December 13, 2013


The NDA. On the News tab of the blog, I wrote:
The New Drug Application ("NDA") (December 11, 2013)
In my On the precipice of… post I categorized potential "menus of choices" for clarity (e.g., Outright or Accelerated Approval for Pop 1, Breakthrough Therapy Designation for Pop 1 and Pop n, Breakthrough Therapy Designation for Melanoma). I felt unsatisfied by the impreciseness of this work, however, because it did not do a good enough job of elucidating the FDA process (to gain approval for PV-10) in which management is engaged.
Figure 1. Click to enlarge the figure.
Prior to writing the post, and subsequent to it, I reviewed thousands of pages of NDA approval packages and their associated administrative and correspondence documents (mainly but not exclusively from CDER), together with FDA and third party materials (see, for example, the illustration above), in an effort to understand Agency processes related to NDA and Biologics License Application ("BLA") reviews.
Is the NDA being touched up in preparation for filing? If so, the next step would be to file it with the FDA (a key milestone). Some companies issue press releases when they file their NDAs. Some do not. Preparing-to-file could be a possibility.
Has the NDA been filed? If so, the subsequent outcome (a major milestone) could be FDA acceptance of it. Following filing, the FDA would complete its review and determine whether Provectus' NDA was sufficiently complete to permit a substantive review. In accordance with 21 CFR 314.101(a), if ultimately acceptable, the company's NDA would be considered filed 60 days after the date the Agency received the application. The Agency might grant a Priority Review classification for it. The FDA also would establish a user fee goal date (i.e., a PDUFA date). Companies issue PRs when their NDAs are accepted. A filed NDA could be a possibility. An accepted-by-the-FDA NDA likely is not, as Provectus undoubtedly would have issued a PR if it had been.
Has the NDA been approved? Following acceptance of the NDA, the Agency and the applicant/sponsor engage in collaborative discussions with the goal of and endeavoring to work towards the approval of the drug in question.
Click to enlarge the figure.
Various topics beyond just safety considerations and efficacy assessments are considered, including labeling, materials validation, supply, etc. If Provectus hasn't issued a PR regarding the NDA's acceptance, it's highly unlikely it has been approved (a much more major milestone).
I will blog about my NDA-related work in greater detail as it relates to Provectus in due course. For the moment, my summary thought is the company is (has to be) engaged at some phase of the NDA review process for PV-10/Pop 1, whether gearing up (post-FDA concurrence) to file an NDA, or waiting to have their NDA accepted by the Agency (and potentially granted Priority Review, possibly together with Breakthrough Therapy Designation).
For some time now I have wondered whether, and if so where, the company is in an NDA review process with the FDA.

Seriously. Think about what I am asking myself. I'm wondering if management is engaged with the FDA to approve PV-10 for, very likely, Stage IIIB-C melanoma patients refractory to treatment ("Pop 1"), rather than if they're still discussing a pivotal metastatic melanoma Phase 3 trial under a special protocol assessment.

Is Provectus at the beginning, in the middle, or near or at the end of an NDA review process with the the Agency?

According to the FDA, "[f]or decades, the regulation and control of new drugs in the United States has been based on the New Drug Application (NDA). Since 1938, every new drug has been the subject of an approved NDA before U.S. commercialization. The NDA application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA. The goals of the NDA are to provide enough information to permit FDA reviewer to reach the following key decisions:
  • Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.
  • Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain.
  • Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity.
The documentation required in an NDA is supposed to tell the drug's whole story, including what happened during the clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged."

A very useful document to better understand the NDA review process is CDER 21st Century Review Process Desk Reference Guide, New Drug Application and Biologics License Application Reviews (NDA/BLA Review Process), Version: September 2012 ("FDA Doc A"). There is a similar chart to Figure 1 above in FDA Doc A.

It appears the review process has six major steps.
Figure 2. Click to enlarge the figure.
Media Relations. Biotechnology companies appear to vary in their approach of communicating their strategy about and position in the NDA review process.

In July 2013 Sarepta Therapeutics chose to say, for whatever reason(s) and rationale(s), it was planning to submit its NDA (PR: Sarepta Therapeutics Announces Plans to Submit New Drug Application to FDA for Eteplirsen for the Treatment of Duchenne Muscular Dystrophy in First Half of 2014).

Some companies, like Pharmacyclics in July 2013, elect to inform the stock market they have submitted their respective NDAs (PR: New Drug Application for Ibrutinib Submitted to the U.S. FDA).

All companies issue a press release after being notified by the FDA that their NDAs have been accepted by the Agency, which are memorialized in approval letters.

Pharmacyclics' Experience. There are a number of examples from which to draw information and knowledge about the NDA review process. One such recent example is Pharmacyclics (NASDAQ: PCYC), which announced the following sequence of events related to Imbruvica (ibrutinib) and mantle cell lymphoma ("MCL"):
  • February 12, 2013: Breakthrough therapy designation ("BTD") for ibrutinib as a monotherapy for the treatment of patients with relapsed or refractory, and also for ibrutinib as a monotherapy for the treatment of patients with Waldenstrom's macroglobulinemia (in April, PCYC received BTD for ibrutinib as a monotherapy for the treatment of chronic lymphocytic leukemia ("CLL") or small lymphocytic lymphoma ("SLL")),
  • July 10, 2013: Submission of a new drug application ("NDAs") for ibrutinib and both MCL and CLL/SLL to the FDA,
  • August 29, 2013: Acceptance of the above mentioned NDA by the Agency for both MCL and CLL/SLL, along with the granting of priority review by the FDA,
  • November 13, 2013: Accelerated approval of ibrutinib for MCL.
Click on the figure to enlarge it.
PCYC's NDA was dated and received June 28, 2013. Pharmacyclics issued a "submission" PR a couple of weeks later. Prior to the Agency application-dated and received dates, and the submission PR, PCYC made amendments to the NDA (see above). Amendments were made up to and on the date of the FDA's November 13th official action.

The FDA has several types of meetings: "A Type A meeting is one that is immediately necessary for an otherwise stalled drug development program to proceed (i.e., a critical path meeting)...Type B meetings are (1) pre-IND meetings (21 CFR 312.82), (2) certain end of Phase 1 meetings (21 CFR 312.82), (3) end of Phase 2/pre-Phase 3 meetings (21 CFR 312.47), and (4) pre-NDA/BLA meetings (21 CFR 312.47)....A Type C meeting is any meeting other than a Type A or Type B meeting between FDA and a sponsor or applicant regarding the development and review of a product in a human drug application as described in section 735(1) of the Act."

The following can be gleaned from PCYC Doc B (notable communications with the FDA).

End-of-Phase 2 ("EOP2), Type B, March 7, 2012
Click on the figure to enlarge it.
EOP2, Type B, December 3, 2012
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CMC, Pre-NDA, Type B, April 9, 2013
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Advice/Information Request, June 13, 2013

NDA Acknowledgement, June 28, 2013: "Unless we notify you within 60 days of the receipt date that the application is not sufficiently complete to permit a substantive review, we will file the application on August 27, 2013, in accordance with 21 CFR 314.101(a)."

Request for Methods Validation Materials, July 7, 2013: "We acknowledge receipt on August 1, 2013, of the sample materials and documentation that you sent to the Division of Pharmaceutical Analysis (DPA) in St. Louis."

Methods Validation Materials Received, August 1, 2013: "We acknowledge receipt on August 1, 2013, of the sample materials and documentation that you sent to the Division of Pharmaceutical Analysis (DPA) in St. Louis."

Information Request, August 1, 2013: "We are reviewing the Quality section of your submission and have the following comments and information requests. We request a written response by August 9, 2013, in order to continue our evaluation of your NDA."

Information Request, August 8, 2013: Impurities, etc.

Advice/Information Request, August 14, 2013: Container labels, etc.

Proprietary Name Request Conditionally Acceptable, August 16, 2013

Information Request, August 16, 2013: "We are reviewing the Quality section of your submission and have the following comments and information requests. We request a written response by August 23, 2013, in order to continue our evaluation of your NDA."

Mid-Cycle Communications, page 150, August 19, 2013
Click on the figure to enlarge it.
Filing Communication - No Filing Review Issues Identified, August 27, 2013: "We have completed our filing review and have determined that your application is sufficiently complete to permit a substantive review. Therefore, in accordance with 21 CFR 314.101(a), this application is considered filed 60 days after the date we received your application. The review classification for this application is Priority. This application is also subject to the provisions of “the Program” under the Prescription Drug User Fee Act (PDUFA) V (refer to: Therefore, the user fee goal date is February 28, 2014."

Late-Cycle Meeting Background Package, September 25, 2013
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Information Request, October 4, 2013: Trial efficacy issue

NDA, October 9, 2013, Type C
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Information Request, October 21, 2013: Post-marketing requirements (PMRs), Post-marketing commitments (PMCs)

Late-Cycle Communications, October 28, 2013

 Major Process Steps of an NDA Review
. These include (quoted directly from FDA Doc A):

1. Ensure Readiness for Application through Pre-Submission Activities: The first step in the process is composed of activities that applicants can take advantage of to improve the quality and content of their NDA/BLA application prior to submitting it to FDA.

2. Process Submission: Applications are received and processed by document control room staff and then distributed to the appropriate review division. The RPM conducts an initial assessment of the NDA/BLA to assure that certain regulatory requirements are met and that a user fee has either been paid, the fee waived, or the application exempted. Reviewer assignments are made at this time.

3. Plan Review of the Application: The review team conducts an initial assessment of the NDA/BLA and associated labeling. Each discipline makes a recommendation on fileability of the application at the filing meeting that is held by day 45 of the review (day 30 for priority reviews). If the application is found fileable a planning meeting is held to further discuss timelines and review activities.

4. Conduct Scientific/Regulatory Review of the Application: During the review phase, the primary reviewers analyze their assigned portion of the application and write their reviews; team leaders interact with reviewers and provide guidance on a regular basis. For PDUFA V “Program” reviews, a late-cycle meeting is held between the review team and the applicant. An additional two months is available for PDUFA V “Program” applications to address complex review issues and attempt to remedy minor problems with the application.

5. Take Official Action on the Application: Based on the signatory authority’s review of the Action Package and on discussions with the review team, the signatory authority determines the action to be taken on the application. The final action decision is conveyed to all team members.

6. Provide Post-Action Feedback to the Applicant: The focus of this activity is on learning from the review experience. This optional meeting can take place as either an End of Review Conference, typically held following an action other than an approval, and/or a post-action feedback/lessons learned meeting. These two meetings can be combined into a single meeting if appropriate.

Provectus. Where, if at all, is the company in the NDA review process? Step 1? Step 2 or 3 Somewhere along Step 4? Waiting for Step 5?

Management continues to say clarity will be achieved before year-end. They seek outright approval, accelerated approval and/or a single arm trial, in that order. How does seeking and achieving regulatory clarity conform with an NDA review process? The answer may (should) lie in what management says next. Lots of things have been said, but we're still left guessing as to whether, and if so how, they fit into an NDA process.

Good (Probably):
 Management will file an NDA.

Great (Possibly): Management is waiting to learn if their NDA has been accepted by the FDA. Other achievements would include granting of Priority Review for the application, and/or BTD for PV-10.

Yippee! (I would be surprised but not shocked if): Management's NDA is approved, which would suggest the principals are much farther along the NDA review process.

Time will tell.

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