Tuck, thanks to Rick for providing the link.
I thave thoroughly reviewed the briefing materials and find the FDA response is very confusing. The protocal CRXA followed which compares the response to Bexxar to the last chemo regime was discussed and initially supported by the FDA.
""This study design, which utilized the patient’s response to recent prior chemotherapy as an historical control, was identified by the Biological Response Modifiers Advisory Committee (BRMAC) as an acceptable study design for drugs intended to treat patients with "chemotherapy-refractory" NHL and as an acceptable alternative to a concurrently controlled trial, using best standard of care or alternative therapy of physician choice, as requested by FDA. ""
Of course the FDA changes the rules after the clinical trials are complete claiming ""FDA believes that this historically controlled trial design has a potential design flaw. Based on the selection criteria for the population (i.e., patients with refractory disease), a successful result could have been obtained with a potentially unacceptably low response rate and/or responses of very limited durability (e.g., 32 days). Given that the toxicity profile (high rate and prolonged nature of toxicity, notably hematologic toxicity), the time with toxicity could exceed the time in response in this study design. This trial design flaw was noted in correspondence with the sponsor.""
Of course the FDA can not deny the efficacy shown in the studies and admits in bold ""The results of the major efficacy trial demonstrated a significantly higher proportion of patients with a longer duration of response following iodine I 131 tositumomab therapy as compared to the most recent standard chemotherapy regimen (p < 0.001, McNemar’s test). Treatment with the tositumomab therapeutic regimen yielded an overall response rate of 47%, a median duration of response of 11.7 months and a complete response rate (CR plus CCR) of 20%. As shown in the table below, response rates ranging from 47% to 68% with a median duration of approximately one year and complete response rates ranging from 20% to 34% were observed in clinical trials conducted in patients with previously treated, follicular and low grade NHL. ""
The FDA clearly is having a hard time explaining the significant sustained response for a subset of Bex responders. I find their theory that takes the position that the length of response can not be dispositive because of the lack of a control group to strain logic. Fact is only BEX has produced very long term (greater than 3 years) complete responses. It is almost as if the FDA does not believe the data even though it was reviewed by an independant board. When you review the specific FDA comments and the patients they seek to exclude you can't help but be convinced that they is a bias against the drug. But WHY?
The FDA ultimately post 4 questions the the Advisory Panel as follows:
FDA will seek advice as to whether the durable responses observed, in the face of the toxicities described, are likely to predict clinical benefit for this agent in patients with low grade and follicular NHL, with or without transformation, where the disease is refractory to chemotherapy.
At the time of the original submission of BLA 125011, several of the trials listed above were ongoing. In responding to FDA’s requests for additional safety and efficacy information, the final study report for CP97-012 was filed along with other clinical data. This is the only study that assesses the activity of the tositumomab therapeutic regimen in patients whose disease is refractory to, or only transiently responsive to, Rituximab. In this study, the overall response rate in the entire study was 63% with a median duration of response of 1.3 years. The requested indication is in patients with follicular lymphoma, a subset of the patients enrolled. In this subpopulation, the activity was similar (ORR 63%, median duration of response 2.1 years). FDA will seek the committee’s advice as to whether the data from this study, supported by the activity in other studies in patients with chemotherapy-refractory disease, are adequate and are reasonably likely to predict clinical benefit for the treatment of patients with follicular NHL that has relapsed following chemotherapy and is refractory to Rituxan.
FDA will seek the Committee’s advice regarding the value of the findings of the retrospectively identified subset of responding patients whose time to disease progression has exceeded one year, in establishing clinical benefit. FDA notes that these responding patients, differ from the general study population in several prognostic factors, have particularly long-lasting responses (median response duration 4.9 years). In particular, FDA seeks advice on the design (e.g., prospective, randomized trial) and appropriate control arm to establish whether treatment with the tositumomab therapeutic regimen reliably produces very durable (>1 year) responses that would support promotional claims for this effect.
FDA will seek the Committee’s advice on the types of studies needed to further assess the safety profile of this agent, particularly with respect to delayed toxicities such as MDS and secondary malignancies, hypothyroidism, and HAMA.
Tomorrow will be interesting indeed.
V1
. |
