DID - Oct. 13, 2009 Issue

Vol. 8 No. 199

Drugmakers Express Concern Over Labeling in PCID Guidance

Several drugmakers have expressed concerns about whether to disclose physical-chemical identifiers (PCIDs) in drug labeling — a decision left to their discretion in a recent draft guidance.

Identifying PCIDs in product labeling could provide information to counterfeiters and thwart anti-counterfeiting efforts, Merck, Sanofi-Aventis and GlaxoSmithKline (GSK) say in comments to the draft. However, nondisclosure could pose a risk to patients.

According to the guidance, applicants can choose whether to revise the labeling of a solid oral dosage form (SODF) drug product to indicate the incorporation of a PCID (DID, July 14). PCIDs, such as colorants and excipients, may be used to authenticate or code products, making them more difficult to counterfeit.

GSK suggests including a simple statement, such as “an inert anti-counterfeiting feature is included” or providing the details of the PCID within a drug master file.

Pharmaceutical companies should perform overall risk-benefit assessments on the impact of disclosing PCIDs and be allowed to make justified decisions based on the type of product, indication, population, likelihood of counterfeiting, allergic potentials of the PCID and other factors, Sanofi-Aventis says.

Sanofi adds that specific text is necessary to allow sponsors to decide not to list the PCID on the drug product or packaged product labeling and not to disclose the specific PCID used in the labeling.

Merck and Sanofi also express concerns about the amount of work needed to incorporate PCIDs into products, particularly products that have approval without PCIDs. Many companies use a single formulation for global distribution and it is unlikely they would want a PCID-protected formulation for U.S. distribution, and an unprotected version for the rest of the world, Merck says.

The companies also requested information including:

  • Clarification on whether PCIDs should be “inactive” or “relatively inert,” as both terms are used in the guidance;
  • Data on the minimum amount of stability data needed in an annual report;
  • The scope of the guidance, for example, prescription or OTC SODFs;
  • An outline of procedures for discussing the incorporation of PCIDs with the agency;
  • Evaluation of the risk of PCID-detection failure and the ability to subvert detection systems;
  • Discussion of process analytical technology and quality by design principles in the incorporation of PCIDs;
  • Specific examples of PCIDs under the categories listed in the draft guidance (inks, pigments, excipients and food additives); and
  • Clarification on whether the agency expects inclusion of analytical methods for testing PCIDs in the chemistry, manufacturing and controls sections of an NDA.

The draft also received an anonymous comment expressing concerns on the potential toxicity of PCIDs.

The draft guidance is available at www.fdanews.com/ext/files/8247dft.pdf. — April Hollis


Flu Patient Dies After Receiving Nebulized Relenza

A pregnant woman with influenza died after receiving the GlaxoSmithKline (GSK) drug Relenza Inhalation Powder in an unapproved nebulized form, the company says in a letter to healthcare professionals.

The patient, who was on mechanical ventilation, received Relenza (zanamivir) for three days in a nebulizer solution administered through the ventilator, GSK says in the statement posted on the FDA’s website. The solution was made by healthcare professionals who were treating the patient, the company says, adding that there is a risk that the lactose in the formulation can obstruct proper functioning of mechanical ventilator equipment.

The incident occurred outside the U.S., according to GSK. The company did not respond to a request for additional information about the incident by press time.

The company and the agency say that some healthcare professionals have been reconstituting Relenza Inhalation Powder in liquid formulations for use in nebulizers or mechanical ventilators. They use the form for patients who can’t take oral medications or use the Diskhaler device.

“Relenza Inhalation Powder should only be used as directed in the prescribing information by using the Diskhaler device provided with the drug product,” the FDA says in a MedWatch alert last week.

The MedWatch safety summary, including a link to GSK’s letter to healthcare professionals, is available at www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm186081.htm. — Martin Berman-Gorvine


AstraZeneca Petitions for Rehearing in AWP Dispute

AstraZeneca has asked a federal court for an en banc rehearing to reconsider a judgment ordering the company to pay nearly $13 million in damages related to a Massachusetts average wholesale price (AWP) case.

The U.S. Federal Court of Appeals for the First Circuit erred in upholding a classwide judgment against AstraZeneca, which was accused of overcharging for the prostate cancer drug Zoladex (goserelin acetate), the company maintains in court documents.

The company was one of 42 drugmakers named in the dispute filed in the U.S. District Court for the District of Massachusetts. The lawsuit accused them of breaking state consumer protection laws because third-party payers and consumers allegedly overpaid for physician-administered medicines, according to court documents. AstraZeneca was found liable and ordered to pay $12.9 million in damages.

However, the District Court relied upon an aggregate classwide damages methodology that couldn’t be used to calculate the damages of any plaintiff or class member, AstraZeneca says in court documents. The appellate court therefore erred when it upheld the decision against AstraZeneca Sept. 23.

At no point did any “witness determine how many prescriptions for Zoladex any plaintiff or class member paid for at AWP,” AstraZeneca asserts. The District Court had no discretion to enter classwide damages without proof of an individual plaintiff’s damages, the company adds.

AstraZeneca also contends the appellate court failed to acknowledge that the company accurately reported physician discounts of Zoladex to the federal government. “Offering physicians discounts off … list prices, and affirmatively and accurately disclosing the discounts to class members and to the government” doesn’t violate the law, the company maintains.

Banning discounts to physicians might have proven a wise policy choice, AstraZeneca maintains, but there is no evidence that state or federal regulators have made that choice.

AstraZeneca filed its petition related to the case In re: Pharmaceutical Industry Average Wholesale Price Litigation Oct. 7. — Elizabeth Jones


Onyx Pharmaceuticals, Proteolix Reach Cancer Drug Agreement

Onyx Pharmaceuticals has made an agreement worth more than $200 million with biopharmaceutical company Proteolix for a multiple myeloma candidate.

Onyx plans to present new data on carfilzomib in December and release top-line data from a Phase IIb trial in the second half of 2010, it says in a statement Monday. The company plans to file an NDA by the end of 2010.

Under the agreement, Onyx will give $276 million to Proteolix after the transaction closes. Additional payments include $40 million in 2010, upon reaching a development milestone, and up to $535 million after certain regulatory approvals in the U.S. and Europe. Of the potential $535 million, a payment of $170 million is based upon the achievement of accelerated FDA approval, Onyx says.

A Phase III trial evaluating carfilzomib is being evaluated in combination with Celgene’s Revlimid (lenalidomide) and dexamethasone as a potential treatment option for relapsed and refractory multiple myeloma is expected to begin in 2010. In addition, carfilzomib is being evaluated in a Phase II trial in relapsed patients with multiple myeloma and is being evaluated in a Phase Ib/II study for solid tumor cancers.

The transaction is expected to close in the fourth quarter.

Separately, the Novartis Option Fund will spend as much as $200 million plus royalties on a G-protein-coupled receptor (GPCR) target under an agreement with Heptares Therapeutics.

UK-based Heptares will use its StaR technology to generate novel drug candidates against an unspecified GPCR target of interest to Novartis, Heptares says in a statement Monday. The company will receive upfront and potential milestone payments of as much as $200 million plus royalties. The StaR technology allows the use of structure-based drug discovery technologies, Heptares says. — April Hollis


CHMP Plans Guidance on Treatment-Resistant Depression Studies

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is taking the first steps toward giving drug manufacturers updated guidance on clinical trials for treatment-resistant depression (TRD).

Researchers have developed new criteria to better define the TRD patient population, “which suffers from clinically relevant impairment and requires alternative treatment options, including augmentation with add-on strategies or monotherapy options,” CHMP says in a concept paper posted online outlining the elements to consider. Comments are due Dec. 31.

Specifically, the planned guidance will focus on:

  • Long-term safety;
  • The choice of endpoints;
  • The presence and acceptance of co-morbidity;
  • Study duration issues, including short-term efficacy and maintenance of effect;
  • Special populations, such as children, adolescents and senior citizens;
  • The validity of diagnostic criteria and measurement tools, such as self- and observer-ratings;
  • The TRD target population, including diagnostic criteria, threshold for severity, and inclusion and exclusion criteria;
  • The inclusion of an active comparator. The guidance will examine whether there is a “gold standard” that would always be acceptable as an active control; and
  • How sponsors can seek a TRD indication for their drugs as a follow-up to established efficacy in major depressive disorder (MDD) or as a stand-alone indication without established efficacy in MDD.

“Despite the many treatment options currently available for MDD … up to one third [of patients] do not adequately respond to treatment and up to 20 percent are considered nonresponders, even if there is good compliance and the treatment has been taken long enough with an adequate dosage,” the concept paper says, adding that “there is a clear unmet medical need for patients, in whom even state-of-the-art antidepressant therapy fails to elicit a sufficient treatment response.”

“Concept Paper on the Need for Revision of Note for Guidance on Clinical Investigation of Medicinal Products in the Treatment of Depression With Regard to Treatment-Resistant Depression Agreed by Efficacy Working Party” is available at www.emea.europa.eu/pdfs/human/ewp/48436609en.pdf. Comments can be submitted to EWPSecretariat@emea.europa.eu. — Martin Berman-Gorvine


South Africa Heightens Standards for Package Insert

South Africa’s Medicines Control Council (MCC) is toughening its standards on the amount of information on adverse events that must be included on product labeling.

Drugmakers marketing products in the country now must include on package inserts an estimate of the overall percentage of patients expected to experience adverse reactions and must avoid statements such as those indicating that the reactions are rare, the MCC says in a guidance posted on its website Monday.

In addition, information relating to individual serious or frequently occurring adverse reactions, for which there is no frequency estimation available, also must now be included, the MCC says, and information from postmarketing studies should be presented separately from pre-marketing clinical trial data.

The changes update the MCC’s guidelines for package inserts that took effect last year and clarified which information drugmakers can include.

According to the guidelines, package inserts must not contain promotional information, comparisons with other medicines or references to the brand name of any product that is not the subject of the package insert. Statements suggestive of any potential advantage over competitors also cannot be included.

When submitting a copy of a package insert to the MCC for approval, manufacturers should present it in double-spaced text in black print and should include the date of the

submission as a header or footer on each page. References for each statement made in the insert should be included in a broad margin on the right hand side of each page.

For drugmakers seeking to amend an already approved package insert, the approved insert, the proposed amendment and the evidence supporting the change should be submitted together, the guidance says. Each insert also should be accompanied by a patient information leaflet reflecting the corresponding proposed amendments.

The MCC guidelines can be found at www.mccza.com/documents/2.16%20PI%20for%20human%20medicines%20Aug09%20v3_ND.doc. – David Belian

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