In the wake of the FDA's approval of Provenge for Prostate Cancer therapy, several recently published articles have downplayed the importance of Dendreon’s contribution to immunotherapy or played up the unlikelihood of another imminent vaccine. Among the cited examples of failed companies and misguided therapies, some have erroneously listed Biovest International or by innuendo questioned the viability of their lead drug candidate BiovaxID.
BiovaxID is a novel and disruptive therapy for the treatment of Non Hodgkin’s Lymphoma and potentially for other B-cell blood cancers. Developed by Biovest International, a majority-owned subsidiary of Accentia Biopharmaceuticals, this patient-specific idiotype vaccine uses samples from the individual’s tumor to create an immune system response capable of selectively targeting only the cancerous B-cells.
The objections stated in the aforementioned articles were not that BiovaxID was ineffective nor were there questions concerning the safety of this immunotherapy. Most commonly cited as barriers to FDA approval were the following:
1) The number of patients projected by the NCI, the designer of the Phase III trial, necessary to fully statistically power (in probability terms, the capability of a test to detect a significant effect) the study was not met. In addition, the projected p-value (statistical significance) of 0.01, also established by the NCI, was not met.
The BiovaxID Phase III trial did not enroll all of the patients initially sought to power a study reaching a p-value of 0.01. However, enough patients were randomized to treatment and non-treatment arms to be able to make a plausible decision rendering a Type I error unlikely within the limits set by the FDA. The demonstrable effects of the vaccine made a larger enrollment pool necessary to achieve the low standard beta used to show the avoidance of a Type II error moot. Had the trial been fully enrolled, there is a high probability an alpha of 0.01 would have been achieved.
“The probability of Type II error is conventionally set at 10 percent to 20 percent. It is in the sponsor’s interest to keep this figure as low as feasible, especially in the case of trials that are difficult or impossible to repeat."
- http://www.bcg-usa.com/regulatory/docs/1998/ICHE9.pdf (pg. 49591 - middle column top)
Please note the phrase - "[i]t is in the sponsor's interest" - as it's not the FDA's interest as far as its by-law role is concerned: to protect public health. Low enrollment numbers are not a bar to approval. The chemotherapeutic agent Taxotere was approved based on a trial with 104 participants."
2) The trial was a modified intent to treat exercise and is inferior for that reason.
The trial was designed and pursued as an intent-to-treat trial. However, in the CFR and the Drug Approval Requirement, proof of efficacy trials “often use intent-to-treat analysis” with the following parameters: “all randomized patients; limited exclusions may be permissible (modified intent-to-treat); defined in advance, based on indication.”
- www.kkblaw.com/publications/DrugApprovalReq.ppt
The BiovaxID Phase III trial protocols clearly stated that patients who did not achieve complete response(CR) to chemo therapy or who relapsed prior to the end of the six month waiting period would not be randomized to receive either the adjuvant+ BiovaxID nor to the adjuvant alone arms of the study.
3) The trial used PACE, an outmoded chemotherapy, which has been supplanted by the use of rituximab in conjunction with chemotherapy.
One misleading point in the PACE comparison is that the trial pitted BiovaxID against a chemo therapy. It did not. The trial was designed to compare the effects of BiovaxID vaccine plus an adjuvant versus the adjuvant alone in patients who had achieved a complete remission due to the chemotherapy. An amendment to use CHOP-R as an agent of remission after rituximab became available was allowed by the FDA.
4) The stringent nature of the FDA, when considering the statistics for a BLA, was alluded to as an insurmountable barrier to approval in the case of BiovaxID.
The FDA must be vigilant in its review of substances or devices purported to be of medical benefit but it is not unaware of the plastic posture that vigilance must sometimes take. As noted in the linked document below from 2003, the FDA periodically reaches out to the scientific and medical communities for guidance in areas without strictly delineated boundaries. One of the subjects explored in this meeting was Health Related Quality of Life Issues - hardly an area of interest for a dispassionate bureaucracy.
The FDA states that Accelerated Approval will not be granted unless the new therapy has a demonstrable advantage over available therapy.
“AA, which can only be granted when the new drug provides an advantage over available therapy, may rely on a less-established surrogate endpoint, a surrogate that is only reasonably likely to predict clinical benefit.”
- http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm120832.pdf
The nature of that advantage does not have to compete directly with the available therapy. A better quality of life, less toxicity or longer disease free survival can all bestow an advantage on a new candidate.
BiovaxID is presenting itself as an adjuvant. This area is unambiguously defined in the above. “FDA has long stated that for adjuvant treatment, disease-free survival (DFS) would be an adequate approval endpoint in disease settings where most patients are symptomatic or where effects on DFS are a reliable predictor of effects on survival.”
If BiovaxID demonstrates longer DFS or complete molecular remission in their secondary endpoints, it would have an advantage over rituximab.
The Code of Federal Regulations as summarized in the FDA power point presentation from 2004 below state the FDA must assess a new applicant on relative efficacy. The FDA may not disapprove a drug on the ground a more effective option is available.
- www.kkblaw.com/publications/DrugApprovalReq.ppt
Other refutable criticisms of Biovest International in these articles have cited that Biovest has yet to submit a BLA with the FDA and that the future of both Biovest and its parent Accentia Biopharmaceuticals remains uncertain due to their ongoing Chapter 11 bankruptcy case.
While a BLA has yet to be filed, one must take into account the chapter 11 status and the struggle of Biovest and Accentia to regain sound fiscal footing. Emergence from bankruptcy will facilitate completion of their regulatory filings with the FDA.
At this time, the Court has approved the company’s settlement with its largest senior secured creditor and Biovest has filed a Plan of Reorganization for approval. Through the terms of the Biovest plan, they expect to emerge from Chapter 11 protection this summer fully restructured. The plan also protects current stockholders through the preservation of common shares. Accentia is in the process of finalizing their Plan of Reorganization for submission in the very near future and is expected to emerge from Chapter 11 simultaneously with Biovest.
In these risk averse times of credit tightening, emerging from bankruptcy while keeping faith with common shareholders is no mean feat and speaks to the integrity and competency of the management and pared down staff of these companies.
Revisiting BiovaxID…
When highlighted as the subject of a plenary presentation at the ASCO 2009 convention, BiovaxID was reviewed in several online blogs as an “interesting immunotherapy.” Although many took notice, the financial precariousness of Biovest and Accentia forestalled any close examination of BiovaxID.
Upon its renewed revelation as a plausible candidate for inclusion in the war on cancer, we have seen several passing references made to what some view as possible weaknesses in the BiovaxID data. However, the pending extrication of the companies responsible for the development of BiovaxID from the intricacies of Chapter 11 protection provide an opportunity to more closely examine this data supporting the treatment and the possibilities it presents.
This article has been collaboratively authored by several biotechnology investors.
Disclosure: These authors hold positions in Accentia Biopharmaceuticals, Inc. and/or Biovest International, Inc.
