial likelihood that the government will succeed on the merits of its claims that the defendants violate the law by causing the introduction or delivery for introduction into interstate commerce of unapproved new drugs and by causing the reimportation of drugs which were originally manufactured in the United States. The Order enjoins the defendants from:

  1. causing, during the pendency of this action, the introduction of any article drug into Interstate commerce;
  2. receiving any commission on the refill of any prescription drug; and
  3. advertising or promoting through any media any service that causes or facilitates the importation of drugs. The Order also requires the defendants to send a letter to their customers notifying them that the defendants' business violates the law and that the safety, purity, and efficacy of drug products obtained with the defendant's assistance cannot be assured.

Judge Eagan found that the defendants frequently dispensed drugs in greater quantities than ordered by the prescribing physician, and that prescription drugs obtained through Rx Depot do not contain the FDA-approved patient package inserts and are not shipped in unit-of-use packaging to ensure the appropriate dose.

Judge Eagan concluded that FDA has "legitimate safety concerns . . . with unregulated commercial reimportation of U.S.-manufactured drugs by someone other than the manufacturer and importation of foreign-manufactured drugs not approved by the FDA.

On March 21, 2003, FDA sent Rx Depot a Warning Letter informing the firm that, "Your actions also present a significant risk to public health, and you mislead the public about the safety of the drugs obtained through Rx Depot." The Warning Letter also advised the firm that it risked possible enforcement action if it continued to promote sales of unapproved drugs, claiming that they were "FDA-approved" and "exactly the same as if purchased in the United States." Despite this warning, the defendants stated that they would continue their activities until ordered by a court to stop. These companies' continuing violations of a public health law creates significant, potential health risks associated with buying unapproved and illegally imported medicines from unregulated sources.

FDA Strongly Supports Oklahoma Action Against Storefront Pharmacy

On March 27, 2003, FDA issued a statement strongly supporting the filing by the Oklahoma State Board of Pharmacy and the Oklahoma Attorney General's Office of a petition for injunction seeking to stop the Rx Depot storefront pharmacy from violating state law. Rx Depot generally obtains unapproved drugs from Canadafor U.S.consumers, exposing the public to the significant potential risks associated with unregulated imported prescription medications and misrepresenting them as being FDA-approved. The State authorities filed a petition in Oklahomastate court, alleging that Rx Depot is illegally operating an unlicensed pharmacy.

FDA is particularly concerned about the practice of making misleading assurances about the safety of the drugs obtained for customers and claiming that they are FDA-approved, which they are not.

FDA Issues Warning Letter to CanaRx Services

On September 16, 2003, FDA issued a Warning Letter to CanaRx Services, Inc., of Detroit, Michigan, advising the firm that the FDA considers its operations to be illegal and a risk to public health. FDA’s Warning Letter stated that CanaRx runs an Internet website and mail operation that illegally caused the shipment of prescription drugs from a Canadian pharmacy into the U.S., subjecting Americans to risky imported drug products and making misleading assurances to consumers about the safety of its drugs.

FDA has been concerned that medications purchased by U.S.consumers from foreign, unregulated drug outlets pose a growing potential danger. CanaRx Services and similar companies often state incorrectly to consumers that their prescriptions are "FDA approved" or use similar language, which could lead consumers to conclude mistakenly that the prescription drugs sold by the companies have the same assurance of safety and effectiveness as drugs actually regulated by the FDA.

For example, FDA has evidence demonstrating that CanaRx shipped insulin, a product that should be stored under refrigerated conditions, in a manner that did not ensure adherence with the storage conditions specified in FDA approved labeling - potentially compromising the safety and effectiveness of the insulin.

State pharmacy boards are responsible for determining whether pharmacies operating within the state are doing so in compliance with state law. In the U.S., state law requires proper licensing for a pharmacy to sell prescription drugs. In this case, it appears that CanaRx is not a licensed Canadian pharmacy subject to regulatory oversight, and so may place patients at additional risk.

Because the medications obtained and shipped by operations such as CanaRx are not subject to FDA’s safety oversight, they could be outdated, contaminated, counterfeit or contain too much or too little of the active ingredient. In this case, these risks are heightened by the fact that many of the products CanaRx sells to U.S. consumers are indicated for serious medical conditions.

Internet Enforcement Activities

Eight Warning Letters Issued for Internet Promotion of Accutane

FDA Issues 8 Warning Letters to Firms Selling Accutane From Internet Sites

On September 9, 2003, as part of its ongoing efforts to protect Americans from dangerous prescription products purchased illegally from Internet sites operating in other countries such as Canada, Thailand and Mexico, the FDA issued eight Warning Letters to firms to stop their illegal sales of an unapproved, mislabeled version of the acne drug Accutane (isotretinoin). The agency believes that this illegal practice may pose a serious health risk to patients, and urges patients not to use these illegal foreign versions.

The FDA sent several Warning Letters to companies telling them to cease marketing these illegal drugs. These drugs included a topical (applied to the skin) gel version of accutane, which is sold only with foreign language labeling to American consumers via Internet sites.

The Warning Letters were based on a review of the websites which disclosed that firms were selling “Accutane” to U.S. consumers. Accutane is the trade name for a prescription drug approved for marketing in the U.S. under an approved new drug application by Roche Pharmaceuticals.

Accutane products approved for marketing in the U.S. are capsules for oral ingestion. Even though Websites’ forms state that the product offered for sale is “Accutane (brand) Roacccutane,” the label of the actual product shipped states that it is “Roaccutane lsotretinoin 10 mg tablet.” “Roaccutane” does not have an approved new drug application, and may not be legally marketed in the United States.

Accutane (isotretinoin) is a systemically administered retinoid approved in 1982 to treat severe recalcitrant nodular acne. Isotretinoin carries significant potential risks, including that it may cause severe birth defects. The approved Accutane labeling states in part.

“Accutane must not be used by females who may be pregnant...must be prescribed under the System to manage Accutane Related Teratogenicity (S.M.A.R.T.), a yellow Accutane Qualification Sticker must be on each prescription,” “meaning special training has been given to the pharmacist, licensed practitioner and the patient) (and no telephone or computerized prescriptions are permitted.)

The approved Accutane is for oral ingestion. FDA has not approved a topical gel version of Accutane or any other isotretinoin drug. Because isotretinoin has serious risks, it is available in the U.S.only under specially created safety controls. These safety controls were bypassed when this drug was purchased from foreign sources or over the Internet, placing patients who use this imported drug at higher risk.

The isotretinoin dispensed via the Internet is also "new drug” and may not be introduced or delivered for introduction into interstate commerce unless an FDA-approved new drug application (NDA) is in effect for such drug. The isotretinoin dispensed is also misbranded because its labeling fails to bear adequate directions for the uses for which it is being offered. This drug is also misbranded pursuant to section 503(b)(1) of the Act because it is dispensed without a prescription. The Warning Letters also noted that false statements were being made on Internet that were aimed at and accessible to American consumers stating in part:

*** Order legally *** offering a huge selection of medications based on brand name and generic name which are approved by FDA***.

False statements again were being made on the Internet that were aimed at and accessible to American consumers stating, “FDA Approved Products" are available on this website. The product was then packaged in Thailand. Inside the package was a U.S. Customs Declaration stating in part, " *** I am United States Citizen *** None of these Medication which I must have access to are for treating a life threatening or debilitating condition ***." These false and misleading statements on the Internet site and Packaging labeling cause the drugs to be misbranded.

The Warning Letters advised these firms to cease these practices and to describe within 15 days of receipt of FDA’s Letters to describe the actions being taken to assure that operations are in full compliance the U.S.law.

Accutane is a drug that can cause birth defects if taken by pregnant women and is subject to a restrictive distribution program known as the System to Manage Accutane Related Teratogenicity (SMART) program.

"Today’s strong action by the FDA illustrates the serious risks patients take when buying unapproved drugs from foreign sources," said Commissioner of Food and Drugs Mark B. McClellan, M.D., Ph.D. "This agency will do everything we can to protect Americans from potentially dangerous unapproved drugs sold illegally via the Internet. We are particularly concerned about the risks of using products containing foreign versions of Accutane, because of the severe birth defects it may cause if taken by pregnant women, and other potential side effects associated with the use of this drug."

Over-the-Counter Products

Nicotine Gum With Latex Pieces Recalled

The FDA’s New York District Office reported that Watson Laboratories, Inc., Copiague, New Yorkwas recalling two lots (4NG02021 & 4NL02133) of Nicotine Polacrilex Gum. The gum was recalled because latex pieces were found in the gum during routine quality assurance checks by the firm. Recall letters went out on or about April 7, 2003. The recalled product was distributed under several labels, including Rugby, Walgreen’s, Leader, and CVS.

Nasal Spray Recalled

In February 2003, the FDA’s New York District Office was notified by Pharmascience, Inc., Montreal, Quebec, Canada, of a recall of two lots of Rhinaris Nasal Mist sold in .33 fluid ounce bottles (physician samples), lot 209281, and 1 fluid ounce bottles, lot 209280. This is an OTC drug product intended to moisten nasal passages. The recall was initiated due to the presence of Pseudomonas fluorescens. The product is distributed in the USthrough the initial importer, Pharmascience, Inc., Tonawanda, New York. The products were shipped to physicians, pharmacies and drug distributors throughout the U.S. The FDA’s New York District Office monitored the recall.

Pharmacy Compounding

Nationwide Alert Regarding Injectable Drugs Prepared by Urgent Care Pharmacy

FDA Issues Nationwide Alert Due to Sterility Concerns with Injectable Drugs

On November 15, 2002, the FDA announced a nationwide alert concerning all injectable drugs prepared by Urgent Care Pharmacy of Spartanburg, South Carolina, based on the lack of assurance that their products are sterile. Non-sterility of injectable products can represent a serious hazard to health that could lead to life-threatening injuries and death. FDA inspection of Urgent Care's facility revealed the firm failed to have adequate controls to ensure necessary sterility, including the absence of appropriate testing for potency and sterility prior to distribution.

On September 16, 2002, Urgent Care recalled all lots of its injectable methylprednisolone acetate based on reports of four patients who developed a rare fungal (wangiella) meningitis (a life threatening infection of the lining of the brain and spinal cord) after use of their product.

These patients were treated at three different North Carolina hospitals/clinics. Spinal fluid from all of these patients tested positive for a fungus consistent with that found in the Urgent Care product analyzed by both the FDA and Centers for Disease Control and Prevention (CDC). One patient later died despite antifungal therapy.

Urgent Care refused to voluntarily recall any other injectable products they prepared and refused to provide FDA with a complete list of products they distributed. FDA worked to identify the recipients of these products so that the agency could directly alert them to the serious risks involved. FDA worked with the CDC, along with officials from both North Carolinaand South Carolina, and will take whatever additional action is needed. In the meantime, the South Carolina Board of Pharmacy issued a Cease and Desist order to halt further sale of products from Urgent Care.

At the time, based on limited information, FDA was aware that Urgent Care had distributed the following injectable drugs to physicians, hospitals, clinics and consumers in Connecticut, Illinois, Indiana, Kentucky, Louisiana, Massachusetts, Mississippi, New Hampshire, North Carolina, South Carolinaand Virginia:

Baclofen Betamethasone Bimix 30:1 (Phentolamine mesylate/papaverine) Clonidine Estradiol Hydromorphone HCl Fentanyl Methylprednisolone acetate Morphine Sulfate/Bupivacaine Papaverine HCl Super Trimix (Papaverine HCl/phentolamine mesylate/prostaglandin) Testosterone cypionateTestosterone/Estradiol.

Urgent Care injectables are labeled as URGENT CARE PHARMACY 2500 WINCHESTER PLACE , STE. 106, SPARTANBURG, SC29301, 800-692-8982.

Warning Letter Issued to Pharmacy

On May 27, 2003, the FDA’s New England District issued a Warning Letter to Owner of Carneys Drug, Rochester, New Hampshire. On August 28, 2002, an FDA Investigator conducted an inspection of this facility. A representative from the New Hampshire State Board of Pharmacy accompanied the FDA investigator on this inspection. The inspection disclosed that the firm compounds Fentanyl oral lozenges “lollipops” ranging in strength from 800 mcg to 4000 mcg.

The Warning Letter stated that in the FDA Modernization Act of 1997, Congress had provided certain conditions under which compounded drugs could be exempt from particular requirements of the Federal Food, Drug, and Cosmetic Act (the Act).

However, as a result of a Supreme Court ruling, those exemptions are no longer available for compounded drugs. Because of the Supreme Court decision, Thompson v. Western States Medical Center (S. Ct.April 2002) FDA determined that the agency needed to issue guidance to the field and compounding industry on what factors the agency will consider in exercising its enforcement discretion regarding pharmacy compounding.

This guidance issued on June 7, 2002, in the form of Compliance Policy Guide (CPG), Section 460.200. The Warning Letter noted that as a result, FDA now applies its longstanding policy to recognize and exercise its enforcement discretion for extemporaneous compounding, where reasonable quantities of drugs are manipulated upon receipt of valid prescriptions from licensed practitioners for individually identified patients.

One factor that the FDA considers is whether or not there is any documentation that demonstrates a medical need for particular patients for a specific variation between a commercially available drug product and compounded drug product. During the inspection, investigators observed Fentanyl oral lozenge products had been compounded in strengths varying from 800 mcg to 4000 mcg. The commercially available product is available in 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg and 1600 mcg strengths.

“In the absence of any documentation of medical need for particular patients for particular variations between the commercially available Fentanyl ‘lollipop’ and the ‘compounded Fentanyl,’ ‘lollipop’ drug products, such compounding would essentially constitute copying of a commercially available drug. The Agency would not consider this activity to be consistent with the regular course of a pharmacy dispensing drugs at retail.”

The Warning Letter noted that FDA remained seriously concerned about the public health risks associated with the compounding of Fentanyl “lollipops” that were being dispensed without the labeling and other packaging and patient safety features. The inspection disclosed that the firm dispenses Fentanyl “lollipops” in a pharmacy bag that is not child-proof.

The commercially available Fentanyl “lollipop” product is distributed with a child-resistant lock used to secure a storage space for the product in the patient’s home. In addition, the commercially available product is dispensed with a portable locking pouch for storage of a small amount of the product for immediate use and a child-resistant temporary storage bottle.

Therefore, in light of the above, the Warning Letter stated that the compounded Fentanyl “lollipops,” in dosage strengths ranging from 800-4000 mcg, are misbranded since the labeling is false and misleading in that it fails to reveal facts material with respect to consequences that may result from the use of the article under conditions of use prescribed in the labeling or under such conditions of use as are customary or usual.

The “lollipops” are also misbranded in that the labeling does not provide adequate warnings against use by children where its use may be dangerous to health in that it lacks information on the proper storage and disposal of the drug to avoid accidental ingestion by children. In addition, the compounding copies of commercially available drug products as described above, caused the products to be unapproved new drugs.

Court Rules on FDA Administrative Inspection of Pharmacy

Court Rules that the FDA Has Jurisdiction to Inspect Pharmacy under the FD&C Act

re: Establishment Inspection of Wedgewood Village Pharmacy, (D.N.J.). On July 7, 2003, U.S. Magistrate Judge Joel Rosen denied Wedgewood Pharmacy’s motion to quash a warrant for administrative inspection issued pursuant to the Act. Wedgewood is a licensed pharmacy that specializes in compounding drugs for human and animal use. On March 10, FDA applied for an administrative inspection warrant because it planned to conduct a joint inspection with the Drug Enforcement Agency, and previous FDA inspectional activity at Wedgewood indicated that a warrant would be necessary.

The court signed the warrant and FDA executed it on March 12, 13, and 14, 2003. Wedgewood filed motion to quash on March 18, after FDA indicated that it planned to continue the inspection. In a 40-page opinion dated July 7, the court denied Wedgewood's motion, concluding that FDA has jurisdiction to inspect Wedgewood under the Act and that FDA appropriately exercised its jurisdiction in both the application for a warrant and its execution to date.

Wedgewood had contended that it was entitled to an exemption for pharmacies in the Act’s inspectional authority and that this exemption deprived FDA of any jurisdiction over state licensed pharmacies. The court, however, found that the limited exemption for pharmacies in the Act’s inspectional authority applied only to records inspection, and did not affect FDA’s general inspectional authority or jurisdiction.

The court rejected Wedgewood’s argument that only registered drug facilities are subject to inspection, and also found that the Act’s provisions regarding new drugs, misbranding, and adulteration apply to pharmacies. The court found that FDA’s choice to seek an ex parte administrative inspection warrant so that it could determine whether the records inspection exemption applies to Wedgewood is a reasonable interpretation of the Act which serves the public interest.

Postmarketing Adverse Drug Experience Reporting

Warning Letter Issued for Violations of PADE

On March 18, 2003, the FDA’s New Jersey District Office issued a Warning Letter to Roger Boissonneault, Chief Executive Officer, Warner Chilcott, Inc., Rockaway, New Jersey. An FDA inspection of the firm on October 7 - 18, 2002, was conducted to determine the firm’s compliance with the Postmarketing Adverse Drug Experience (PADE) reporting requirements of the Federal Food, Drug, and Cosmetic Act. The inspections disclosed the following violations:

  • Failure to review and submit to the FDA adverse drug experience reports;
  • Failure to detain records of all adverse drug experiences, including raw data and any correspondence relating to adverse drug experiences;
  • Failure to submit to the FDA serious and unexpected adverse drug experience reports within 15 calendar days of initial receipt of information; and
  • Failure to develop adequate written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experience to FDA.

The Warning Letter also emphasized that, “We [FDA] want to re-emphasize that we consider your firm’s inability to establish and implement adequate standard operating procedures for the handling of adverse drug experiences (ADEs), and your firm’s failure to evaluate and submit to FDA reports of ADEs, as very serious problems. Your response referred to general corrections to be implemented within the next 60 days.

We would like to see a detailed written plan of corrective actions you will implement, with a specific timetable for their implementation. We also want to know how you will be processing ADE data received before the implementation of these corrective actions, to ensure immediate and adequate follow-up and timely submission of initial and follow-up reports.”

Unapproved Drugs

FDA Enforcement Policy Regarding Expectorant Drug Product

In October 2002, FDA sent Warning Letters to 18 manufacturers and 48 repackers and distributors of unapproved single-ingredient guaifenesin extended release products. The Warning Letters addressed the marketing of these extended-release drug products without the necessary FDA approval for marketing.

The Warning Letters followed the agency's July 2002 approval of one such product, Adams Laboratories' Mucinex. The Warning Letters and the follow-up letter explained that companies are required by law to submit scientific evidence demonstrating the safety and effectiveness of marketed drug products.

Following the Mucinex approval, the agency reviewed the marketing status of all strengths of single ingredient extended-release guaifenesin. FDA determined that such products should no longer be marketed in light of the existence of an FDA approved product.

FDA concluded that the unapproved products were on the market illegally and that taking them off of the market after a reasonable grace period when the similar approved product became available would, among other things, preserve the incentives for companies to develop and submit new drug applications as required by law. The scientific evidence provided in the new drug application is essential to prove the safety and effectiveness of drug products.

With respect to the single ingredient extended release guaifenesin products, FDA's longstanding policy is that all extended release drug products must obtain FDA approval. This policy has been codified in the Code of Federal Regulations since 1959.

To minimize disruption in the marketplace, FDA allowed the warning letter recipients a limited grace period to manufacture and distribute their products. But the agency made clear that all unapproved products were to be off the market by the end of November 2003.

On October 17, 2003, FDA issued a Press Release (P-03) entitled, “FDA Proposes Steps to Assure the Safety and Efficacy of Certain Currently Unapproved Medicines.” In the Press Release, FDA announced anew draft Compliance Policy Guide (CPG) entitled Guidance – Marketed Unapproved Drugs – Compliance Policy Guide. This new draft CPG describes how FDA intends to exercise enforcement discretion with regard to drugs marketed in the United Statesthat do not have required FDA approval for marketing.

The draft guidance explains that FDA will continue to give priority to enforcement actions involving unapproved drugs: (1) with potential safety risks; (2) that lack evidence of effectiveness; and (3) that constitute health fraud. It also explains how the agency intends to address those situations in which a firm obtains FDA approval to sell a drug that other firms have long been selling without FDA approval.

The full text of the new draft CPG is available on FDA’s website at: http://www.fda.gov/cder/guidance/5704dft.pdf.

The full text of FDA’s October 2003 Press Release is available on website: http://www.fda.gov/bbs/topics/NEWS/2003/NEW00962.html. In addition, FDA published a question and answer document which is also available on FDA’s Internet at: http://www.fda.gov/cder/compliance/CPG_QandA.htm.

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