Outlaw

Health insurance coverage in the USA is declining, driven by the expiration of enhanced Affordable Care Act (ACA) subsidies and post-pandemic Medicaid unwinding. Millions are dropping out of the market due to unaffordable premiums, while those who retain plans face narrower networks, stricter coverage denials, and higher out-of-pocket costs.

The decline in US health insurance coverage is a multi-layered crisis defined by three core issues:

Expiration of ACA Subsidies: The termination of enhanced premium tax credits caused premiums to skyrocket for millions. Consequently, an estimated 5 million customers are projected to exit the ACA marketplaces, with significant drops in monthly enrollment already being tracked state-by-state.

Medicaid Unwinding: The end of pandemic-era continuous enrollment rules resulted in massive Medicaid disenrollment, driving the first increase in the uninsured rate in recent years.

Rising Employer Costs: The soaring cost of employer-sponsored plans (averaging roughly $27,000 annually for families) has caused the percentage of small firms offering health benefits to drop. Meanwhile, approximately one in five privately insured adults reports coverage denials for doctor-recommended care.

You can track the state-by-state breakdowns of these changes using the KFF Uninsured Population Report or explore the Commonwealth Fund 2025 Affordability Survey regarding denied care.

Dear Drs. xxxxxxxxxxxx and xxxxxxxxxxxxxxx,

I write to inquire whether the Journal of Clinical Epidemiology would consider a Perspective manuscript entitled xxxxxxxxxxxxxxxxxxxxxxxx.

The manuscript (~5,100 words, 37 references) addresses a problem that experienced clinical epidemiologists and HTA reviewers recognize but that the published literature has been reluctant to name directly: when Phase 3 trials produce overall survival benefits measured in weeks to a few months — statistically significant, clinically marginal — the center of gravity in value assessment shifts to forward-looking economic models that extrapolate survival curves decades beyond the observed trial window. At that horizon, the distinction between a conservative, empirically grounded projection and a flagrantly optimistic one is not self-evident from the model output. Both can be produced using individually defensible methods. Both will pass peer review. Only one approach will be systematically favored by the pharmaceutical sponsors preparing regulatory submissions.

This manuscript identifies where that asymmetry lives. It reverse-engineers five core analytical domains — parametric survival extrapolation, partitioned survival model construction, Markov state transition engineering, utility and QALY construction, and healthcare resource utilization modeling — and in each case distinguishes the conservative, realistic application from the optimistic, advocacy-oriented one. The analysis is not a theoretical taxonomy. It uses worked numerical examples and recent Phase 3 trial data across four tumor types to show concretely how selection among statistically equivalent model specifications produces lifetime survival estimates that diverge by years, and how those divergences compound across domains into cost-effectiveness conclusions that bear little resemblance to what the trial actually demonstrated.

The argument is structural, not accusatory. This is not an allegation of fraud or bad faith, and the manuscript does not contest the clinical efficacy of any compound discussed. The claim is that the dossier production process contains well-defined leverage points that systematically favor optimistic extrapolation, that these leverage points are individually defensible and collectively distorting, and that HTA bodies and payers currently lack the auditing vocabulary to identify them reliably. The manuscript closes with four low-cost, implementable transparency reforms — pre-specified survival model selection criteria, independent extrapolation, OS maturity thresholds before PFS-based models are accepted for formulary decisions, and mandatory disclosure of all fitted parametric specifications — that address the problem without imputing misconduct.

The author is an independent scholar and Director of Health Outcomes Research and Causal Evidence at the Institute for Neuroplasticity Research in Oak Ridge, Tennessee, with direct prior experience in pharmaceutical HEOR and survival analysis across hematologic oncology and solid tumor treatment compounds at major biopharma firms and smaller start-ups. He has no current financial relationship with any pharmaceutical firm or ongoing oncology trial. That independence is material: the manuscript carries no industry sponsorship or trial affiliation, and its argument does not need to accommodate any sponsor’s dossier interests.  The Journal of Clinical Epidemiology is one of the few venues whose editorial tradition — including its sustained engagement with surrogate endpoint validity, research bias, and the translation of trial evidence into policy — makes it the right home for this article.

I would be pleased to submit the full manuscript for your consideration as a Perspective.

Thank you for your time.

Michael A. S. Guth
Michael A. S. Guth, Ph.D., J.D.
Director, Health Outcomes Research & Causal Evidence
Institute for Neuroplasticity Research
[email protected] | (865) 483-8309 www.linkedin.com/in/populationhealthmanagement

“Pioneering spirit should continue, not to conquer the planet or space, but rather to improve the quality of life.” — Bertrand Piccard

Clinical Evidence Generation & Publications Track Record:

• https://authors.elsevier.com/a/1n0uP4r9Rkz1l6  Target validation case study: GPR149 – Drug Discovery Today (April 2026) [Elsevier-provided link for free access/download through June 19, 2026]

Adeno-associated virus serotype 9 (AAV9) is highly valued in gene therapy because it can cross the blood-brain barrier. It is primarily used to treat monogenic neurological and neuromuscular disorders, most notably Spinal Muscular Atrophy (SMA).

AAV9 vectors deliver functional genetic material to replace or suppress faulty genes. Approved treatments and advanced clinical trials using AAV9 include:

Spinal Muscular Atrophy (SMA): The FDA-approved therapy Zolgensma (onasemnogene abeparvovec-xioi) uses AAV9 to deliver a functional copy of the SMN1 gene to motor neurons in children under two years old.

Pompe’s Disease: AAV9 gene therapies are in late-stage clinical development to deliver a working GAA gene to infants and patients, improving motor function and cardiac outcomes.

GM1 Gangliosidosis: Intravenous AAV9 gene therapy is in clinical trials (such as AAV9-GLB1) to address the central nervous system degeneration and enzyme deficiency in this rare lysosomal storage disease.

Other Neurological & Rare Diseases: AAV9 is actively being investigated in clinical trials for conditions such as Giant Axonal Neuropathy, Rett Syndrome, Friedreich’s Ataxia, and CLN7 Batten Disease.