Statistically and Clinically Significant Paths to Value Proposition

Ira Studin, PhD, President, Stellar Managed Care Consulting

When health plan and pharmacy benefit manager (PBM) clinical decision-makers review a Phase II or Phase III product profile, they can’t evaluate the agent’s value proposition because there is no price. But they can evaluate its quality. This is where statistical and clinical significance comes into play.

In multiple market research studies tasked with reviewing product profiles, a frequent criticism is that data are statistically significant but not clinically significant.

Statistically significant means there is a very high likelihood the drug impacted its target. But if data are not clinically significant, it means the benefit is relatively modest, possibly even inconsequential for patients.

When manufacturers design a clinical trial regime to study their drug candidate’s performance, as important as it is to home in on variables permitting the cleanest possible determination of statistical significance, the underlying priority is to evaluate results for clinical significance.

In the same way there is no value proposition without a
price, there is no path to a strong value proposition without clinical significance.

Outcomes and surrogate markers

Ideally, clinical trials produce outcomes data that attest to the clinical significance of a drug.Classic outcomes include survival rate, hospitalization, symptoms, activities of daily living, and hospitalization.

However, a major limitation in clinical trials is that time is typically insufficient for generating data capable of demonstrating statistical significance for the intended outcome. Consequently, manufacturers measure impact on surrogate markers as the primary endpoint.

Changes in surrogate markers occur earlier, more frequently, and can be easier to detect than clinical outcomes.The challenge is that often, a statistically significant relationship between drug and surrogate marker is insufficient for achieving clinical significance.

Surrogate marker experience

Dystrophin level, a surrogate marker for muscle health, has been used as the clinical target for treating Duchenne muscular dystrophy. Payers will frequently mention that even though treatments impacting dystrophin levels achieved statistical significance, benefit for patients is not clinically significant.

As one pharmacy director from a regional health plan put it: “You can look at any of the exon skipping therapies that have only shown improvement in dystrophin levels; none of them have ever shown any improvement in actual clinical outcomes.”

Similarly with enzyme replacement therapy there is considerable uncertainty that statistically significant effects translate to clinically significant results: organ damage may persist even if enzyme levels normalize; patients may still experience disease progression despite increased enzyme activity; and measured enzyme levels in the blood don’t necessarily reflect activity in target organs.

Flipping the table on surrogate markers, fetal hemoglobin is highly correlated with clinical significance in treating sickle cell disease. Drawing on comments from a medical director for a national health plan: “the new gene therapies produce fetal hemoglobin; they don’t produce adult hemoglobin. But it’s been known for years that if patients reach a certain percent of fetal hemoglobin in the blood they would not sickle, not have vascular occlusive crises and should do well.”

Two more examples: lowering hemoglobin A1C and LDL are both widely accepted surrogate markers for drugs that treat diabetes and hypercholesterolemia. In each case, statistically significant reductions that get patients to a target range represent clinically significant results.

Trial planning

While time creates inherent limitations for delivering meaningful outcomes data from a Phase III trial, the importance of ensuring a high degree of certainty that the surrogate outcome aligns with clinical significance cannot be overestimated.

As manufacturers develop their clinical trial program for future products, at least part of the strategy that informs the science should address how well statistically significant results with the surrogate endpoint predict clinically significant results for patients.

Suffice it to say, the greater that success, the greater the likely benefit for patients, the greater the premium price potential for products and the greater the prospect for a value proposition that works against payers adding barriers to patient access.

Ira Studin, PhD, is President, Stellar Managed Care Consulting.
He can be reached at istudin@stellarmc.com.