Drug Industry Daily - Feb. 26, 2010 Issue

Vol. 9 No. 39

FDA Outlines Process to Demonstrate Product Sterilization Control

Drugmakers can meet sterility requirements for their products — and avoid conducting a formal sterility test — if they can demonstrate control of the sterilization process through parametric release.

Parametric release is a sterility assurance program based on an assessment of an applicant’s proposed critical process parameters and how they are controlled, the FDA says in a draft guidance Thursday.

The process demonstrates reliability of the production terminal sterilization cycle, microbiological control and monitoring and control of production cycle parameters within established validated limits, the guidance says.

The FDA’s approval of a parametric release program will be based on how well a company has addressed the risks of product contamination, the agency says. Drugmakers should provide a risk assessment statement that describes the current strategies for control of the terminal sterilization program, the risk that these strategies might fail to ensure sterility and how prior manufacturing experience and knowledge were incorporated into the risk assessment.

Manufacturers should also develop a control strategy, the FDA says, which is used to ensure that the acceptance criteria of the parametric release process and terminal sterilization cycle are met in order to ensure product sterility. The control strategy should include:

  • The rationale for the methods implemented to monitor and control the terminal sterilization process used for the product release;
  • The rationale for the selection of critical process parameters;
  • A description of the acceptance criteria for parametric release;
  • A description of the drug product and container closure system; and
  • A description of the microbiological monitoring plan for the product and components prior to terminal sterilization or a statement that the plan has not changed since last validated.

The parametric release program also should include a risk assessment that focuses on the risk of failure to achieve the minimum required probability of a non-sterile unit for each unit of every batch.

The FDA’s draft guidance can be found at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072180.pdf. — David Belian


KV Subsidiary to Plead Guilty, Pay $25.8 Million to End Justice Probe

Ethex, a KV Pharmaceutical subsidiary, has agreed to plead guilty to two felony counts and pay $25.8 million in fines and restitution to resolve the Justice Department’s investigation into its failure to file field alert reports when some generic drugs did not meet specifications.

Under the settlement, which is subject to court approval, Ethex will plead guilty to failing to file field alert reports for out-of-specification dextroamphetamine and propafenone tablets in September 2008, KV said Thursday.

The company recalled several lots of generic drugs in November 2008, including dextroamphetamine and propafenone, because they may contain oversized tablets that could have as much as twice the amount of active ingredient (DID, Nov. 11, 2008).

Ethex will pay $2.3 million in restitution to the federal government as part of the $25.8 million fine. It also will pay about $1.8 million to Medicare and Medicaid. In exchange, Justice agrees not to pursue further prosecution, according to a KV SEC filing.

HHS could exclude Ethex from federal healthcare programs such as Medicare and Medicaid in light of the guilty plea, but KV says the Office of Inspector General does not intend to exercise this authority, according to the SEC filing.

KV entered into a consent decree with the FDA a year ago following a production and shipment hold related to oversized tablets of beta-blocker Toprol (metoprolol succinate) (DID, March 3, 2009). KV plans to cease operations at Ethex, but it intends to resume manufacturing of its generic products once the requirements of the consent decree have been met, the company says in the SEC filing.

The settlement would not restrict KV’s manufacturing of generic drugs, the company says.

KV did not respond to a request for comment by press time. — Lauren Lentini


White House Healthcare Summit Debates Medicare Part D Gap

Closing the doughnut hole in Medicare Part D drug coverage emerged as a focus for congressional lawmakers at a White House summit on healthcare reform.

Lawmakers including Senate Majority Leader Harry Reid (D-Nev.) advocated for the measure Thursday, which would be largely funded by the drug industry. He cited the measure as a reason for continuing the process.

Even if Congress fails to pass a bill for President Barack Obama’s signature, the doughnut hole provision probably would be revived, Edmund Haislmaier, a senior research fellow at the Heritage Foundation, told DID.

“If this all collapses, I think they will try to pull that out and try to take it as a separate” bill, Haislmaier said. “At this point I think the drug industry is going to be hit with it one way or another.”

Much of the funding for the doughnut-hole proposal would come from PhRMA’s $80 billion deal with the White House — reached last summer as a means of financing reforms. As part of the deal, which was included in the healthcare bill passed by the Senate, drugmakers would provide a 50 percent discount off the negotiated price for brand drugs covered in plan formularies when Medicare Part D beneficiaries fall into the doughnut hole (DID, June 23, 2009).

The closing of the doughnut hole also was cited by Obama earlier this week as a justification for increasing annual fees for the drug industry (DID, Feb. 23).

The president’s proposal can be found at www.whitehouse.gov/sites/default/files/summary-presidents-proposal.pdf. — David Belian


FDA Issues First Draft Guidance on Adaptive Trial Design

The FDA has proposed the first draft guidance on adaptive design protocols for clinical trials, including details for SOPs, methods for controlling bias in the studies and encouraging sponsors to have early meetings with the agency.

The guidance recommends submitting a detailed description of all of a proposed trial’s important design features as well as procedures, quality control, data management, planned endpoints, and criteria for success, according to the draft to appear in the Feb. 26 Federal Register. Comments are due before May 26.

Special consideration should be given to two principal issues, according to the draft: whether the process has introduced error and increases the chance of a false conclusion that the treatment works and whether the adaptation process led to study results that are hard to interpret.

Shielding investigators as much as possible from knowledge of the adaptive changes chosen by the sponsor is important to reduce the likelihood of operational bias and help avoid false-positive conclusions about study results. Another important challenge in planning adequate and well-controlled (A&WC) effectiveness studies is deciding a sample size at the study design stage because the power of a study to predict an effect relies on sample size.

To further protect against bias, sponsors should submit standard operating procedures (SOPs) that indicate whether an outside statistician or one who works for the sponsor will perform unblinded analyses of interim data and whether sponsor personnel will make recommendations on adaptation. The FDA expects that sponsors will submit about 180 SOPs a year.

Sponsors should seek meetings with the FDA while planning and conducting adaptive design studies, the draft says. Those designing a protocol for an A&WC study with complex adaptive features should meet with the FDA early to allow time to carefully consider the plan and revise and re-evaluate it without slowing development. This early discussion should address the adaptive methodology in general and the suitability of the selected approach to achieve the study’s goals.

A practical  adaptive trial design can modify only a limited number of design aspects so only the most critical or least understood aspects should be included, such as dose, regimen, population, endpoint, among others.

When study designs with multiple factors have to be considered at the same time in the adaptive process, trial simulations are recommended. Performed before the study, simulations can help evaluate the multiple-trial design  options and the clinical scenarios that might occur when the study is actually conducted, and can be an important planning tool. An estimated 90 simulations and their analyses will be sent to the FDA every year, according to the draft.

The FDA should be given results of computer simulations assessing statistical uncertainty in trial adaptations and a summary of what is known about a drug product from other studies, according to the draft.

When evaluating a completed study, the draft advises that adaptive study design is part of a development program with the ultimate goal of obtaining study data essential to market approval of a product, so the complete program should characterize the dose-response relationship of favorable and negative responses and patient subsets that respond well or poorly.

The guidance recommends the use of data monitoring committees (DMCs) in adaptive trials with strict rules of operation that include a description of its responsibilities. Since a DMC is unblinded to interim study results, it can help implement decisions according to the prospective adaptation algorithm. However, it should not be in a position to otherwise change the study design except for serious safety-related concerns that are the usual responsibility of a DMC, the draft says.

Care should be taken that the DMC, which has access to the unblinded interim data, does not introduce bias to the otherwise blinded study — one of the hazards of an adaptive trial design, the guidance says.

The draft guidance can be found at www.fdanews.com/ext/files/AdaptiveDesign.pdf. — Owen Skoler


Genzyme’s Fabrazyme Shortage Extended Through June

Genzyme’s shortage of Fabry disease drug Fabrazyme will last longer than previously expected.

Genzyme had planned to ship 70 percent of Fabrazyme (agalsidase beta) demand in April but now plans to ship at 30 percent until June, company spokeswoman Lori Gorski told DID Thursday.

Gorski rejected recent media reports that the company would continue shipping 30 percent of demand after June. “We’re hopeful that in June and beyond we’ll be able to provide at an increased rate,” she said. She noted that while Genzyme is shipping 30 percent of demand, it is producing an additional amount to create an inventory buffer.

The company plans to provide a Fabrazyme supply update in May. Cerezyme and Fabrazyme have been in short supply since last year, after a viral contamination temporarily shut down Genzyme’s Allston, Mass., facility (DID, June 17, 2009).

Part of the reason the shortage has been extended is that restarting fill-finish operations at the Allston, Mass., facility has taken longer than planned, Genzyme said last week. Additionally, Fabrazyme bioreactor productivity has remained at the low end of its historical output.

Genzyme said it is working to increase manufacturing productivity and has developed a new working cell bank, with production under way at the 2,000-liter scale. Output from this process is expected in June, pending regulatory approval.

The company also is working to build up an inventory buffer for its Gaucher’s disease drug Cerezyme (imiglucerase). The company will ship 50 percent of demand for an eight-week period that began this week. Previously, patients were expected to be able to resume normal dosing schedules this quarter.

Shire has said it expects FDA action on its Cerezyme competitor Vpriv (velaglucerase alfa) by next week (DID, Feb. 22). It was encouraged to accelerate the product’s development by the FDA in the wake of the Cerezyme shortage. The company also filed a BLA for Replagal in December to treat Fabry disease. — April Hollis


FDA: Drugmakers Should Improve Risk Communication

Many drugmaker messages to consumers lack clarity about product risks and don’t focus enough on the target audience.

The industry should also consider tips given by the FDA’s Risk Communication Advisory Committee, such as using fewer words and more pictures or diagrams, Nancy Ostrove, FDA director for risk communications, told DID Thursday. She also noted drugmakers could share research into public communication.

Risk Communication panel members at Thursday’s meeting also suggested ranking communications by risk severity and using bulleted lists and boxed sections to highlight crucial information.

Ostrove noted the agency itself is making progress on its Strategic Plan for Risk Communication. The FDA has formed an internal network of working groups and has developed plans and timelines for goals, especially those it pledged to complete by the end of September, including:

  • Designing a series of surveys to assess the public’s understanding of, and satisfaction with, FDA communications about medical products;
  • Creating and maintaining a useful, easily accessible internal database of FDA and other relevant risk communication research;
  • Posting pictures of FDA-regulated products affected by Class I or high-priority Class II recalls as part of recall notices/information; and
  • Developing detailed action plans at both agency and center levels for implementing and achieving proposed action steps (DID, May 1, 2009). — April Hollis


Top-Level Post for Rare Diseases Created by FDA

The FDA has created a new position at CDER to help makers of rare disease treatments  navigate complex regulatory requirements to reach the market.

Anne Pariser was appointed acting associate director for rare diseases and will report to the Office of New Drugs (OND), the FDA said Thursday.

Pariser, a former medical officer and medical team leader at OND, will coordinate an initiative to develop CDER policies and procedures for reviewing and approving rare disease treatments. She also is tasked with ensuring staff is appropriately trained to review rare disease products, according to the FDA. The agency plans to move quickly to fill the position permanently.

The new review process will complement the work of the FDA’s Office of Orphan Products Development. The office will continue to offer financial incentives to drugmakers to manufacture rare disease products with orphan status, the agency said. — Owen Skoler

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Reporters: Lauren Lentini, David Belian, April Hollis, Owen Skoler

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