Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

The US Food and Drug Administration has answered some core industry questions regarding the changes made to US Pharmacopeia General Chapter <467> in July 2008 with an unofficial guideline. The agency issued a 

 in August 2008 to help industry implement the chapter’s new standards, but several concerns and questions remained.   (See back 

To gain clarification, industry representatives from the International Pharmaceutical Excipients Council, the Generic Pharmaceutical Association, the Consumer Health Products Association, and the Pharmaceutical Research and Manufacturers of America, among others, established the Coalition for Rational Implementation of USP <467> and have been carrying out a dialogue with FDA’s Office of Generic Drugs and Office of Pharmaceutical Science since last fall.

As a result of the Coalition’s work, FDA agreed in November 2008 to work with industry to put together an industry guidance document to address core questions related to the chapter and its new requirements. That 

, although not an official regulatory guidance, has been reviewed by FDA, according to David R. Schoneker, coordinator of the Coalition and former chair of IPEC-Americas. FDA is in agreement that the answers to the core questions that they had provided to the Coalition during a Nov. 7 teleconference are properly described in this document. FDA is also supportive of the Coalition providing this document broadly throughout industry and the media to get the word out on the agency’s current thinking regarding this topic, according to Schoneker.

“The goal is to help companies better understand FDA's expectations when filing residual solvent information with abbreviated new drug and new drug applications,” Schoneker says. 

Some questions addressed in the document include: Why are active pharmaceutical ingredients not listed in the language? What type of evidence does OGD expect to see in submissions to verify that the sponsor understands the manufacturing process and controls regarding 467 levels? And, What is required for a Class 2 or Class 3 solvent to be considered “likely to be present” in the product?


Articles

The US Food and Drug Administration has agreed to address some core industry questions regarding the changes made to US Pharmacopeia General Chapter <467> in July 2008.

FDA Answers Key Residual-Solvent Testing Questions

The US Food and Drug Administration issued a Draft Guidance for Industry entitled 

Submission of Summary Bioequivalence Data for Abbreviated New Drug Applications

, the draft guidance is meant to help ANDA applicants comply with a 

 published in January 2009, which requires the submission of 

 bioequivalence (BE) data obtained for preapproval and postapproval studies of generic-product formulations. Required data includes results from studies that fail to determine BE. This information is important to FDA because it “increases the agency’s knowledge and understanding of bioequivalence and generic drug development and promotes further development of science-based bioequivalence policies,” according to the Apr. 17 publication.

The new draft guidance includes: information on the types of ANDA submissions covered by the new BE final rule; a recommended format for summary reports of BE studies; and the types of formulations FDA considers to be the “same drug product formulation” for different dosage forms based on differences in composition. Definitions and details are provided for immediate-release and extended-release drug products, semisolid dosage forms, and complex dosage forms.

Comments on the draft guidance must be submitted by July 16, 2009, to the Division of Dockets Management (HFA–305), FDA, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, or electronically at  

The US Food and Drug Administration issued a draft guidance for industry on the Submission of Summary Bioequivalence Data for Abbreviated New Drug Applications (ANDAs).

Draft Guidance Defines Bioequivalence Data for ANDAs

In late March 2009, the US Food and Drug Administration sent 

 to nine companies asking them to stop manufacturing 14 unapproved narcotic drugs. Less than two weeks later, on Apr. 9, 2009, the agency 

 those letters when it realized that one particular unapproved opioid (a high concentrate of morphine sulfate oral solution) is desperately needed by patients.

  As part of FDA’s unapproved drugs initiative, launched in June 2006, the original Warning Letters went to: Boehringer Ingelheim Roxane (Columbus, OH), Cody Laboratories (Cody, WY), Glenmark Pharmaceuticals (Mahwah, NJ), Lannett Company (Philadelphia, PA), Lehigh Valley Technologies (Allentown, PA), Mallinckrodt Pharmaceuticals Group (St. Louis), Physicians Total Care (Tulsa, OK), Roxane Laboratories (Columbus, OH), and Xanodyne Pharmaceuticals (Newport, KY). The letters asked the companies to stop manufacturing and distributing unapproved products that included high-concentrate morphine sulfate oral solutions and immediate-release tablets containing morphine sulfate, hydromorphone, or oxycodone (oxycodone capsules were not included).

 about the nine Warning Letters stated, “FDA has determined that removal of the unapproved narcotic products will not create a shortage for consumers.” The agency had to backtrack when it received “concerns from patients and healthcare professionals in the palliative care community” that one of the affected opioid products (specifically 20 mg/mL morphine sulfate oral solution) is used to alleviate pain in terminally ill patients. FDA’s Apr. 9 release therefore stated, “The agency has determined that this dosage form is medically necessary, and should remain on the market until an approved alternative becomes available to the patients that need it.”

  Companies manufacturing versions of high-concentrate morphine sulfate solution can now continue to do so, but only on an interim basis. 

  The very next day, Apr. 10, FDA announced 

  against contract manufacturer Neilgen Pharmaceuticals (Westminster, MD) and its parent company, Advent Pharmaceuticals (East Windsor, NJ), to prevent them from manufacturing and distributing any unapproved, adulterated, or misbranded drugs. An injunction was also filed against two of the companies’ officers, Bharat Patel and Pragna Patel. Neilgen, which operates as Unigen Pharmaceuticals, had been manufacturing unapproved prescription cough and cold products. The companies signed a consent decree to destroy their drug supply and to stop manufacturing and distributing any new drugs without FDA approval.

In late March, the US Food and Drug Administration sent warning letters to nine companies to stop manufacturing 14 unapproved narcotic drugs. Less than two weeks later, on Apr. 9, the agency amended those letters when it realized that one particular unapproved opioid (a high concentrate of morphine sulfate oral solution) is desperately needed by patients.

FDA Backtracks on Unapproved Drug Warning Letters

The US Food and Drug Administration issued 

 last week to pharmaceutical companies in violation of the Federal, Food, Drug, and Cosmetic Act for publishing misleading and misbranded information about their drug products online. FDA’s Division of Drug Marketing, Advertising, and Communications (DDMAC) found the violations by reviewing various Internet search engines such as Google.com. The primary violation noted was that companies had sponsored links on various websites promoting drugs that 

The companies cited were: Biogen Idec, Sanofi-Aventis US, GlaxoSmithKline, Forest Laboratories, Cephalon, Bayer Healthcare Pharmaceuticals, Johnson & Johnson Pharmaceutical Services, Pfizer, Novartis Pharmaceuticals, Genentech, Boehringer Ingelheim Pharmaceuticals, Merck & Co, Eli Lilly and Co, and Hoffman-LaRoche.

Other violations were cited as well. The untitled letter to Bayer, for example, also noted that the sponsored links for “YAZ and Mirena inadequately communicate the drugs’ indications, and the sponsored links for Mirena overstate the efficacy of the drug. Furthermore, all of the sponsored links fail to use the required established names.” GlaxoSmithKline was cited for omitting risks information for its drugs, Avandia, Avandamet, Avandaryl, Avodart, Coreg CR and Tykerb, four of which have black box warnings. 

 200.200, 201.100(f), 202.1(e)(2)(i), promotional materials that include the name of the drug product but do not include indications relative to the drug product must disclose risk and other information, according to the GlaxoSmithKline untitled letter.

  The exception is reminder advertisements, which note a drug product’s name but do not carry any information about its indication, use, or efficacy. 

FDA asked all 14 companies to immediately stop disseminating the violative promotional materials and to submit written response letters to the agency. The untitled letters also suggested the companies review and address any other promotional materials that may have similar violations. 

The US Food and Drug Administration issued 14 untitled letters last week to pharmaceutical companies in violation of the Federal, Food, Drug, and Cosmetic Act for publishing misleading and misbranded information about their drug products online.

FDA Issues 14 Untitled Letters for Online Ad Violations

The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) seized nearly half a million pounds worth of counterfeit medicines on Mar. 26, 2009 in Middlesbrough, England, according to a MHRA press release. The enforcement team arrested four Chinese nationals allegedly involved in the sale and supply of counterfeit drugs.

“Enquiries suggest that the counterfeit medicines originated from China,” said MHRA’ Head of Enforcement Mick Deats in the release. The seized drugs were for erectile dysfunction, anxiety, and weight loss.

The UK and European Commission have stepped up their attacks on counterfeiting after counterfeit drug seizures increased throughout the European Union by nearly fivefold in 2005 alone (see back story, 

). GS1 UK, an independent supply-chain standard development organization, completed the EU’s Pharma Traceability Pilot program just a few months ago as part of these efforts. The EU pilot tracked 15 drugs in an effort to stress track-and-trace technology and to decrease the potential for counterfeiting (see back story, 

GS1 UK Successfully Completes Traceability Pilot

). Also on the EC’s agenda is legislation to implement tighter auditing controls of active ingredients.

The United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) seized nearly half a million pounds worth of counterfeit medicines on Mar. 26, 2009 in Middlesbrough, England, according to a MHRA press release.

MHRA Cracks Down on Counterfeit Drugs, Seizes $500 Million Worth of Fake Meds

President Obama’s plan for increasing drug comparative-effectiveness research is moving forward. The 15 members of the Federal Coordinating Council for Comparative Effectiveness Research, which was created to manage the $1.1-billion allocation designated for the research in Obama’s American Recovery and Reinvestment Act of 2009, were named last week, according to a Mar. 19, 2009, press release from the US Department of Health and Human Services (see back story, 

Stimulus Bill Opens Door to Comparative Effectiveness

).  The new members, largely from HHS, are listed below and their full bios can be found 

	Anne C. Haddix,   chief policy officer, Office of Strategy and Innovation  at the Centers for Disease Control and Prevention

	Thomas B. Valuck,   medical officer and senior advisor at the Center for Medicare Management  and the  Centers for Medicare and Medicaid Services

	Peter Delany, director, Office of Applied Studies, SAMHSA

	Carolyn M. Clancy, director, Agency for Healthcare Research and Quality,  at the US Department of Health and Human Services (HHS) 

	Deborah Parham Hopson, associate administrator, HIV/AIDS Bureau , Health Resources and Services Administration

	David Hunt, chief medical officer, Office of the National Coordinator

	James Scanlon,  acting assistant secretary for Planning and Evaluation

	Elizabeth Nabel, director, National Heart, Lung, and Blood Institute,  National Institutes of Health

	Garth N. Graham, deputy assistant secretary, Office of Minority Health

	Jesse L. Goodman, acting chief medical officer, US Food and Drug Administration , and director, Center for Biologics Evaluation and Research, FDA

	Michael Marge, acting director, Office on Disability

	Neera Tanden, counselor,  Office of the Secretary, HHS

	Joel Kupersmith, chief research and development officer,  Veterans Administration

	Michael Kilpatrick, director of strategic communications for the Military Health System,  US Department of Defense

	Ezekiel J. Emanuel, special advisor for health policy , Office of Management and Budget

The Act placed the Institute of Medicine (IOM) in charge of recommending research priorities for the funds. IOM held its first agenda meeting, including representatives from the Center for Science in the Public Interest, the Association for Clinical Research Organizations, and the National Pharmaceutical Council, on Mar. 20, 2009, in Washington, DC. IOM is 

  through Mar. 27, 2009, on funding priorities. IOM’s first report is due to Congress and the president no later than June 30, 2009. 

President Obama's plan for increasing drug comparative effectiveness research is moving forward. The 15 members of the Federal Coordinating Council for Comparative Effectiveness Research, created to manage the $1.1 billion allocation designated for the research in Obama's American Recovery and Reinvestment Act of 2009, were named last week, according to a Mar. 19 press release from the US Department of Health and Human Services