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By Shabnam Sigman

December 15, 2003 |  SAN FRANCISCO -- Speakers at the recent BioPharm Summit 2003* generally had two items in common on their holiday wish lists: a new R&D paradigm and better interaction with the FDA. Each presented a perspective on why the pharmaceutical industry is spending more on R&D but getting less in return, and each pitched a favored solution to the problem of Phase III drug failure.

“We are generating more data but not being more successful,” said Mervyn Turner, senior vice president of worldwide licensing and external research at Merck. “There is a zone of chaos, when in vivo takes over, and we understand very poorly what goes on there. We can wander around in the zone for years. At Merck, 50 percent of molecules die from toxicity (due to unpredictable long-term safety in animals). One-third die from man -- our understanding … is less profound than we thought.”

His solution is to stuff the pipeline with more compounds and overwhelm the odds. Others argued such brute force only perpetuates the failure cycle. A better answer is to get rid of Phase I and II clinical trials, argued Ray Lipicky, director of Lipicky LLC, and former director of the FDA’s Division of Cardio-Renal Drug Products at the Center for Drug Evaluation and Research.

In 21 years of processing new drug approvals, Lipicky said, “the number of times a Phase I trial has been important is zero.”

Amid this spirited search for solutions, the most familiar refrain came from Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development, who ticked off  familiar reasons for lower productivity in the drug pipeline: a highly competitive marketplace; lower market caps; a “blockbuster mentality” that results in research being market-driven instead of science-driven; and mergers and acquisitions.

“The [market] demands on drug developers are why the investor market dropped out of biotech [in the first place]. You have basic scientists trying to make complex decisions,” he said. But he credits this inefficient system for drawing attention to itself and “forcing a change in R&D … [which] I think is the best news for the biotech industry.” Faster development times and an increase in clinical success rates can lower total development costs, he reminded the audience.

Kaitin’s recommendation was to “kill early and kill often” -- in essence, to stop a drug with uncertain chances for approval before it gets to Phase III rather than just trying to push it through. His vision of an improved R&D process (within drug companies) includes better decision making, managing of resources, and communication with the FDA; more involvement throughout the trial process -- not only during Phase III; and faster adoption of new technologies.

Poor Management

But management incentives encourage keeping drugs in the pipeline, according to Sam Holtzman, co-founder and CEO of Rosa Pharmaceuticals. “Biotechs and pharmas live and die according to their share price,”  he said, which Wall Street links directly to the size of their pipelines. Holtzman argued that biotech and pharma managers are encouraged to waste resources and dismiss technology that could kill their drug early.

Michael Hensley, president of Hensley & Pilc, and former vice president for medical and regulatory affairs at Quintiles, offered, “People hurry because milestones have to be met, investors have expectations, and payments are based on milestones. But people don’t manage time very well, so timelines get extended.” He suggested hiring successful, deadline-oriented managers and limiting the authority of scientists when it comes to time management.

All the speakers agreed FDA guidelines need to be revamped. “The only way you’re going to reboot the system is to change the ground rules,” Hensley said.

Recalling his time at the FDA, Lipicky said changing the status quo at the FDA isn’t quite that simple. “The whole time I was at the FDA, it didn’t issue a single guideline. If it did [such a thing], the rules would change before it was issued,” he said. “If you do get a guidance document from the FDA, it has to almost say nothing because it has to satisfy everyone in the FDA.”

More Is Better

To improve overall productivity, Turner urged companies to push more compounds into the pipeline to increase the probability of success with better target validation and by using predictive toxicology.

But completely replacing Phase I and II trials with “adaptive trials” was Lipicky’s decidedly offbeat message. In response to the argument that the FDA requires Phase I trials, Lipicky shrugged and said, “There is no ‘FDA.’ There are only divisions within the FDA.” In his view, early trials rule out only a very small incidence of adverse effects of a new chemical entity.

Lipicky recommended that companies instead perform only one large trial -- which could save two to four years of development -- with a wide dose range to define dose-limiting problems. “The burden of proof rests upon those who wish to market [drugs] … not upon the FDA,” he said. “Don’t think Phase I, Phase II, Phase III.”

Turner didn’t concur.  “There’s not a huge amount you can wring out [of Phases I and II] if you’re doing things the right way. It’s very hard to beat five years -- and that’s if everything goes flawlessly,” he said. “What about the behind-the-scenes [issues] that aren’t addressed when you just focus on clinical development time? What’s the point of doing [trials] in people if you can’t do them in animals?” When asked about the possibility of a drug being successfully developed in such a manner, he responded curtly, “I’m not taking it.”


*BioPharm Summit 2003: Why Drugs Fail; San Francisco, Oct. 29, 2003.

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