FDA

The FDA’s cautionary Hall of Shame: 22 ‘breakthrough’ drugs that suddenly crashed in PhIII

We still don’t know who will run the FDA under Donald J. Trump, the 45th American president. Commissioner Robert Califf steps down at noon today. But Trump’s high-profile sit-downs with some unorthodox candidates for the job have put the spotlight on some new clinical shortcuts that could be used to speed drug development.

Some on the libertarian side have said they want to simply toss out the gold standard on efficacy and safety altogether, excoriating the old rules of market engagement.

That toxic argument raises some important questions about each stage of drug development. And there’s a new report out from the FDA that covers just what you can miss if you cut Phase III out altogether.

The authors raised some important and timely questions with their review of 22 case studies — you could also call them cautionary tales — of drugs that fell notoriously short of the regulatory mark. And they include a batch of potentially dangerous therapies that made it through Phase II looking like solid additions to the nation’s pharmacopeia.

The Hall of Shame includes:

  • Darapladib, the GlaxoSmithKline cholesterol drug that investigators were absolutely convinced was helping cardio patients. GSK went on to recruit 28,000 patients for two Phase III trials that proved they were flat wrong.
  • Eli Lilly’s notorious semagacestat for Alzheimer’s. Yes, the drug did have an impact on amyloid beta, the suspected toxic clusters often found in patients’ brains. It also doubled the risk of skin cancer and a host of other lethal side effects while actually worsening outcomes for patients. Lilly, though, doubled down on Alzheimer’s with solanezumab, which also failed multiple clinical studies.
  • Figitumumab from Pfizer, which also cleared the Phase II hurdle as an add-on treatment for non-small cell lung cancer, only to demonstrate worse adverse events in Phase III. Pfizer went on to retract three of their studies, citing discrepancies in the data.
  • Sanofi touted both better survival rates and promising tumor responses for iniparib at one point. But this PARP inhibitor, to the extreme embarrassment of Sanofi, wasn’t even a PARP inhibitor. In Phase III, the outcomes looked very similar to standard chemo.

Sure, new technologies offer added insights at an earlier stage of development, notes the FDA report. But Phase IIIs were crucial in these cases, and likely will be in others.

And something for the libertarians in Silicon Valley to remember:

As a result of the Phase III studies discussed in this paper, patients outside of clinical trials were not subjected to drugs that would not benefit them or to the risk of unnecessary serious toxicities, and did not suffer unnecessary financial expenditures. Where effective alternative therapies existed, they were not diverted from proven treatments…

Close to 38% of all drugs in the Phase III/NDA phase of development never make it to an approval. In Phase II/III, the chances of success are 35%, according to a Tufts study of the development process. That leaves some big margins for error.



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