FDA Policies Should Be Amended To Allow Pharmaceutical Manufacturers To Disseminate Information Regarding Potentially Fatal Toxicities That Occur with Off-Label Use of Oncology Agents: A Policy Recommendation Based on Review of Thalidomide-Associated Thromboembolism Cases by the RADAR Project.

Background– Although thalidomide (Th) was granted FDA approval in 1998 for erythema nodosum leprosum, >99% of its use is off-label for cancer. As with all off-label therapies, FDA regulations prohibit dissemination of clinical information by the manufacturer. Nonetheless, concern over off-label toxicities arose in a 2001 phase III study in which 28% of myeloma patients developed deep vein thrombosis (DVT) and pulmonary embolism (PE) with concurrent Th-chemotherapy. We investigated the clinical characteristics and reporting quality of all adverse event (AE) reports describing Th-associated thromboembolism (TE).

Methods– Data sources included 190 AE reports obtained from the FDA and 38 published phase II and III trials with 1,857 Th-treated individuals (for rate estimation), with exclusion of cases/trials reported in duplicate. AE reporting quality comparisons were made for events, which occurred in clinical trials (n=49) or in clinical practice settings (n=141).

Results– Overall, 190 cancer patients were reported as having Th-associated TE, based on AE reports submitted to the drug manufacturer (n=49 from prospective clinical trials and n=131 from non-clinical trial setting) or directly to MedWatch (n=10). Only 6 cases were reported through the System for Th Education and Prescriber Safety (STEPS), an FDA mandated teratogenicity-focused safety program. DVT/PE occurred at a median of 52 days Th use (range, 6 to 469 days). Completeness and certainty of DVT/PE diagnoses were best for AE reports submitted directly to the manufacturer from clinical trials versus those from non-clinical trial settings (p<0.0001). Highest rates of TE were among patients who received concurrent Th-chemotherapy (18%, versus 13% with Th-corticosteroid combinations and 5% with single-agent Th; p<0.0001 for each comparison).

Conclusions– AE information reporting is most complete for events that occur in clinical trials. The FDA should adopt policies that allow for dissemination of adverse events occurring frequently in off-label settings. This policy revision is especially important for Th, as it is the only cancer drug whose use in the recently initiated Medicare demonstration project for oral chemotherapy agents is exclusively off-label, and current FDA regulations prohibit Medicare beneficiaries from receiving AE information describing Th-associated TE. Moreover, the STEPS program currently does not provide patients, pharmacists, or providers with information on TE, and revision of this program should also be considered.

Comparison of clinical and diagnostic completeness of TE complications amongst Th-treated cancer patients in the FDA’s AE Reporting System database