What Is the FDA’s Role in the Development of New Antibiotics?: The Case of Recarbrio

(A version of this article appeared in the January 2024 issue of Public Citizen’s Health Letter.)

Around the world, infections that are caused by bacteria or fungi that can no longer be treated with antibiotic or antifungal drugs (collectively, antimicrobial-resistant infections) are on the rise.[1] According to the Centers for Disease Control and Prevention, in the United States alone, antimicrobial resistant infections occur about 2.8 million times each year and cause more than 35,000 deaths.[2] Although this is a serious public health concern, the development of new antibiotics targeting resistent infections has been slow.[3]

One reason development of new antibiotics has stagnated is that it is not very lucrative for pharmaceutical companies. For example, manufactures often claim that, although the costs for drug development are very high, antibiotics are only associated with limited profits. This is especially true when compared to other types of drugs, such as cancer medications, antidepressants, insulins or heart mediations, which are typically prescribed for extended periods.[4] For this reason, Congress enacted the Generating Antibiotic Incentives Now (GAIN) Act in 2012, which was aimed at making the development of antibiotics targeting drug-resistant infections more financially attractive.[5] For instance, the GAIN Act enables the classification of certain drugs as so-called Qualified Infectious Disease Products, which are automatically eligible for several preferential and faster review categories by the Food and Drug Administration (FDA). These qualifying drugs also are protected for an additional five years from generic drug competition.[6]

However, some critics argue that the way these incentives are set up lets pharmaceutical companies benefit from them regardless of whether or not they develop new classes of antibiotics targeting antimicrobial-resistant infections. Moreover, these incentives also reward manufacturers who simply modify existing drugs instead of developing new drugs.[7] In fact, as of 2018, only about half of the drugs that the FDA designated as Qualified Infectious Disease Products were drugs with new mechanisms or otherwise truly novel drugs; the other half were modifications of existing drugs, such as new indications or dosages.

A recent study found that, between 2016 and 2019, the FDA approved antibiotics that were supported by fewer trials with lower numbers of enrolled subjects.[8] The study also found that the approval decisions were more likely to use measurements that did not directly assess patient outcomes, or to have only limited follow-up after the drug’s approval. Additionally, more than half of the studies used to support drug approval were trials with a non-inferiority (not worse than) trial design that does not even assess whether the new drug is better, but only whether it is not worse, than the drug it is compared to. A non-inferiority trial design is best suited for drugs where a small trade-off in efficacy may be worthwhile given improved drug safety or ease of drug administration, which is usually not the case for antibiotics.

The researchers also found that, in many cases, these antibiotics were not even tested on patients with resistant infections, even when the drugs were specifically approved for patients with limited or no treatment alternatives.[9] Thus, it is difficult to assess whether recently approved antibiotics — which are often much more expensive than older drugs — are more effective for the treatment of antibiotic-resistant infections.

An egregious example of the low standards for new antibiotics is the FDA’s approval of RECARBRIO.[10] Recarbrio combines imipenem and cilastatin, originally approved as PRIMAXIN in 1985, with relebactam. Relebactam was added with the aim of restoring the effectiveness of imipenem and cilastatin in infections resistant to these two drugs alone.

In July 2019,[11],[12] this drug combination was approved for adults with complicated urinary tract infections or complicated intra-abdominal infections who have limited or no alternative treatment options and then, nearly one year later, to treat adults with ventilator-associated bacterial pneumonia or hospital-acquired bacterial pneumonia.[13]

Recarbrio, which can be up to 40 times more expensive than Primaxin and is made by the same company, was classified as a Qualified Infectious Disease Product and was granted two favorable review designations.[14] The company, Merck, thus benefited from several incentives designed to encourage the development of effective antibiotics for antimicrobial-resistant infections.

A recent investigation by the medical journal The BMJ criticized the fact that Recarbrio was not tested for patients who have no other treatment options.[15] Instead, Merck tested the drug “in patients who already had effective options.” The BMJ investigation also concluded that Recarbrio was approved despite the fact that it did not demonstrate substantial evidence of clinical effectiveness.

Although it approved the drug, the FDA was similarly critical of Recarbrio’s effectiveness.[16] In its review, for example, the agency stated that the studies submitted for the approval “are not considered adequate and well-controlled” and thereby limit “the ability to draw scientifically reliable conclusions from these trials.” Even the drug’s label clearly states that the approval was based on “limited clinical safety and efficacy data.”[17]

The two studies of Recarbrio in subjects with complicated urinary tract infections or complicated intra-abdominal infections only compared the effectiveness of the drug with imipenem and cilastatin, the components of Primaxin, and only in subjects who had infections that were not resistant to imipenem and cilastatin. The benefit of the addition of relebactam for resistant infections was not studied.

According to the Federal Food, Drug, and Cosmetic Act, the contributions of each component of a new drug combination needs to be demonstrated.[18] Although the FDA stated that relebactam’s contribution could not be studied alone and was, therefore, only tested in animal models and in-vitro studies,[19] The BMJ investigation maintained that well-controlled studies could have assessed this new component more directly.[20] The BMJ, citing a former medical reviewer for the FDA, further argued that relying on non-clinical studies for a drug approval should only be acceptable when well-controlled human studies are neither feasible nor ethical.

Moreover, although the FDA usually recommends a non-inferiority margin of 10% for clinical trials examining treatments for complicated urinary tract infections, in the case of Recarbrio the agency allowed this new drug to be up to 15% less effective than imipenem and cilastatin, citing the new drug’s intention of targeting drug-resistant infections.[21] The clinical trial in patients with complicated urinary tract infections showed, however, that Recarbrio did not even meet this lower threshold, as it was up to 21.3% less effective than imipenem and cilastatin.

A third trial, which enrolled some subjects with several antimicrobial-resistant infections, was small and showed highly variable results between Recarbrio and the combination of imipenem and another antibiotic, colistimethate. The FDA described the results of the third trial as “difficult to interpret.”

Shockingly and inexplicably, despite the FDA’s concerns over the available data, the agency approved Recarbrio, stating that there is substantial evidence of effectiveness. This conclusion relies mainly on data from studies of imipenem and cilistatin, and in-vitro and animal models for the addition of relebactam. The FDA did recommend that Recarbrio should be reserved for “patients who have limited or no alternative treatment options” because of the limited data available.[22]

The FDA’s approval of Recarbrio demonstrates that the agency’s standards for approving antibiotics for antimicrobial-resistant infections are dangerously low. The approval also demonstrates that current incentives for drug manufacturers are insufficient to ensure that newly developed antibiotics offer better outcomes for patients than existing treatments. Addressing the serious public health concerns regarding antimicrobial-resistant infections requires higher standards for both the development and clinical testing of new antibiotics, and for regulatory approval.
 

References

[1] Darrow JJ, Kesselheim AS. Incentivizing antibiotic development: why isn’t the Generating Antibiotic Incentives Now (GAIN) act working? Open Forum Infect Dis. 2020;7(1):ofaa001.

[2] Centers for Disease Control and Prevention. About antimicrobial resistance. Reviewed: October 5, 2022. https://www.cdc.gov/drugresistance/about.html. Accessed December 5, 2023.

[3] Mitra-Majumdar M, Powers JH 3rd, Brown BL, et al. Evidence at time of regulatory approval and cost of new antibiotics in 2016-19: cohort study of FDA approved drugs. BMJ Med. 2022;1(1):e000227.

[4] Ibid.

[5] Food and Drug Administration. Generating Antibiotic Incentives Now. https://www.fda.gov/files/about%20fda/published/Report-to-Congress-on-Generating-Antibiotic-Incentives-Now-%28GAIN%29.pdf. Accessed December 5, 2023.

[6] Darrow JJ, Kesselheim AS. Incentivizing antibiotic development: why isn’t the Generating Antibiotic Incentives Now (GAIN) act working? Open Forum Infect Dis. 2020;7(1):ofaa001.

[7] Ibid.

[8] Mitra-Majumdar M, Powers JH 3rd, Brown BL, et al. Evidence at time of regulatory approval and cost of new antibiotics in 2016-19: cohort study of FDA approved drugs. BMJ Med. 2022;1(1):e000227.

[9] Ibid.

[10] Food and Drug Administration. RECARBRIO (imipenem/cilastatin/relebactam). Multi-disciplinary review and evaluation (NDA 212819). October 12, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212819Orig1s000MultidisciplineR.pdf. Accessed December 5, 2023.

[11] Merck Sharp & Dohme. Label: RECARBRIO (imipenem, cilastatin, and relebactam). May 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=be32f468-738b-40df-a425-591e12f65159&type=display. Accessed December 5, 2023.

[12] Food and Drug Administration. FDA approves new treatment for complicated urinary tract and complicated intra-abdominal infections. July 17, 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-complicated-urinary-tract-and-complicated-intra-abdominal-infections. Accessed December 5, 2023.

[13] Food and Drug Administration. FDA approves antibiotic to treat hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. June 4, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-antibiotic-treat-hospital-acquired-bacterial-pneumonia-and-ventilator-associated. Accessed December 5, 2023.

[14] Mitra-Majumdar M, Powers JH 3rd, Brown BL, et al. Evidence at time of regulatory approval and cost of new antibiotics in 2016-19: cohort study of FDA approved drugs. BMJ Med. 2022;1(1):e000227.

[15] Doshi P. Did the FDA break its own rules in approving the antibiotic Recarbrio? BMJ. 2023 15;381: 1048.

[16] Food and Drug Administration. RECARBRIO (imipenem/cilastatin/relebactam). Multi-disciplinary review and evaluation (NDA 212819). October 12, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212819Orig1s000MultidisciplineR.pdf. Accessed December 5, 2023.

[17] Merck Sharp & Dohme. Label: RECARBRIO (imipenem, cilastatin, and relebactam). May 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=be32f468-738b-40df-a425-591e12f65159&type=display. Accessed December 5, 2023.

[18] 21 C.F.R. § 300.50.

[19] Food and Drug Administration. RECARBRIO (imipenem/cilastatin/relebactam). Multi-disciplinary review and evaluation (NDA 212819). October 12, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212819Orig1s000MultidisciplineR.pdf. Accessed December 5, 2023.

[20] Doshi P. Did the FDA break its own rules in approving the antibiotic Recarbrio? BMJ. 2023 15;381: 1048.

[21] Food and Drug Administration. RECARBRIO (imipenem/cilastatin/relebactam). Multi-disciplinary review and evaluation (NDA 212819). October 12, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212819Orig1s000MultidisciplineR.pdf. Accessed December 5, 2023.

[22] Ibid.