Drug labeling authority, UDI program reviewed by Harvard-based researchers

Regulatory NewsRegulatory News | 17 May 2021 |  By 

Two papers in JAMA Internal Medicine highlighted separate, but important issues concerning the US Food and Drug Administration’s authority to modify package inserts and the effect of a recently shuttered agency initiative.
In a Viewpoint, Bishal Gyawali, MD, PhD, and colleagues at the Program on Regulation, Therapeutics and Law (PORTAL) research group at Harvard Medical School and Brigham & Women’s Hospital suggested improving FDA’s authority to modify drug package insert for situations such as drug repurposing and de-escalation of therapy. The authority to change drug labels outside of considerations for new safety information “could encourage third parties, such as academic investigators, insurance companies, and cooperative trial groups, to initiate such changes,” they wrote.
“These initiatives could support insurance coverage of previously off-label uses, prevent costly new drugs from inappropriately receiving preferential regulatory treatment that is intended for drugs with no FDA-approved alternatives, and better inform clinicians by providing evidence-based information about how drugs should be used,” they noted.
As examples, the authors cited remdesivir – formerly an unsuccessful Ebola drug – and dexamethasone – a generic drug widely available for decades – being repurposed as COVID-19 treatments. In the case of dexamethasone, Gyawali and colleagues said it is “unlikely that any manufacturer of generic dexamethasone would seek FDA approval for this indication, because it would incur costs in doing so but would have no mechanism to recoup those costs by preventing other companies from enjoying the benefits of the labeling expansion, which is known as a ‘free-rider’ problem.”
The proposed new authority over label changes also would help in situations where a drug has been found to work as well at a dose lower than the FDA-approved dose. Prescribing guidelines for a drug like zoledronic acid, for example, have recommended administration every 3 months rather than once per month to reduce “toxic effects, inconvenience, drug volume, and cost,” but the manufacturer “had not applied for approval of this potentially revenue-decreasing schedule, and every-third-month use remains off label,” the authors wrote.
“To facilitate revised drug labeling when new evidence supports drug repurposing or de-escalation of therapy, the FDA should be given clearer authority to accept and act on citizen petitions that support efficacy-based labeling changes, including the addition of new indications,” Gyawali and colleagues said.
The removal of the word “safety” and changing the phrase “reduced effectiveness” to “information related to effectiveness (including information related to new indications)” within the relevant US code would help support this endeavor. The authors acknowledged the potential for an influx of new or inappropriate citizen requests, and suggested FDA create guidance for “the types and amount of evidence required to add new indications or to support labeling for de-escalation of therapy.”
“Improved drug labeling would help the agency fulfill its mission of advancing public health by promoting evidence-based use of drugs for new indications or with dosing schedules that are clinically and financially parsimonious. Facilitating third-party submission of labeling change requests could also make it more likely that insurance companies or other payers would generate new evidence once patents expire and manufacturers no longer have sufficient incentives to generate this information,” they concluded.
In a separate Research Letter, Simon J. Gunter, MPhil, and his colleagues at the PORTAL research group provides an analysis of the effect of market exclusivity of drugs under FDA’s Unapproved Drug Initiative (UDI). In November 2020, FDA ended the UDI program, which was designed to gather data for legacy drugs that were never reviewed for safety and effectiveness prior to 1938. The initiative was shuttered due to concerns that the price of some legacy drugs in the US market was rising while not generating new clinical data on those drugs.
The team analyzed UDI-approved drugs between January 2006 and July 2020, during which 21 drugs were approved under the program. The median exclusivity of UDI-approved drugs was 3.42 years, and 11 of 21 drugs in the initiative (52%) had exclusivity of at least 3 years. There were 13 drugs (62%) “for which therapeutically similar but noninterchangeable drugs were approved before interchangeable generic versions,” and the median full exclusivity for these drugs was 0.64 years, while partial exclusivity was 2.02 years, the authors said.
After 5 years, the median number of manufacturers of 8 UDI-approved self-administered drugs decreased from 5.5 manufacturers to 3.0 manufacturers, and the number of manufacturers declined for 6 drugs. In addition, 5 drugs increased in price (median relative increase, 157%).
“The UDI disrupted market competition for many years. Our analysis raises concerns about market exclusivity periods as an incentive for such regulatory programs,” the authors said.
“Although the UDI was enacted with good intentions, the FDA was wise to end it,” Gunter and colleagues concluded. “Any future programs of this sort should include administrative or other mechanisms to maintain market competitiveness.”
JAMA Intern Med Gyawali et al.
JAMA Intern Med Gunter et al.


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