The problem is FDA and the company evaluate the trial results differently. Especially the seven patients (61-53=8) left out when the company evaluated the data.
Company's opinion:
Depocyt treatment: 33% (8) of 24 responded
Methotrexate: 17% (5) of 29 responded
ODAC's opinion:
Depocyt treatment: 8 of 31 (24 plus 7 who were not evaluable in company's opinion and who did not respond)
Methotrexate 6 (5 plus 1 who was not evaluable according to the company and happened to be a responder) of 30 (29 plus 1)
So the company and ODAC were looking at the same data, but somehow the company excluded the data from 8 patients who were regarded by ODAC to be 7 nonresponders to Depocyt and 1 responder to Methotrexate. The inclusion of these patients would significantly change the median survival time for each group.
The company must have realized that the effects if exist are very marginal and more data was needed to convince FDA, so they started phase IV right away. But I doubt if the ODAC had a chance to see the data, at least not mentioned in the news. Also FDA is very suspicious about results from clinical trials with small number of patients.
Here is a old news from Depo where I got the numbers:
CHIRON AND DEPOTECH ANNOUNCE ADDITIONAL PHASE 3
CLINICAL TRIAL RESULTS FOR DEPOCYT
New Drug Delivery Technology Enhances Effect of Cancer Drug
EMERYVILLE, CA AND SAN DIEGO, CA October 21, 1996 - Chiron Corporation
(NASDAQ: CHIR) and DepoTech Corporation (NASDAQ: DEPO) today announced additional
results of a Phase 3 clinical trial of DepoCytTM, an anti-cancer drug, in patients with neoplastic
meningitis (NM) arising from solid tumors. If 24 evaluable patients treated with DepoCyt, the
median survival was 168 days compared to 87 days for 29 evaluable patients receiving the
control drug, methotrexate (MTX). A secondary endpoint of the study of these 53 patients were
evaluable for the survival analysis based on prospectively defined criteria. For all solid tumor
patients, mean time to NM disease progression as measured by neurological examination or death
from any cause.
The companies previously announced that DepoCyt showed a higher complete response rate
compared to MTX. Following a recent review of these and other trial data with the U.S. Food
and Drug Administration, the companies agreed that a New Drug Application (NDA) for
DepoCyt would be submitted as soon as practicable.
The clinical trial was a multi-center, controlled, non-blinded study of DepoCyt, in which a total
of 61 patients were randomized to treatment either with DepoCyt or MTX, a generic
chemotherapy agent that is the current standard of care of NM arising from solid tumors. Patients
initially received a dose of DepoCyt every 14 days, compared to twice per week dosing the
MTX.
Of the 24 evaluable patients treated with DepoCyt, 33 percent showed a complete response
versus 17 percent of 29 evaluable patients treated with methotrexate (MTX). Response in this
study was defined as the absence of malignant cells in two consecutive samples of cerebrospinal
fluid taken from patients and lack of NM disease progression as assessed through neurological
evaluation at the end of the initial 28 days of treatment. Among patients receiving DepoCyt,
median survival was 168 days, compared to 87 days among patients receiving MTX.
"We are gratified that these data appear to support consistently the potential value of DepoCyt
over the current standard of treatment," said Edward L. Erickson, president and chief executive
officer of DepoTech.
"We look forward to working together with DepoTech to submit the DepoCyt NDA," said
Magnus Lundberg, president, Chiron Therapeutics.
Neoplastic meningitis occurs when metastases form solid tumors, leukemia, or lymphoma spread
to the tissue surrounding the brain and spinal cord. Of the approximately 65,000 cancer patients
who are afflicted with this disease annually in the U.S., most have NM arising from solid
tumors. Conventional therapy requires frequent, repeated injections and has limited efficacy.
DepoCyt is an injectable, sustained-release formulation of the chemotherapy agent cytarabine
encapsulated in DepoFoamTM, DepoTech's proprietary lipid-based drug delivery technology.
When commercially available, DepoCyt will be marketed by Chiron in the U.S., Canada, and
Europe, and manufactured by DepoTech at its San Diego production facilities. In the solid tumor
arm of the Phase 3 trial patients received a dose of DepoCyt every 14 days, compared to twice
per week dosing with methotrexate. |
