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Yes, that’s my read. In the past, NICE attempted to review all treatments within 90 days after licensing by the MHRA, but in order to speed access to patients, NICE is attempting to review and collaborate with the MHRA during the licensing assessment stage to have a decision as soon as a drug or treatment receives a license. This Parliament discussion reveals that due to bureaucracy and other issues, NICE is not actually working with the MHRA as intended, and the NICE review in some cases, is not keeping up with the faster timelines.
Thanks flipper, I’ve seen this in a few instances. (AstraZeneca’s Tagrisso for one) I think it’s through the Cancer Drugs Fund (CDF) which funds certain promising cancer drugs for a short period until NICE publishes the final approval.
I agree senti, but a NICE decision may take longer than some here suggest. NICE still hasn’t caught up with the new expedited licensing routes in the UK, and if this recent debate is any indication, it does not appear that the situation will improve anytime soon:
UK Parliament Debate on Cancer Drugs: Licensing and Approval
Volume 815: debated on Monday 8 November 2021
https://hansard.parliament.uk/lords/2021-11-08/debates/0A9856B1-F71E-4FAA-A708-0949118BB93F/CancerDrugsLicensingAndApproval
Nice timeline Dude. Factually, data lock occurred on October 4, 2020, but was announced on October 5:
Overview
The Company is focused on developing personalized immune therapies for cancer. We have developed a platform technology, DCVax®, which uses activated dendritic cells to mobilize a patient's own immune system to attack their cancer.
Our lead product, DCVax®-L, is designed to treat solid tumor cancers that can be surgically removed. We recently completed our 331-patient international Phase III trial of DCVax-L for newly diagnosed Glioblastome multiforme (GBM).
As previously reported, the data collection and confirmation process was completed by the independent contract research organization (CRO) who managed the trial and by other independent service firms, and we reached Data Lock for the Phase III trial on October 4, 2020. As explained in our prior announcements, following Data Lock the independent statisticians conduct analyses of the raw data and Trial results for review by the Company, the Principal Investigator, the Steering Committee of the Trial, the Scientific Advisory Board, and a panel of independent brain cancer experts, in preparation for scientific publication and for public announcement. During this process, any questions or comments from the experts will be addressed as part of the preparation of the results for publication and public reporting.
https://sec.report/Document/0001104659-21-004396/
Well done senti.
Advanced Therapies Week January 25th - 28th 2022 (formerly Phacilitate Leaders World)
A Who’s Who in the advanced therapy industry, where literally anyone who has anything even tangentially related to an advanced therapy, is present in some form. Apparently Northwest Bio is too busy. (Kwok Pang, COO of Autolomous is remotely related)
Sponsors and Exhibitors
https://advancedtherapiesweek.phacilitate.com/sponsors-partners/
Speakers
https://advancedtherapiesweek.phacilitate.com/advanced-therapies-speakers/
BTW - I’m not sure if anyone else was notified (I’ve been contacted 3 times by phone from London) but the 3rd Glioblastoma Drug Development Summit has been changed to an all-digital event (Dr. Bosch still speaking):
https://glioblastoma-drugdevelopment.com
Happy Holidays Everyone!
No way ex. Either you can’t count, or you conveniently can’t remember. You didn’t think I would let you forget about this estimate, did you?
No way.
I doubt they will be certified this year. They are still about 6 to 8 weeks (LP time) away from having an application in (LP time). And I am guessing the UK has a serious backlog in the GMP inspection process right now, which is never fast to begin with.
I would take June or July 2022 as a better guess.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=162678792
I think you’re probably right senti, not only the visibility given in the UK, but also the due diligence on this board! I know it was just authorized today, but surely the MHRA notifies the company (or at least Advent) prior to posting.
Thanks Lykiri, great news! It figures that you would be the one to find it, but I'm a little surprised that this wasn't announced by Northwest Bio.
Thanks flipper, this patent is for Flaskworks’ BATON system, not the MicroDEN system that will be used for DCVax-L. The BATON system cultures two types of cells using two different culturing methods; dendritic cells in an adherent container, and T-cells in suspension. It was developed by Shashi Murthy to manufacture Neon Therapeutics’ neoantigen immunotherapy with his first grant from the National Science Foundation in 2016.
I’ve wondered if this system will be tailored and further developed to produce DCVax-Direct, which cultures the dendritic cells in suspension. I think I read somewhere that the company intends to develop the Flaskworks’ technology for DCVax-Direct, after development for DCVax-L has been completed.
BTW - This is the system that Shashi Murthy was making presentations about dendritic cell manufacturing systems at conferences like Phacilitate, where I believe he caught the attention of Linda Powers, who potentially encouraged the development of the MicroDEN system.
Shashi Murthy Wins NSF Grant for Cell Therapy Manufacturing with Neon Therapeutics
Via Northeastern | September 2, 2016
Chemical Engineering Professor Shashi Murthy has received funding from the National Science Foundation to develop novel manufacturing technologies for cell-based cancer therapies. This project will be a collaborative effort with Cambridge, MA-based Neon Therapeutics which is developing neo-antigen-based therapeutic vaccines and cell-based therapies for cancer. Cell-based therapies represent the next major frontier in the treatment of cancer and their personalized nature presents unique challenges in manufacturing. This project brings together an interdisciplinary team of engineers and immunologists to design innovative automated bioreactors that can be optimized for biological function. This grant provides $300,000 in funding over a two year period to be shared equally by Northeastern and Neon Therapeutics.
https://aimbe.org/college-of-fellows/COF-2015/
National Science Foundation
Award Abstract # 1645205
EAGER: Biomanufacturing: BATON: Bioreactor System for Autologous T-Cell Stimulation
https://nsf.gov/awardsearch/showAward?AWD_ID=1645205&HistoricalAwards=false
Thanks Lykiri, excellent details!
flipper, it’s general knowledge in the industry. But a while back I did post a document from the EMA intended to clarify guidance around the comparability issue, which confirms what I’m saying. Some of the new “manufacturing experts” on the board may also benefit from reading it:
Comparability considerations for Advanced Therapy Medicinal Products (ATMP)
Q12: What is the comparability exercise needed when a new manufacturing site is added to an existing authorisation?
A: When several manufacturing sites are introduced under the same authorisation procedure, a high degree of comparability is expected to be demonstrated. The comparability of the product manufactured at different sites should be comprehensively substantiated. The first step should be to perform a comparability assessment of the manufacturing process and equivalence of the analytical methods on both sites by evaluation of process parameters and in-process control, to validate the process transfer. Secondly, the comparability of the product itself through release and suitable characterisation testing should be demonstrated. (See also Questions 4, 6 and 9)
https://www.ema.europa.eu/en/documents/other/questions-answers-comparability-considerations-advanced-therapy-medicinal-products-atmp_en.pdf
meirluc, the Flaskworks’ comparability study cannot be initiated in one manufacturing facility (London) and then completed in another facility (Sawston). The entire study (start to finish) will be conducted in one facility (Sawston). There are a multitude of variations between labs (personnel, equipment, media, etc.) which can have an effect on a product, so any change in a manufacturing site is considered a change in manufacturing, and will require its own comparability study. The level of a comparability exercise that needs to be conducted should be commensurate with the degree and timing of the change.
In my conversations with DI, what I have deduced, and caution this is MY personal opinion on what I heard, is that they are already testing Flaskworks on their own; in a parallel stream to vaccine creation testing/training via standard clean room technology. I believe they are targeting end of Q1, early Q2 2022 completion for Flaskworks certification.
Cell culture systems are configured with interchangeable cartridges, allowing versatility and scalability. Systems are configured to have multiple connected cell culture chambers, which allows parallel processing. . .
Certain aspects of the invention are directed to methods of determining a cell culture protocol. The methods comprise receiving data associated with cells to be cultured; connecting to one or more databases to receive data about cell culture protocols; and determining a cell culture protocol for the cells to be cultured.
In some embodiments of the invention, methods further comprise updating the cell culture protocol based on feedback during cell culture. The feedback is from one or more sensors disposed on a cell culture apparatus and communicatively coupled with a controller. In some embodiments, the feedback is associated with at least one of pH, glucose concentration, lactate concentration, dissolved oxygen, total biomass, cell diameter, temperature, cell type, media type, and fluid flow rate.
Thanks for the details Jack. So Les told you . . . yes, that would explain it. Of course I believe you, and I appreciate your perspective.
Yes, I think that 40-45 patient number is the production capacity using the current manual process. The last paragraph of that PR discussed the Flaskworks system:
As previously reported, the Company has also been moving forward on optimization of the Flaskworks system for manufacturing of dendritic cell vaccines. The buildout of the Sawston facility is purposefully being done in phases, both for efficiency in the timing of capital costs and to allow flexibility in operations and usage. It is anticipated that implementation of the Flaskworks system will enable the buildout of some or all of the rest of the 88,345 square foot facility, beyond the initial manufacturing suites, to be simplified and streamlined at reduced cost.
https://nwbio.com/northwest-biotherapeutics-announces-development-completed-for-initial-production-capacity-of-sawston-uk-facility/
Maverick, I actually agree with your previous sentiment that they may not reach 40 “specials” patients a month. I know that several posters have been throwing around that 45 patients per month number, but it may be time to remind everyone what that PR actually said:
The Sawston facility contains a total of 88,345 square feet on two floors. The initial production capacity comprises two manufacturing suites, occupying approximately 4,400 square feet on the ground floor. These two suites, together with some additional support and storage space, have a potential production capacity of dendritic cell vaccines for about 40 to 45 patients per month, or approximately 450 to 500 patients annually, subject to regulatory approval.
https://nwbio.com/northwest-biotherapeutics-announces-development-completed-for-initial-production-capacity-of-sawston-uk-facility/
I’ll share a story with you Maverick since you’re new here. My grandfather was diagnosed with Glioblastoma and his oncologist gave him about a year to live. The Optune “helmet” was recommended after standard of care as the only “treatment” available that might extend his life. It cost $20k a month and it wasn’t covered by Medicare at the time. He was not wealthy but his house was paid for and he had some savings. He didn’t want to spend the money because he wanted to leave it for my grandmother to have a comfortable life. My grandmother begged and pleaded with him to pay for it because she was terrified of losing him and being alone since he had always taken care of her. He could never say no to my grandmother. I’ll spare you the ugly details, but he battled one of the worst cancers you can imagine for ten months, and it cost his entire life savings. You might not understand what people are willing to do to live a little longer until you’ve been there.
Thanks Biosect. The board, and you in particular, are usually pretty good about challenging the flood of false narratives and misinformation. The posts I’ve seen that project minimal revenue and no profit during the initial phase of Sawston production, were from posters that have little credibility with me, so I wanted to give Jack a chance to show if there is a factual basis for it.
My thinking is; if the production in London was performed at cost, then the savings achieved from manufacturing at higher production volume in Northwest Bio’s own facility, could be kept as profit by Northwest Bio.
Jack, I asked if you can provide a link to prove that your information is fact, but you only repeated it. I posted the regulations and guidance around the issue of unlicensed medicinal products for “specials,” and it does not state that a profit cannot be made. However, you are correct that it does state that these products cannot be advertised. Price lists are allowed though.
Is that a fact Jack? Or is it simply your understanding that companies supplying unlicensed medicines (specials) can’t make a profit? If it is a fact, can you post a link?
Yes they can charge cost but not profit at all from it. It’s modest direct costs only….
UNLICENSED MEDICINAL PRODUCTS IN THE UK
CHARGING FOR SUPPLY
The 2012 Regulations do not place any restrictions on companies charging for the supply of unlicensed medicinal products, and historically there were no other restrictions on pricing or pharmacies’ ability to seek reimbursement for unlicensed medicinal products under the NHS.
However, concerns that some pharmacies were making excess margins on unlicensed medicinal products led to the introduction of a new Part VIII B of the Drug Tariff (see NHS: Electronic Drug Tariff: Arrangements for payment for Specials and Imported Unlicensed Medicines). As at August 2016 this set limits on prices of 250 high-cost, high-volume unlicensed medicinal products prescribed commonly and supplied on NHS prescription, using sales and volume data from suppliers (see NHS: Part VIIIB: August 2016).
https://www.arnoldporter.com/~/media/files/perspectives/publications/2017/02/unlicensed-medicinal-products-in-the-uk.pdf
Thanks, but that’s not indicative of MM’s loading. It looks like Moloney Securities Asset Management already held around 160,000 shares and increased it by 5%, which is a little over 8,000 shares over an entire quarter . . . and they’re not a market maker in NWBO.
They are still managing the authorized share limit, and can continue to survive hand to mouth for a while. Not sure if this was posted, but there was some disagreement on the number of shares available under the authorized limit back in August.
At September 30, 2021, approximately 30,882,000 shares were technically available under the authorized share limit, however, an addition 3.4 million shares should have been issued by September 30 but were not, so a more accurate number may be 27.42M shares available: (BTW - What warrant/option agreement wasn’t finalized? Linda’s?)
The Company also received approximate $0.8 million cash proceeds from investors prior to September 30, 2021, for which the corresponding exercise agreement was not finalized and thus, common stock totaling 3.4 million was not issued as of September 30, 2021. Accordingly, such amounts are included in Investor advances in the accompanying condensed consolidated balance sheet as of September 30, 2021.
Subsequent Events
In total, the Company received $8.2 million from exercises of warrants and issuance of notes between October 1, 2021 and November 12, 2021.
During October and November 2021, 34.8 million shares of common stock were issued upon warrant exercises of $6.9 million. Approximately 0.9 million shares of common stock are pending to be issued.
During October 2021, the Company entered into multiple four-month note agreements (the “Notes”) with various individual lenders (the “Holders”) with an aggregate principal amount of $1.14 million for net proceeds of $1.1 million. The Notes contain a conditional piggy-back right to independently purchase shares from the Company, which provides a right for the Holders, contingent on the release of clinical trial data and the next private placement offering (“Next Offering”) after this release, to (a) purchase shares from the Company within seven days following such Next Offering at a 12% discount from the share price of the Next Offering for a variable number of shares equal to an amount up to 50% of the principal amount of the loan and (b) exchange some or all of the outstanding loan amount for a variable number of shares, within seven days after the Next Offering at a 12% discount, resulting in a reduced cash amount repayable under the loan agreement.
In October 2021, the Company entered into multiple note extension agreements whereby the maturity date of the notes was extended for additional 2-4 months.
Yes Northwest Bio has stated their intention to file for accelerated approval and should qualify for RMAT designation, so I think it’s highly likely that it has been considered, and may be used eventually. But why haven’t they applied or announced it yet? My point was that the reason may be that they are considering another accelerated approval route first.
DCVax should meet the criteria for an Innovation Passport but it may be too late in development. This is the relevant section of the guidance:
When to enter the pathway
The ILAP enables multiple entry points depending on:
* the stage of development of the product
* the data available
* the ambition of the applicant to engage with UK stakeholders
* the applicant’s appetite for new innovative ways of working
Therefore, the pathway will allow entry very early, based on non-clinical data, where all the tools described below might be options, as well as catering for products with mid-development ‘global’ dossiers. However, to maximise the benefits, applicants are encouraged to apply early in the development of their products. Products that are towards the end of their development programme are generally not suitable for the ILAP unless there are one or more indications still under active investigation.
The ILAP does not replace the Early Access to Medicines Scheme (EAMS), which remains an important flexibility for earlier patient access towards the end of the development programme in areas of unmet medical need and where major advantage over existing therapies can be demonstrated. The ILAP is broader in scope and is open to all innovative products.
Early pipeline discussions with developers are encouraged. These can be conducted with the MHRA and partners in the context of broader scope meetings, for example.
Thanks Lykiri, it’s good to hear that they wouldn't provide that information since they state:
Data sharing and confidentially
Any information shared during the ILAP is considered as confidential. It will be held on a secure shared digital platform for access by the ILAP partners, as agreed by the applicant. In order to maximise the benefits of collaborative working with multiple UK stakeholders, the current and future sharing of relevant data is highly recommended. The partners will adhere to relevant institutional confidentiality and non-disclosure agreements.
I suspect that Northwest Bio will first take advantage of a more favorable route in the UK, and may have applied for the Innovation Passport, which is the entry point for the Innovative Licensing and Access Pathway (ILAP). Nineteen applications were filed in only the first few months of the year, yet to date, only about a half dozen have been publicly announced. (some may have been denied)
Les has stated privately to a number of investors of their intention to apply for approval first in the UK, and Dave Innes talked enthusiastically about the various new regulatory pathways in the UK, and continues to state that getting DCVax to market is the primary goal. Compared to the FDA, the MHRA (post-Brexit) seems far more eager to bring new and innovative treatments to patients as rapidly as possible, and is also very willing to assist companies through the regulatory process.
RECOMMENDED READING:
MHRA Innovation Office
The MHRA Innovation Office is open to ideas for innovative medicines, medical devices and manufacturing processes. It provides free and confidential expert regulatory information, advice and guidance to organisations of all backgrounds and sizes based nationally or internationally. Call our customer services team on 0203 080 6000.
https://www.gov.uk/government/groups/mhra-innovation-office
Innovative Licensing and Access Pathway
A new pathway supporting innovative approaches to the safe, timely and efficient development of medicines to improve patient access.
https://www.gov.uk/guidance/innovative-licensing-and-access-pathway
The Target Development Profile Toolkit
This toolkit is for Innovation Passport holders following the Innovative Licensing and Access Pathway (ILAP) and provides activities to support the design and development of medicines.
SOME HIGHLIGHTS:
Certifications
Building on the Agency’s scientific advice approach, the Certification tool provides developers with an enhanced official regulatory review of packages of Common Technical Document (CTD) data (including Module 1). The process will provide applicants with specific and actionable feedback on the expectations for marketing authorisation and the regulatory requirements, highlighting potential deficiencies and where there are key issues to address.
This tool is not part of a formal marketing authorisation application but provides expert advice on how ‘regulatory ready’ a particular part of the development is.
How it works
You must confirm in the TDP which aspects of the CTD you are interested in having certified. We would expect this to be within Module 1, Module 3, Module 4 or Module 5, not necessarily a full module.
You can apply to have packages of CTD data assessed by an MHRA multi-disciplinary team including licensing, pharmacovigilance and inspectorate colleagues who will review the submission against marketing authorisation requirements and expectations for regulatory compliance.
Packages of CTD data might include quality, non-clinical or clinical and pharmacovigilance aspects. Early engagement on the acceptability of the submission will provide the developer with the opportunity to make timely changes to their programme in advance of a formal marketing authorisation application.
For biological medicines, such as vaccines, blood products and other immunological biotherapeutics, you will be able to engage early on with the National Institute for Biological Standards and Control (NIBSC) scientists. Interactions will facilitate the rapid establishment of the relevant tests and make sure that, where possible, legally mandated batch testing can be performed in parallel to manufacturer’s in-house testing, ensuring no delays in access to these medicines.
Certification may be considered for the whole of one module or a subsection or across modules if agreed. You can request more than one certification over time for different modules.
Following the submission, the team will assess the modules against the regulatory framework and standards. The outcome of the certification will be a letter summarising the regulatory view of the data, the parts that are satisfactory and the major deficiencies if they exist and opportunities for further scientific advice as needed.
Delivery partners
If you use the Certifications tool you will work with experts from the MHRA divisions and centres.
Related tools
The Certification tool could be used alongside rolling review in the Innovative and Flexible Licensing tool and Adaptive Inspections tool.
Innovative and Flexible Licensing Routes
The tool is intended to provide support and guidance in the choice of routes for products in the ILAP. Some of these routes may be available as options to companies with products outside of ILAP.
The Innovative and Flexible Licensing Routes tool can provide expedited timelines for review, pragmatic approaches to evidence requirements and international options where appropriate and available.
Regulatory licensing flexibilities can be used to expedite the approval process once a product or new indication has sufficient data for regulatory review. Independent laboratory testing can also support authorisations based on reduced data packages through the generation, post-licensure, of data supporting batch-to-batch consistency.
The routes are:
* Accelerated assessment
* Rolling review
* Approval with conditions
* Conditional Marketing Authorisations
* Approval under exceptional circumstances
* Project Orbis
* Access Consortium
Accelerated Assessment
An accelerated assessment procedure will reach opinion on approvability of a marketing authorisation application within 150 days of submission of a valid application. This option is available for good quality marketing authorisation applications for both new and existing active substances.
Eligibility will also include those applications seeking an orphan MA approval in Great Britain and those submitted for conditional and full marketing authorisations as well as those submitted for approval under exceptional circumstances.
Rolling Review
The Rolling Review is a new route for marketing authorisation application intended to enhance development of novel medicines. It does this by offering ongoing regulatory input and feedback. The process is envisaged as a phased, modular, iterative approach to evaluation of marketing authorisation applications.
The quality, non-clinical and clinical parts may be submitted singly or in combinations depending on the individual circumstances as data becomes available. It is expected that each module will be near completion to avoid multiple iterations of assessment of the same module. Each assessment phase will progress independently permitting early identification of issues.
Each assessment cycle with points of clarification raised will offer the applicant the opportunity and time for a comprehensive update of the modules prior to final submission. The final phase will involve submission of a complete application including the remaining module together with updated versions of the modules evaluated previously.
Approval with Conditions
Conditions are obligations that are imposed at the time that the marketing authorisation is granted. Conditions include PASS/ PAES that can be used to provide reassurance that gaps in the evidence generation will be filled appropriately.
Conditional Marketing Authorisation
In order to meet unmet medical needs of patients and in the interest of public health, it may be possible to grant marketing authorisations on the basis of less complete data than is normally required. In such cases, the granting of a marketing authorisation is subject to certain specific obligations to be reviewed annually.
These medicines are for the treatment, the prevention or the medical diagnosis of seriously debilitating diseases or life-threatening diseases, medicinal products to be used in emergency situations, in response to public threats and medicinal products for rare diseases. Conditional marketing authorisation will allow medicines to reach patients with unmet medical needs earlier than might otherwise be the case and will ensure that additional data on a product are generated, submitted, assessed and acted upon.
Approval under exceptional circumstances
For licensing under exceptional circumstances, the applicant must demonstrate that they are unable to provide comprehensive data on the efficacy and safety under normal conditions of use. This may be because:
* the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence or
* in the present state of scientific knowledge, comprehensive information cannot be provided or
* it would be contrary to generally accepted principles of medical ethics to collect such information
Under these circumstances an authorisation may be granted with a reduced clinical data package than would ordinarily be required.
Project Orbis
Project Orbis is an initiative of the Food and Drug Administration (FDA) Oncology Center of Excellence (OCE) that provides a framework for concurrent submission and review of oncology products among international partners including the UK.
Access Consortium
The Access Consortium is a collaborative initiative of medium-sized regulatory authorities between Australia’s Therapeutic Goods Administration (TGA), Health Canada (HC), Singapore’s Health Sciences Authority (HSA), the Swiss Agency for Therapeutic Products (Swissmedic) of Switzerland and MHRA. The purpose of the consortium is to build synergies and share knowledge amongst the regulatory authorities thereby enhancing the efficiency of regulatory systems.
How it works
The TDP will recommend the most suitable routes to market based on the product and patient population to treat in the context of the ongoing development programme.
Regulatory licensing flexibilities can be used to expedite the approval process once a product or new indication has sufficient data for regulatory review. Independent laboratory testing can also support authorisations based on reduced data packages through the generation, post-licensure, of data supporting batch-to-batch consistency.
Early engagement with NIBSC will enable the rapid establishment of the relevant tests to make sure that, where possible, legally mandated batch testing can be performed in parallel to manufacturer’s in-house testing, ensuring no delays in access to these medicines.
Novel methodology and innovative clinical trial design
The Novel Methodology and Innovative Clinical Trial Design tool, co-developed by MHRA, NICE and SMC, is designed to establish a system and culture that is receptive and supportive of novel methodologies in both the clinical and pre-clinical space to develop new medicines or new indications. This includes innovative clinical trial designs, manufacturing, and endpoint development. We will also demonstrate that innovative methodologies are acceptable to all stakeholders, for example by issuing an opinion on the proposed methodology or technology.
The tool has the potential to significantly accelerate development and bring safe, effective medicines to patients faster, balancing the risks and benefits of any novel approaches, with a strong patient focus.
Novel trial designs with virtual and decentralised elements will increase patient-centricity in trials and reduce the burden of taking part, improving recruitment and retention. Qualification and multi-stakeholder regulatory acceptance of novel methodologies will de-risk and reduce the costs of development. The tool will encourage and facilitate the proactive use of novel trial designs for evidence generation – including master protocols – to ensure a flexible regulatory approach that can react to emerging data with a focussed, efficient use of resources.
How it works
According to the individual requirements of the applicant, key outputs from the tool include:
* securing multi-stakeholder agreement for novel and innovative approaches to evidence generation
* qualification of the new methodologies and support via (joint) scientific advice procedures (e.g. with NICE) offered during the ILAP, including targeted inspections of novel technologies
* guideline documents on topics of interest
* encouragement and facilitation of the use of novel trial designs, including master protocols, to ensure a flexible regulatory approach that can react to emerging data with a focussed use of resources
* regulatory assurance on the requirements and acceptability of virtual, AI and decentralised elements in trial conduct
* regulatory assurance on new e-systems technologies that may be used to support any such novel trial designs
You should expect regulatory assurance on the requirements and acceptability of, for example, use of Artificial Intelligence (AI), virtual and decentralised elements in trial conduct, and e-systems technologies used to support such novel trial designs. Developers will also see use of new approaches for qualification of new methodologies, technologies, use of modelling and simulation, and novel endpoints.
https://www.gov.uk/guidance/the-target-development-profile-toolkit
Amgen’s timeline for Sotorasib using RTOR and Project Orbis: (which seems typical of BP's)
October 5, 2020 - Amgen announces positive topline phase 2 results for investigational KRAS G12C inhibitor sotorasib in advanced non-small cell lung cancer.
https://www.prnewswire.com/news-releases/amgen-announces-positive-topline-phase-2-results-for-investigational-kras-g12c-inhibitor-sotorasib-in-advanced-non-small-cell-lung-cancer-301145947.html
December 16, 2020 - Amgen Submits Sotorasib New Drug Application To U.S. FDA for its use in patients with KRAS G12C–mutant locally advanced or metastatic NSCLC
https://www.amgen.com/newsroom/press-releases/2020/12/amgen-submits-sotorasib-new-drug-application-to-u-s--fda-for-advanced-or-metastatic-non-small-cell-lung-cancer-with-kras-g12c-mutation (Reviewed under RTOR Pilot Program)
December 24, 2020 - Amgen submit sotorasib marketing authorization application to the European Medicines Agency.
http://pharmabiz.com/NewsDetails.aspx?aid=134343&sid=2
May 28, 2021 - FDA Approves sotorasib the First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy
https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug
June 24, 2021 - Abstract published in NEJM
https://www.nejm.org/doi/full/10.1056/NEJMoa2103695
September 13, 2021 - UK’s MHRA approves Amgen’s sotorasib for non-small cell lung cancer (MHRA’s 2nd approval using Project Orbis)
https://www.pharmaceutical-business-review.com/news/uks-mhra-sotorasib-lung-cancer/
Still waiting for approval by EMA????
Well, precise isn’t a word that I would use to describe Linda speak. But I agree that she definitely covered her bases there by throwing in “hope” and “around” which does allow a stretch into October.
Actually, Linda DID say “by around the end of the third quarter this year” at the ASM according to the transcript provided by IkeEsq:
5. Sawston
"The next category of subject matter that was asked about was the Sawston, UK facility. I think probably a number of the questions came before our announcement, our press release last week which was on this subject. And I hope everybody had a chance to see our press release last week. Because it was announcing that a quite important milestone was reached. The milestone was the completion and the submission to the UK regulatory authority, the FDA of the UK, of the whole application package for the initial licensing of the Sawston facility. I think everyone knows, but just to provide the background, all facilities that produce medical products for human patients are required to be licensed by the regulator in that country. Every facility has to go through this. And the application that was submitted and that we announced last week as we said in the announcement, was the culmination of more than two years of work by a large team and a whole lot of expert consultants. So that was a quite important step, a quite important milestone. Looking ahead, looking forward, we are hopeful that the process, the next steps are for the regulatory authority to make an on-site inspection, in person of the facility. There’s some lead-time for scheduling that, there’s some time involved in the regulatory authority writing up the results after the inspection and if there is anything to address then having that be addressed. So we are hopeful that that process those steps will proceed quickly over the coming months. And we hope to have the initial license for the Sawston facility by around the end of the third quarter this year. Something in that time frame. Once we have the initial license, then we expect to begin producing vaccine products for our existing programs as we’ve been doing at the small facility in London that we’ve been using up ‘til now. So that’s the update on the Sawston facility and the discussion related to the questions we got on that."
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=163888870
Yes, Life Sciences is a product division of Corning. It was a “Supply Agreement” with Corning to supply the single-use plastic parts, and the contract was terminated and re-sourced, so they are not manufacturing for Flaskworks.
(iv)a duly executed termination agreement between Flaskworks and Corning Incorporated (“Corning”) with respect to that certain Supply Agreement between Corning and Flaskworks, as amended and supplemented to date, in form and substance reasonably satisfactory to the Buyer;
Vesting; Settlement; Termination.
(a)Subject to the other conditions set forth in this Agreement, the Rights shall become vested as follows:
(i)Twenty-five percent (25%) of the Rights shall vest upon completion of all of the following:
(A)delivery to the Company by Recipient of a document listing all technical and regulatory requirements for the deployment of the EDEN system to manufacture DCVax-L, together with a detailed timeline;
(B)the initiation of EDEN system consumable sourcing from Saint Gobain or an equivalent supplier, via issued purchase order;
(C)the technology transfer of all relevant Company manufacturing protocols for DCVax-L to Flaskworks’ Boston site;
Wrong. Corning was the manufacturer for the single-use plastic parts of the MicroDEN™ system.
The Corning MicroDEN system is composed of the MicroDEN unit manufactured by Flaskworks, and closed-system consumables manufactured by Corning, such as tissue culture-treated polystyrene flasks, storage bottles, and tubing. The Corning MicroDEN system is jointly branded with Flaskworks and will be marketed, sold, and supported globally by Corning.
https://www.selectscience.net/product-news/corning-launches-corning-microden-automated-system-for-generating-dendritic-cells/?artid=49927
Fikst provides transitional manufacturing A traditional pain point in the product development process is the transfer to contract manufacturing. Fikst can smooth this process by producing 1-50 instruments and 1-5,000 consumables to allow you to have production units for data gathering, clinical trials, user feedback studies, or for evaluation by potential partners.
Fikst offers a wide range of capabilities from concept to manufacturing. We also frequently partner with industrial design and electrical engineering firms as required to meet the needs of a project.
Innovation
* Product Planning
* Brainstorming
* Intellectual Property Development
Engineering
* Engineering
* Design for Manufacturing and Assembly
* Injection Molding Part Design
* System Design
* Optical Design & Computer Vision
* Analysis & Simulation
Design Evaluation
* Prototyping (in house FDM, SLA and CNC)
* Force Testing
* Leak Testing
* Benchmarking
Manufacturing
* Documentation Packages
* Work Instructions
* OEM Sourcing
* Vendor Qualification
* Short-Run Assembly
* Optical Inspection
* Transfer to Contract Manufacturing
Fluidics
* Microfluidics
* Millifluidics
* CFD
Electronics Prototyping
* Microcontroller Integration and Firmware
* Motor Control
* Prototype PCB Design and Build
* Cable Assembly
* Touch Screen Integration
Representative Projects
* Point-of-care diagnostic instruments and cartridges
* Bioreactors that simulate in vivo conditions
* Devices for specialized pharmaceutical delivery and analysis
* Microfluidic particle generators
* Imaging systems for biological samples
* DNA processing instrumentation
* Automation equipment for heat sealing, filling and part forming
* High-speed rotating equipment for precision medical imaging
* Part and tooling design for very high volume multi-layer polymer packaging
https://www.fikst.com/capabilities/
Flaskworks Enabling Immunotherapeutics to Save Lives.
https://www.fikst.com/clients/
Lomustine’s lack of coverage doesn’t pave the way for DCVax, it’s just corporate greed. Some people aren’t going to be able to get the drug, and sadly, may die because of it.
Rogue drug maker first inflates the price of lomustine, then says No to Medicare coverage
July 16, 2021
Over the past year, we have witnessed the awesome power of American pharmaceutical and biotechnology companies.
With unprecedented speed, at least three different U.S. companies created vaccines that will significantly curtail the spread of a deadly global pandemic.
Yet, while some headlines nearly deified these pharma giants, a darker story about the power of American pharmaceutical companies was unfolding in the world of brain cancer.
At the start of 2021, oncologists and patients learned that the vital chemotherapy drug lomustine (abbreviated as CCNU and now marketed as Gleostine) will no longer be covered by Medicare because the drug company NextSource Pharmaceuticals—the sole manufacturer of the drug—has decided to withdraw it from the nation’s safety net insurance program.
This is the only known time that a company with a drug eligible for coverage under the Medicare Part D drug benefit has made the radical choice to leave the program.
This decision by NextSource and company CEO Robert DiCrisci is potentially catastrophic for brain cancer patients who, according to research from the National Brain Tumor Society, may now face bills between $1,500 and $3,000 every six weeks.
Those kinds of bills force families to make wrenching choices between medication and other essential living expenses. These are choices that families should never have to make.
Lomustine—then called CeeNU—was first introduced in 1976 and has been part of standard treatment protocols for many patients with malignant brain tumors for nearly half a century. It is one of only a small handful of treatment options for patients with a recurrence of glioblastoma, the most common and most deadly malignant primary brain tumor, and it has also been shown to improve overall survival for certain other types of brain cancers.
The drug is also used against other cancers. For example, it is a second-line option in the treatment of Hodgkin Lymphoma.
NextSource acquired the rights to the drug (off-patent) in 2013 and promptly rebranded it as Gleostine. Since taking over manufacturing rights, NextSource has become the single-source manufacturer of lomustine in the U.S., a position the company has exploited by consistently and exponentially raising the drug’s price (The Cancer Letter, Sept. 29, 2017; Nov. 8, 2019; Nov. 8, 2019).
The path forward demands that action be taken to reduce the risk posed to patients by single source manufacturers. No single CEO should hold the power to so tangibly and dramatically impact health outcomes for tens of thousands of Americans.
Today, NextSource’s list price for the highest dose of lomustine is some 1,900% higher than it was just eight years ago, when it was being manufactured and sold by Bristol Myers Squibb.
Media reports indicate that, in 2020, tens of thousands of Americans, including hundreds of patients at Duke University, were prescribed lomustine, generating—by even the most conservative estimates—tens of millions in annual sales for NextSource.
With no approved generic alternatives to lomustine, patients have been forced to absorb these extortionately high price increases. And, since the average age at diagnosis for glioblastoma patients is 65, this includes many Medicare patients who have Part D drug coverage under which they are responsible for up to 25% of the price of a brand-name drug.
Think this smacks of price gouging?
A bipartisan group of U.S. senators did. In 2018, Sens. Susan Collins (R-ME) and Catherine Cortez Masto (D-NV) and then-Sen. Claire McCaskill (D-MO) sent an inquiry to NextSource about market share and revenue after observing the precipitous price increase for lomustine. Only then did the company stop raising the price, but also they did not lower it.
Now, NextSource has gone even further.
By withdrawing lomustine from Medicare, patients who already had few good options have even fewer. A small number of low-income patients are eligible for financial assistance from NextSource, but everyone else is left to pay the exorbitant out-of-pocket cost, come up with creative cost-saving solutions with their medical care provider or, unimaginably, forego treatment.
Even for well-resourced cancer centers, it is proving very difficult to quickly source lomustine from suppliers outside the U.S., to say nothing of the additional administrative burden on already stretched medical office staff.
And, switching patients to another chemotherapy drug can not only impact treatment plans but can also subject them to a host of harsh side-effects if they do not tolerate the new treatment as well.
Importantly, the implications of NextSource’s choice do not stop at current brain cancer patients. Removing lomustine from Medicare coverage could derail progress on the development of desperately needed brain cancer drugs far into the future.
Lomustine is currently being used as a control arm in more than 30 clinical trials. Now, with insurance coverage being denied and the cost skyrocketing, some important trials are already having trouble enrolling and maintaining patients.
So, what does this all mean? In the short term, it means that oncologists, oncology trialists and other medical providers and researchers need to speak up for our patients and progress in our field.
NextSource’s actions shine a light on the stranglehold pharmaceutical companies have on patients, providers and our federal government, particularly its capability to impose reasonable limits on drug pricing.
Organizations like the Society for Neuro-Oncology and the National Brain Tumor Society are actively engaged with a wide range of stakeholders from Congress and the executive branch of the U.S. federal government to experienced manufacturers of generic drugs and even with NextSource themselves in a near-frantic effort to resolve this complex problem.
Our patients don’t have time to wait.
Physicians and advocates hope that NextSource will reconsider and come back to the table for the many patients and families who are right now depending on lomustine to extend their precious time together. The company should put profits below the progress of science in the field of brain cancer and commit to making lomustine available and affordable for clinical trials.
But, even if NextSource were to reverse itself and begin participating in the Medicare program again, there is still a fundamental issue that is much, much bigger than NextSource.
NextSource’s actions shine a light on the stranglehold pharmaceutical companies have on patients, providers and our federal government, particularly its capability to impose reasonable limits on drug pricing.
This one company’s actions can be seen as a sort of parable, a reminder that the all-powerful just might choose to wield their strength against the powerless. If one company can giveth, one company can taketh away.
The path forward demands that action be taken to reduce the risk posed to patients by single source manufacturers. No single CEO should hold the power to so tangibly and dramatically impact health outcomes for tens of thousands of Americans.
Our policymakers can make us all less dependent on the generosity or greed, as the case may be, of pharmaceutical company leaders. Our government should, at a minimum, consider options for incentivizing drug companies to consistently enter the market for rare diseases and produce different, more affordable versions of drugs even when the underlying agent is no longer under patent protection.
As NextSource plainly shows, until we effectively protect the most vulnerable, the most powerful can threaten us all.
https://cancerletter.com/trials-and-tribulations/20210716_7/
It’s a single certificate of GMP compliance that will name the manufacturer, and the site. (Sawston Business Park, Cambridgeshire, CB22 3JG, United Kingdom)
I’ve never seen a GMP compliance certificate that lists a CDMO, so I’m not sure if it will actually name Advent as the manufacturer, but I think we’ll find out very soon.
Agreed Dendream. Perhaps there is a misunderstanding about the “certification.”
The GMP compliance certificate issued to a pharmaceutical manufacturing facility by MHRA after conducting the inspection by MHRA inspectors is called the “Certificate of Compliance” or MHRA certificate for the concerned facility.
A certificate of Good Manufacturing Practice (GMP) is issued to a manufacturer if the outcome of the inspection confirms that the manufacturer complies with the principles of Good Manufacturing Practice.
Although the facility is in the UK, and the regulator is the MHRA, the inspection process is similar to the FDA’s as outlined here:
FDA Takes Quality Systems Approach to CGT Inspections
Jerry Chapman
November 12, 2020
In June, CBER Division of Manufacturing and Product Quality Facilities Reviewer and Investigator Ekaterina Allen spoke at the ISPE Biopharmaceutical Manufacturing conference about the current regulatory landscape for cell and gene therapy products. Part I covered her remarks about the current manufacturing challenges. This is the second part of the series and it looks at the most common agency observations made during inspections of cell and gene therapy manufacturing facilities by the quality system.
When an FDA inspection team performs inspection, it is done using a systems approach that has been developed by the agency. There are seven key systems that are looked at during CGT inspections:
* Quality
* Production
* Facilities and equipment
* Materials
* Laboratory control
* Packaging and labeling
* Donor eligibility (this is mostly for allogeneic products)
In every system, there are three elements that are evaluated: standard operating procedures (SOPs), training, and documentation. Depending on what type of inspection it is the scope is a little different. If it is the first inspection—a prelicensing inspection—the inspection team is trying to evaluate all the key systems. If it is a Team Bio inspection, they will look at the quality system and then pick and choose depending on how in-depth an inspection was planned and what they see during the inspection. . . . .
https://redica.com/pharma-fda-takes-quality-systems-approach-to-cgt-inspections/
Right flipper, I’ve seen that building information model before, and yes it shows what I’m talking about, but that could be considerably different than the current design.
Thanks Lykiri, really great DD. I wondered if any current staff from King’s College Hospital would be willing to migrate out of the city to the Sawston facility, so this key hiring of Cristina Trento, with her outstanding qualifications, is very encouraging news on a couple levels.
ex, you might want to read the article that you posted. EDEN is the single-use plastic parts that contain the fluids of the MicroDEN system, so what you’re saying makes no sense. The MicroDEN system can produce 20-25 million DC’s per batch, which is sufficient for 10 individual doses (of 2.5M) that were used in the clinical trial.
(Northwest Bio now refers to this system as the Flaskworks’ system because “MicroDEN™” is trademarked by Corning)
Yes, Advent’s single cleanroom in London can produce 4 or 5 batches a month, but it may be wrong to assume that it will be the same for the cleanrooms at Sawston, since Advent had them specifically designed knowing the initial startup production will use the manual process. Have you heard of isolators? If each process step, and each patient’s cells are isolated, it would be possible to “potentially” produce the 40+ batches per month that Northwest Bio has discussed in two cleanrooms. Installing isolators is expensive and normally wouldn’t make sense for a closed automated process, but for a prolonged interim manual step, it would make sense, and it may be what Advent has done to produce revenue and train new staff, while they work on the Flaskworks’ automated process.
The Flaskworks device as of the time they bought the company was only useful for pre-clinical research
M&A rife in manufacturing space, driven by big CDMOs and PE
by Dan Stanton
Thursday, August 19, 2021 7:35 am
The CDMO space is perceived as fragmented and particularly lucrative says GlobalData, with private equity (PE) firms and large established players investing heavily in the sector.
A report from data and analytics company GlobalData entitled ‘M&A in the Contract Manufacturing Industry: Implications and Outlook – 2021 Edition’ has found that dealmaking in the sector has been particularly rife over the past few years, predominantly led by PE firms and big contract manufacturing organizations (CMOs).
“Investors perceive the CMO industry as particularly lucrative,” Adam Bradbury, PharmSource Analyst at GlobalData, told BioProcess Insider.
He attributed the rapid rise of investment to the Tax Cuts and Jobs Act of 2017, which reduced corporation tax rates and made it more profitable to be a private equity firm. “During 2018-2020 the most common type of acquirer was private equity/venture capital (VC)/investment firms, which increasingly view the CMO industry as a prudent choice to provide a good return on investment.”
As such, money has flown into CMOs. Some examples include Recipharm, which was delisted from the stock exchange and became a private company owned by private equity firm EQT IX earlier this year; PCI Pharma Services, which saw Kohlberg & Company take a majority stake in 2020; and Cambrex Corp, which was acquired by global investment firm Permira Funds in 2019.
While the bulk of PE investment in the contract development and manufacturing organization (CDMO) sector focused on the small molecule side, Bradbury highlighted that biologic and multi-service offering CMOs represent some of the highest potential returns for investors. However, “there is a limit on the number of CMOs with biologics capabilities (compared to other service offerings) to acquire but the industry and investors do view these capabilities as high value, in particular for gene and cell therapy manufacture. “Private equity will continue to seek out biologics capabilities in future.”
Big CDMOs
According to Jim Miller, content advisor/consultant for DCAT, 32 CDMO acquisitions took place in the first six months of 2021. This comprised of 19 full company acquisitions, four acquisitions of business units divested by their parent companies, and nine facility acquisitions. Of these, two were done by private companies, five by PE firms, and eight by PE-backed companies. The bulk (17) were undertaken by public companies.
Some by the bigger players in the CDMO and wider life sciences space drove these acquisitions.
Catalent acquired plasmid DNA maker Delphi in February, Promethera’s cell therapy manufacturing subsidiary Hepatic Cell Therapy Support (HCTS) in May, and stem cell maker RheinCell Therapeutics in June.
New, but heavily-funded, player Resilience bought assets from Therapure Biopharma, a facility from Sanofi-Genzyme, and CDMO Ology Bioservices in the first half of the year, and continues on its M&A rampage paying $110 million for Bluebird bio’s North Carolina lentiviral vector manufacturing facility last month.
Such deals are expected to continue, said Bradbury, with both big CDMOs and others picking up the smaller players.
“There are many small private CMOs operating in the CMO space. However, the industry is dominated by large CMOs already, with this group gaining a large proportion of commercial stage contract manufacturing service agreements,” he told us.
“Small CMOs can often lack capabilities to produce innovative products and this often restricts them to manufacturing relatively low value products. We expect large CMOs to continue to acquire other CMOs either to enhance their capabilities or their scale, to essentially aim to provide high value advanced technologies or full service offering for clients.”
Bioprocess giants
Another sector flexing its buying prowess are traditional bioprocessing companies.
Thermo Fisher led the charge when it jumped from a life sciences tool and equipment vendor into the CDMO space in 2017, through the $7.2 billion acquisition of Patheon. Since then, the multinational has bought several other CDMOs and manufacturing assets, including paying $1.7 billion for gene therapy CDMO Brammer Bio in 2019. Since the beginning of the year, the firm has acquired divested assets from Novasep and expanded into the contract research organization (CRO) space through the $17.4 billion acquisition of PPD.
Meanwhile, fellow bioprocess giant Danaher – which owns both Cytiva and Pall – is seemingly shifting focus to the pureplay CDMO space, buying Aldevron for $9.6 billion in June.
According to Bradbury, the synergies between different parts of these business could place these bigger and more diverse players in enviable positions, especially as the marketed landscape for drugs continues to shift towards advanced therapies.
“Many small pharma companies will struggle to manufacture these products, so opportunities for CMOs operating in that space will continue to rise,” he said. “CMOs which can afford to acquire or develop cell and gene manufacturing capabilities will be looking to do so as even the largest pharma companies find it difficult to develop this relatively novel class of product.”
https://bioprocessintl.com/bioprocess-insider/deal-making/ma-rife-in-manufacturing-space-driven-by-big-cdmos-and-pe/
FYI: Biotech Week Boston September 20-30, 2021
Delivered As a Hybrid Event Both Digitally and at Boston Convention and Exhibition Center
https://informaconnect.com/biotech-week-boston/
THE CELL, GENE & IMMUNOTHERAPY EVENT FOR GROUND-BREAKING BIOPROCESSING, MANUFACTURING AND SUPPLY CHAIN STRATEGIES
Speakers:
SHASHI MURTHY, PHD
Founder & CTO at Flaskworks
Panel Discussion: Exploring the Massachusetts Biotech Ecosystem; Fostering Innovation, Spinning out, & Maximising Growth Potential
* Reviewing the Incubator model and advantages of going down this path.
* Best practices for spinning out from academia
* Considering manufacturing capacity early to secure investment and maximise growth potential.
* Working with corporate partners to move towards commercialization
Exhibition Hall Content
Thursday, 23 September 2021 10:30am - 11:15am
EST/EDT (Eastern Daylight, GMT-4)
https://informaconnect.com/cell-therapy-bioprocessing/