Draft FDA guidance on anti-infectives for children: It’s (mostly) all about PK and safety

Dear All (wonkish alert … the first 3 segments are non-wonkish but the last 2 are in the wonkish zone … titrate your plasma caffeine level appropriately),

Part 1: FDA has recently released a draft guidance entitled Development of Anti-Infective Drug Products for the Pediatric Population (link). This timely guidance builds on related guidance documents covering pediatric study plans and labeling (link to list of guidances).

As (i) children come from the same species as adults (although you do sometimes wonder about teenagers) and (ii) most infections have the same pathophysiology in all age ranges (neonates being the most common exception), it is no surprise that the key points in this guidance are:

1. Efficacy can usually be extrapolated from data in adults provided that…
   • …the compound is dosed in children to give PK similar to the PK seen in adults.
2. Safety needs to be assessed but is usually similar to that seen in adults
   • The recommended size of the safety database considers disease prevalence, expected use, and safety profile in adults.
   • Safety data from adults is used to provide supportive information
3. Significant flexibility is possible for inclusions/exclusions, prior antibiotics, and comparator antibiotics.
   • Parallel enrollment across all ages is encouraged (rather than step-wise exploration of steadily younger children)
4. Laboratory assessments should be minimized.

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Part 2: As context, EMA’s position is very similar. Here are the papers you need:

• EMA’s 2018 draft addendum on developing antibacterial agents in pediatrics (link)
• For more detail, see also the notes from a June 2018 workshop discussing the draft (link)

LIke FDA, EMA’s focus is on PK bridging to adult efficacy data for most indications. EMA states that safety might (at least in part) be extrapolated from adult data but that age-specific issues do arise and hence safety data should be collected insofar as possible. As a slight contrast, note that FDA speaks of adult safety data as supportive — FDA never uses the term ‘extrapolate’ with respect to safety data.

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Part 2.1: 8 July 2020 amendment: I tumbled today to two papers that speak to the challenges with collecting data in this space, even with these updated guidelines:

• (link) Folgori L et al. Standardising neonatal and paediatric antibiotic clinical trial design and conduct: the PENTA-ID network view. BMJ Open. 2019;9(12):e032592.
• (link) Thompson G et al. Global shortage of neonatal and paediatric antibiotic trials: rapid review. BMJ Open. 2017;7(10):e016293.

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Part 3: When are efficacy data needed in children? As stated above, efficacy is generally presumed if PK can be matched. But, there are exceptions and both agencies offer thoughts on this. The exceptions are diseases (or disease presentations) that are really different in children or that are primarily pediatric. Here’s a merged list of exceptions from the two documents:

• TB in children < 2 years of age is more often disseminated vs. the primarily pulmonary manifestations of TB in older ages
• Impetigo and acute otitis media (AOM) are mostly seen at < 5 years of age: adult data are not possible
• Infected atopic dermatitis is mostly a pre-pubertal disease
• Acute hematogenous osteomyelitis in children has a different pathophysiology than trauma- or device-related osteomyelitis
• Acute group A streptococcal pharyngitis appears more difficult to eradicate in pediatrics and thus the ability to extrapolate is less certain.

Finally, EMA’s pediatric addendum provides extended comments on the design of efficacy trials for all of the above except TB; EMA’s thoughts on developing for TB in children are in their 2017 TB-specific addendum (link). FDA’s guidance on TB also mentions children (link); to my knowledge, there is no specific guidance on the other indications.

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Part 4: Very wonkish sidebar on AOM (Acute Otitis Media): In reviewing the EMA’s extended by-disease guidance, I am reminded of the problem of clinical trials of new therapies for AOM.

The tension here centers on whether or not you think that the data from the last two placebo-controlled trials of AOM (Tähtinen NEJM 2011;364:116-26 [link] and Hoberman NEJM 2011;364:105-15 [link]) provide sufficient data to support a non-inferiority trial of therapy for AOM, whether you should (and can ethically) conduct a placebo-controlled superiority study, and the best endpoint for such studies.

Although both of the 2011 studies observed lower rates of clinical failure and a trend towards fewer serious complications with antibiotic therapy, adverse events (notably, diarrhea) were more common with antibiotic therapy. Net, however, an accompanying editorial (Klein NEJM 2011;2011;364:168-169 [link]) concluded that “more young children with a certain diagnosis of acute otitis media recover more quickly when they are treated with an appropriate antimicrobial agent.”

That said, the overall data on the impact of antibiotics are limited and the available guidances suggest that more work would be needed to permit design of trials in this indication.

FDA’s most current AOM guidance is dated 2012 (link). It discusses the idea of both superiority and non-inferiority trials but unlike guidance documents for other major infections (see Rex CID 2016;65:141-6 [link] for a list), the guidance does not offer any suggestions on statistical parameters for such trials. And with respect to a non-inferiority design, companies are told to “discuss with the FDA the scientific data needed to support selection of a noninferiority margin.” 

EMA seems to start with a more encouraging stance in their 2018 guidance (link) by saying, “It is considered that published data support acceptance of a non-inferiority trial design provided that the patient population is aged from 6 months to 3 years, has adequately defined AOM and the comparator is specified.” However, EMA goes on to say, “Nevertheless, the available data do not provide an unequivocal indication of the primary endpoint and non-inferiority margin to apply.”

At the end of the day, neither of these guidance documents provide a pathway that is good to go. My personal guess is that we’re unlikely to again see drugs developed for AOM … the path is just too murky.

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Part 5: And if you really want to go deeply into pediatric development issues, follow these further links:

1. FDA
   • Key guidance documents are summarized at this link.
   • FDA has held a series of workshops on Advancing the Development of Pediatric Therapeutics (ADEPT). An an example, ADEPT6 was held in 2019 and was entitled Pediatric Clinical Trial Endpoints for Rare Diseases With a Focus on Pediatric Patient Perspectives (link). The prior workshops are easily found by searching the web.
   • Separate from the ADEPT series, there was a workshop in 2017 entitled “Pediatric Trial Design and Modeling: Moving into the Next Decade” (link)
   • There is a webpage that tracks statistics of pediatric development programs (link)
2. EMA
   • There is a general webpage that summarizes EMA’s activities related to pediatric R&D (link)
   • A related webpage provides links and guidance for creating a pediatric investigation plan (link)
   • There is an interesting 2017 general report from the EC to the European Parliament on the impact of the first 10 years of the European pediatric legislation (link).

And that’s enough for today! All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.