DID - Nov. 5, 2009 Issue

Vol. 8 No. 216

OTC Liquid Drug Guidance Advises More Accurate Delivery Devices

Manufacturers of liquid OTC drugs need to ensure markings on companion delivery devices, such as measurements on dosage cups, are consistent with drug labeling instructions to prevent accidental overdoses.

Some liquid drug-delivery devices contain superfluous measurements or are missing the markings needed to determine doses, according to a draft guidance to be published in the Nov. 5 Federal Register. The draft guidance applies to OTC liquid drug products packaged with dosage delivery devices, such as calibrated cups, droppers, syringes and spoons. Comments are due Feb. 3, 2010.

Some consumers do not use the dosage-delivery devices provided with OTC drug products, the guidance adds. It suggests manufacturers secure the devices to drug products.

Despite several warning letters and recalls in the early 1990s related to misleading or incompatible labeling on dosage-delivery devices, an increasing number of OTC liquid drug products are packaged with measuring devices that are incompatible with product dosage directions, the draft guidance says.

OTC liquid drug products frequently are used for children, making the issue of particular concern.

The guidance recommends:

  • Including dosage delivery devices with all liquid OTC drug products;
  • Advising consumers to use only the devices included with products;
  • Listing decimals or fractions as clearly as possible;
  • Avoiding use of extraneous or unnecessary markings;
  • Using the same calibrated units of measure and abbreviations on the device that are specified in the directions on any packaging or other written instructions;
  • Ensuring the devices are not much larger than the largest dose in the directions and permit clear measurement and delivery of the smallest labeled dose; and
  • Ensuring the markings on the devices are clearly visible and not obscured when the liquid product is poured into the device.

The agency also advises manufacturers conduct usability studies to ensure dosage-delivery devices are easily understood and accurately used by consumers.

The draft guidance, “Dosage Delivery Devices for OTC Liquid Drug Products,” is available at www.fdanews.com/ext/files/UCM188992.pdf. — April Hollis


FDA’s Safe Use Initiative May Increase Number of Drugmaker REMS

The number of required risk evaluation and mitigation strategies (REMS) may increase under the Safe Use Initiative launched Wednesday by the FDA.

As part of the initiative, the agency will collaborate with drugmakers to identify specific drugs and drug classes associated with significant amounts of preventable harm from four sources — medication errors; unintended exposure, intentional drug misuse and drug quality defectsthe agency says in a report issued Wednesday on the initiative.

The agency will then analyze the medicines or drug classes to determine whether regulatory or non-regulatory actions, including the implementation of a REMS or public awareness campaign, will improve medication safety.

The FDA plans to begin the initiative by seeking comment from drugmakers and other stakeholders on specific drugs or and drug classes that are associated with significant amounts of preventable harm, Janet Woodcock, director of CDER, said in a press briefing Wednesday.

Under the initiative, the agency will:

  • Develop a general list of drug and pharmaceutical class candidates for analysis and intervention;
  • Hold meetings to gather public input as the list is being developed;
  • Collaborate with federal partners to develop population-based national estimates of preventable harm from medications, categorized by drug, drug classes and the way they are administered;
  • Open a public docket for comments on the report, risk management and proposed candidates; and
  • Implement a small number of regulatory and nonregulatory interventions with an explicit plan for measuring impact, within the initiative’s first 12 months.

Despite the potential for an increase in the number of REMS, “the measures that the [FDA] discussed today fit in with PhRMA's goals of ensuring that patients receive the right medicine and the right dose at the right time to treat his or her condition,” Ken Johnson, PhRMA’s senior vice president, told DID.

Collaborations that might be considered under the new initiative include: acetaminophen toxicity and drug-delivery devices (see related story).

The launch of the initiative follows a 2006 report from the Institute of Medicine in 2006 that says the federal government and industry must overhaul the way medications are named, labeled and packaged in order to curb an ever-growing number of medical errors involving the administration and prescription of drugs (DID, July 24, 2006). The FDA also released a guidance on REMS for drugs and biologics last month, sparking concerns from industry that it may add too much time to the approval process (DID, Oct. 1).

The FDA’s report outlining the Safe Use Initiative can be found at www.fda.gov/downloads/Drugs/DrugSafety/UCM188961.pdf. — David Belian


OCP Must Hold Briefings on Complex Pediatric NDA Supplements

Drugmakers who submit pediatric supplement NDAs with potentially complicated or controversial clinical pharmacology or biopharmaceutical issues should be aware that CDER’s Office of Clinical Pharmacology (OCP) is now required to hold briefings on them, according to a revised Manual of Policies and Procedures (MaPP).

Most of the changes from the previous 1997 version are relatively minor, OCP Director Lawrence Lesko told DID. He said the requirement to hold an office-level OCP briefing for complicated or controversial pediatric supplement NDAs was made “because we wanted to use this as an opportunity to review the quality of submissions and the quantity of pediatric information in the submissions.” The revision posted to the CDER website this week has already taken effect.

Drugmakers whose products may be the subject of an OCP briefing can submit information in the office’s Question Based Review (QBR) format, Lesko told DID. Using the new QBR format is voluntary, he added. Examples of information drugmakers can provide this way include:

  • The mechanism for observed adverse events;
  • Whether there is dose-response information for the drug under review;
  • Whether there are genetic factors contributing to variability in pharmacokinetics and dose-response; and
  • The magnitudes of change in drug exposure with concomitant administered drugs, and whether these changes require dosing adjustments.

Both versions of the MaPP say OCP briefings are required for new molecular entities that are first in a pharmaceutical or therapeutic class. Also included are NDAs that present unique scientific problems and those which the OCP intends to recommend rejecting due to clinical pharmacology or biopharmaceutical issues. The MaPPs also cover briefings for NDAs that are to be reviewed at an advisory committee meeting and have potentially controversial clinical pharmacology or biopharmaceutical issues.

The list of topics recommended for OCP briefings has several new items, including proposed Phase IV recommendations, essential pharmacokinetic characteristics of a new drug and pertinent dose-selection information.

“There are no additional mandates for CDER staff either [in the new MaPP],” Lesko said. “Many voluntarily attend the briefings to learn about the science and the process of how studies are reviewed and interpreted.”

The new version of the MaPP can be accessed at www.fdanews.com/ext/files/UCM188700.pdf and the previous version is at www.fdanews.com/ext/files/ucm079572.pdf.  — Martin Berman-Gorvine


Watson Boosts Generic Pipeline Spending in Quarter

Watson Pharmaceuticals has increased its generic R&D spending by 17 percent to $37 million during the third quarter as it awaits FDA action on about 60 ANDAs under review.

Overall R&D spending grew 15 percent to $52 million, CEO Paul Bisaro said on the drugmaker’s third-quarter earnings call Wednesday.
The company has launched patent challenges to Allergan’s Sanctura XR (trospium chloride), an overactive bladder treatment, it says in a statement Wednesday. It also is waiting to hear from the FDA on a generic version of Ferrlecit (sodium ferric gluconate complex) to treat iron-deficiency anemia in hemodialysis patients receiving supplemental epoetin therapy (DID, July 30).

Watson’s generics business brought in net revenue of $398 million, reflecting the launches of 25-mg and 50-mg strengths of metroprolol ER; Next Choice (levonorgestrel), a generic version of Plan B; and Azurette, a generic version of Duramed Pharmaceuticals’ oral contraceptive Mircette (desogestrel/ethinyl estradiol). Watson also plans a strong push into biosimilars, Bisaro said.

Watson expects a pending acquisition of generic-drug maker Arrow Group to close in the fourth quarter and may see savings from the companies’ combined generic development pipelines, it says. “We are already exploring potential generic and brand product filings in some of Arrow’s markets,” Bisaro said, noting nicotine gum and overactive bladder treatment Gelnique (oxybutynin chloride) are two examples.

The company also expects a launch in the first half of 2010 of its long-acting form of prostate cancer treatment Trelstar (triptorelin pamoate), Bisaro said. Watson responded to an FDA complete response letter during the quarter (DID, July 15).

Separately this week, Germany’s Fresenius reported that generic-drug sales helped revenue in the company’s first three quarters. The drugmaker recently acquired APP Pharmaceuticals, which makes injectable generic drugs, and had a 16 percent sales increase during that period. — April Hollis


Ivax to Pay $14 Million as Part of Kickback Case

Ivax Pharmaceuticals has agreed to pay $14 million to resolve civil allegations that the company engaged in kickback schemes with Omnicare, the nation’s largest nursing home pharmacy.

The Justice Department alleges that Ivax, now a subsidiary of Teva Pharmaceutical Industries, paid $8 million in kickbacks to Omnicare in exchange for Omnicare’s agreement to purchase $50 million of its drugs, according to a Justice statement this week. The allegations are detailed in a complaint unsealed this week that was originally filed under the qui tam, or whistle-blower provisions of the False Claims Act, Justice says.

Omnicare agreed to pay $98 million to settle allegations that it engaged in kickback schemes with several parties, Justice says in the statement. The company also allegedly sought and received kickbacks from Johnson & Johnson (J&J) in exchange for agreeing to recommend that physicians prescribe J&J’s antipsychotic Risperdal (risperidone) for nursing home patients, the Justice statement says.

J&J was accused of paying rebates for Omnicare’s participation in the drugmaker’s Active Intervention Program for Risperdal, with some payments disguised as educational grants, the statement says.

Omnicare acknowledges the settlement but denies the government’s allegations related to the kickback schemes, the company says in a statement. The company has voluntarily agreed to enter into a five-year corporate integrity agreement with HHS that will monitor its compliance with the laws and regulations governing pharmacies.

J&J did not respond to the government’s allegations, but says it was served in April with complaints in two civil qui tam cases relating to marketing of prescription drugs to Omnicare. Several employees of the company’s pharmaceutical subsidiaries have been subpoenaed to testify before a grand jury in connection with this investigation, the company says, but the government has not yet announced whether it will intervene.

Ivax also denies any liability relating to the government’s allegations, Denise Bradley, a spokeswoman for Teva, told DID. The actions in question took place “years before Ivax was acquired by Teva,” Bradley said. “However, to avoid the uncertainty and expense of litigation, Ivax decided to settle and put the matter to rest.”

The settlement in United States of America, et al., ex., rel. David M. Kammerer v. Omnicare, Inc., and Ivax Pharmaceuticals, Inc. follows a separate settlement earlier this year between Ivax and MassHealth, the Massachusetts Medicaid program, in which the company agreed to pay $7 million to settle a False Claims Act case pending in a Boston court (DID, Jan. 7). The state alleged that Teva, Ivax and 11 other companies falsely inflated the prices they reported to national pharmaceutical price reporting services. — David Belian

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