Real Time Coverage Morning Session on Precision Oncology: Advancing Precision Medicine Annual Conference, Philadelphia PA November 1 2024
Reporter: Stephen J. Williams, Ph.D.
Notes from Precision Medicine for Rare Diseases 9:00AM – 10:50
Precision Medicine and markers Cure models vs disease models Dr Ekker from UT MD Anderson
- UT MD Anderson zebrafish disease model program now focusing more on figuring the mechanisms by which a disease model is reverted to normal upon CRISPR screens
- Traditional drug development process long and expensive
- 2nd in class only takes 4 years while 3rd in class drugs take only 1.5 years
- Health-in-a-fish: using a CRE system to go from disease to normal
- The theory is making a CRE or CURE avatar; taking a diseased zebrafish and reverse engineering the disease genome
- He used transposon based CRE mutational mutants with protein trap and 3’ exon trap (transposon based mutagenesis)
- He reverted the diseased gene by CRE
- He feels that can scale up to using organoids to develop more cure based models
FDA Christine Nguyen MD regulatory perspective of framework of drug approval for rare diseases
- 1 in 10 Amercians have rare diseases; 70% genetic and half are children
- Due to Orphan Drug Act in 2023 half of novel drugs approved for rare diseases
- CDER and FDA 550 unique drugs for over 1000 rare diseases
- Clinical and surrogate validated endpoints are important for traditional approvals
- For accelerated approval need predictive surrogate endpoint of clinical benefit
- For accelerated approval needs completion of a confirmatory trials so FDA has new authority under FDORA; FDA can dictate trial milestones
- Candidate surrogate endpoints: known to predict (validated) for traditional approval but reasonably likely to predict for accelerated approval
- Does surrogate endpoint associated with a causal pathway? Also important to understand the magnitude of benefit so surrogate should be quantitative not just qualitative
- RDEA is a series of 3 public workshops at FY2027 to promote innovation and novel endpoints and guidance
Frank Sasinowski FDA regulatory flexibility beyond One Positive Adequate and Well Controlled Trial
- As we move to rare diseases we may only have one well controlled study so FDA feels we need new regulatory frameworks and guidelines especially for rare disease clinical trails especially with precision medicine
- Accelerated approval does not mean your evidence is any less stringent that traditional approval (only difference is endpoint but quality of evidence the same)
- Confirmatory evidence is a primary concern
- In 2021 FDA coordinated with the two divisions CBER and CDER
- Sometimes a primary endpoint shows positive benefit but secondary endpoints may not; FDA now feels that results from one well designed AWC gives confirmatory evidence
- FDA can be flexible by taking in consideration the quantity and quality of confirmatory evidence and the totality of evidence
- So pharmacology studies, natural history etc. can be enough
- For a drug like Lamzede for mannosidosis there were no positive endpoint studies or for ADA SCID disease there was other compelling evidence
- The FDA does have flexibility when it comes to advanced precision medicines and ultr rare diseases
10:50 Do we Really Need Liquid Biopsy? A Panel Discussion on the Issues Hampering the full Adoption of Liquid Biopsy
- In Mexico leading cancer is colorectal but only have the FIT test and noone except one organization who issupplying health access
- Access to precision medicine is a concern: the communication between the patient, who is pushing this more than healthcare, needs to be coordinated better with all stakeholders in care
- We also need to educate many physicians even oncologists (like in Virginia) a better understanding of genetics and omics
- FT3 consortium does testing to therapy (multistakeholder group comprised of patient advocacy groups); focus on amplifying global efforts to increase access; they are trying to make a roadmap to help access in other countries; when it comes to precision medicine it is usually the nurses that are aksing for training because they are usually the first responders for the patient’s questions
- In rural areas just getting access to liquid biopsy is a concern and maybe satellite sites might be useful because the time to schedule is getting worse (like 3 or more months)
- A recent paper showed that liquid biopsy may actually perpetuate health disparities and not ameliorate them
- BloodPAC: there are barriers to LB access and adoption so consortium felt that there were many areas that need to be addressed: financial, access, disparities, education
- ctDNA to define variants was the past focus; there is growing realization that there are representatives populations in your R&D studies
- Submission of data to BloodPac is easier to do for tissue not for liquid biopsy; there is lack of harmonization across many of these databanks
- Reimbursement: is a barrier to access for liquid biopsy
- Illumina: challenge finding clinical utility for payers; FDA approval is not as hard; show improved outcomes for patients; Medicare is starting to approve some tests but the criteria bar keeps changing with payers;
- How do we leverage the on-market data to support performance of your diagnostic test or genomic panel
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