Drug Industry Daily - June 25, 2010 Issue

Vol. 9 No. 123

Pfizer Suspends Development of Phase III Osteoarthritis Candidate Tanezumab

Pfizer is once again facing a development setback as it is halting the Phase III development program of tanezumab as a treatment for osteoarthritis of the knee because of adverse event concerns.

The drug giant announced the clinical hold late Wednesday following a request from the FDA. Some osteoarthritis patients on tanezumab experienced worsening of the condition, leading to joint replacement.

As a result, the company has stopped dosing patients and suspended trial recruitment.

The FDA asked Pfizer to meet later this week to discuss the implications on tanezumab in other indications it is pursuing where osteoarthritis is a comorbidity, including cancer pain, interstitial cystitis, chronic lower back pain and diabetic peripheral neuropathy.

The company will give the agency “our assessment of whether or not we should continue the entire clinical program,” Pfizer spokesman MacKay Jimeson told DID.

Tanezumab works by targeting nerve growth factor, a protein associated with pain, and is dosed by infusion every eight weeks.

Last year, Pfizer suspended development of two Phase III compounds under investigation to treat fibromyalgia and generalized anxiety disorder (DID, Feb. 25, 2009). In 2006, the company ended Phase III development of torcetrapib, a successor to its blockbuster cholesterol drug Lipitor (atorvastatin), due to an increased risk of death (DID, Dec. 5, 2006). — Jonathan Block


FDA Approves Merck’s Asthma Drug Dulera

Merck has received approval from the FDA for its asthma inhalant Dulera, to be used in patients 12 years and older.

The drug is a fixed-dose combination of mometasone furoate, an inhaled corticosteroid, and fomoterol fumarate, a long-acting beta2 agonist (LABA), Merck said Thursday.

Dulera’s approval was based on the results of two Phase III clinical trials. Results showed that patients receiving Dulera experienced significant improvement from baseline in lung function, a primary efficacy endpoint in the trials, Merck said.

Because the drug contains a LABA, Merck is required to develop a risk evaluation and mitigation strategy (REMS) and conduct postmarket trials, Tara Camp, a Merck spokeswoman, told DID.

Dulera, which is expected to hit the market next month, will compete with asthma medications such as GlaxoSmithKline’s Advair (fluticasone propionate/salmeterol xinafoate) and AstraZeneca’s Symbicort (budenoside/formoterol fumarate dihydrate).

Advair had worldwide sales of about $8 billion in 2009, and Symbicort had worldwide sales of about $2.3 billion.

Merck also is seeking approval for Dulera in several other countries, with an application pending in the EU, Camp said. — David Belian


FDA’s Foreign Posts Increasing Collaboration With Regulators, Industry

The FDA’s foreign posts are working more with regulators and industry to improve the safety of products made overseas.

Foreign staff is educating counterpart regulatory agencies and overseas companies to improve quality standards and explain expectations for products to be admitted to the U.S., Murray Lumpkin, FDA deputy commissioner for international and special programs, said Tuesday at the Association of Food and Drug Officials 114th Annual Education Conference.
The 10 foreign posts — an 11th will open in Italy later this year — have been “interacting with local inspectorates to learn more and more about what these people are doing, how they do their inspections and the kind of information we’re all willing to share,” Lumpkin said. “The idea is for these people to obtain better information … so our centers and border officials can make better decisions about the admissibility of products from overseas.”

In China and India in particular, two of the largest drug product importers to the U.S., interactions have increased over the past year, he added.

His comments echoed those made by FDA Commissioner Margaret Hamburg during a same-day speech at the Woodrow Wilson International Center for Scholars.

“We will work closely with our sister regulatory authorities, with international and national organizations, and with industry,” Hamburg said. “We will find new ways to share information. And we will learn, step by step, to leverage international resources to accomplish FDA’s domestic mission.”

For instance, the FDA and its foreign counterparts are evaluating how they should regulate combination products as they become more of a mainstay. The agency and other regulators are looking at science issues, good manufacturing practices (GMPs), and the challenge of using both GMPs and quality system regulations.

Another collaborative effort with foreign regulators is the FDA’s active pharmaceutical ingredient (API) inspection pilot with the European Medicines Agency and Australia’s Therapeutic Goods Administration to help the agencies plan inspections of third-world API manufacturers.

The FDA is about 10 months into the pilot, Lumpkin said, adding that the agencies share where they plan to inspect in the next six months and try to split inspections that overlap. “Some we do together, some individually, but everybody ends up making their own decisions,” he said.

But the agency has backed off somewhat on efforts toward third-party auditors of foreign companies. “We haven’t been engaged quite as much this year in developing trusted third parties to be auditors,” Lumpkin said. “But we’re already beginning to lay the groundwork for this if indeed it becomes final policy.” — April Hollis


GSK Fails to Convince NICE of Arzerra’s Worth in Leukemia

The UK’s National Institute for Clinical Health and Excellence (NICE) has rejected GlaxoSmithKline’s (GSK) leukemia treatment Arzerra for reimbursement by the National Health Service (NHS).

GSK’s data relied on interim results from a small subgroup of patients in an ongoing clinical study and was not strong enough to recommend the use of Arzerra (ofatumumab) over available best supportive care, according to a draft guidance issued Thursday.

Arzerra is indicated for the treatment of chronic lymphocytic leukemia that does not respond to fludarabine and alemtuzumab (Genzyme’s Campath). It works by targeting the CD-20 protein on the surface of B lymphocytes and cancer cells. Patients receive intravenous doses once a week for eight weeks and then once a month for a total of four months.

In deciding against Arzerra, the review group said use of nonresponder data from the study and data from the subgroup makes it hard to predict the drug’s benefit in the actual treatment population. Moreover, Arzerra’s effects on overall response rate, progression-free survival and overall survival are unclear, the guidance adds.

NICE also notes that GSK’s data only compared the cost-effectiveness of Arzerra and best supportive care and did not assess how much extra benefit Arzerra may offer patients versus the comparator.

GSK charges $272.54 for a 100-mg vial, according to the guidance. Total costs with Arzerra were about $58,031, compared with $4,307 with the comparator.

The company agreed to a patient access program, but the discounted price was considered too expensive for the uncertain benefit the drug holds for patients, NICE says.

Arzerra received conditional approval from the FDA in October and from the European Medicines Agency in April, pending additional research to prove its clinical benefit.

Stakeholders have until July 19 to comment on the preliminary guidance, which can be accessed at www.nice.org.uk/guidance/index.jsp?action=folder&o=49337. — Meg Bryant


Guidance Lists Postapproval CMC Changes Permitted in Manufacturer Annual Reports

Manufacturers making postapproval changes to products’ chemistry, manufacturing and controls (CMC) must determine which changes are to be reported to the FDA in an annual report and which are significant enough to require a supplement.

A new draft guidance lists CMC postapproval changes — previously submitted under manufacturing supplements — that the FDA has determined are of low enough risk to product quality to be reported in an annual report. Comments are due Sept. 23.

The changes are categorized according to types of manufacturing changes and are either additions or revisions to the classifications listed in a previous guidance, “Changes to an Approved NDA or ANDA.”

The changes that may now be submitted in an annual report include:

  • A new supplier of inactive ingredients that have a minimal effect on product performance, providing that acceptance criteria remain unchanged;
  • An addition of barriers to prevent routine in-process human intervention in a filling or compounding area that is qualified and validated by established procedures;
  • An addition of a specification for existing excipients;
  • An addition of a test for packaging material to provide increased assurance of quality;
  • A tightening of an existing acceptance criterion; and
  • A reduction of expiration dating for a drug product for reasons other than stability failures.

However, the FDA expects application holders to determine whether a change presents a minimal potential to have an adverse effect on the product or whether it should be submitted as a supplement.

Notification Contents

A notification of change submission in an annual report must include a full description of the CMC changes that the applicant believes did not require a supplemental application.

The applicant should describe changes in enough detail that the FDA can quickly determine whether the appropriate reporting category has been used. The company also should include the list of changes in the summary section of the annual report.

If a change is inappropriate for an annual report, the FDA will notify the applicant of the correct category and any additional information needed, the guidance says.

The guidance, “CMC Postapproval Manufacturing Changes Reportable in Annual Reports,” is available at www.fdanews.com/ext/files/UCM217043.pdf. — April Hollis

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