How many therapies that would have cured diseases, or extended lives, or limited side effects or pain, are not available because their champions cannot afford the often astronomical costs of Phase 1, Phase 2, and Phase 3 clinical trials? Nobel-Prize-winning economist Milton Friedman favored eliminating the F.D.A., but as a more politically palatable step-in-the-right-direction, favored limiting F.D.A. mandates to approving safety through Phase 1 and Phase 2 clinical trials (and no longer mandating proving efficacy through Phase 3 clinical trials, which usually cost much more than Phase 1 and Phase 2 clinical trials, combined). Perhaps an even more politically palatable, but tinier, step-in-the-right-direction is proposed in the commentary quoted below. This modest step would allow in Phase 3 clinical trials the use of less costly biomarker “surrogate end-points” in place of far more costly clinical end-points, such as years of added life. In the case discussed in the article quoted below, the surrogate end-point was the percent of arginine in the patient’s blood.
(p. A17) Discovering treatments for rare diseases is a daunting task. Recruiting even a few dozen people for a clinical trial requires doctors and drug companies to identify a large share of the patient population. And since the market for such therapies is necessarily small, it’s nearly impossible to attract investment. So when news emerged about Aeglea BioTherapeutics’ ARG1-D therapy pegzilarginase, we could hardly believe it. Pegzilarginase is an enzyme engineered to lower the body’s levels of arginine. The randomized placebo-controlled study of pegzilarginase included 32 patients with ARG1-D.
The results speak for themselves. The amount of arginine present in blood plasma declined by 80% for patients on pegzilarginase. After only six months, 90.5% of patients who received pegzilarginase had normal arginine levels, and this was sustained over time. The data also suggested progressive improvements in motor function compared with a placebo. And most patients tolerated the therapy quite well.
These numbers were jaw-dropping. Which is why the FDA’s decision is incomprehensible.
The FDA even refused to look at Aeglea’s data. Instead, the agency demanded that the firm compile additional data suggesting pegzilarginase will produce a clinical benefit in addition to eliminating excess arginine. But for ARG1-D and other rare diseases, measuring clinical outcomes can take years, while measuring biomarkers likely to produce clinical benefits can take weeks.
. . .
Evaluating clinical benefits could force sick patients to remain in placebo groups for months. That the FDA would put its rigid rules before the convincing data we already have is unethical. If the FDA doesn’t correct its error soon, patients with ARG1-D will lose their best chance at full, productive lives.
For the full commentary see:
(Note: ellipsis added.)
(Note: the online version of the commentary has the date September 26, 2023 [sic], and has the same title as the print version.)