USMA Identifies “Multiple Irregularities” by the FDA When Considering New Medications
As many of our members are aware, the United States Medical Association (USMA) submitted an amicus brief in the Mifepristone case filed against the Food and Drug Administration by the Alliance for Hippocratic Medicine. The case arose from a dispute regarding the multiple irregularities exhibited by the FDA in its granting of multiple authorizations for the marketing and use of the drug.
In reviewing the merits of the case and the necessity for our involvement, we discovered multiple actions by the FDA that gave us pause and compelled us to share them with our members. These are examples of decisions being repeatedly undertaken by the FDA implying a wanton disregard for safety and of its own regulatory requirements. These actions raise questions regarding the impartiality and integrity of the agency charged with ascertaining the safety and efficacy of medicinal products in the United States.
For starters, the USMA uncovered significant and recurrent irregularities in the FDA’s consideration of mifepristone dating back to the original NDA proceedings in 2000. For starters, in 2006, the Subcommittee on Criminal Justice, Drug Policy and Human Resources regarding Mifepristone found that the drug’s approval was unlawful based on the FDA’s failure to comply with the requirement in 21 CFR 314.126(e) that “uncontrolled studied or partially controlled studies are not acceptable as the sole as the sole basis for the approval of claims of effectiveness.” Startingly, the Subcommittee found that unlike the requirements in law, the trials upon which the FDA relied to grant mifepristone’s New Drug Authorization (NDA) were randomized trials nor were the subjects “concurrently controlled.” Instead, the agency’s findings on drug effectiveness were based on a comparison “to a historical control of the expected rate of continued pregnancy.”
The Subcommittee also learned from a Letter by the Assistant Commissioner for Legislation FDA to the Subcommittee’s Chair that the “historical control to which the Deputy Commissioner referred consisted of “the well-established data and pool of medical knowledge concerning both the natural course of pregnancy itself, included the well-documented rate of spontaneous abortion on miscarriage (less than 20%) and surgical abortion.” Additionally, the Subcommittee found that the FDA’s addition of misoprostol as an adjuvant to the mifepristone treatment represented a highly irregular approval of an unapproved use since the misoprostol “was actually contraindicated at the time.”
We also found other irregularities in the process, including:
1. The postponement and procrastination regarding Plaintiffs petitions for greater than 6,000 days;
2. The FDA’s failure to ascertain that the trials upon which it relied when initially approving mifepristone require 1) that each woman receive an ultrasound to confirm gestational age and exclude ectopic pregnancy; 2) that physicians have experience at performing surgical abortions and admitting privileges at medical facilities providing emergency care; 3) that all patients were within one hour of the medical facilities and of the principal investigator; and 4) that women be monitored for four hours following the administration of mifepristone;
3. The misapplication of a provision in law restricting rapid consideration of NDAs to the treatment of illnesses, which pregnancy clearly is not;
4. The FDA’s disregard for the federal legal prohibition on mailing abortifacients;
5. The FDA’s lack of reliance on appropriate studies when 1) eliminating the requirement for prescribers to report all nonfatal, serious, adverse effects; 2) extending the allowable maximum gestational age to 70 days; 3) eliminating the in-clinic administration of misoprostol; d) discontinuing in-person follow-up requirements; and e) allowing non-physicians to dispense chemical abortion drugs; and
6. The FDA’s lack of reliance on studies of a generic formulation of mifepristone when providing its 2019 generic approval
We then found that the FDA’s misconduct was not limited to its consideration of mifepristone. On May 21, 1999, the FDA granted authorization to market rofecoxib (Vioxx) a novel nonsteroidal anti-inflammatory medication. By the year 2000, and perhaps even at from the outset, information appeared making the association between the use of rofecoxib and myocardial infarction.
Despite these associations, the FDA’s Arthritis Committee did not meet to consider this information until two years following its approval of rofecoxib. In fact, the elevation in cardiovascular events was unexpected resulting in a “Special Communication” released in the Journal of the American Medical Association by the American Medical Association (“AMA”) (one of the Amici in the Fifth Circuit Court that surprisingly wrote in favor of the FDA). In it, the AMA called for the FDA to undertake further evaluation on the association between rofecoxib and cardiac issues. The FDA, which had the authority to demand such a study, never did. Instead, four years later, after over 80 million people were exposed to the medication, rofecoxib was removed from the market, not because of the FDA’s actions, but because the manufacturer (Merck) voluntarily recalled it.
Although no specific death was ever proven to have been cause by rofecoxib, through statistical analyses, tens of thousands of patients were estimated to have experienced adverse events because of exposure to the medication.
More recently, the FDA’s handling of aducanumab (Aduhelm) has also been called into question. Aducanumab is a monoclonal antibody for the treatment of Alzheimer’s disease. The drug’s approval, which took place on June 7, 2021, raised so many questions that an investigation was undertaken by two congressional committees. Here, the Committees found that the drug approval process “was rife with irregularities” including the presence of “atypical collaboration and interaction between [the] FDA and Biogen”; a failure on the part of the FDA to follow its own documentation procedure; the inappropriate and inadequate joint misrepresentations of the differing views within the FDA by the agency and Biogen; the unusual manner in which the FDA “pivoted” to an accelerated approval process in considering the medication; and the unexpected issuance of a “brown label indication” regarding the medication.
In short, as was the case with mifepristone, the Committees found that the “FDA’s lapses in protocol” in the Aduhelm approval process “raise[d] serious concerns” and bring to question the integrity of its review process.
Interestingly, within a week of our filing our amicus brief detailing the many concerns raised by the FDA’s conduct, Bloomberg published an article detailing how the FDA’s handling of its “accelerated approval” process like the one employed in mifepristone is “minting” billions of dollars for drug manufacturers. Of note, the Bloomberg piece was largely centered on irregularities exhibited by the FDA in its approval of Exondys 51, a novel medication for the treatment of Duchenne muscular dystrophy whose efficacy remains in doubt.
Needless to say, the ongoing disregard for regulatory requirements exhibited by the FDA in considering the safety and efficacy of vaccines and medications is an issue of great concern to the professionals that prescribe them.
As the Voice of America’s Doctors the USMA will continue to employ all available resources to guarantee that those agencies tasked with providing physicians the direction needed to safely prescribe medications are doing their jobs in an impartial and objective manner.
Dr. Julio Gonzalez is n orthopaedic surgeon practicing in Venice, Florida, and a former Florida State Representative. He is President of the United States Medical Association.
