Copyright STAT
Something remarkable, and controversial, is unfolding in American medicine. The Food and Drug Administration says it is fast-tracking leucovorin, a long-established drug, for potential use in treating cerebral folate deficiency, a condition connected to the presence of folate receptor autoantibodies estimated to be present in up to 76% of children diagnosed with autism. Like many parents of children with autism for whom there are no other treatment options, I had asked my child’s physician about prescribing leucovorin off-label after hearing about it on Facebook groups and other social media. The excitement surrounding leucovorin, or folinic acid, isn’t unfounded. Small clinical studies have shown improvements in language, communication, and adaptive behavior among children with autism, particularly those with folate receptor autoantibodies that block folate transport to the brain. The biological rationale is plausible: Folinic acid can bypass that blockade, restoring folate metabolism and possibly improving neural function. Leucovorin is a well-known drug that has been used safely for decades to mitigate chemotherapy toxicity and treat certain metabolic disorders. That long safety record, combined with suggestive early data in autism, has prompted regulators to consider a shortcut: approval first, large studies later. For families, this feels like long-overdue action. Advertisement For scientists, it’s an unsettling precedent. History is littered with treatments that appeared miraculous in small studies only to falter, or even cause harm, once widely adopted. Ordinarily, a new drug or indication must prove itself through multiple phases of clinical trials treating thousands of patients over several years before the FDA gives its blessing. These trials don’t just confirm benefit, they reveal who benefits, at what dose, and at what risk. When that process is abbreviated, the burden of discovery shifts to what happens after the drug reaches the public. In other words, the experiment moves from the laboratory to the living room. If we skip the traditional trial pathway, we must replace it with something equally rigorous. That’s why the United States urgently needs to establish a national leucovorin-autism patient registry: a structured, transparent system to track how this drug performs in real life — its successes, its failures, and its risks. A national registry is not a bureaucratic tool; it is a scientific necessity. It would let us learn, in real time, which children benefit, which do not, and what unforeseen side effects emerge. A registry would collect standardized data from every child prescribed leucovorin for autism, capturing diagnosis, genotype, dosage, lab results, and clinical outcomes measured on validated autism scales. Periodic follow-ups would document progress or setbacks. Linked to electronic health records, it could automatically log adverse events, hospitalizations, and long-term outcomes. Advertisement Such a system would allow researchers to analyze thousands of cases, uncovering trends invisible in small studies: which genetic or metabolic profiles predict benefit, which dosing schedules work best, and whether improvements persist or fade. By publishing annual summaries, aggregated outcomes, side-effect profiles, and subgroup analyses, a registry would serve as a neutral, data-driven source of truth. Parents could see population-level results; clinicians could benchmark their experiences; scientists could access anonymized datasets for deeper study. Without such expert analysis families will be left with social-media anecdotes or fragmented physician reports. Registries can be costly and imperfect, but their challenges are solvable. Integrating participation into electronic medical records minimizes clinician workload, while modest reimbursement and standardized outcome measures ensure consistency and engagement. Modern analytic tools — such as propensity matching and self-controlled case series — can correct for bias, and strict privacy safeguards keep data de-identified, encrypted, and ethically governed. Funding should be shared: Federal agencies can provide the backbone, academic centers can coordinate, and foundations or patient groups can sustain operations. A fraction of what is spent on large clinical trials could support a registry that continuously learns from every patient treated. Similar registries have been established for cancer treatments, medical devices, and vaccines. These systems have prevented harm, guided practice, and shaped policy. However, these registries were established for treatments that had passed the traditional regulatory approval process. While the FDA has promised post-market surveillance for leucovorin for autism, all stakeholders have to trust the process. Such surveillance should not be left to the drug manufacturers, as is typically the case. A further complication is that there will likely be several vendors for the drug and there will be a large market for over-the-counter supplements of folinic acid. Oversight by a consortium of government agencies, academic institutions, and autism advocacy groups is essential to ensure credibility of scientific data and its analysis. Advertisement Autism is emotionally charged terrain. A rumor earlier this year of a planned autism registry raised concerns about government intrusion and overreach among stakeholders. Families, physicians, and researchers are often divided between hopeful early adopters and cautious skeptics. A transparent registry focused on leucovorin treatment could bridge that divide. Public transparency is also vital for trust. Approving a drug for autism without large trials invites scrutiny. Openness about what’s working and what’s not would reassure the scientific community that speed and rigor can coexist. Fast-tracking leucovorin for autism is a bold act of regulatory flexibility, but boldness must be matched with accountability. A trusted national registry would provide families with evidence-based guidance, help clinicians refine dosing, and allow policymakers to make informed coverage decisions. Science does not end with approval — it evolves with every patient. If the nation chooses to act quickly on leucovorin, it must also choose to act wisely by building the infrastructure to learn from real-world experience. That is not just innovation; it is responsible medicine. Srinivas Sridhar is university distinguished professor and former vice provost at Northeastern University.
