Bristol Seeking Two NDAs For UFT Combos In Response To Rebetron Debate

Bristol-Myers Squibb's submission of two separate NDAs for the combination use of UFT and leucovorin appears to be a new filing and approval strategy for the development of bundled multi-ingredient products.

Bristol has two NDAs pending for the treatment combination of UFT (uracil/tegafur fixed combination) and leucovorin for metastatic colorectal cancer. The initial application was filed Feb. 26 for the fixed combination and leucovorin.

A second application was filed about one week later for the same combination therapy packaged together as a unit, which will carry the brandname Orzel. The applications are identical, save for the packaging, Bristol says.

FDA's Oncologic Drugs Advisory Committee will review the clinical package for UFT/leucovorin on Sept. 16 (¹ (Also see "Bristol-Myers Squibb UFT" - Pink Sheet, 23 Aug, 1999.)). Bristol says that the advisory committee will not review whether to permit fixed combination packaging of the drugs.

The separate NDA submissions for UFT and leucovorin may be a response by Bristol to the type of debate engendered by FDA's approval in June 1998 of a Schering-Plough combination therapy for hepatitis C.

Last year, FDA approved one NDA for the combination of Schering's Intron A and ICN's Rebetol as a combined package product. Schering markets the product under the separate trademark, Rebetron.

The Rebetron combination improves viral eradication rates over Intron A both for naive patients and patients who relapse after Intron A (interferon alfa-2b) alone.

Rebetol (ribavirin tablets), a nucleoside analog exclusively licensed by Schering from ICN Pharmaceuticals, has not shown antiviral efficacy alone in hepatitis C, or in about 25 other viral infections, Schering says. The ICN product is not marketed as an oral dosage form except as part of the Schering combination product (² (Also see "Schering Rebetron Hepatitis C Therapy Five Year Phase IV Data Requested" - Pink Sheet, 8 Jun, 1998.)).

At the advisory committee review of Rebetron, some members noted that hematological adverse events of ribavirin might necessitate dosing adjustments in some patients and suggested that the two treatments not be bundled as one product (³ (Also see "Schering Intron A/Rebetol Treatment-Naive Hepatitis C Data Close To Filing" - Pink Sheet, 11 May, 1998.)).

By bringing two applications to FDA for the UFT/leucovorin cancer combination treatment, Bristol is providing the agency the option of taking the safety and efficacy decision to its advisory committee without raising the issue of whether it should be a single packaged product.

From Bristol's point of view, the company may be able to get NDA protection at two levels: the combination use of the ingredients and the single package version.

The tegafur component of the UFT/leucovorin combination is not approved currently for use in the U.S.

Two Phase III trials were conducted to support the UFT/leucovorin NDAs. For the experimental arm, one study used a dose of 300 mg/m2 of UFT in combination with 90 mg of leucovorin and the other study used the same dose of UFT in combination with either a 90 mg or a 75 mg tablet of leucovorin. UFT was not studied in the absence of leucovorin.

Bristol says the Orzel combination is being submitted to offer patient and physician convenience. Bristol maintains that compliance would be higher if both pills were together. A prepackaged combination may also help to reduce medication dispensing errors. Bristol cites potential confusion between leucovorin and an unrelated oncologic from Glaxo Wellcome, Leukeran.

Schering provides nine different dosing combinations of Rebetron. The combined product contains intramuscular or subcutaneous interferon syringes and ribavirin tablets. The different dosing options are designed to permit use of lower doses of ribavirin.

Schering maintains that "co-packaging Rebetol and Intron A in a single presentation ensures that maximum efficacy and safety can be achieved in accordance with the data derived from our clinical trials. Modification of the clinically proven regimen could result in sub-optimal treatment results, unanticipated or more severe adverse reactions and might lead to development of viral resistance."

Schering charges a premium for the hepatitis C combination. The ribavirin component adds to the drug component of treatment cost by more than two times the single ingredient cost. A 48-week course of Rebetron carries an average wholesale price of $17,280, compared with an AWP of $5,130 for Intron A alone.

That increased price for the combination has evoked complaints from hepatitis C patient advocacy groups. The Hepatitis C Action & Advocacy Coalition, for example, contends that Rebetron is beyond the reach of uninsured patients.

Bundled into Rebetron, ribavirin cannot be obtained for use with other interferon treatments such as Roche's Roferon and Amgen's Infergen, HAAC points out.

The advocacy group has requested unbundling of ribavirin and a reduction in price of ribavirin from roughly $1,100 per month AWP for a 1,200 mg daily dose (the difference in Intron A and Rebetron pricing) by 75% to $255 per month. HAAC noted that ribavirin costs over three times more than Glaxo's Ziagen (abacavir), the most expensive nucleoside analog, and ribavirin is priced 265% lower in the EU and Mexico, where it is sold as a single agent.

FDA has previously approved a drug for a specific combination under separate packaging; Glaxo's Epivir (lamivudine, 3TC) was originally approved only for combination use with Glaxo's Retrovir (zidovudine, AZT). Later, the drugs were combined to make Combivir, which had the benefit of lowering daily pill intake, but they remain separately available.

FDA does not have the authority to approve the drugs outside the Rebetron combined package, as that was not requested in Schering's NDA. The agency has left open the option for Schering to apply for approval outside of the specific Rebetron combinations.

In a Nov. 12 letter to Schering, FDA pointed out that "approval of the Rebetron Combination Therapy package in no way restricts, nor precludes a request by Schering Corporation to market the individual components separately for their approved use. Should you wish to discuss alternative marketing package options that would make available the ribavirin component alone, [FDA] is open to such discussions."

Schering has not submitted a request to sell ribavirin alone, stating that the company "has no plans to change the packaging of Rebetron." Schering addresses the premium price for the combined ingredients, noting that it conducted long-term trials of the combination and continues trials in special populations as well as developing a follow-on version of ribavirin and PEG-Intron A, another verison of interferon.

HAAC is trying to get Congress to look at the bundling. HAAC says that it will meet with House Commerce/Health and Environment Subcommittee Chairman Bilirakis (R-Fla.) in mid-September. HAAC is also meeting with the Federal Trade Commission.

In April, Rep. Smith (R-N.J.) forwarded a letter to Bilirakis stating that bundling of Rebetron prevented research of ribavirin in combination with other therapies, including interferons, and that the American Medical Association "has 'ethical concerns'" about the combined product. Smith noted that FDA does "not have statutory authority to require the manufacturer to unbundle Rebetron." Rep. Pallone (D-N.J.), also advocated "unbundling" of Rebetron to allow greater treatment flexibility and research.

In May, Rep. Pelosi (D-Calif.) requested that Bilirakis hold a hearing on Rebetron: "Some physicians wish to have the flexibility to prescribe ribavirin with other interferons, and to prescribe dosages that are different than those available in the bundled product." She acknowledged that "no one disputes the company's right to make a reasonable profit on this investment," and recognized Schering's research investment.

Responding to the pricing criticism, Schering has broadened eligibility for its "Commitment to Care" program. On Feb. 1, the program began covering uninsured patients with income below 325% of the poverty line. Previously, the threshold was 140% of poverty. The company estimates that "the program will triple in 1999 to approximately 12,000 patients."

The New York City-based People With AIDS Health Group is assisting patients with prescriptions for ribavirin to obtain the drug from Mexico. FDA allows importation of up to a three-month supply of a drug for personal use. PWA sells 18 ribavirin 400 mg tablets for $82, equivalent to $410 for a month at 1,200 mg/day.

Ribavirin capsules are also available from compounding pharmacies. Fisher's Specialized Pharmacy in Pittsburgh began offering compounded ribavirin capsules on July 9, after the compound patent on ribavirin expired. ANDA applications are prevented by Waxman/Hatch exclusivity until June 3, 2001. Fisher's will compound different doses of ribavirin per a physician's prescription. A 200 mg capsule is sold for $1.25, which projects to $225 per month for the 1,200 mg/day standard dose.