In the ----------------- submission to the FDA, the sponsor identified 75 long-term responders from the five clinical studies. In the ------------------ submission, the sponsor identified 78 patients with long-term responses following tositumomab therapeutic regimen. This subset was also derived from Studies RIT-II-000, RIT-II-001, RIT-II-002, RIT-II-004, and CP 97-012. The criterion for selection of this subset was time to disease progression of more than 12 months. The basis for this criterion as being a clinical relevant cut-point remains unclear.

The sources of the sponsor-defined long-term responder population and distribution across the efficacy/activity study population are as follows:

A: Study Population in the Long-Term Responder Data Set

FDA’s review of the case report forms and other documentation identified the following two patients in whom long-term response could not be confirmed.

After teleconferences on ----------------------------------, between FDA and the sponsor, agreement was reached to exclude these two patients from the "Long-term responder" subset. Due to insufficient time to re-analyze the dataset, some of the analyses below include these 2 patients, however inclusion of these patients does not alter the conclusions drawn from these analyses. The analyses will be updated for the December 17, 2002 ODAC meeting. Based on the agreement with the sponsor, the "long-term responder" data set contains 76 patients.

Among the 76 patients, eight patients received a dose and/or schedule of the tositumomab therapeutic regimen that differs from the regimen under review for licensure and for which approval is being sought. FDA believes that the following eight patients from study RIT-II-000 should be treated as a separate group, since they received more than one dosimetric dose: These patients (by patient ID number) are: 000-002-006, 000-002-010, 000-002-013, 000-002-015, 000-002-016, 000-002-020, 000-002-022, 000-002-025.

The confounding factor introduced by receiving more than one dose of unlabelled antibody is illustrated by the observation that in study RIT-II-002, when comparing the efficacy of labeled and unlabeled antibody therapy, there were also some patients with long-term responses in the unlabelled antibody group.

The following case included in the long-term responder group by the sponsor further underscores the point.

Since pooling the data from patients who have received multiple doses of unlabeled antibody may not be appropriate, FDA analyses were conducted both including and excluding this subset of patients who received an alternate tositumomab regimen.

B: What Were The Disease Parameters Being Measured?

The eligibility requirements regarding measurable disease differed among the five studies. The Phase I study, RIT-II-000, required ‘evaluable and measurable’ disease with no specific requirements in terms of tumor dimensions. Study RIT-II-001 required either evaluable disease (which included unidirectionally measurable disease if it had ill defined margins and lesions <0.5 cm diameter, or less then distance between two CT cuts) or bi-dimensionally measurable disease. Study RIT-II-002 at its inception required patients to have evaluable or –bi-dimensionally measurable disease that was amended on ---------- to require lesions of ³ 2 cm in both perpendicular dimensions. Study RIT-II-004 required at its inception bi-dimensionally measurable or evaluable disease, which was amended to requiring bi-dimensionally measurable disease on --------- with at least 1 lesion to be ³ 2 cm diameter. The study CP-97-012 required that at least one lesion be ³ 2 cm in perpendicular diameters from the onset.

C: How Was the Follow-Up Conducted?

The follow-up requirements as specified in the protocols differed among the five studies. .

Study RIT-I-000 required frequent monitoring during the treatment phase and then at ‘standard’ evaluations during long term follow-up. This was amended on --------- to tumor response evaluations at appropriate intervals and further amended on ---------- to evaluations every 6 months during the first two years and long term follow up after that. Study RIT-II-001 required follow-up studies every 3 months during the first 2 years and every six months after that. Study RIT-002 required frequent follow-up during first 12 weeks, then every 3 months for the first two years and every 6 months thereafter. RIT-II-004 also required response evaluation every 3 months for 2 years and every six months thereafter. Study CP-97-012 required frequent follow-ups during first 6 months and then every 6 months for the first two years and long term follow-up after that. The long term follow up consisted of obtaining information about disease status by direct or telephone contact with patient, physician or family member. Radiographic scans and medical notes related to the response evaluation were obtained retrospectively by the sponsor.

D: How was the Long-term Responder Population Derived?

An independent review of the response assessments was performed by the MIRROR (Masked Independent Randomized Radiology and Oncology Review) Panel. This review was performed for all patients enrolled in studies RIT-II-004, RIT-II-002 and CP-97-012. This review was prospectively planned and primary source documentation for review prospectively collected for study RIT-II-004. The collection of data and proposal for MIRROR panel review was performed retrospectively, after the completion of accrual, for studies RIT-II-002 and CP 97-012, per an amendment to the protocols in 2001.

A retrospective review of the Investigator’s assessment of response was conducted by the MIRROR panel in October 2001 for patients from studies RIT-I-000, RIT-II-001, RIT-II-002, and RIT-II-004 who were identified by the sponsor as long-term responders. A subsequent, retrospective review of other patients with low-grade NHL was conducted in June/July 2002 for patients from studies RIT-I-000 and RIT-II-001. In July 2002, the FDA requested a confirmatory independent re-review of 37 patients from studies RIT-I-000, RIT-II-001, RIT-II-002, RIT-II-004, and CP-97-012. Each of the 37 patients had a time to progression of at least 12 months on their original MIRROR Panel review. The majority (26 of 37 patients) were patients enrolled in the earlier studies RIT-I-000 or RIT-II-001, which were the two studies with MIRROR Panel review performed on only a subset of patients. According to the MIRROR2 panel charter, measurable lesions were defined as having a bi-dimensional size of ³ 2.0 cm x 2.0 cm. All lesions having a product of greatest perpendicular diameters = 4.0 cm² were considered to be measurable disease. Lesions with products of perpendicular diameters between 1.0 cm² and 4.0 cm², were considered to be evaluable, but not measurable disease. These lesions were documented in the baseline lesion tabulation for reference.

The MIRROR2 Panel, convened to assess long-term responders, identified six patients for whom an earlier response assignment of progressive disease was made in error by them. In each case, the MIRROR2 Panel members re-classified the patient as a responder at later assessment time points. In addition, the MIRROR2 Panel identified three patients without measurable disease, but with evaluable disease, at baseline. Each of the three patients was eligible based on the protocol entry criteria in use at the time of their enrollment and each patient had all lesions decrease to <1 x 1 cm².

E: Analyses of the Long-term Responder Subpopulation

Additional Review Comments:

The retrospective manner in which the long-term responder population was identified and the duration of response assessed, impinges on the robustness of the findings. Retrospective judgment passed on lesions with the benefit of hindsight may not represent the real time clinical decision-making process regarding whether further treatment is truly contemplated in this indolent lymphoma population. Following the FDA review of long-term responder population, teleconferences were conducted between the FDA reviewers and the sponsor on ------------------------- regarding 17 patients that the FDA reviewers did not feel confident in endorsing the assessment provided by the sponsors. As stated above, the sponsor agreed to remove two patients from the durable response population, bringing the total number of patients in this group to 76. The FDA review team agreed with the sponsor on one case. While the FDA would like to afford the sponsor the benefit of the doubt, copies of the sponsor’s response, which also contain the gist of FDA queries is provided as an appendix.