As a follow-up to my previous comment to the FDA regarding "drugs to treat early Lyme disease," please take a moment to read the comment below registered by the team at TruthCures. We all agree that early Lyme with bulls-eye rash does not represent the entire patient population and has been used by the IDSA and CDC to control and manipulate the narrative in order to support the vaccine business model of patent royalties and pharmaceutical profits. Chronic Lyme disease DOES NOT fit that model!
Comment from TruthCures:
Response to Docket No. FDA-2022-D-2315 for “Early Lyme Disease as Manifested by Erythema Migrans: Developing Drugs for Treatment”
As a patient advocacy organization working to bring valid diagnostics and effective treatments to people with Lyme disease (LD), TruthCures supports innovation in therapeutics and properly designed trials to ascertain their efficacy. Thank you for the opportunity to comment on this guidance.
Trial Population
The trial population suggested in this guidance consists of “…subjects with early
localized (i.e., a single EM lesion) or early disseminated (i.e., multiple EM lesions)
disease, who reside in or traveled to a Lyme-endemic area.” Limiting any therapeutic trial to only cases presenting with erythema migrans (EM) rash will restrict the trial population to a minority cohort that may not be representative of the broader patient population.
The Centers for Disease Control and Prevention (CDC) estimates 476,000 LD cases in the United States each year (Kugeler et al 2021). However, in 2020, only 44,937 LD cases were reportable as “confirmed” or “probable” based on CDC surveillance criteria (CDC 2020). For diagnosis of a reportable case of early LD, CDC surveillance criteria require either a physician-diagnosed EM rash or laboratory confirmation of infection by methods that may include culture, nucleic acid amplification, immunohistochemical assay on biopsy or autopsy tissues, or two-tier serological testing (CDC 2022).
In clinical practice, diagnostic criteria set forth by the Infectious Diseases Society of
America are virtually indistinguishable from the CDC surveillance criteria (IDSA 2006). With both sets of criteria requiring physician-diagnosed EM rash and/or laboratory confirmation, it stands to reason that the vast majority of EM rashes are being counted in the reported surveillance cases. In the public discourse, the absence of such context promotes a misconception that the prevalence of EM rash is based on the total of LD cases rather than the reported cases, creating an inflated perception of the prevalence of EM rash with Lyme.
A simple mathematical analysis illustrates the staggering difference between the
narrative and reality.
● The literature frequently cites an EM rate of 60% - 80% (IDSA 2006,
Steere et al 1998, CDC 2021). For calculation purposes we will use 70%.
● The public incorrectly believes EM cases are calculated as 70% of
476,000, or 333,200.
● Published studies state the EM rate is calculated based on reported LD
cases—those meeting the IDSA and/or CDC surveillance reporting criteria
(Kugeler 2020, Smith et al 2002, Seltzer et al 2000). For 2020, EM cases
would be 70% of 44,937, or 31,456.
● Therefore, the effective rate of EM is about 6.6% (31,456 out of
476,000).
It should not have to be said that results of a treatment trial limited to 6.6 percent of patients would not necessarily extrapolate to the entire Lyme disease patient
population—particularly when it is unclear why the minority exhibit a distinct cutaneous manifestation. Indeed, Kannangara and Patel note, “EM seems to correlate more with the arthropod than the associated pathogen. The common belief is that EM is caused by B. burgdorferi. The presence of an organism in a skin biopsy culture or PCR does not necessarily mean that it is the cause of EM.” (Kannegara 2020)
Efficacy Endpoints
From the guidance document:
“Clinical success should be defined as resolution of EM and continued absence
of objective manifestations of Lyme disease without need for additional
antibacterial treatment for Lyme disease."
“Clinical failure should be defined as the presence of unresolving or recurrent
EM, objective manifestations of Lyme disease, or the need for additional
antibacterial treatment for Lyme disease.”
Remission of cutaneous symptoms has not been determined to correlate with disease cure (IDSA 2006, Steere et al 2016, Feder et al 2011), and, as is common knowledge, there is no diagnostic method available to determine either cure or disease stage.
It is commonly reported in the literature that EM rash resolves on its own in three to four weeks (Kardos 2002, Feder 1993, Nadelman 1997, Wheaton 2012, Dressler 1999). Therefore, the definition of clinical success (“resolution of EM”) could not necessarily be attributed to the treatment. Likewise, clinical failure could not be attributed to lack of efficacy if efficacy itself is not ascertainable. Lacking the ability to determine success or failure based on EM resolution, an alternative would be to run a separate trial to determine whether the therapeutic has any effect on time to resolution of EM.
Additionally, there is the possibility that patients present with EM rash and no other symptoms. In these cases, without the ability to correlate disease cure with resolution of EM, there is no other way to gauge efficacy of a therapeutic.
Conclusion
Using only patients who present with EM rash for a therapeutic efficacy trial would
exclude 93% of patients, with no insight into the factors (e.g. genetic or comorbidities) that cause certain people to develop the rash. Resolution of EM rash is not an indication that Lyme disease has been cured or spirochetes eradicated.
TruthCures’ mission is to enable Lyme disease victims to obtain a valid diagnosis and effective medical care. While we support endeavors to discover novel treatments, we believe valid diagnostics must come first. As long as Lyme disease cannot be accurately and consistently diagnosed, therapeutics cannot be developed for the right patients using the right efficacy endpoints.
Following a complaint to FDA’s Office of Criminal Investigation, TruthCures presented to investigators in-person, in October 2021. We provided evidence that Lyme disease diagnostics have been predicated on improperly cleared devices going all the way back to 1995. The investigators agreed with our diagnostic device regulatory expert’s assessment of those devices. We suggest focusing FDA’s Lyme disease efforts on completing that investigation so valid tests can be developed and marketed rather than daisy-chaining off a manipulated standard.
It is well known that seronegative Lyme presents one of the biggest challenges in
validating diagnostics. The gap between reported surveillance cases (44,937 in 2020) and CDC’s estimated annual cases (476,000) indicates more than 400,000 patients per year may be falling through the cracks due to the inability of serology to properly diagnose them. Many of these victims lose everything—family, friends, job, home, retirement savings, education, and more—due to chronic illness and the stigma of having a “contested” disease. We respectfully request you take a step back and reassess whether it makes sense to produce any guidance that effectively leaves those patients out of the equation once again.
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