Monday, April 26, 2021

Very Brief Blog: A flurry of new policy items in precision oncology

Monday April 26, 2021 - A small flurry of public policy documents or articles relevant to precision medicine.

FDA Reviewing a Set of ImmunoOncology Drugs in Advisory Meetings

This week the FDA is holding panels on a substantial cohort of oncology drugs which each have indications in the "limbo" between somewhat aging accelerated approvals and conversion to full approvals.  

Recall that accelerated approvals may be based on single-arm trials and surrogate biomarkers (like tumor response), as long as there is unmet need and the drug seems promising.   

FDA Places Article on Accelerated Approvals in the NEJM

Timed to the FDA meetings, see an article in NEJM by Julia Beaver and Richard Pazdur; Pazdur is the longtime head of Oncology at FDA.   Here.  The article is called " 'Dangling' Accelerated Approvals in Oncology."   

A table includes 3 "dangling" approvals for atezolizumab, 4 for pembrolizumab, 2 for nivolumab, and 1 for durvalumab.   

Authors note that a failure of the follow-up confirmatory trial need not be fatal, but the circumstances need to be evaluated carefully when that occurs.   In addition, the evolving status of "unmet need" for that indication needs to be evaluated as well.   

I consider this a precision medicine issue; most accelerated approvals are in oncology and of that, many in immunooncology.   The status and performance of immuno-oncology biomarkers (TMB, PDL1, MSI, and others) remains very much in evolution (see section ImmunoOncology Biomarkers at bottom.)  

ICER Releases Stringent Suggestions to Improve "Accelerated Approval"

Separately, see a brand new 40-page white paper by ICER on "Strengthening the Accelerated Approval Pathway," which mostly takes the form of describing holes and weaknesses in the accelerated approval pathway.   Here.   

Again, it's a precision oncology issue in as much as many accelerated approvals are in oncology and often involve biomarkers or surrogate outcomes.  Topics covered in the 40-page review include:

  • Manage uncertainty better:  (1) Better Surrogate endpoint use; (2) Threshold for "meaningful change' in surrogate endpoint [e.g. 30% change in the endpoint, not 8%]; (3) Issues with lack of randomization (one arm studies).  
  • Process issues include: (1) delayed confirmatory studies, (2) Inconsistent decisions [one drug to the next]; (3) high prices of drugs with only conditional/accelerated approval.
  • Proposals for FDA's adoption include:  Use standard templates for info [promotes comparability and uniform processes in review]; greater use of RCTs instead of single-arms; robust requirements to finish confirmatory trials; sunset rules.
  • Payment ideas include:   Mandatory rebates for drugs sold under "accelerated approval," or sale only at "marginal cost price" or under "outcomes based contracts."   (Note that laws for payment issues are generate separate from laws for FDA approval issues.)
Legislation Tightens Drug Definitions

At the White House, Biden signs two bills relative to drug policy, one of which (S.415) tweaks the definition of "active moiety" which relates to new chemical entities (and their privileges) in FDA law.  Here.  How to get bills passed today?  This one had a "unanimous consent" action in the Senate in March and quick voice vote in the House.

Combining Endpoints in New Ways - Surrogate, Process, Outcome

Any time we measure biomarkers, we measure against some endpoint, so how rigorous is the endpoint?  

Regarding endpoints, we're use to composite clinical endpoints like "stroke or death."   What about combining process or other endpoints?   See an essay at Endpoints News by Camarero that recommends combining oncology objective response rate and duration-of-response (ORR/DOR) into a composite endpoint that would have its own rules and acceptance as a benefit.  Here.   
  • (I recall seeing a similar theme in a paper on better antibiotics outcome measures, combining two different process measures at once, see Evans et al., 2015, combining the "DOOR" and "RADAR" rankings into one antibiotics outcome measure - here. See also op ed by Molina & Cisneros).

ImmunoOncology Biomarkers

Graphic:  PubMed Hits for "Immunoonology + Biomarkers," 2010-2020.  See an open-access 2020/2021 reviews, here, here.