The nomination of Dr. Scott Gottlieb for FDA commissioner, a political appointee, has created the usual bipartisan furor. He is called unqualified, a renegade, not committed enough to FDA orthodoxy, an industry darling by some and a maverick by others. All the while FDA lobbyists are singing the praises of an agency already highly efficient with speedy approvals and streamlined processes.
Looking back at the last 15 years, the memories of FDA heavy-handedness with anti-infectives regulations and drug evaluations come back, and they still haunt us. We cannot forget the demands for new studies supposedly because “the science had changed” when it had not, the occasions when minor deviations from guidelines became show-stoppers, when the Agency reneged on prior commitments, and when advertised ‘flexibility’ was absent when dealing with Phase 3 studies or a submission dossier.
We cannot easily get over the demands for ‘superiority’ trials, still on the books but never attempted, which remain an oddity in the testing of antibiotics. Remember the FDA push for ‘placebo’ controlled studies not only for otitis/ABOM, sinusitis/ABS and bronchitis/ABECB trials but also in CABP? How many sessions did FDA organize, how much time was wasted rationalizing an NI margin that in the end looked exactly like the one we had before?
Poorly executed studies from the 1930’s were presented in support of the ‘new science’ – what a fine twist!
We dare to challenge the usefulness of historical controls for quantitative analysis in general, but FDA’s torture of historical data from Snodgrass publications dating back to1937 in order to derive M1 and M2 and then applying an arbitrary ‘discount’ was actually quite comical. A very entertaining exercise in contortionist thinking. No wonder the EMA did not go along with this.
Antibiotics still have to demonstrate efficacy over placebo, disregarding myriads of studies which have proven the concept. We choose to ignore Bayesian concepts of statistics which would allow us to build on the rich experience from prior trials. A wasteful practice only rich countries can afford
Let us be clear: We don’t find fault with the agency’s reviewers and the work they do. Their attention to quality, detailed reviews and rigorous data analysis are outstanding. What is less endearing to us are the onerous regulations that have reached a level of indescribable stupidity.
Strong words? Not really. The new requirements made clinical studies almost impossible to execute for about a decade. Expert clinicians admonished FDA not to lose sight of the bigger picture, not to change what was not broken. Their advice went unheeded; zealots and statistical purists usurped the agenda and imposed their imprimatur on the regulations now in place.
Today we want to highlight just one example of the “good work” done by FDA philosophers which greatly impacts our ability to generate data in US patients.
CABP Guidance – Fall-Out from the “No Prior Antibiotics” Rule
In the US, it is rare for a pneumonia patient not to get antibiotics shortly after arrival in the ER. Analyses of large data sets have shown that delaying the administration of antibiotics negatively affects outcomes; hence, most hospitals strive to start them within the first 4 hours.
It takes time in the ER to process patient intake data, do an H&P, obtain labs and the microbiology and imaging studies to establish a diagnosis of CABP. Obtaining a respiratory sample of decent quality is good practice in general, although required for registration studies. This step alone can be quite time-consuming as sampling of respiratory secretions may require the assistance of a respiratory therapist and inhalation treatment. Four hours go by fast in the best of settings.
Then there is this thing called Informed Consent. Unless you ask your CAP patient to sign this document blindly, it takes time to go over all the pages with an acutely ill patient. How much time doctors really spend explaining study details, risks and benefits, and all the other yada, yada on the consent form is open to question, but withholding antibiotics while enrolling a patient into a CAP study becomes a race against time.
FDA insists that no more than 25% of patients receive even a single dose of non-study antibiotics prior to enrollment. Actually, this 25% figure was a hard-fought compromise as FDA did not want to accept any patients receiving even a single dose of prior antibiotics.
As a consequence of this “No Prior Antibiotics Rule”, US centers are no longer able to contribute patients to international trials. Recent CABP studies make up for this by recruiting ‘antibiotic-naïve’ patients in far-away places, preferably in Eastern European countries where health care standards seem to be more lenient and medicine is practiced in a way that makes it easier to comply with FDA wishes.
In the recent Solithromycin CABP trial 301, only 11% of patients were from the US, and 5% were African-American. In the ceftaroline CABP program only 2% of patients came from the US. In another recently completed CABP trial, barely 5 US patients could be recruited.
FDA’s justification for not allowing even one prior dose of antibiotics was based on the analysis of the failed daptomycin CABP study[1]. Since then we have newer data suggesting that a single prior dose of antibiotics does not affect outcomes. Contrary to some ideologues, FDA’s ‘purist’ approach does not add much to the interpretability of the efficacy data.
We argue that the loss of representative US data is a costly trade-off, with much lost for little gain. Currently, the demographics of CABP studies are certainly no longer representative of the US population, just the opposite.
FDA seems to believe that the health care practices of the old Russian Satellite countries are similar enough to the US population. When one reviews the CRFs from these countries, one comes away with a slightly different impression.
As it stands right now, FDA will get used to seeing a lot more data from the Ukraine, Poland, Estonia, Latvia, or Russia – all countries of choice for CROs conducting CABP trials these days.
In the Teflaro (ceftaroline program, only 1 pivotal CAP trial (Study 08) enrolled US patients amounting to 4% of study population. Quoting the Medical Reviewer: “Of particular interest is the fact that the Applicant categorized Hungary and Poland as part of Western Europe”
This FDA ‘No Prior Antibiotic Rule’ has backfired because it diverged too much from clinical practice. It will take more than fine-tuning to get back to a realistic practicable approach for CABP trials. The same holds true for other indications.
Our belief in evolutionary change is gone…let’s give the new leadership a try, please!
References:
[1] P Pertel. Effects of Prior Effective Therapy on the Efficacy of Daptomycin and Ceftriaxone for the Treatment of Community-Acquired Pneumonia. CID 2008; 46:1142
As European born, raised, and educated Regulatory Affairs Manager that moved to the United States a couple of years ago, I have to say the level of globalization of the FDA is remarkable, seeing how localized most institutions in this country are.
The line between safety and non-practicability is always a fine one and agreeably sometimes makes clinical trials difficult and more expensive as it needs to be. But when confronted with the choice between reliable data and savings for the industry – I will always chose the former one.
All things considered, I think the FDA is doing a great job in harmonizing regulatory requirements and pharmaceutical standards on a global level. And yes, that does mean some regulations become more restrictive, but it opens international opportunities as the data for other regions is already obtained.
The one change the FDA (and the US laws behind it) could use, would be a higher influence on the drastically exaggerated prices of US prescription drugs. But that is a long process and needs a more unified health care sector.
Torsten, looking at recent regulations affecting anti-infectives drug dev, I am not sure I agree with many of your statements.The FDA is not in a position to regulate prescription drug pricing given its current remit, if anything, they have helped to drive up drug prices. If you think that FDA’s efforts have produced more reliable data as you suggest, I would like to see the evidence. FDA is forfeiting its prior global leadership by setting up its own US-centric study criteria (eg, in CABP) forcing companies to incorporate both FDA and EMA outcome endpoints into a single trial. All this is against the spirit of ICH, and costly to society without a compensatory benefit.