May 6, 2014

...endpoints considered “reasonably likely to predict clinical benefit...”

"...The Advancing Breakthrough Therapies for Patients Act was introduced and included as a component of the 2012 re-authorization of the Prescription Drug User Fee Act (Food and Drug Administration Safety and Innovation Act; FDASIA) to expedite development of new, potential “breakthrough” therapies." (quote link) More specifically, breakthrough therapy designation ("BTD") was introduced in July 2012.

About a year later, in April/June 2013, Reevaluating the Accelerated Approval Process for Oncology Drugs was authored by Wyndham Wilson (National Cancer Institute), David Schenkein (Agios Pharmaceuticals), Cheryl Jernigan (Susan G. Komen for the Cure), Janet Woodcock (CDER, FDA) and Richard Schilsky (American Society of Clinical Oncology) in Clinical Cancer Research.

The article's abstract was:
For a new therapy to qualify for the accelerated approval pathway, it must treat a serious disease for which there is “unmet medical need”—defined as providing a therapy where none exists or providing a therapy that may be potentially superior to existing therapy. The increasing number of available therapies, coupled with the lack of accepted endpoints considered “reasonably likely to predict clinical benefit” and the lack of clarity early in development about circumstances in which a new product will qualify for accelerated approval, is pushing developers to pursue accelerated approval in heavily pretreated patients to fulfill an unmet need. To optimize the accelerated approval pathway, we propose here a reevaluation of what constitutes “unmet medical need” and “available therapy” in oncology. We also discuss ways for new endpoints to become qualified for use in supporting accelerated approval, and propose a structured process for pursuing accelerated approval.
The authors observed "[s]ince the implementation of accelerated approval twenty years ago, the endpoints considered suitable for this pathway have changed little."

Further, "[m]any have called for the FDA to accept new endpoints for accelerated approval, such as novel imaging endpoints or biomarkers that can be measured earlier than ORR or PFS, or can be used in settings where conventional ORR and PFS cannot be readily or reproducibly assessed."

The article provides an example:
An example of a recently qualified endpoint is pathologic complete response (pCR) in locally advanced breast cancer. In May, 2012, the FDA announced its acceptance of pCR as an endpoint to support accelerated approval in certain breast cancer settings (e.g., neoadjuvant) and published a draft Guidance, Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval, to describe this endpoint and the basis for its qualification. In this Guidance, the FDA provided a formal regulatory definition of the proposed endpoint, pathologic complete response; explained the rationale for using this endpoint in the setting of neoadjuvant breast cancer therapy; summarized the evidence that supports the utility of pCR, and described the types of trials that would be appropriate for use of pCR to support accelerated approval. Importantly, the guidance noted that the analyses supporting use of pCR are currently limited to analyses of treatment response and stressed that future prospective studies are needed to fully understand the relationship of pCR to ultimate clinical benefit. Given the lack of alternative endpoints considered suitable for regulatory use in early-stage breast cancer, pCR is acceptable despite this uncertainty in situations with significant unmet medical need (e.g., high-grade, triple negative breast cancer). 
Breakthrough therapy is a designation, a gateway to a potentially faster process to approval or "yes" (or a quicker "no"). It is not a specific pathway. The steps, and thus the pathway, to approval unfolds following the granting of BTD. Management has communicated it believes the FDA considers the 28-patient subset of Provectus' metastatic melanoma Phase 2 trial in which all disease [of this subset of patients] was treated sufficient to merit application and consideration for BTD.

The target indication, of course, is locally advanced cutaneous melanoma (i.e., earlier stages of the disease), and not metastatic melanoma (late to very late stages of the disease).

Consider the article's theme of more novel endpoints to support accelerated approval.

It would seem part and parcel of evaluating and granting of BTD to establish the appropriate and necessary endpoints for and under which Provecus' data and application should and very likely would be considered, as those endpoints also would be, presumably, utilized in whatever steps follow BTD to establish an initial pathway to approval of PV-10.

Tumor-based endpoints.

From Provectus' January 24th press release Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes.
The Agency agreed with Provectus that treatment of cutaneous and subcutaneous tumors in patients with locally advanced cutaneous melanoma (i.e., recurrent, in-transit or satellite melanoma that has not yet spread from the skin to distant sites) could provide clinical benefit to such patients, particularly if the measured objective responses in patients' disease correlated to a demonstrated treatment effect on one or more symptoms of their disease (e.g., pain, infection or significant bleeding). 
The Agency agreed to work with Provectus to quantify symptom control in this patient population. 
In reference to discussions on the potential for breakthrough therapy designation, "FDA advised Provectus to provide objective response rates with adequate information to evaluate the symptomatic treatment effects (e.g. pain, infection, bleeding) in patients presenting with locally advanced cutaneous melanoma who received PV-10 to all lesions."
What's the novel endpoint, and could/will it be used to [accelerated] approval? We should learn more shortly, but I can't help but think the FDA and Provectus have already established the endpoint.

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