Clinical Equipoise in the Management of Lead-Exposed Children
Clinical guidance regarding the management of lead-exposed children was largely based on guidance from the CDC (1985) and the American Academy of Pediatrics (1987). These statements recommended initiating chelation therapy in children with BLLs >55 µg/dL and clinical discretion between 25 and 55 µg/dL — a range which directly reflected the CDC's definition of an elevated BLL (≥25 µg/dL). However, by 1990, new research showed IQ loss occurred as low as 10 µg/dL, raising concerns among clinicians as to whether the current recommended thresholds for intervention were sufficiently protective.
Another controversial recommendation was that prior to chelating children with BLLs below 55 µg/dL, clinicians should use EDTA provocation tests — in which a single intravenous (IV) dose of chelator is followed by urinary lead measurement to estimate 'chelatable lead'. Despite their widespread use, these tests had limited diagnostic value, and animal studies suggested single EDTA doses might paradoxically increase brain lead concentrations, intensifying safety concerns and confusion among clinicians.
The three primary pharmacological agents in use at the time included dimercaprol (BAL) — administered via a painful intramuscular injection in peanut oil solution; calcium disodium EDTA — administered by IV; and D-penicillamine — an orally administered off-label drug approved for Wilson Disease but found to be somewhat effective at increasing urinary lead excretion. Each of the drugs in use carried unique risks, which were gradually coming to light through emerging studies and clinical experience. The 1985 CDC statement identified succimer (DMSA; dimercaptosuccinic acid) as a promising new, but unapproved, oral chelator.
In light of the disarray and lack of consensus among clinicians, in 1990, the Health Resources and Services Administration funded a national survey to determine current chelation practices being used at U.S. academic hospitals. The survey revealed widespread variability in treatment thresholds at levels as low as 20 µg/dL. Succimer, the oral compound mentioned in the 1985 CDC statement, was utilized by only one clinic participating in a special project as it awaited FDA approval.
Bock Pharma had submitted succimer for orphan drug designation in 1984, under the recently passed Orphan Drug Act (1983), and by 1990 preliminary studies suggested succimer was safer, more effective, and easier to administer than the other chelators in clinical use.
Medicaid Reform, FDA Approval, and the 1991 Convergence
Starting January 1st, 1991, the Medicaid Drug Rebate Program (MDRP) came into effect. This meant that if a manufacturer wanted Medicaid to cover its outpatient drugs, the manufacturer would later "true up" the price by sending Medicaid a rebate check tied to how much Medicaid used the drug. Under the new law, state Medicaid programs were legally required to cover any FDA-approved drug if a manufacturer signed a rebate agreement. Most importantly, the law mandated coverage for all "medically accepted indications," which included off-label uses supported by major medical compendia.
On January 30th, 1991, the FDA granted final marketing approval of succimer as an orphan drug for treatment of lead poisoning in children, specifically children with BLLs >45 µg/dL. McNeil Pharmaceuticals, who would market the drug, was given seven years of market exclusivity. Orphan drugs carried numerous incentives and benefits for pharmaceutical companies, and succimer's development was largely subsidized by federal grants.
Later that year, in October 1991, the CDC released their long overdue guidance update: "Preventing Lead Poisoning in Young Children." The statement included three conflicting recommendations:
- Lowered the hard line for chelation from 55 to 45 µg/dL, aligning clinical guidance with the FDA-approved indication for succimer. Critically, the guideline allowed clinicians discretion on chelating patients with BLLs 20–45 µg/dL.
- Lowered the BLL of concern to 10 µg/dL (a level shared by an estimated 1.7 million children), aligning it with evidence of neurotoxicity and creating new cases by definition.
- Recommended universal lead screening for every 1- and 2-year-old child, substantially increasing the detection of these newly defined cases.
By late 1991, the CDC had mandated screening to find a massive new population of poisoned children, most of whom were low-income Medicaid patients. The MDRP had created a legal mandate for Medicaid to pay for their treatment, even if off-label. And McNeil Pharmaceuticals held a monopoly on the only safe, oral drug that made mass treatment feasible.