Facet Life Sciences Quarterly Update Q1 – 2024

FACET ALL HANDS MEETING – NEW ORLEANS STYLE
Annually, Facet’s entire all-remote team meets face to face for an extended weekend of fun, team building, and strategizing, usually in January. This year was no different with the team haunting the French Quarter in New Orleans.  We all enjoyed the Pirates Walking Tour of the French Quarter and our tour on the steamboat Natchez as part of the weekend.

FACET HELPS SMALL ORGANIZATION HOLD SUCCESSFUL FDA MEETING
Small organization reaches FDA agreement on BLA requirements for novel diagnostic in Type C meeting.  Facet often works with organizations developing novel and innovative products that have no regulatory precedent.  When this occurs, it is necessary to have frequent communications with FDA to ensure the most rapid and cost-effective development possible.  Facet worked with a small company struggling to come to agreement with FDA on the required efficacy and safety data needed for a regulatory approval of their novel biological diagnostic imaging agent.  Facet provided overarching strategic guidance and helped the company prepare for the FDA meeting.  As part of the meeting, there was an extensive discussion of the Sponsor’s planned pivotal studies, desired indication, and use of supporting data from the literature.  Several agreements were achieved, and the Sponsor received important, actionable information about FDA’s position on the required safety database, safety monitoring, and possible indications for the product.

FACET HELPS SECURE RELEASE FROM POSTMARKETING REQUIREMENTS
Facet sets the strategy and drafts a successful argument for PMR release. A very large ex-US company received FDA approval several years ago for a novel pediatric product for an unmet medical need.  The approval letter outlined several pharmacokinetic postmarketing study requirements (PMRs).  For a variety of reasons, the product remained unmarketed for several years.  The company recently divested the product to a small ex-US company that wanted to bring the product to patients in need.  Facet and the company prepared a sound and scientific justification that was partially based around the ethical concerns of PK testing in children FDA guidance, Ethical Considerations for Clinical Investigations of Medical Products Involving Children (September 2022) supporting the release of the postmarketing requirements.  After FDA’s review, all PMRs were lifted and the company is now preparing for commercial launch.

Chinese Biotech In the Spotlight
Over the last decade, small, medium-sized, and even large biopharmaceutical companies have come to rely on inexpensive manufacturing and nonclinical product development support from Chinese organizations.  However, since COVID, this offshoring approach to save time and money has received greater scrutiny.  From US government sources (including FDA) to industry working groups (e.g., Bio), to major political news outlets, it seems that everyone is talking about the limitations and risks of developing and manufacturing products in China.  National security concerns top the list, including risks associated with arming the Chinese government with genetic and health information of Americans.  However, issues around IP protection, mandatory sharing of technology with the Chinese government, and even IP theft have many companies shying away from development in China.  Finally, data quality and data integrity issues have led Sponsors to have to re-run nonclinical and clinical studies to satisfy FDA requirements.  We have been asked by many of our clients whether they should be concerned about offshoring CMC support and nonclinical studies (including planned, ongoing, or recently completed studies with WuXi) to China.  Sociopolitical and IP issues aside, Facet experts have seen FDA readily accept CMC, nonclinical, and clinical data generated by Chinese organizations (including WuXi) to support INDs and marketing applications (NDAs and BLAs).  In line with Facet’s counsel to our customers, we expect that FDA will continue to accept data from Chinese organizations (and really any third party, regardless of geographic location) as long as Sponsors carefully oversee third party support and ensure that what is provided complies with global and local (FDA) regulations and guidances.

DANA BLUE APPOINTED TO AMWA 2024 ANNUAL CONFERENCE COMMITTEE

For the second year in a row, Dana Blue, Facet Strategic Program Champion has been asked to serve on the AMWA annual conference committee.  The role of committee members involves supporting the development, promotion, and evaluation of educational programming at the 2024 Medical Writing & Communication Conference that is being held in New Orleans, Louisiana, from October 23-26, 2024.  Along with the other committee members, Dana will be reviewing proposals, attending conference calls, and helping to create a balanced and engaging educational experience for annual meeting attendees. Congratulations, Dana!  Thank you for your continued contributions to the industry!

FACET’S REGULATORY INNOVATION HUB HIGHLIGHTS 2 NEW CBER APPROVED PRODUCTS
By Dr. Jason Mercer, RAC
On March 7, the CBER updated the list of biologic products that have been approved in 2024.  So far, there have been two:

• Casgevy (exagamglogene autotemcel (exa-cel)) from Vertex Pharmaceuticals was approved in January for the treatment of patients 12 years and older with sickle cell disease with recurrent vaso occlusive crises with or without transfusion-dependent β-thalassemia.
• Amtagvi (lifileucel) from Iovance Biotherapeutics was approved for treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.

Both products represent exciting advances in medicine.  Casgevy is the first gene therapy approved to treat patients with sickle cell disease and joins the short list of fewer than 20 approved gene therapies.  Amtagvi is the first FDA-approved tumor-infiltrating lymphocyte (TIL) based therapy.  Amtagvi uses lymphocytes harvested from a patient’s tumor and expanded ex-vivo before re-introduction into the patient to target the tumor.  This is a novel approach for immune-oncologic cell therapies as the other currently approved products utilize ex-vivo introduction of a transgenic T cell receptor into T cells harvested from the patient to target the tumor.  We look forward to more advanced therapy approvals for treatment of rare diseases during the coming year!

RARE DISEASE DAY – March 1, 2024
FDA’s virtual public meeting was another success!   If you missed it, you can still view the recorded event on YouTube here:
https://www.youtube.com/live/j6H1jeqdm4I?si=xViz2CgxQbujIY39

Facet’s strategic and tactical regulatory affairs, statistics, regulatory writing, and commercialization experts lead small organizations to faster and more efficient product development, US registration, and commercial launch.

Facet’s regulatory experts can help you decide if you are ready to meet with the FDA and/or submit the IND for your product.  Let us help you minimize risk and improve the probability of success in gaining agreement with FDA in your formal meetings and getting IND clearance.

Facet statisticians provide necessary and important expertise in FDA meetings to answer clinical trial design, methodology, sample size, power, and data interpretation questions.

A Market Understanding can help you establish the right niche for your product and help you to focus and streamline development.  Even if you are not planning to take your product to US approval, a robust Market Understanding adds value to your asset and helps you communicate your product’s value with potential acquirers/partners.

FDA Urges Sponsors to Conduct Third Party Validations Prior to Submission – Since the start of 2024, there have been several high-profile cases in which unreliable, incorrect, and even fabricated data have been generated by third parties.  This includes, but has not been limited to, the manufacture of drug substance, drug product, clinical trial data collection, and clinical trial statistical results and output.  The FDA has urged Sponsors to carefully evaluate the third parties and to independently verify third party results before submitting to the FDA.  For over a decade, Facet has worked with Sponsors and third-party auditors to ensure support provided by partners meets or exceeds FDA requirements.  Facet’s strategic statisticians can provide important third-party validation of nonclinical and clinical trial results so that you can have confidence in the trial results and conclusions when you submit your final study reports.  If you have third party validation needs, contact Facet today!

Updates on FDA’s LDT proposed rule  – Results from laboratory developed tests (LDTs) provide physicians and patients with important health information on which medical decisions are made.  As a result, FDA and other stakeholders have argued that it is critical that the results of these tests are accurate and reliable.  Historically, LDTs have been regulated predominantly under the Clinical Laboratory Improvement Amendments (CLIA) of 1988, and to a lesser extent, under enforcement discretion by FDA under the Medical Device Amendments.  LDTs undergo CLIA certification (specific quality standards, and accuracy and reliability evaluations) and the Centers for Medicare and Medicaid Services (CMS) are responsible for CLIA certification enforcement.  In 2010, FDA expressed concerns that LTDs were becoming more widely used and complex.  A few noteworthy cases of unnecessary surgeries resulting from LDT inaccuracies (false positives for ovarian cancer blood markers as discussed in Miller et al., 2024) led FDA to argue that CLIA certification was no longer adequate to manage the risk to patients.  FDA urged Congress to give FDA sole authority (and financial support) to regulate LDTs.  In 2020, the Verifying Accurate, Leading-edge IVCT Development (VALID) Act was proposed to create a new, LDT- and IVD-specific regulatory framework, however, the VALID Act has yet to be passed by Congress.  In September 2023, FDA got tired of waiting and proposed a draft rule that LDTs and IVDs would be regulated as medical devices under the Federal Food, Drug, and Cosmetic Act.  The announcement was met with widespread regulatory, legal, financial, and practical criticism.  On March 21, 2024, these criticisms were further discussed in the House Energy and Commerce subcommittee hearing.  In an interesting stroke, notice was made public that the Office of Management and Budget received the draft final LDT rule on March 1 (prior to the subcommittee hearing), suggesting that FDA is done incorporating feedback and has moved to have to the final rule published.  If you have an LDT/IVD currently in use under CLIA certification or you are developing an LDT/IVD, contact Facet today to discuss how you can comply with FDA’s proposed (soon to be final) LDT rule.

Miller MB, Watts ML, Samuel L. FDA’s proposed rule for the regulation of laboratory-developed tests. J Clin Microbiol. 2024 Feb 14;62(2):e0148823. doi: 10.1128/jcm.01488-23. Epub 2024 Jan 11. PMID: 38206042; PMCID: PMC10865810.

FDA eSTAR for 513(G) Submissions  – The electronic Submission Template And Resource (eSTAR) is an interactive PDF form that facilitates the preparation of a complete medical device submission.  For some time, Sponsors have been required to use the eSTAR for 510(k) submissions (unless exempted), 510(k) combination product submissions, and Dual 510(k)/CLIA Waiver IVD submissions.  In fact, Facet was one of the first to use the eSTAR for a combination device-led application!  Use of the eSTAR has been and continues to be voluntary for De Novo, PMA, and Pre-Submissions.  For the first time ever, FDA is now encouraging (but not requiring) Sponsors to use the eSTAR for 513(g) requests for information.  Facet strongly encourages the use of the eSTAR whenever possible because it increases Sponsor efficiency through automation, ensures Sponsors prepare and submit a robust and complete application, and facilitates timely review by FDA.  Our experience with the eSTAR has led to important tips and tricks that can help you when you are preparing medical device submissions to FDA using the eSTAR.

Total ESG submissions to FDA Jan – Mar 2024:  over 30!

Early-stage development highlights:  led 2 formal FDA meetings, over 25 IND amendments (e.g., new protocols/amendments, CMC updates, nonclinical study reports, annual reports, safety reporting/DSURs); prepared several gap analyses and regulatory development plans; ongoing review of public-facing information (e.g., websites, flyers, conference presentations) for investigational products; responded to numerous FDA information requests; secured 1 rare pediatric disease designation; secured 1 breakthrough designation; clinical trial simulations to improve trial design and probability of success; third party validation of CRO clinical trial results.

Lage-stage development highlights: prepared Phase 2 and 3 clinical regulatory strategies; used statistical modeling and simulations to design Phase 3 clinical trials for 2 NCEs; active regulatory submission planning for 2 NDAs; designed and authored several protocols and clinical study reports; maintained CT.gov postings; actively engaged in investment/funding partnership support; and ongoing ad promo strategy and document review.

FDA eSTAR for 513(G) Submissions  – The electronic Submission Template And Resource (eSTAR) is an interactive PDF form that facilitates the preparation of a complete medical device submission.  For some time, Sponsors have been required to use the eSTAR for 510(k) submissions (unless exempted), 510(k) combination product submissions, and Dual 510(k)/CLIA Waiver IVD submissions.  In fact, Facet was one of the first to use the eSTAR for a combination device-led application!  Use of the eSTAR has been and continues to be voluntary for De Novo, PMA, and Pre-Submissions.  For the first time ever, FDA is now encouraging (but not requiring) Sponsors to use the eSTAR for 513(g) requests for information.  Facet strongly encourages the use of the eSTAR whenever possible because it increases Sponsor efficiency through automation, ensures Sponsors prepare and submit a robust and complete application, and facilitates timely review by FDA.  Our experience with the eSTAR has led to important tips and tricks that can help you when you are preparing medical device submissions to FDA using the eSTAR.