The citizen petition was instrumental in facilitating FDA safety actions, which probably would not have occurred until several years later had it not been filed. In 2003, the FDA requested that the product label be revised to inform physicians that thrombotic events had been reported in patients treated with thalidomide, that patients with inflammatory diseases or cancer have an increased incidence of VTEs, and that it is not known if concomitant therapy with other medications had been contributory. In 2005, the sponsor informed the FDA that safety concerns for thalidomide treatment of multiple myeloma were similar to those for ENL: somnolence and neurotoxicity (failing to highlight VTE).12
As noted by reviewers at the FDA Office of Drug Safety in FDA communications in 2005, the impetus for review of thalidomide-associated VTEs was the report from C.L.B. identifying cancer trials with high VTE rates with thalidomide and concomitant dexamethasone or chemotherapy.44
Among patients with multiple myeloma, VTE rates were as high as 33% when thalidomide and concomitant chemotherapy were administered. In this communication, FDA reviewers from the Office of Drug Safety reported that they had reviewed thalidomide-associated VTEs in the setting of multiple myeloma. This review identified VTE rates of 3% to 5% with thalidomide, 8% with thalidomide and dexamethasone, and 8% to 28% with thalidomide and concomitant chemotherapy. The reviewers indicated that they agreed with C.L.B.'s report on high VTE rates with thalidomide with corticosteroids or doxorubicin, and communicated this safety concern to the acting director of the Division of Oncology Drug Products. One month later, the acting director communicated this concern to the manufacturer and informed the manufacturer that this new finding necessitated a delay in the sNDA approval of thalidommide. This was the first mention of VTE risks in communications from the Division of Oncology Drug Products to the manufacturer.12
This experience highlights a deficiency in the FDA safety review process—a majority of safety concerns that reviewers of NDAs and sNDAs evaluate are identified by sponsors.25–27
On May 25, 2006, the FDA recommended, and the sponsor agreed to, a revised black-box label, dear doctor letter, and medication guide describing VTE risks with thalidomide-dexamethasone treatment of myeloma.25
The AG received a letter from the acting director of the Division of Oncology Drug Products indicating that the FDA had reviewed the requests from the AG.
The observation that dissemination of VTE risk notification occurred after the filing and resolution of the petition suggests that the petition was instrumental in bringing about FDA safety actions. The VTE rate of 23% with thalidomide-dexamethasone treatment of multiple myeloma and low rates of VTE prophylaxis among patients in the phase III licensing study were described in a 2008 publication.26
This information had been included previously in the revised product label issued by the manufacturer in May 2006. The first mention of this high VTE rate observed the clinical trial in communications by the FDA Division of Oncology Drug Products occurred in February 2006, 2 months after the original decision date for action on the sNDA. Had the sNDA been approved in 2005, as seemed likely, absent VTE concerns raised by the petition, it is doubtful that the manufacturer would have included this information in the product label at that time.
VTE concerns remain. In 2008, hematologists recommended individualized-risk approaches with thalidomide, with consideration of viscosity and concomitant high-dose dexamethasone or chemotherapy administration.28
Guidelines identify VTE risks when patients with multiple myeloma receive thalidomide with dexamethasone, doxorubicin, or erythropoietin.43,45
Whereas the petition identified thalidomide-associated VTE risks for several cancers, the FDA commented only on multiple myeloma, despite thalidomide use for many cancers. VTE prophylaxis trials continue to be requested by clinicians.43
In 2012, the manufacturer has yet to successfully negotiate with the FDA a study protocol of VTEs among patients with thalidomide-treatment multiple myeloma.
Multiple factors contributed to the success of the petition. Approximatley 200 citizen petitions are filed annually.46
Pharmaceutical manufacturers often petition for delays in approval of competitor products. The Public Citizen organization frequently petitions for stronger warnings or withdrawal of FDA approval for drugs with serious toxicities. Advocacy groups often petition for access to novel therapeutics and expanded FDA approval. Overall, the FDA denies 70% of these petitions.46
It should be noted that this petition was drafted over months. Several versions were revised by C.L.B. and assistant AGs. This effort was time consuming and conducted because of a strong concern from the AG that thalidomide was being prescribed almost exclusively off label as a cancer drug to thousands of individuals. From the AG's perspective, the petition placed policy concerns squarely before relevant agencies; it was a measured approach for raising investigative findings and seeking solutions, and it offered an alternative to litigation.
This study highlights issues related to the use of the citizen petition to address safety concerns. Petitions can be perceived as intrusive in the internal workings of an administrative agency. However, familiarity with the law, a solid scientific basis for petitioning the FDA, the degree of relation between the requested actions and safety concerns raised, and timing of a petition contributed to a petition being viewed more positively. The saliency of the subject drug with its storied past may also have affected the processing of this petition. Furthermore, the amount of new information that the petition brought to the attention of the FDA may have positively affected its success. Another consideration was that it addressed safety concerns involved in off-label use.
The successful petition for thalidomide benefited from a unique confluence of factors—the most important of which was perhaps the timing of the petition, coinciding with the premarket thalidomide sNDA. The approval of the sNDA was particularly important to the manufacturer, because thalidomide was the primary drug marketed by the manufacturer; the only FDA approval for thalidomide at that time was for erythema nodosum leprosum, and the previous sNDA application for thalidomide treatment of multiple myeloma had been rejected. With the revised sNDA under review, FDA officials may well have understood that the sponsor had a great incentive to comply with requests for labeling changes. The petition was filed at a time when the FDA was able to leverage its strong preapproval power to command certain postapproval labeling changes (in area in which FDA authority is generally weaker).
The response to the petition highlights the dichotomy between ex ante
(preapproval) and ex post
(postmarketing) FDA powers.3,4,47
Before approval of a new drug, the FDA is the sole arbiter of the marketability of a drug. Without FDA approval, a new drug cannot be prescribed or sold. Once approval is granted, the postmarketing powers of the FDA are limited.
Our experience shows that the passage of the Prescription Drug User Fee Act in 1992, which permitted expedited drug approval, may have exacerbated the inability of the FDA to hold manufacturers accountable for postapproval safety actions. Congressman Ed Markey of Massachusetts and the Government Accountability Office reported that the FDA had not required sponsors to complete several agreed-on postaccelerated approval commitment studies.19,26
The FDA rejected these conclusions, emphasizing accrual barriers to phase IV postapproval trials.29
We identified a different concern—the FDA and sponsor have yet to agree on even the protocol design for a postaccelerated approval epidemiologic study of thalidomide, 6 years after the commitment was negotiated. Since 2007, the FDA has the authority to impose civil penalties for failure to complete postapproval commitment studies.48
Financial penalties could induce the sponsor to conduct this study.
Future research should identify factors associated with successful petitions and how these factors relate to the internal workings of the FDA. These analyses should explore whether factors that conform to the procedural legitimacy of the FDA, or factors that recognize the powerful influence of attorneys within the agency, are more likely to receive a positive outcome. The nonprofit organization Public Citizen has the most experience with successful petitions. It would be of broad interest to learn of the factors that characterize successful Citizen Petitions; however, it should be noted that the organization has a litigation group that facilitates comprehensive filings of FDA petitions.
We conclude that the petition facilitated translation of research findings into practice. However, delays in initiating mandated postapproval studies for thalidomide have occurred, similar to those reported for postapproval commitments involving clinical trials.21,24
Additional safety actions for VTEs associated with thalidomide, beyond the filing of citizen petitions, are needed. We also emphasize the observation that safety reviews do not end with revision of a product label and dear doctor letter. The manufacturer and FDA have yet to negotiate the details of an agreed-on epidemiologic study of thalidomide-associated VTEs, and the clinical uncertainty of VTE prophylaxis with thalidomide persists. Attention must be paid to pharmaceutical safety over the entire lifetime of a drug, particularly one with as storied a history as thalidomide.