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James Hill, MD  

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  • FDA Panel Flubbed in Arena’s Lorcaserin Disapproval [View instapost]
    The link broke to the rat fibroadenoma article finding no progression to cancer. Here is an updated link:

    Don't be surprised if lorcaserin is approved before further studies are required. The science and FDA policy should warrant such approval, even if only conditioned upon post-appoval studies.
    Oct 4, 2010. 05:23 PM | Likes Like |Link to Comment
  • FDA Panel Flubbed in Arena’s Lorcaserin Disapproval [View instapost]
    @Dr. Ritacca:

    Elucidation of a mechanism for development of rat mammary gland fibroadenomas would be helpful, but as to its applicability to human breast cancer, the article cited below suggests that as of 2006, no common molecular pathways between rat and human fibroadenomas, and no significant progression from fibroadenoma to adenocarcinoma in rats, had been identified.

    Quoting the article: “We conclude that in the [rat mammary gland] fibroadenoma tumours examined here, no progression to adenocarcinoma is likely.”

    Perhaps there are more recent data that contradict these findings, but I have not yet found any yet.
    Sep 22, 2010. 05:24 PM | 1 Like Like |Link to Comment
  • FDA Panel Flubbed in Arena’s Lorcaserin Disapproval [View instapost]
    Thanks to all who pointed out I cited the ARNA brief to the FDA, not the later FDA staff brief. I was unaware of the latter when I wrote the article, but I’ll review it and probably either write an updated article or further provide comments here.

    To my knowledge so far, the ARNA rat tumor data cited in the article is still correct, though the FDA properly notes there is not enough information to conclude that the rat’s tumorigenesis is prolactin-mediated.

    In any event, Michael Murphy appears correct that “ARNA really should have given up on the 'prolactin caused the tumors' argument and just said: ‘We don't know the mechanism of action that caused the tumors in these rats at these high doses, but it is not relevant to the panel's decision.’”

    In view of (a) the very high dose of lorcaserin needed to demonstrate a significant increase in rat breast cancer, and (b) FDA’s prior industry guidance on testing for drug-induced rodent cancer, ARNA’s prolactin argument seems a little like saying, “Santa Claus didn’t come this year because he was sick with the flu,” then wasting time trying to prove he really had the flu.
    Sep 22, 2010. 04:22 PM | Likes Like |Link to Comment
  • Biovest Meets Skeptic's Requirements for 'The Next Dendreon' - Part 4 [View article]

    It was disappointing the FDA failed to approve DNDN's Provenge in 2007, going against its own advisory committee's vote of 17-0 for safety and 13-4 for efficacy.

    Nevertheless, the FDA had a rationale for rejection: Provenge missed statistical significance (p < 0.05) for its primary endpoint of time to progression, with a p = 0.053. It may be close, but the FDA said no cigar.

    BiovaxID, by contrast, has statistical significance for its primary endpoint of disease-free survival, with a p = 0.045.
    Jun 5, 2010. 01:05 AM | 2 Likes Like |Link to Comment
  • Biovest Meets Skeptic's Requirements for 'The Next Dendreon' - Part 4 [View article]
    @Bio Burt:

    Good question. Here are two examples of cancer drugs granted FDA accelerated approval on the condition the manufacturers run post-marketing, confirmatory trials:

    1) Avastin (bevacizumab) for progressive glioblastoma following prior therapy.

    The FDA approved Avastin in 2009 for this indication after a phase 2, open-label, non-comparative study of 167 patients with glioblastoma who had progressed following temozolomide chemotherapy and radiation. Patients were randomized into two arms: Avastin alone or Avastin in combination with irinotecan. A primary endpoint was objective response rate, assessed by MRI, and decreased or stable corticosteroid use.

    Responses were observed in 26% of the 85 patients treated with Avastin alone, and the median response duration was 4.2 months.

    The other 74% of patients did not respond.

    No wonder the FDA asked Genentech for confirmation, by post-marketing studies, that Avastin actually works in this category of brain cancer patients. In the meantime, Genentech is free to market, label, and sell Avastin for this indication.

    2) Iressa (gefitinib) for progressive non-small cell lung cancer following prior therapy with platinum-based chemotherapy and docetaxel.

    The FDA approved Iressa in 2003 for this indication in view of a phase 3 trial involving 216 patients, 142 of whom had tumors no longer responsive to treatment. Response to Iressa was determined by tumor shrinkage by at least 50%, maintaining a smaller tumor size for at least a month.

    Results showed an overall response rate of 10.6%, and the median response duration was 7 months.

    Response rates were highly variable in subgroups: 5.1% (4/79) in males, 17.5% (11/63) in females, 4.6% (5/108) in previous or current smokers, 29.4% (10/34) in nonsmokers, 12.4% (12/97) with adenocarcinoma histology, and 6.7% (3/45) with other NSCLC histologies.

    The FDA went so far as to approve Iressa over the strenuous objection of many, including consumer advocacy group Public Citizen, who told the FDA: “The FDA would be putting patients in jeopardy by approving a drug that is already showing itself to be ineffective and dangerous.” Sidney Wolf, MD, director of Public Citizen’s health research group, said, “The severity of adverse events… should be a red alert to the agency.”

    Understandably, AstraZeneca was required by the FDA to conduct additional trials to prove the drug really works. In the meantime, the FDA allowed AstraZeneca to market, label, and sell Iressa, as freely as an eagle soars, in the US for this indication.


    How could the FDA approve these drugs on such weak but highly promising data, you may ask? Cancer patients need treatment; they need it soon, and they need alternatives.

    “FDA believes it is crucial for cancer patients to have many safe and effective treatment options available to them.” -- statement by former FDA commissioner Mark McClellan, MD, PhD, upon the conditional approval of Iressa)

    Although I have reviewed only press reports of the Avastin and Iressa data, and not the original data, it appears BiovaxID’s reported efficacy data are more impressive. And BiovaxID’s reported safety profile is unquestionably better.
    Jun 5, 2010. 12:28 AM | 1 Like Like |Link to Comment
  • Biovest Meets Skeptic's Requirements for 'The Next Dendreon' - Part 4 [View article]
    @Bio Burt:

    There are big differences between CTIC and BVTI:

    In the case of CTIC's pixantrone, they reportedly stopped the trial early, violated their SPA, failed to achieve statistical significance, and showed significant toxicity.

    quoting from www.pharmastrategyblog... :


    Approximately 20 minutes into [FDA's] Richard Pazdur's opening introduction.

    In particular, the FDA felt that:

    "Pixantrone has demonstrated evidence of biologic activity, but the mere demonstration of biologic activity is not sufficient for approval."

    Ouch! At that point it becomes incumbent upon the company presenters to argue persuasively to the nine panel members to convince them otherwise. However, that was going to be a tall order given the FDA concerns regarding:

    1. Neutropenia and infections were higher in pixantrone than the control
    2. Cardiac toxicity was higher in pixantrone than control, including heart failure and ejection fraction

    As highlighted in the original analysis of the pixantrone filing, the FDA were also unhappy about the shortened study given only 140 people were enrolled out of the planned 320, leading them to conclude:

    1. Study was not well executed or complete.
    2. Study was inconsistent (only 8 people enrolled in the US and none had a complete response).
    3. Trial did not demonstrate statistical significance or robust findings.


    BVTI says it stopped the BiovaxID trial early for ethical reasons, because of significant differences in PFS between the treatment and control groups.

    They underrecruited patients because the standard of care changed to include rituximab after the trial began (per Ten's comment above).

    They achieved statistical significance at p = 0.045.

    There were no serious adverse events.

    BVTI could certainly run a new trial, and the FDA will probably require it. But they can do it as a phase 4 following accelerated (conditional) approval from the FDA. The vaccine appears safe and extends cancer-free survival. There is therefore little similarity to the pixantrone story.
    Jun 3, 2010. 03:01 AM | 1 Like Like |Link to Comment
  • Biovest Meets Skeptic's Requirements for 'The Next Dendreon' (Part 1) [View article]
    Yes, ABPIQ.PK and BVTI.PK are in bankruptcy, but they appear to be close to emerging with their common shares intact and with a reduced royalty owing on vaccine sales:
    May 21, 2010. 10:29 AM | Likes Like |Link to Comment
  • Who has the next approvable cancer vaccine? [View instapost]
    @User 492995: You make good points.

    I'm more heavily weighted in ABPIQ than BVTI mainly because, at a market cap of only $64M, ABPIQ seems more undervalued than BVTI, especially given its large stake in the latter. I don't know if the public will see this initially, though, when the share prices jump.
    May 17, 2010. 01:53 AM | Likes Like |Link to Comment
  • Who has the next approvable cancer vaccine? [View instapost]
    Thank you, Ten.

    @Larry Luv: I'll try to post more information on the phase 3 trial later.
    May 17, 2010. 01:45 AM | Likes Like |Link to Comment