DID - July 17, 2009 Issue

Vol. 8 No. 138


Shire Gaucher’s Disease Treatment Gets Fast-Track Status

Shire’s investigational drug velaglucerase alfa for Type I Gaucher’s disease has received fast-track designation from the FDA.

The fast-track designation follows the company’s recent filing of a treatment protocol for the enzyme replacement therapy. Approval would allow physicians to treat Gaucher’s disease patients with the drug on an early-access basis, ahead of the regular market debut. Shire would provide the drug at no cost at first so as many patients as possible could receive it quickly, the company says in a statement Thursday.

The FDA had asked Shire and Protalix Biotherapeutics to submit separate treatment protocols for their experimental Gaucher’s disease medicines and said it would try to complete a review in 30 days because it expects shortages of the approved Cerezyme (imiglucerase) treatment for Gaucher’s disease after Genzyme’s temporary plant closure (DID, July 7).

Shire is finishing a clinical program that includes three simultaneous Phase III trials enrolling more than 100 patients at 24 sites in 10 countries. Using the fast-track process, Shire can file the NDA for velaglucerase alfa in sections as it completes them, and the agency can review them as they come in.

Protalix confirmed the clinical, nonclinical and chemistry requirements for its NDA with the agency Wednesday and plans to file its application by year’s end (DID, July 15). Protalix’s lead product candidate, prGCD, is a plant-cell expressed recombinant form of glucocerebrosidase and is being tested in a Phase III clinical trial.

Shire’s velaglucerase alfa is made with its proprietary technology in a human cell line. The enzyme produced has the exact human amino acid sequence and carries a human glycosylation pattern, the company says.

“We’re still in continuous conversations with the FDA and hope to hear by the end of July about the approval of the treatment protocol,” spokeswoman Jessica Cotrone told DID. — Martin Berman-Gorvine


Final Guidance Advises Generic Makers on Impurities

A final guidance for generic-drug makers revises recommendations on what chemistry, manufacturing and controls information on drug substances produced by synthesis should be included in ANDAs, drug master files and ANDA supplements.

Drugmakers should include a list of impurities in specifications for a drug substance and describe acceptance criteria for them in their submissions, according to the guidance issued this week. Stability studies, chemical development studies and routine batch analyses can help predict likely impurities in a commercial product, it adds.

The FDA identifies “specified impurities” as individual impurities with a specific acceptance criterion that are included in the specification for a drug substance. Specified impurities can be identified or unidentified.

The agency recommends including specified identified impurities in the list of impurities. Manufacturers also should include specified unidentified impurities estimated to be present at a greater level than the threshold given in an International Conference on Harmonisation (ICH) guidance. Where applicable, the drug substance specification should include a list of organic impurities, inorganic impurities and residual solvents.

Acceptance Criteria

The first critical consideration for establishing impurity acceptance criteria is whether an impurity is specified in the U.S. Pharmacopeia (USP), the guidance says. If there is a monograph in the USP that includes a limit for a specified impurity, the acceptance criterion should be set no higher than that. If the level of a specified impurity is above that level, the agency recommends qualification. If appropriate qualification is achieved, an applicant can petition the USP for revision of the acceptance criterion.

If the USP does not include a limit for a specified impurity, the agency recommends qualifying the impurity by comparing it to the observed amounts in the reference listed drug (RLD). The acceptance criterion should be similar to the level observed in the RLD. Acceptance criteria also may be set based on a qualified level that is justified by scientific literature, metabolite data or toxicology studies. In some cases, the acceptance criteria may need to be set lower than the qualified level to ensure drug substance quality, the guidance notes.

The ICH guidance “Q3A Impurities in New Drug Substances” includes recommendations on impurities for NDAs. The FDA says much of the ICH guidance applies to ANDAs as well, particularly sections I–V and an attachment on thresholds.

The final FDA guidance recommends setting acceptance criteria for unspecified impurities in ANDAs to the lower of the two levels when comparing the identification threshold in Attachment 1, Q3A or acceptance criteria listed in the USP monograph.

The guidance also gives recommendations on qualifying impurities — acquiring and evaluating data that establish the biological safety of an impurity or a given impurity profile at the level(s) being considered. An impurity is considered qualified when it meets at least one of the following conditions:

  • The observed level and proposed acceptance criterion for the impurity do not exceed the level observed in the RLD;
  • The impurity is a significant metabolite of the drug substance;
  • The observed level and the proposed acceptance criterion for the impurity are adequately justified by the scientific literature; and
  • The observed level and proposed acceptance criterion for the impurity do not exceed the level that has been adequately evaluated in toxicity studies.

The Q3A guidance provides recommended qualification thresholds based on the maximum daily dose of the drug substance. When those thresholds are exceeded, manufacturers should qualify impurity levels, the FDA says. The final guidance includes a decision tree describing what to consider for the qualification of an impurity when the Q3A threshold is exceeded.

Methods for qualifying impurities include comparative analytical studies, scientific literature and significant metabolites and toxicity studies. Toxicity tests are the least preferred method to qualify impurities, the guidance notes.

The final guidance, “ANDAs: Impurities in Drug Substances,” is available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM172002.pdf. The ICH guidance is available at www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127984.pdf. — April Hollis


Merck, Schering-Plough Resolve Drug Marketing Investigations

Merck and Schering-Plough will pay $5.4 million to end an investigation into whether the companies violated states’ consumer protection laws by delaying the release of negative clinical trial results from their combination cholesterol drug Vytorin.

The settlement, which includes 35 states and Washington, D.C., resolves an investigation into the alleged delay in making public negative results from the ENHANCE trial, which studied Vytorin, a combination of Merck’s Zocor (simvastatin) and Merck and Schering-Plough’s Zetia (ezetimibe), versus Zocor alone (DID, Dec. 13, 2007).

ENHANCE ended in May 2006, and a partial reporting of negative results did not occur until January 2008. Complete results weren’t published until three months after that. Vytorin was promoted in direct-to-consumer (DTC) advertisements before the data were released, the Oregon Department of Justice, the leading investigative body in the case, says in a statement Wednesday.
The settlement agreement doesn’t require the companies to make any other payments to the states and doesn’t require them to admit to misconduct or liability.

The “agreement is consistent with our belief that the companies conducted the ENHANCE trial in good faith and that their promotion of Vytorin and Zetia was in compliance with the law,” Bruce Kuhlik, Merck’s executive vice president and general counsel, says in a statement.

Thomas Sabatino, Schering-Plough’s executive vice president and general counsel, says in the statement, “Resolving these inquiries for an amount equal to the states’ investigative costs is in the interests of all stakeholders.”

Terms of Settlement

The Oregon Department of Justice says the settlement calls for extensive injunctive relief including requiring the drugmakers to:

  • Obtain preapproval from the FDA for all DTC television advertisements;
  • Comply with the FDA’s suggestions to modify drug advertising;
  • Register clinical trials and post their results;
  • Refrain from ghostwriting articles;
  • Reduce conflicts of interest for data safety monitoring boards; and
  • Comply with detailed rules prohibiting the deceptive use of clinical trial results. — Elizabeth Jones


Draft Advises Sponsors on Meeting Postmarketing Requirements

The FDA requires companies submitting NDAs or BLAs to conduct postmarketing studies or clinical trials when the agency deems it scientifically necessary or when adverse event reporting and pharmacovigilance would be insufficient to ensure safety, according to a draft guidance.

The FDA has the power to impose this requirement under the FDA Amendments Act of 2007 (FDAAA), which imposes a distinction between studies and clinical trials.

Postmarketing studies may include observational epidemiological research and research involving animals or laboratory experiments, the FDA says. If the agency wishes to require that a sponsor perform a full postmarketing clinical trial, it must decide that a postmarketing study would be insufficient.

The draft also distinguishes between postmarketing requirements (PMRs), which are regulatory mandates, and postmarketing commitments — studies or clinical trials that sponsors have agreed to conduct but that are not required by law.

The focus on safety is paramount. “Although almost any study or clinical trial might be broadly construed to evaluate safety, FDA does not intend to consider all postmarketing studies and clinical trials as PMRs,” the draft says.

Evaluating Risk

PMRs under FDAAA generally include observational pharmacoepidemiologic studies about the drug’s risk, or studies to evaluate factors that affect the risk of serious toxicity, such as drug dose, timing of exposure or patient characteristics, the draft says.

Such studies should have a protocol that prespecifies hypotheses, and a control group unless there is a scientifically valid reason not to have one, according to the draft guidance. Data sources for such studies could include administrative healthcare claims data, electronic medical records, registries or prospectively collected observational data.

PMRs also may include clinical trials with a primary safety endpoint that is evaluated based on prespecified assessments. An example would be a clinical trial designed to see how often an inhalation treatment for asthma is associated with exacerbation of the condition, according to the draft guidance.

Other examples of PMRs include studies or clinical trials to evaluate the drug’s pharmacokinetics in the labeled population or a subpopulation at risk for high exposure that could lead to toxicity, as well as studies or clinical trials designed to evaluate drug interactions or bioavailability when scientific data indicate the potential for a serious safety risk.

Reporting Requirements

In general, the FDA will interpret the periodic reporting requirement for PMRs and other studies and trials conducted independently to be the yearly status reports required under 21 CFR 314.80, 314.81 and 601.70 unless the FDA says otherwise, the draft advises.

Sponsors are required give the FDA a timetable for completing PMR studies or trials. They also must file periodic status reports including trial registration information, whether subject enrollment has begun and the number of participants enrolled, and whether there have been any difficulties completing the study. Sponsors also must report to the FDA about any postmarketing studies or clinical trials they have independently undertaken.

The draft can be viewed at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM172001.pdf. Comments are due Oct. 13 — Martin Berman-Gorvine



FDA Safety Review Looks at Asthma Drug Xolair

Genentech’s asthma drug Xolair (omalizumab) is the focus of a safety review by the FDA on whether there is an association between the drug and an increased risk of arrhythmia, stroke, heart attack and heart failure.

The potential association was based on interim results from a current study, the FDA says in an emailed announcement Thursday. The agency also issued a MedWatch notice to healthcare providers about the review. The FDA says it is not advising doctors to stop prescribing the drug and patients should continue treatment.

Genentech is conducting the study as a postmarketing commitment to assess the long-term safety profile of Xolair in patients followed for five years, company spokeswoman Tara Cooper told DID. Interim data submitted by Genentech suggest a disproportionate increase in arrhythmias, cardiomyopathy, heart failure, ischemic heart disease, pulmonary hypertension, cerebrovascular disorders, and embolic thrombotic and thrombophlebitic events in patients treated with Xolair compared with the control group, the FDA says.

Genentech and Novartis Pharmaceuticals, which jointly market Xolair in the U.S., are in discussions with the FDA and are gathering more information about the cardiovascular and cerebrovascular events from the study, Cooper said. She added that limitations of the data preclude a definitive association with Xolair use. “There is insufficient information for the companies to change their assessment of the benefit-risk profile for Xolair.” 

The study — Evaluating the Clinical Effectiveness and Long-Term Safety in Patients with Moderate to Severe Asthma (EXCELS) — is observational, so there could be differences in underlying risk factors for cardiovascular and cerebrovascular events between the study groups, the agency says. Any new findings will be communicated when the FDA’s analysis of the interim safety data is complete, it adds. Final results from the study are expected in 2012.

Xolair is approved for use by adults and adolescents 12 years and older with moderate-to-severe persistent asthma who test positive for reactivity to a perennial airborne allergen and whose symptoms are not adequately controlled with inhaled corticosteroids.

In 2007, Genentech added a boxed warning to Xolair’s labeling about the risk of anaphylaxis (DID, July 3, 2007). The MedWatch and the safety review documents are available at: www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm172406.htm. — April Hollis


FDA Lifts Partial Clinical Hold on Genmab Cancer Drug

Danish drugmaker Genmab can resume patient enrollment in trials of zalutumumab as a treatment of head and neck cancer because the FDA lifted a partial clinical hold on the research.

Zalutumumab has received a fast-track designation for the head and neck cancer indication in patients who previously have failed standard therapies. The studies are being conducted to support an IND application.

Genmab announced the partial hold last month after the FDA requested an updated analysis of safety data on the drug. The affected studies were a Phase II trial in patients with head and neck cancer considered incurable with standard treatment and a Phase I/II study of zalutumumab combined with chemoradiotherapy as a first-line treatment, according to a company statement Thursday.

The partial hold didn’t affect the two ongoing Phase III studies of zalutumumab in head and neck cancer or a Phase I/II study of the drug in combination with radiotherapy. 

“We have worked diligently to meet the FDA’s request for additional zalutumumab safety information and are pleased that enrollment in the studies can be resumed so quickly,” Genmab CEO Lisa Drakeman says in the statement.
The company hasn’t provided details on when recruitment will be completed and has no update on the studies that weren’t affected by the hold, a Genmab spokeswoman told DID. — Elizabeth Jones


Mylan Gets FDA Approval for Generic Cytomel

The FDA has approved Mylan’s ANDA for a generic version of the Cytomel thyroid-deficiency treatment.

The agency approved the company’s liothyronine sodium tablets in 5-, 25- and 50-microgram doses, and the company has begun shipping the product, Mylan says in a statement Thursday. Cytomel is made by King Pharmaceuticals.

The approval is Mylan’s second ANDA to receive FDA clearance this month. The company received approval last week to market a generic version of AstraZeneca’s Casodex (bicalutamide) prostate cancer treatment (DID, July 8).

Cytomel had U.S. sales of about $54 million for the 12 months ended March 31, Mylan says. The drugmaker says it has 120 ANDAs pending FDA approval representing $84.7 billion in annual brand sales. Thirty-five of the ANDAs are potential first-to-file opportunities, representing $16.6 billion in annual brand sales, it adds. — David Belian


Wyeth Recalls One Lot of Prevnar Vaccine

Wyeth is voluntarily recalling one lot of its Prevnar pneumococcal 7-valent conjugate vaccine and says the prefilled syringes involved pose no public health risk.

Part of a bulk lot of single-dose, prefilled syringes of the vaccine, which was not intended for commercial use, was inadvertently packaged and distributed with the commercial product, the FDA says in a statement Thursday. The lot number is D50002. 

The product met Wyeth’s quality acceptance criteria, and the company performed a medical assessment, concluding that the affected syringes present no health or safety risk to patients and that there is no need to revaccinate.

Wyeth “is taking steps to make sure this situation does not recur,” spokeswoman Lili Gordon told DID. Of the 96,280 doses in the lot, 16,000, or about 17 percent, were at issue, she said. — Martin Berman-Gorvine

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