AstraZeneca's Vandetanib Approval Includes REMS With Distribution Restrictions

The medullary thyroid cancer drug's Risk Evaluation and Mitigation Strategy requires mandatory enrollment and certification of prescribers and pharmacists, which should help ensure the drug is used primarily in patients with symptomatic, progressive disease.

FDA's approval of AstraZeneca's vandetanib suggests the agency concluded a restricted distribution program was necessary to ensure the thyroid cancer drug is used primarily in patients with symptomatic, progressive disease.

FDA approved vandetanib, an oral, multi-tyrosine kinase inhibitor, for treatment of symptomatic or progressive medullary thyroid cancer (MTC) on April 6. The approval includes a Risk Evaluation and Mitigation Strategy with a restricted distribution program that requires mandatory enrollment and certification of prescribers and pharmacists.

The restrictions should serve to discourage prescribing to patients with stable disease or for whom vandetanib's toxicities may be worse than the symptoms.

At an advisory committee meeting on the product, AstraZeneca said it was prepared to work with FDA on a Risk Evaluation and Mitigation Strategy with a Medication Guide and a physician education component. Restricted distribution was not specifically addressed.

Launching Without A Trade Name

In an unusual move, AstraZeneca is planning to launch vandetanib soon without a brand name, the company's executive director for development, Joe Cordaro, said in an interview.

AstraZeneca's proposed trade name, Zictifa, was rejected by FDA. Cordaro said the company continues to work on a new name but has confirmed with the agency that launching an unbranded product is feasible.

Vandetanib becomes the first drug approved in the U.S. to treat MTC, a rare disease with approximately 1,300-2,200 new cases every year, FDA said. The therapy also is the first that AstraZeneca has developed and brought to market under U.S. orphan drug designation, the company said.

The approval came one day ahead of the product's April 7 user fee date, which was extended by three months following submission of a proposed REMS (Also see "Pharma News, In Brief" - Pink Sheet, 10 Jan, 2011.).

Vandetanib is indicated for treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Labeling states that use in patients with indolent, asymptomatic or slowly progressing disease should be carefully considered due to treatment-related risks.

The indication is narrower than that originally sought by AstraZeneca, which had requested approval for treatment of unresectable, locally advanced or metastatic MTC. However, the approval tracks the recommendations of FDA's Oncologic Drugs Advisory Committee.

In December, a majority of committee members said vandetanib's indication should be limited to patients with progressive or symptomatic disease to reduce the population at risk for drug-related toxicities, the most concerning of which is QT interval prolongation (Also see "FDA Committee Backs AstraZeneca's Vandetanib For Narrower Population Of Thyroid Cancer Patients" - Pink Sheet, 2 Dec, 2010.).

FDA staff also raised concerns about cases of sudden death, Torsades de Pointes, interstitial lung disease, cerebrovascular events, Stevens-Johnson Syndrome and diarrhea. Vandetanib's toxicities may be worse than the symptoms of untreated MTC and have to be considered in the context of a drug that could be taken for many years, reviewers said (Also see "Toxicity Of AstraZeneca's Vandetanib Expected Focus For FDA Advisory Committee" - Pink Sheet, 30 Nov, 2010.).

Nevertheless, ODAC panelists were hesitant to restrict the drug's use, particularly in patients who may be at risk for serious complications once their thyroid tumors progress.

REMS Plans

Under the approved REMS, the drug will only be available through the Vandetanib REMS Program. Prescribers and pharmacies must be certified with the program to prescribe and dispense the drug.

To be certified, prescribers must review the educational materials, agree to comply with the REMS requirements and enroll in the program. Pharmacies must enroll in the program, train their pharmacy staff to verify that each prescription is written by a certified prescriber before dispensing to a patient, and agree to comply with the REMS requirements.

Vandetanib will be dispensed exclusively through the pharmacy business unit of Biologics Inc., an integrated oncology management company, AstraZeneca said.

QT Risk Is Focus Of MedGuide, Boxed Warning

The REMS also includes a MedGuide that focuses on the risk of QT prolongation, serious skin reactions, breathing problems, stroke and other potential adverse events.

The risks of QT prolongation, Torsades and sudden death are highlighted in a boxed label warning, which advises that electrocardiograms to monitor the QT interval should be performed at baseline, two to four weeks and eight to 12 weeks after starting treatment and every three months thereafter. Serum potassium, calcium, magnesium and thyroid-stimulating hormone levels also should be monitored at these intervals.

Vandetanib was approved on the basis of a single, 333-patient Phase III trial showing robust efficacy, with a significant 65% reduction in the risk of disease progression compared with placebo.

Though it represents a small patient population, MTC provided a commercial lifeline for vandetanib after efficacy data in non-small cell lung cancer were not sufficiently robust to support approval for that far more lucrative indication. AstraZeneca continues to study vandetanib for a variety of solid tumor types (Also see "Vandetanib Shows Heightened FDA Focus On Dose Optimization For Cancer Drugs" - Pink Sheet, 6 Dec, 2010.).

Further Dose Exploration Post-Approval

At the ODAC meeting, the committee voted 10-0 to require AstraZeneca to explore the optimal vandetanib dose in post-marketing studies and FDA's approval follows this recommendation.

AstraZeneca is required to conduct an 80-patient, post-marketing trial comparing the safety and efficacy of the current 300 mg starting dose with a 150 mg dose, Jim Vasselli, AstraZeneca's medical science director for vandetanib, said in an interview. The trial will run for two years, and a final study report is due in December 2014.

At the ODAC meeting, FDA Office of Oncology Drug Products Director Richard Pazdur suggested that given the small MTC patient population, AstraZeneca might be able to conduct post-approval dosing studies in other tumor types and extrapolate the results to the MTC setting.

This was not the approach ultimately adopted, however, as the required post-marketing study will be conducted in MTC patients, Vasselli said.

-Sue Sutter ([email protected])