Experts Urge FDA to Speed Approval of New Treatments, Preventative Measures for Recurrent C. Diff

The organizations emphasized the need to better understanding the patient experience for those with recurrent CDI.

Several non-profit advocacy organizations have partnered and submitted a letter to the FDA, urging officials to prioritize and accelerate the development of treatments and preventative measures for recurrent C. difficile infection (CDI).

In a letter submitted in April 2022, the organizations emphasized the need to better understand the patient experience for those with recurrent CDI. There are nearly 500,000 CDI cases in the United States each year and individuals over 65 years of age face a higher mortality rate. Similarly, despite having slightly lower rates of CDI, Black Americans have worse outcomes with regard to length of stay, severity of disease, and mortality. One in 5 patients diagnosed with CDI will also experience a recurrence of symptoms within 2 to 8 weeks of their initial diagnosis.

One of the partnering organizations, the Peggy Lillis Foundation, is working to build greater public awareness of patient experiences with recurrent CDI, including significant physical, emotional, and financial hardships. Current standard of care treatments do not meet the needs of patients with CDI, and can actually worsen recurrent CDIs, according to the letter.

Furthermore, no new treatment options have been approved for CDI since 2011 and no first-line treatment has been approved to address the unmet need for recurrent CDI. For most of the approximately 100,000 patients diagnosed with CDI each year, fecal microbiota transplant (FMT) is the treatment of last resort. Although this is permitted by the FDA through enforcement discretion, accessibility and coverage have been challenging and the COVID-19 pandemic has made FMT even more difficult to obtain.

Because of the vague treatment landscape and unmet needs, physicians have broad discretion when deciding a treatment path, according to the letter. Patients can receive multiple courses of vancomycin or fidaxomicin and may receive a tapered or pulse-tapered antibiotic course. Although many physicians will refer patients for FMT following their second recurrence, others sometimes wait for a third or fourth recurrence before making this recommendation.

During this process, patients struggle with their symptoms, which can include diarrhea 20 to 30 times per day, nausea, fever, and fatigue. In a 2020 paper cited in the letter, 70% of patients with recurrent CDI described physical pain, weakness, and weight loss; 71% reported psychological distress including anxiety, depression, and fear; and 74% noted that the infection impacted their daily activities.

Recurrent CDI also greatly increases the risk of developing sepsis, with 43% of patients experiencing a third recurrence of CDI also developing sepsis. Recurrent CDI also has a significant financial burden for patients and the health care system, with hospital length of stay and cost doubling for patients with recurrent CDI versus a single occurrence.

Finally, the letter notes that recurrent CDI has long lasting impacts, with 87% of patients fearing that it will return and 97% fearing that they will have to take antibiotics. These stressors can impact patients’ health, their ability to work and care for themselves, and their ability to participate in daily activities.

Despite these concerns, several new treatments for recurrent CDI have completed or are expected to soon complete phase 3 clinical trials. Narrow spectrum antibiotics, which align with CDC and FDA mandates for antimicrobial stewardship, mostly offer patients a reduced rate of recurrence whereas microbiome therapies interrupt the cycle of recurrence by restoring balance to the patient’s gut. Although the letter does not endorse any specific treatments, it notes that the number of treatments and the variety in development seems to be promising.

Importantly, the letter urges the FDA to engage patients and caregivers to develop a robust understanding of the patient experience. This inclusion will enable the agency to fully see the role various treatments could play in preventing primary CDI, reducing recurrence, and interrupting recurrence as early as possible.

Specifically, the authors asked the FDA to consider several steps. First, the letter said a broader clinical trial endpoint should be considered instead of simply measuring for less than a specific number of bowel movements per day. Many patients with recurrent CDI continue to experience at least some gastrointestinal disruption even after FMT, so having a narrow and potentially misleading endpoint could risk keeping good treatments off the market, according to the letter.

Second, the letter says considering the socio-emotional impacts of recurrent CDI could change the perspective of the disease. Using a patient-reported outcome scale could help weigh these factors along with clinical data when considering new narrow spectrum and microbiome therapies for CDI.

Finally, the authors urged FDA officials to consider the societal implications of using broad spectrum antibiotics in situations in which narrow spectrum antibiotics are available. During the COVID-19 pandemic, the authors said another “silent” pandemic of antimicrobial resistant infections has spread.

One such pathogen is vancomycin-resistant enterococci, which develops in individuals who have been previously treated with antibiotics for long periods of time, including patients with recurrent CDI. The authors said the harm of using such broad spectrum antibiotics must be considered alongside the relative expensive of newer antimicrobial and microbiome therapies.

The authors concluded by offering to discuss these issues with appropriate FDA officials, given that the new products are expected to enter the approval process shortly. Organizations included in the letter include the Alliance for Aging Research, the Amputee Coalition, the Antibiotic Resistance Action Center, the Infectious Disease Society of America, NTM Info & Research, OpenBiome, the Partnership to Fight Infectious Disease, the Peggy Lillis Foundation, and the Sepsis Alliance.

REFERENCE

Letter to FDA – rCDI Unmet Need. Letter. Peggy Lillis Foundation; April 2022. Received May 11, 2022. Email.