FDA, Goalposts and Antibiotic Trial Design - YAY!!!

It was a remarkable day yesterday.  In spite of new guidance (still flawed in my view) on clinical trial design in pneumonia and in skin infections, the FDA review of the data developed under the old guidelines by Cerexa/Forest for ceftaroline was balanced and informative.  The incredibly tight data and very well designed studies saved the day.  Not only did the ceftaroline data, with studies powered for a 10% NI margin, come in at 4 or 5% overall, but almost all of the subgroup analyses carried out by both the sponsor and the FDA (and some of these subgroups were small!!) came in with NI margins under 10% compared to either ceftriaxone in the pneumonia studies or vancomycin plus aztreonam in the skin infection studies. But in addition, the spectacular data allowed the FDA to accept studies carried out under an old paradigm and to use a post-hoc approach to examine putative new endpoints in an exploratory way.  I discussed the idea to use this approach with the FDA back in April.  

The advisory committee voted unanimously to approve ceftaroline for both community acquired bacterial pneumonia and acute bacterial skin and skin structure infections (http://www.reuters.com/article/idUSN0723105820100907).  Breakpoints remain a key issue. 

Aside from the good news on ceftaroline, a number of important issues for antibiotic development were discussed at this meeting.

FDA and Pneumonia –

In the FDA analysis of the ceftaroline data – here is how they defined their modified intent to treat group:

 - The inclusion criteria for enrollment in the (ceftaroline) trial required signs and symptoms consistent with pneumonia, chest radiograph confirmation of an infiltrate, and pneumonia of specified severity based on PORT Risk Class. Therefore the FDA-mITT population included randomized patients who received any amount of study therapy and had demonstration of a baseline pathogen as stated below:

Patients with sputum specimens as the respiratory specimen for culture were required to have at least 10 WBC/LPF and < 10 squamous epithelial cells (Applicant required only presence of WBCs and < 10 squamous cells).

Patients with adequate sputum specimens as defined above or blood culture positive for the following organisms or positive urinary antigen for S. pneumoniae were included:

-Streptococcus pneumoniae

 -Haemophilus influenzae

-Moraxella catarrhalis

 -Streptococus pyogenes

 -Staphylococcus aureus

 -Klebsiella pneumoniae

Note: Haemophilus parainfluenzae was not considered to be a pathogen in the FDA population

Patients with certain Gram-negative enteric organisms were included if the patient was classified as PORT III or greater, the sputum specimen was adequate as described above, or isolate was from another appropriate sample, such as bronchiolar lavage or pleural fluid.

FDA also included patients from whom Legionella spp. was identified.

The Agency reviewers’ endpoint (at day 4) required subjects to fulfill two criteria:

1. Clinical stability as defined by the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) Consensus Guidelines for the Management of Community-Acquired Pneumonia in Adults. The IDSA/ATS criteria for clinical stability, primarily determined by vital signs, were as follows:

Temperature ≤ 37.8°C, measured orally, rectally, or tympanically

Heart rate ≤ 100 beats/min

Respiratory rate ≤ 24 breaths/min

Systolic blood pressure ≥ 90 mm Hg

Oxygen saturation ≥ 90%

Normal mental status

2. Symptom improvement criteria involving four components:

Cough

Dyspnea

Pleuritic chest pain

Sputum production

The FDA-MITT population from the ceftaroline data analyzed by prior vs. no prior antibiotics was too small to yield meaningful data.

Skin infections –

Analysis population - Randomized patients who received any amount of treatment with lesion size ≥ 75 cm² having one of the following infection types: ‘major abscess’ with ≥ 5 cm of surrounding erythema, ‘wound infection’, deep/extensive cellulitis’ or ‘lower extremity SSSI in patients with diabetes mellitus or PVD’. The Applicant (Cerexa) also presented information on 19 patients with infection type defined as “bite” that met size criteria and were not of human or animal origin and were consistent with literature reports of MRSA infection; these patients were also included in the FDA-MITT population.

Endpoint – day 3 – cessation of spread of lesion and afebrile.

In patients with no prior use of antibiotics within 24 hours, treatment differences were inconsistent across trials, favoring ceftaroline in one study but favoring vancomycin + aztreonam in the other.

Discussion points for the committee (Tom Fleming in this case) were around vital signs vs. clinical symptoms and signs. Dr. Fleming believes (apparently so does the Institute of Medicine) that vital signs are biomarkers that require rigorous validation whereas clinical signs are actually linked directly to how a patient feels and therefore are OK as endpoints. Most infectious disease physicians would take issue with the fact that slowing pulse, slowing respiratory rate and decreasing temperature in pneumonia patients need validation – but apparently Dr. Fleming doesn’t care.  Where does the FDA stand?

Another area for discussion revolved around the measurement of lesion size in trials of skin infections.  For the ceftaroline trial, lesions were measured in two dimensions – length and width, to get a rectangular area.  Several committee members rightly pointed out that cellulitis is not rectangular.  I think that now that halting of lesion spread is a clear endpoint for the FDA (we can all argue about whether this is appropriate or not), more sophisticated measure will be required – but are easily feasible these days.  

In another really good sign, Dr. Follman, a statistician at NIH, noted how conservative the FDA determinations were for both the treatment effect and for the NI margin required – see my previous blog on this as well.