Wednesday, September 15, 2010
While at the ICAAC meeting (ending today), I learned a great deal about the emerging threat of the NDM-1 (New Delhi Metallo) beta-lactamase and its rapid spread throughout the world. Beta-lactamases are enzymes found in resistant bacteria that hydrolyze penicillin, cephalosporin and carbapenem antibiotics. While they do not hydrolyze the monobactam antibiotics of which oly aztreonam is sold on the market, most organisms that have NDM-1 also have other enzymes that hydrolyze aztreonam. So this means that our most powerful and least toxic antibiotics are off the table to treat these infections. In fact, most strains are only susceptible to two or three antibiotics. Tigecycline, a drug I helped develop, remains active against most strains. Colistin is active in vitro, but since we don’t exactly know how to use it or how toxic it is, physicians are hesitant to use it unless absolutely necessary. Many strains are also susceptible to an antibiotic called fosfomycin that is mainly used for urinary tract infections.
One good approach to NDM-1 bearing pathogens is to combine aztreonam with an inhibitor of the aztreonam hydrolyzing beta-lactamase enzymes. There are currently two such inhibitors in clinical development – NXL-104 from Novexel and now at Astra-Xeneca and Forest, and MK-7655, a very similar molecule from Merck. These inhibitors are currently being developed in combination with ceftazidime (Astra Zeneca), ceftaroline (Forest) and imipenem-cilastatin (Merck). None are pairing them with aztreonam. When the clinical development of these inhibitors was first contemplated, metallo-beta-lactamases were not the threat that they are today. The options for the companies are to add yet another combination for treatment of metallo-beta-lactamase bearing pathogens using the inhibitor plus aztreonam or to replace their current partner with aztreonam or do nothing and hope the NDM-1 problem will fizzle. At ICAAC, David Livermore made an impassioned plea for the development of the combination with aztreonam.
Governments could, in fact, provide additional funding for the companies to develop such a combination and could commit to purchasing some minimum volume of drug. I would hate to bring the government in to such considerations because they move even slower than big pharma. But this is something that governments should now be contemplating – especially the one in the UK where the numbers of NDM-1 infected patients are rising rapidly.
In discussing the FDA Guidance for mild infections with a highly placed FDA official recently, I discovered something new – an appreciation of reality. The FDA realizes that no one has stepped forward to try and conduct trials in acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) since the superiority trials required are simply infeasible. Of course, we do not need (mostly) a new antibiotic for these infections today – but who knows what we will need in 10-15 years. During our discussion, the FDA official underlined the fact that the current guidance does not apply to severe exacerbation where patients are intubated, since they recognize that antibiotics play a lifesaving role in therapy and that withholding antibiotics from such patients is clearly unethical. But the Cochrane database suggests that even patients with moderate disease exacerbations will benefit from antibiotic therapy (http://www.ncbi.nlm.nih.gov/pubmed/16625602). Furthermore, the treatment effect of antibiotics overall was on the order of 50% for clinical endpoints and 23% for mortality. A careful analysis of the database and additional attempts at examining antibiotic benefit in patients more moderately as opposed to very severely ill would be very helpful in this regard.
Based on my discussions, I am looking for a volunteer sponsor. They would need to do the appropriate literature research, propose an NI margin, provide a protocol synopsis and discuss a clinical trial plan with the FDA. Another option is for the FNIH group to do this work.
But I believe the door to non-inferiority trials in acute bacterial exacerbations of COPD could be opening just slightly if we can make the right arguments. Are there any volunteers out there?
Wednesday, September 8, 2010
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:
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:
Pleuritic chest pain
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.
Friday, September 3, 2010
Watershed or Waterloo
In a previous blog, Watershed or Waterloo, I discussed the upcoming September 7 FDA Anti-infectives Advisory Committee (AIDAC) meeting on Forest/Cerexa’s antibiotic, ceftaroline. I noted that the data presented by the company either in abstract or in publication form was impressive and robust. Well, the briefing materials for the meeting have just been released to the public by the FDA (FDA briefing document ceftaroline) and they indicate that the FDA agrees with me and with Forest/Cerexa that the data are, in fact robust, no matter which way you analyze them. It looks like the FDA will agree that their endpoints correlate well enough with the new early endpoints proposed for pneumonia and skin infections that they will be satisfied with these data. So, I think it is likely to be watershed rather than Waterloo, but I’ll be watching on September 7.
IDSA and FDA
The infectious diseases society has recently sent a letter to Janet Woodcock of the FDA regarding the development of new antibiotics for resistant bacterial infections. In their letter, they correctly note that current clinical trials guidance fails to meet the needs for new antibiotics active against our most difficult resistant pathogens. They urge the FDA to focus on this problem. They further suggest that one approach might be to establish a consortium of centers, perhaps through the NIH, where there are higher populations of patients infected with such pathogens such that clinical trials can be practically executed. My own view is that this will require that the FDA go back to Mark Goldberger’s suggestion from 2002 – use a low quantity of high quality patients. If the FDA would be willing to allow salvage studies of small numbers of patients where the studies would not really be statistically powered, and then add other supporting data such as in vitro data and non-clinical and clinical PK/PD studies, we might be able to get somewhere. This was the essence of Mark’s suggestion (which got nowhere). While I think the IDSA is once again to be commended for their efforts, it will be important to keep the discussion sharply focused on feasibility.
Government and Roadblocks
While catching up on journals over the past month, I ran across a wonderful Perspective from the New England Journal on government roadblocks to comparative effectiveness research. Having worked for the VA for many years, the article immediately caught my eye. The authors, Martin et. al., discussed the example of trials of Avastatin compated to ranibizumab in the treatment of “wet” age-related macular degeneration (AMD). These trials became necessary because ranibizumab had an extremely high cost whereas Avastatin, which had a similar mechanism of action, was much less costly. The National Eye Institute jumped into the void and approved monies for such a trial. The cost to Medicare for ranibizumab alone for the trial would have been on the order of$25 million. Medicare initially refused to cover this cost. Medicare also would not pay the copay (20%) that would be required for trial participants who did not have supplemental insurance and who received ranibizumab. The grant did not cover this cost. Finally, the National Eye Institute was able to identify a mechanism to provide funds for these costs – but the trial was delayed for over a year. Then the investigators ran into the problem of masking drugs (for a blinded trial) so that neither patients nor physicians would know who was getting what. But with billing systems, this became impossible. The trial finally got underway but enrollment was slowed by the cobbled together payment and blinding systems. None of this gives one confidence that antibiotics trials run by the NIH where elderly patients will be treated with approved drugs will do any better.