Within all their DC patent applications (eventual patents) they detail various manufacturing processes and in each one, they cover DC technology manufactured by their own TFF method, which had only been an application up until that point. So that is a patent DC proprietary technology, using a patented manufacturing method. Talk about thinking ahead. They TFF patent application process began in 2002. And so yes, I do agree that once they received the TFF they immediately had the FDA okay on its use as they had planned for it in advance of receipt.
Here's an interesting Guidance document, and so reading parts of it, shows FDA flexibility with cancer vaccines, particular autogolous ones. I pasted some areas I found interesting [mine]. :)
Guidance for Industry?Clinical Considerations for Therapeutic Cancer Vaccines
Co-development of cancer vaccines and tests for targeted antigen When the proposed mechanism of action involves a specific antigen or other therapeutic target, consideration also should be given to developing an assay or mechanism to measure the target antigen expression in tumor tissues of individual patients and using that information in subject selection or response monitoring. These assays are generally regulated by the Center for Devices and Radiological Health (CDRH). Therefore, sponsors developing cancer vaccines who are considering including the use of an assay in the labeling of the cancer vaccine, or sponsors of such assays who are planning to develop the assay for use with a specific cancer vaccine should request a meeting with both the relevant product review office (CBER) and the relevant device review division (CDRH). Discussions begun early in the development process, ideally before submission of an IND and/or Investigational Device Exemption (IDE), may help ensure that product development provides data that establish the safety and effectiveness of the therapeutic product and assay pair. This is particularly important where use of the assay turns out to be necessary to the safe and effective use of the therapeutic product (referred to as companion diagnostics) (Refs. 3-5).
In later phase clinical trials, to provide data regarding the types, magnitudes and duration of response and the possible correlation with clinical efficacy parameters. A clinically effective anti-tumor response involves a multi-component process; therefore, multiple monitoring assays may be needed to identify and measure the components of the immune responses. Assays that measure the immune response(s) thought to be the most important and relevant components of the anti- tumor response should be developed. If possible, at least two immunological assays should be used in an attempt to monitor the proposed immunologically- mediated anti-tumor response. Assay standardization should include specific parameters to control for general variability in an immune response across study sites. The assay parameters, such as assay conditions, sensitivity and specificity of the assay, any in vitro amplification step involved, positive and negative controls, cutoff values for determining the positive and negative test results from patients’ specimens, and the statistical analytical methods to be used for the test results, should be clearly described in the clinical protocol prior to the initiation of the clinical trials.
Multi-antigen vaccines Cancer vaccine formulations may contain multiple tumor-associated antigens in order to generate multiple tumor-specific immunologic responses and potentially hinder potential tumor escape mechanisms. In general, each component of a multi-antigen vaccine may not need to be individually evaluated for safety and activity, this will be considered on a case-by-case basis.
2. Endpoints One of the most important aspects of designing a late phase trial is to choose a clinically meaningful endpoint. Demonstrable clinical benefits vary with cancer type and status of disease. Clinical benefits that have supported drug approval have included important clinical outcomes (e.g., increased survival, symptomatic improvement) but also have included effects on established surrogate endpoints. Consideration of the recommendations in the FDA guidances entitled “Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics,” dated May 2007 (Ref. 2), “Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products,” dated May 1998 (Ref. 8), and “Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims,” dated December 2009 (Ref. 9), may be particularly useful for both design and endpoint selection. Endpoints based on tumor assessments, as discussed in section III.B of the May 2007 guidance, may not be appropriate endpoints for a late phase clinical trial for a cancer vaccine.
3. Statistical issues The overall clinical effect of a cancer vaccine should be evaluated in the context of the currently available therapeutic options. FDA recommends use of a superiority trial design to demonstrate a cancer vaccine’s treatment effect on a chosen endpoint.
In certain clinical settings, the effect size of the available therapy(ies) may be well established. In these limited situations, a noninferiority (NI) trial design and analysis may be considered. However, the design of a NI trial is complex; therefore, sponsors should include early consultation with the FDA and careful consideration of the recommendations in the FDA draft guidance entitled “Guidance for Industry: Non-Inferiority Clinical Trials,2” dated March 2010 (Ref. 10).
Adaptive trial designs will be considered on a case-by-case basis. Sponsors should consider the recommendations in the FDA draft guidance entitled “Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics3,” dated February 2010 (Ref. 11).
Imbalances in subsequent therapies may confound the interpretation of study results, particularly when the primary endpoint is overall survival. Therefore, the study should document the nature and duration of subsequent therapies, and appropriate sensitivity analyses should be pre-specified. [I found this part above interesting]
5. Delayed vaccine effect As a consequence of their immunological mechanisms of action, cancer vaccines may require considerable time after administration to induce immunity. Therefore, tumors in subjects treated with cancer vaccines may show early progression followed by subsequent response. This potential phenomenon should be considered in the design of later phase clinical trials, particularly if nonclinical data or early phase clinical trials suggest that the phenomenon exists and time-to- event endpoints are used. Due to delayed effect of the vaccine, the endpoint curves may show no effect for the initial portion of the study. If the vaccine is effective, evidence of the effect may occur later in the study. This delay in the effect may lead to an average effect that is smaller than expected and thus may require both an increase in sample size to compensate for the delay and a careful assessment of trial maturity for the primary analysis. In addition, possible violation of the proportional hazards assumption should be considered when selecting a statistical method for the primary analysis.
6. Autologous vaccine trials Design of studies using autologous vaccine products that are derived from the subjects’ own tumors poses unique challenges and deserves special consideration. Manufacturing such vaccines may take up to several months. If complete remission or stable disease is an eligibility criterion, the time required for manufacture may mean that some trial subjects may become ineligible for vaccine administration because of disease recurrence or progression.
Additionally, manufacture of autologous vaccine product may not be possible for every subject for a wide variety of source material and/or manufacturing process reasons. Regardless of the cause, a sponsor’s inability to treat randomized subjects with the vaccine may adversely affect the statistical power of the clinical study. Therefore, consideration should be given to optimization of the vaccine manufacturing process before the late phase clinical trials are initiated, to increase the proportion of the randomized subjects who receive the vaccine.
7. Accelerated approval regulations FDA’s accelerated approval regulations in 21 CFR Part 314, Subpart H (for drugs) and 21 CFR Part 601, Subpart E (for biologics) apply to new drug and biological products that (1) have been studied for their safety and effectiveness in treating serious or life-threatening illnesses, and (2) provide meaningful therapeutic benefit to patients over existing treatments (e.g., ability to treat patients unresponsive to, or intolerant of, available therapy, or improved patient response over available therapy) (21 CFR 314.500 and 601.40). In this setting, FDA may grant approval on the basis of adequate and well controlled clinical trials establishing that the drug or biological product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit?(21 CFR 314.510 and 601.41).4
[This section above makes me wonder if crossover can help the study apply for AA].
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