Replies to post #359859 on NorthWest Biotherapeutics Inc (NWBO)

[akblack]

One of the best posts I've read so far. Thanks for the details and links !!!!

I knew nothing of these programs and processes. Wow!

More bullish than ever.

[VikingInvest]

Big fan, both here and on Twitter. I don't think that, regardless of being the lead RA, FDA will be first to approve DCVax-L. I think Dr. Ashkan has been engaged with the MHRA for quite a while and that they will be first to approve. If you look at the ramp up of employees at Advent, it is clear to me that they are close to getting there in terms of being approved for commercial production. That ramp up has to be related to the ongoing discussions/BLA that is happening in the UK.

[Madame Brie]

Wow you are the best ATLnsider :) have a nice weekend and give us more good news ;)

[Dr Bala]

Great post, ATLnsider.

[highwayman4life]

Couldn't agree more with your assessment ATL!!

Has it taken longer than investors wanted? Has it taken longer than management anticipated? Yes and Yes.

BUT...IMO we are on the cusp on something very special not only from an investment standpoint but for patients and families who have crossed paths with GBM. Validation is coming soon and for those who have stayed the course, they will be rewarded!!

Thanks for ALL the DD you have done and made available to this board!!

GLTA

[ahp123]

it actually sounds like a possible plan. If that's what's going on right now and the data is good enough to get
implemented that plan, then I must admit I have been wrong about Linda P.
It is at least the most convincing argument for what is happening at the moment if one is to believe that TLDs are as good as one hopes for.
BW

[sentiment_stocks]

It only makes sense that they would request (or have requested) an RTOR.

Thanks for providing all the detail and links!

[McFly021]

Give this man a cookie!

Also one for Jonny4Fingers..

I mean Shooter

[Bob_LobLaw]

this is a fantastic post, thank you for replying. I only made that comment based on someone else's conversation with DI today

As Flipper noted in a response to that poster:

”Nothing new. They made a strategic decision to publish results before releasing topline based on expert recommendations. This is to support the application for approval and to set a precedent moving forward.”

Why would DI say the experts are recommending a publication before TLD to "Support the application for approval". FDA does not need a publication and would probably 100% disregard any publication during their review.

I know you did not make these comments so I am not asking you to defend it. If this is in fact what DI stated then one would conclude that the BLA process has not yet begun.

Again thank you for the reply nonetheless, your contributions are top notch no doubt.

[reachjo]

Great explanation alt! Excellent!

[ison929]

Excellent post. Thanks

[Chiugray]

Very nice.

[danielboog2]

Thanks for the clarity on the probable FDA BLA Process....AWESOME

Did you happen to post this info 3 or 4 months back?

Thanks again

[10baggerz]

Pretty amazing Friday night posts by everyone, especially ATL. Added a wee bit at 1.26, feeling good despite a rough week/month... wouldn’t it be something if they surprised investors with the ultimate good news this year, after all these years of abuse (for lack of a better word).

[sukus]

Thanks ATL. Great post.

[biosectinvestor]

Fascinating and excellent information ATL! What a great post!

[skitahoe]

ATL. where you say all the company has to provide is TLD to begin the RTOR process I believe that the meaning of TLD is different from the few paragraphs the company would normally issued as the TLD statement. I believe that the raw data might be a better way of describing what the FDA receives, essentially the same information provided by PCTL's contractors to the company after they consolidated the data after the trial was locked.

If I'm wrong about this please let me know, but people use the symbol TLD to mean so many things. A TLD statement is normally just a few paragraphs highlighting what the trial determined, I believe the FDA has received far more than that and we really should refer to it as something like the trial data.

Gary

[Kam8]

Amazing post. Thank you

[eagle8]

Thank you ATLnsider.

Fantastic post!

GLTU

[BWIS]

Why do you believe NWBO is using the RTOR process?

Because it exists?

[BigAl2020]

Great info ATL... thanks for sharing

[john1045]

Great post! Agree with you 100%!

Bob_LobLaw, I disagree that this loan for $11 million means that the new DCVax-L BLA process has not already started. Especially if the DCVax-L top line data (TLD) is as good as we all believe it is.

I believe that the FDA is the lead regulatory agency (RA), and it will review the DCVax-L TLD first. I am already on record stating that I believe NWBio may already be using the new FDA Real-Time Oncology Review (RTOR) program, that allows new and supplemental drug & biologic applications to be submitted, reviewed, and approved faster. NWBio only has to submit the DCVax-L TLD to the FDA to get the DCVax-L BLA process started via RTOR.

https://www.fda.gov/about-fda/oncology-center-excellence/real-time-oncology-review-pilot-program

In fact, the average time from submission of a new BLA or NDA to FDA approval was 3.3 months under the FDA RTOR program:

https://clincancerres.aacrjournals.org/content/27/1/11

DCVax-L is perfectly suited to take advantage of the FDA RTOR program.

Quote:
The FDA’s Real-Time Oncology Review (RTOR) pilot program aims to create a more efficient review process that ensures treatments are made available to patients as early as possible. The FDA Oncology Center of Excellence launched RTOR in 2018 to allow sponsors to submit clinical data supporting the NDA as they become available, rather than waiting for the full NDA. This effort is a testament to the importance that regulators have placed on advancing innovations for cancer patients

https://www.amgen.com/stories/2020/12/decoding-5-recent-regulatory-and-development-steps-for-sotorasib

The FDA oncology group is clearly reinforcing the very deliberate message that cancer patients would not be forgotten even as the pandemic became public health priority number one.

Quote:
It is, however, in keeping with recent efforts in the Oncology Center of Excellence to innovate and accelerate regulatory processes. Most notably, the adoption of so-called “Real Time Review” is clearly accelerating the timeline for action on cancer applications with unequivocal efficacy results.

So ahead of schedule approvals are also becoming almost routine in oncology. The various cancer divisions at FDA approved 10 new drugs more than a month early in 2019 and seven in 2018.

https://pink.pharmaintelligence.informa.com/PS143715/US-FDAs-Three-Review-Speeds-Standard-Priority--And-Oncology

Not only do I believe NWBio may be using the FDA RTOR program for DCVax-L, I also believe NWBio may be using the FDA new Project Orbis program in conjunction with the RTOR program.

The FDA Oncology Center of Excellence (OCE) established Project Orbis to allow for the concurrent submission, review and approval of new oncology drugs and biologics in 6 different countries, by 6 different regulatory authorities at the same time.

These countries include: US, UK and Canada. I believe that DCVax-L could be approved in at least 3 different countries at the same time, and within 3 to 6 months from submission of the completed & accepted new BLA.

Quote:
Project Orbis is intended for high-impact oncology products – those products that have the potential to benefit patients the most. A driving factor behind establishing Project Orbis was to bring highly effective therapies to patients with cancer earlier, especially in countries where there would otherwise have been delays with regulatory submissions. Companies with applications seeking to participate are generally expected to meet the criteria for FDA’s priority review, which include a medical product that is intended to treat a serious condition and that, if approved, would provide a significant improvement in safety or effectiveness.

https://www.fda.gov/news-events/fda-voices/project-orbis-strengthening-international-collaboration-oncology-product-reviews-faster-patient

[hyperopia]

Yep ATLnsider, I’m also convinced of the Project Orbis route (which starts with the FDA), and potential simultaneous approvals. I wonder if the construction delays at Sawston held up the actual submission a few months while the company submitted preliminary data and held preliminary meetings with the various regulators. I think this could be the first submission with the UK included, and the process may take a little ironing out. Anyway, it appears that Northwest Bio has the necessary funds to carry this forward. Here’s another link to add to your excellent post:

Project Orbis: Implications for Access and Pricing in the UK
February 17, 2021
Marc Matar, Graham Tatham, Rachel Rowbottom, Sam Calderwood, Katerina Stavri

Post-Brexit, the UK’s MHRA is looking to join Project Orbis, a global program to speed up patient access to innovative cancer treatments. This article looks at the implications of Project Orbis for commercialization in the UK and the key considerations for industry in considering the project as a pathway.

With the UK leaving the European Medicines Agency (EMA) regulatory process in late 2020 as part of Brexit, the UK Government and the Medicines and Healthcare products Regulatory Agency (MHRA) rolled out new approaches for the commercialization of pharmaceuticals. One central tenet was to establish the UK as an attractive market with the potential for fast marketing authorization pathways, and a keynote program was the UK joining Project Orbis.

Project Orbis is a global, collaborative, program launched by the FDA Oncology Center of Excellence (OCE) in 2019, which aims to speed up patient access to innovative cancer treatments through a framework of concurrent regulatory submission and review. Today, there are six Project Orbis Partners (POPs): Australia (TGA), Canada (Health Canada), Singapore (HSA), Switzerland (Swissmedic), Brazil (ANVISA) and most recently the United Kingdom (MHRA). While FDA serves as the coordinator for application selection and review, each country remains fully independent on their final regulatory decision.

Project Orbis Process
Selection of applications for Project Orbis is coordinated by FDA, although the participating regulatory agencies can also identify candidate products. When selected, the FDA approaches the manufacturer and, once confirmed, a product or indication is shared with all POPs to confirm interest in participation. Notably, manufacturers can be selective in the markets they include in their Project Orbis submissions, even down to engaging only one other POP market in addition to the FDA. This permits manufacturers to assess the accelerated approval opportunity-risk trade-offs per market, and only include markets where there is a positive case for their commercialization strategy.

There are three types or Project Orbis submissions which depend on the timeline of submission to the FDA and the POPs:

Type A – Regular
Applications submitted concurrently or near-concurrently (within 30 days) to FDA and the POPs; Type A submissions allow for maximal collaboration during the review phase and the possibility of concurrent marketing authorization with the FDA

Type B – Modified
Applications submitted with a greater than 30-day delay or a regulatory action greater than 3 months of the FDA action. These allow the possibility of concurrent review with FDA but no concurrent marketing authorization

Type C – Written report only
In cases where FDA has already taken regulatory action, it allows the FDA to share their completed review documents with the POP but there is no concurrent review or marketing authorization with FDA.

The First Year of Project Orbis
In an analysis from de Claro et al.,1 we find that in the first year of Project Orbis, to June 2020, 60 marketing applications were submitted across the 6 participating markets (FDA + 5 POP), across 16 unique products. 21 of these applications were to the FDA with a median of 2 additional POPs involved; the most included POPs were Australia (N=14) and Canada (N=12), notably both cost-effectiveness driven HTA markets like the UK. No application included all markets, and Brazil only received one application under Project Orbis.

From these applications, 38 marketing authorizations were granted; the FDA approved 18 of 21 applications (86%), Australia’s TGA approved 7 of 14 (50%), Health Canada approved 8 of 12 (67%) Swissmedic approved 1 of 7 (14%), Singapore’s HSA approved 4 of 5 (80%) and Brazil’s ANVISA had not approved the single marketing application it received at time of analysis.

Impact on time to marketing authorization
Since leaving the EMA Centralized Authorization Procedure, the MHRA,2 has published guidance on eight new routes by which a manufacturer can apply for a license to market a medicine in the UK, including 6 national routes and 2 international routes. Most products are expected to be assessed through the national routes, with a procedure timelines ranging from 67 to 150 days, depending on the type of application, level of innovation and whether the product is already marketed in another country.
?
Project Orbis is one of the two available international routes, aiming to speed up regulatory approval timelines for innovative oncology products. From a patient access point of view, Project Orbis has received significant positive press however an open question remains on whether access timelines are truly expedited in all markets.

From the analysis of de Claro et al., the median time-to-approval of all products in the first year of Project Orbis was 4.2 months for FDA submissions (range 0.9–6.9, N = 18) and 4.4 months for the POPs (range 1.7–6.8, N = 20). For new active substances, the timeline was slightly longer taking a median of 5.1 months for the FDA (range: 3.9-6.9, N=6) and 5.9 months for the POPs (range 3.9-6.8, N = 7).

These timelines are significantly shorter that the average EMA marketing authorization timelines which last around 1 year, suggesting MHRA marketing authorization under Project Orbis hold potential to deliver faster access than if the UK had remained part of the EMA.

It is worth noting however, that whilst some national routes are depended on other regulatory body processes (e.g., EC Decision Reliance Procedure) the standalone MHRA process is the National procedure, which is expected to take 150 days for marketing authorization. Comparing this to the Project Orbis timelines of 5 to 6 months, MHRA timelines are projected to lead to faster UK access than engaging in Project Orbis.

Regardless of the type of Project Orbis submission, to be eligible for Project Orbis in the UK, the drug under consideration must also qualify for the national Innovative Licensing and Access Procedure (ILAP). While the manufacturer does not necessarily have to have engaged with the ILAP prior to requesting inclusion in Project Orbis with the UK as a POP, the MHRA will arrange an “Innovation Passport” meeting to confirm eligibility. Reversing this rationale, manufacturers who do not want to engage the UK in Project Orbis are likely to remain eligible for, and gain the advantages of, other innovative access routes into the UK.

While considering the advantages and risks of Project Orbis, the second “Access Consortium” international route must also be considered, defined as work-sharing procedures between national regulators. Notably this consortium includes all Project Orbis markets, excluding the US and Brazil, and not restricted to oncology indications. While there may be synergies through this approach, offering a more attractive commercial opportunity than to the UK market alone outside the EU, the benefits of this route will likely be dictated by manufacturer engagement and submission.

Implications for UK market access and pricing
In the UK, NICE acts as primary gatekeeper to the public coverage of the majority of the population, with reimbursement recommendations derived from clinical and cost-effectiveness assessments. Aligning the UK marketing authorization process with the US through Project Orbis potentially expedites marketing authorizations and as a result expedites HTA assessments. With a significant proportion of oncology drugs going through the FDA accelerated approval route in parallel to Project Orbis, and in some cases approval granted in advance of trial data publication or before key efficacy endpoints (such as overall survival) reach maturity, it can be inferred that these expedited NICE HTA assessments could be conducted with a limited and early data package. Consequently, this will result in less robust evidence submissions, greater uncertainties surrounding the product’s efficacy and therefore greater difficulty in demonstrating cost-effectiveness.

Oncology therapies launching in the UK with limited evidence packages (e.g., immature outcomes) are able to utilize the UK’s Cancer Drugs Fund for funding through time-limited Managed Access Agreements whilst awaiting future clinical trial read-out. However, there are current uncertainties on the future composition of the CDF, potential changes to the entry requirements and risk of proportional rebates on budget overspend. Furthermore, additional discounts are expected on entering the CDF resulting in lower net prices for the interim funding period and potentially a signal of the net price potential during reappraisals. In the current policy, the net price agreed through the Managed Access Agreement is disconnected from any future achieved price through routine commissioning (although a true separation is unlikely in practice).

One response for manufacturers is to pursue marketing authorization through Project Orbis and then delay HTA evidence submission until further supportive data becomes available, a trend that can be observed in other comparable markets. This enables manufacturers to take advantage of a single Marketing Authorization submission across several markets, and expedited licensing, but pursue reimbursement at a commercially viable subsequent timepoint. For example, the five latest TGA submissions through Australian participation in Project Orbis, indicate a delay between marketing authorization and HTA submission to PBAC. New chemical entity priority review submissions of Qinlock (ripretinib) and Tukysa (tucatinib), which received marketing authorization through Projsct Orbis in July and August 2020 respectively, have yet to go through a PBAC assessment. Both are expected to be evaluated in March 2021, more than 6 months after marketing authorization. Similar delays in submission between marketing authorization and HTA evidence submission can be observed in the other cost-effectiveness-based market, Canada, and across multiple products, including Qinlock (ripretinib), Tukysa (tucatinib) and Calquence (acalabrutinib).

Conclusions and key considerations
The entry of the UK into Project Orbis presents an opportunity to leverage a coordinated submission approach across multiple markets and to gain patient access earlier with marketing authorization feasible with less mature data. However this must always be considered alongside reimbursement expectations; consequent delays to NICE submissions or data collection agreements through the Cancer Drugs Fund may be required to ensure data is available to support cost-effectiveness.

We outline three considerations for pharmaceutical manufacturers to evaluate whether the UK should be one of the markets engaged through Project Orbis, if invited to make a submission.

1. Consider Project Orbis and ILAP early in clinical development
Alignment across Medical, Regulatory and Market Access functions will be required to evaluate the feasibility of meeting UK ILAP requirements depending on clinical trial data cuts. Early cross-functional understanding of the requirements of the UK ILAP Target Development Profile and Global-to-Local support in its development with the MHRA is essential to reflect expectations for clinical outcomes and increase chance of success.

2. If UK early marketing authorization through Project Orbis is feasible, consider the potential NICE evaluation outcomes
The implication of NICE Single Technology Assessment based on the clinical evidence submitted for Project Orbis must be anticipated. Modelling cost-effectiveness based on the early data cut will be required, and areas of uncertainty identified. The likelihood of a recommendation at an acceptable cost-effective net price must be taken into consideration as part of the decision to pursue Project Orbis regulatory approval for the UK. Therefore close dialog between Global/Regional and UK affiliate Market Access and HEOR teams is required, with consideration for the net price floor and international list price referencing implications.

3. Evaluate alternative funding routes available in the UK
A focus on cancer funding in the UK has delivered earlier access for patients in the UK through mechanisms such as the Cancer Drugs Fund. While this may be undergoing changes, into the £500 million Innovative Medicines Fund, this has been reported to include a ring-fenced budget for oncology. However, uncertainty on the future entry requirements, opening to wider therapeutic areas and net price position signaling may make the CDF a less attractive option for manufacturers in the future, thereby risking the benefits of an earlier marketing authorization.

Marc Matar is a Partner, Graham Tatham is a Partner, Rachel Rowbottom is a Director, Sam Calderwood is a Senior Consultant, and Katerina Stavri is a Consultant in Simon-Kucher & Partners Life Sciences division based in the company’s London office.

https://www.pharmexec.com/view/project-orbis-implications-for-access-and-pricing-in-the-uk

[Evaluate]

re FDA Real-Time Oncology Review (RTOR) program:
https://www.zs.com/insights/pedal-to-the-metal-assessing-the-fda-s-real-time-oncology-review-program
(Note: I do not see a date for when the above link was posted)
includes:

Currently, the RTOR pilot is only accepting applications for supplemental indications for drugs that have already been approved by the FDA, meaning that new molecular entities (NMEs) are ineligible.

&

So far, there have been four oncology therapeutics (Kisqali, Keytruda, Kyprolis, Adcetris) that have been granted new or extended indications via RTOR, and another four (Tibsovo, Kadcyla, Venclexta, Darzalex) that are currently being reviewed under the RTOR program.

So it appears that DCVax was not under review by RTOR at the time of the article.