Statements that have the words ‘FDA’ and ‘flexibility’ in a single sentence need to be approached with some skepticism. Especially if made by the Agency.
‘Flexibility’ always sounds better than ‘less rigidity’. Regulators are tasked with providing a certain sense of consistency or stability in the drug development jungle where every applicant feels entitled to ‘special’ consideration. We value FDA as a provider of standards and guidances, not so much as an arbiter or referee in individual situations.
Indeed, FDA has proven to be a strict defender even of rules that have outlived their usefulness. Case in point: single-organism antibacterials. In the world of indication-driven labeling originally developed in the era of broadly active drugs, daptomycin was an anomaly bucking the regulatory paradigm. How is anyone supposed to develop a drug for MRSA, Pseudomonas, Acinetobacter, or MDR pathogens? Companies developed plans, ran them by the FDA and ended up getting nowhere – for a long time. It is hard to work outside of the FDA rule book.
Hence, flexibility is not the word that comes to mind in these situations.
Exceptions were made by FDA, of course, and in particular, statistical parameters were handled with some flexibility, depending on the situation.
The NEJM article by the new FDA leadership on the “One Pivotal Trial” requirement comes as a surprise. The authors are Drs. Prasad and Makary, and they claim that this was really not something new, as FDA showed flexibility to forego a 2nd trial, if supporting evidence were available. With the clarion call ‘the science has changed’, we are told that this new standard will not compromise a rigorous review process going forward.
Why these changes, and why now? Well, we know there is a new sheriff in town shaking things up. We see many benefits with this new philosophy and applaud the Agency for taking this bold step, which stands to bring more variation to the drug development process. We are on board with this change.
While the authors mainly concentrate on oncology, our experience is more in the field of anti-infectives and autoimmune diseases. We can say with authority that in the past FDA had zero flexibility demanding 2 mutually confirmatory studies for new antibiotics in a certain indication, be it ABSSSI or CABP or even cUTI. Nobody can claim that the ‘science’ of bacterial susceptibility was less developed in the early 2000s than now; linezolid and omadacycline were subjected to 2 virtually identical trials for the ABSSSI indication, although supporting evidence from in-vitro susceptibility data and animal efficacy studies plus PK/PD were readily available. There was no need to compare omadacycline to linezolid, and thereafter to moxifloxacin as well.
We are referring to omadacycline also for another reason. While FDA was okay with a single CAPB trial for omadacycline and showing some flexibility, the EU CHMP was not: the argument at the time was that the ‘more severe indication’, i.e., CABP, needed to have convincing efficacy data from 2 mutually confirmatory studies. There are many other examples of this rigid ‘belt-and-suspender’ regulatory approach.
To reiterate: we are glad that Prasad and Makary are shaking things up. From the industry’s perspective, this is a welcome change. As mentioned in the article, the cost of clinical trials has risen over the years. We still don’t know how valuable the 2nd trial was in terms of assessing efficacy, or whether the cost in time and money was a reasonable investment.
It is unclear whether the 2-study rule was ever justified. Remember that the alpha in pivotal trials is actually a one-sided p = 0.025 which sets a very high hurdle already.
We assume FDA reviewed their extensive internal database to check how often 2 pivotal studies gave divergent results and were not mutually confirmatory. We want to remind readers of the Xigris / drotrecogin sepsis approval. A very large single Phase 3 study led to an approval for severe sepsis. However, none of the follow-up studies were able to replicate a treatment benefit; eventually, Xigris was withdrawn. There may be a few other examples in which the ‘2 trial dogma’ may have added value. Here we are not defending the old system, we just would like FDA to show us their analysis in support of the One-Pivotal Trial rule change.
We applaud the Agency for trying something new. It should reduce program costs for sponsors who now can invest this money into better-designed post-approval trials. We may also see a trend towards larger Phase 2b trials to provide further supportive data.
We do not think this change was brought on by scientific progress; instead, we believe it was driven by a different philosophy. The old system was not broken, and the new system will not be perfect.
Remember the arguments for and against the Frequentist and Bayesian approaches to study statistics? The FDA group around Prof. Fleming prevailed in the early 2000s, arguing for an exclusive use of the Frequentist approach which ignores preexisting supportive data. Prasad rightly points out that many of what he calls ‘factors’ are captured in a Bayesian interpretation of trials. That’s not new science, just 2 different approaches, each with their own good justifications. The pendulum just swung to the other side of the debate.
We expect that sponsors and PhARMA will be supportive of the new philosophy. What is less clear is whether it will also be accepted by other regulatory authorities. ICH was not mentioned in the Prasad article. Has the One-Trial concept been ‘harmonized’ with other major regulatory bodies, like EMA and PMDA? After all, global drug development cannot survive well when regionally different rule books emerge.
Two more points:
- The efficacy of imatinib / Gleevec was nothing short of spectacular. Patients with end-stage CML experienced a Lazarus effect. None of the >150 new oncology drugs approved in the last 25 years comes close. It is not useful to defend a policy change by citing an exception, a unique situation rarely seen.
- Regarding the statement that this change in regulations would bring down costs of development and the price of prescription drugs: even if the former happens, the latter never will. Did cost savings from manufacturing efficiencies ever trickle down to the consumer? This conjecture is wishful thinking.
ABBREVIATIONS
ABSSSI acute bacterial skin skin structure infection
CABP community-acquired bacterial pneumonia
CHMP Committee for Medicinal Products for Human Use
CML chronic myelocytic leukemia
cUTI complicated urinary tract infection
EMA European Medicines Agency
ICH International Council for Harmonization
PhARMA Pharmaceutical Assoc of Research-based Manufacturers
PMDA Pharmaceuticals and Medical Devices Agency / Japan
REFERENCES
Prasad V. One Pivotal Trial, the New Default Option for FDA Approval — Ending the Two-Trial Dogma. NEJM 394;8: 815, 2026
