NorthWest Biotherapeutics Inc (NWBO)

[sentiment_stocks]

Some things to consider regarding Orphan Drug Designation, Priority Review, Accelerated Approval, and BLA filings.


We know that DCVax-L received an orphan drug designation. I don’t have the link for that handy but I’m sure flipper has it close by if newer investors here were unaware of this.

Now part of what that means is that makes DCVax-L's trial eligible for any number of speedier FDA review programs.

For drugs that are intended for use with serious or life-threatening conditions for which unmet needs for treatment exist, FDA has instituted additional options—fast track status, accelerated approval, and priority review—to speed reviews and provide more extensive and timely guidance to sponsors about the nature of the evidence that is needed to support approval (FDA, 2009a; Schact and Thomas, 2009). Sponsors of orphan drugs frequently qualify for these mechanisms, and one analysis indicated that applications for orphan drugs were more likely than other applications to have done so

(Seoane-Vazquez et al., 2008).

http://www.ncbi.nlm.nih.gov/books/NBK56185/

And here...

A drug that is classified as an "orphan drug" is eligible to receive some or all of the following incentives:

Priority review of new drug applications (a 6-month review rather than the standard 10-month review);

A guaranteed 7-year monopoly on drug sales for the first company to obtain FDA marketing approval of a particular drug;

Federal tax credits for the research done (up to 50% of costs) to develop an orphan drug;

Waivers of drug approval application fees and annual FDA drug fees;

FDA assistance with protocol development; and

Research subsidization and grants.

http://smart-therapeutics.com/Drug-Pipeline/Rare-Neglected-Diseases/FDA-Orphan-Drug-Program

Something to consider is whether NWBO, with its orphan drug designation, was granted a priority review voucher. Now, according to this FDA document, if a sponsor does receive an expedited drug development designation, they often will initiate a more rapid manufacturing program to provide a quality product is available to meet market demand.

A. Manufacturing and Product Quality Considerations
The sponsor of a product that receives an expedited drug development designation may need to pursue a more rapid manufacturing development program to accommodate the accelerated pace of the clinical program. The sponsor’s product quality and CMC teams should initiate early communication with FDA to ensure that the manufacturing development programs and timing of submissions meet the Agency’s expectations for licensure or marketing approval.40

When sponsors receive an expedited drug development designation, they should be prepared to propose a commercial manufacturing program that will ensure availability of quality product at the time of approval. The proposal should consider estimated market demand and the commercial manufacturing development plan. The proposal should also consider manufacturing facilities and a lifecycle approach to process validation. Additionally, the proposal should include a timeline for development of the manufacturing capabilities with goals aligned with the clinical development program. After the initial discussion following designation, frequent communication during development will generally facilitate meeting manufacturing development goals and product quality goals.

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Now some may be familiar with the fact that the April 2013 protocol suggested that if the primary endpoint (PFS) is met, the company intended to request Accelerated Approval. Whether is actually what is taking place is really anyone’s guess, educated or not.

However, with orphan drug designation, it’s entirely possible they may have requested a priority review. If granted, this would give them a 6 month review process for a BLA. Now it seems that a priority review is requested AT THE TIME that a BLA is submitted.

1. When to Send a Designation Submission
Sponsors may request priority review designation when they submit an original BLA, NDA, or efficacy supplement. The Agency does not anticipate that priority review designation requests will be made after the filing of a BLA, NDA, or efficacy supplement.

(page 33 - same link)

And from the same paper, the criteria for a Priority Review Designation is

Serious Condidion

Demonstrating the Potential To Be a Significant Improvement in Safety or Effectiveness

(check to both of those - page 24 - same link)

So the FDA then determines, on a case-by-case basis at the time of that BLA submittal whether the proposed drug would be a significant improvement in the safety (we know that’s a check) or effectiveness (well, Linda L did say they were all living longer) of the treatment, prevention, or diagnosis of a serious condition.

Significant improvement may be illustrated by the following examples:

Evidence of increased effectiveness in treatment, prevention, or diagnosis of a condition (still waiting)

Elimination or substantial reduction of a treatment-limiting adverse reaction (uhhh… yep)

Documented enhancement of patient compliance that is expected to lead to an improvement in serious outcomes (remains to be seen for all of us)

Evidence of safety and effectiveness in a new subpopulation (rumor is that this is the case with mesenchymal)

(the above is found in the same link on page 24 and 25)

To receive a priority review designation (again, done at the same time as the BLA), a company is also allowed to use for comparison of their investigational drug:

- historical controls…

- or show the drug can treat effectively (as well as?) the available therapy in an improved manner.

- If a patient is unable to tolerate the available therapy, or their disease has failed to respond to the available therapy, or show that the drug can be used effectively with other critical agents that cannot be combined with available therapy (remember that other UCLA trial set to end at the same time as the P3 trial using other adjuvants?).

Although such evidence can come from clinical trials comparing a marketed product with the investigational drug, a priority review designation can be based on other scientifically valid information. Generally, if there is an available therapy (see section III.B.), sponsors should compare their investigational drug to the available therapy in clinical testing with an attempt to show superiority relating to either safety or effectiveness. Alternatively, sponsors could show the drug’s ability to effectively treat patients who are unable to tolerate, or whose disease failed to respond to, available therapy or show that the drug can be used effectively with other critical agents that cannot be combined with available therapy. Although such showings would usually be based on randomized trials, other types of controls could also be persuasive, for example, historical controls.37 (page 25)

Although these additional comparisons that come with a priority review are not used in arguing for the BLA, it seems they certainly can be used for arguing for a priority review. And under those comparisons, I think DCVax-L would fare well.

And if the company submitted both a request for a priority review at the same time as a BLA, when might they have submitted it? And could they have submitted a BLA while the trial marched on? And if this is the case... and it were granted, they wouldn't have PR'd it as it would have been part of the whole BLA process.

I know there will be some who are not invested that will say otherwise, but one has to acknowledge that whatever is happening, it’s unusual.

On page 27 of the same document, it does indicate that the sponsor should anticipate that the FDA will need to inspect the clinical trial and to be prepared for inspections in order to allow the reviewers to have timely access to adequate and accurate data in the BLA, NDA or supplement submissions. That section does seem to indicate an expectation that some trial sites will be inspected during the BLA process - possibly meaning the trial is still on-going - however I may be reading that incorrectly.

Sponsors should anticipate the Agency’s need to inspect clinical trials, including, if applicable, the analytical component of bioavailability or bioequivalence studies. Sponsors should be prepared for inspections to be scheduled by the Agency early in the application review process so inspection results are available to inform the review division and to allow time for the sponsor to address significant inspection findings. To select sites for clinical inspections, it is important for reviewers to have timely access to adequate and accurate data in BLA, NDA, or supplement submissions. Sponsors should initiate early communication with FDA about information required for inspection planning and conduct. (page 27)

And in a separate FDA link, it also states that the FDA will conduct these clinical trial investigation sites as well… to verify the quality and integrity of the data submitted.

The Quality of Clinical Data  
The Food and Drug Administration relies on data that sponsors submit to decide whether a drug should be approved. To protect the rights and welfare of people in clinical trials, and to verify the quality and integrity of data submitted, the FDA's Division of Scientific Investigations (DSI) conducts inspections of clinical investigators' study sites. DSI also reviews the records of institutional review boards to be sure they are fulfilling their role in patient protection.

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm289601.htm


Some other interesting notes…

the FDA will not grant AA to products that meet the standards for traditional approval. Sponsors considering a development program for accelerated approval based on an intermediate clinical endpoint should discuss their development program with the appropriate review division early in drug development. (page 19)

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

I guess that would mean that if they were able to meet the requirements of efficacy for the primary endpoint of PFS already, that could possibly rule out applying for AA. Yes, I know, that’s a jump, but it’s also possible given some of the very efficacious results found in the P1/2 trials. And granted, while the Info Arm only tells us the results of OS… most of us who are actually invested acknowledge that those patients were primarily rapid progressors. And the double rapid progressors' OS showed around 5 months median OS over standard of care OS for rapid progressors.

And the main arm patients WILL NOT include rapid progressor patients and so all should perform better (yes - including control patients). And, as flipper and others have pointed out, these patients should have a higher immunogenicity than the rapid progressors would. And a higher immunogenicity has been shown to respond well to L - and so may likely result in a response that is stat sig in PFS. Anyway, I'm merely trying to make a case for the possibility here.

So it's possible they went straight for the BLA along the more traditional means... but are using a Priority Review to speed that process up.

So let's look at the TFF method of manufacturing that has recently been postulated is already in use in the trial.

Another FDA source cites that one of the problems a sponsor often encounters when applying for approval involves manufacturing issues. The sponsor needs to demonstrate that there are no quality control issues involved with scaling up. As stated below, the sponsor has to prove that the product that’s going to be marketed is the same product that they tested.

Bumps in the Road  (interesting, that’s the same thing Woodford said)
If the FDA decides that the benefits of a drug outweigh the known risks, the drug will receive approval and can be marketed in the United States. But if there are problems with an NDA or if more information is necessary to make that determination, the FDA may issue a complete response letter. 

Common problems include unexpected safety issues that crop up or failure to demonstrate a drug's effectiveness. A sponsor may need to conduct additional studies--perhaps studies of more people, different types of people, or for a longer period of time.

Manufacturing issues are also among the reasons that approval may be delayed or denied. Drugs must be manufactured in accordance with standards called good manufacturing practices, and the FDA inspects manufacturing facilities before a drug can be approved. If a facility isn't ready for inspection, approval can be delayed. Any manufacturing deficiencies found need to be corrected before approval.

"Sometimes a company may make a certain amount of a drug for clinical trials. Then when they go to scale up, they may lose a supplier or end up with quality control issues that result in a product of different chemistry," says Kweder. [color=red]"Sponsors have to show us that the product that's going to be marketed is the same product that they tested.”[/color

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm289601.htm

Sorry for how long this is ... but I when I came across the fact that Priority Review can often come with orphan designation, I thought it worth looking into how it might apply to the current situation.