The development of Vertex Pharmaceuticals Inc.’s cystic fibrosis therapy Kalydeco (ivacaftor, VX-770) is a model for how to efficiently and effectively get a drug through the approval process, Stephen Spielberg, FDA’s Deputy Commissioner for Medical Products & Tobacco, told the Biotechnology Industry Organization’s CEO & Investor Conference in New York Feb. 14.

“It’s a paradigm for how things can work if done right,” Spielberg said.

FDA’s Temple, Woodcock and others are reviewing FDA data to determine what sort of innovative study designs work, Deputy Commissioner Spielberg said.

The first disease-modifying drug for the genetic disease, Kalydeco is a personalized medicine that targets an underlying genetic defect Also see "Early Success For Kalydeco Is Just The Beginning For Vertex’s CF Drug" - Pink Sheet, 6 February, 2012.. But it is not only the scientific specificity that makes it an exemplar of modern drug development – the path of discovery and development is also a model others are looking to emulate.

“First, it required an advocacy group, the Cystic Fibrosis Foundation, keeping CF on everybody’s mind,” Spielberg stated. “Second, it required them setting up an investigative network around the country.”

The Cystic Fibrosis Foundation contributed more than $75 million to the discovery phase of Vertex’s CF program. It played a major role in the early stages of innovation, identifying the CFTR gene as a cause of CF and characterizing the biological and biochemical function of the protein and its link to the disease process. The foundation also used its clinical trial network of 80 sites to enroll patients rapidly in the clinical trials Also see "CF Patients Breathe Easier With Vertex Drug" - Pink Sheet, 23 February, 2011..

“I can’t tell you how hard it is doing clinical investigation in real time rapidly and effectively right now when you don’t have those networks in place, and how much time and how much money is lost in the process of doing clinical trials with investigators who don’t know the disease,” he added.

Spielberg said understanding the molecular biology of cystic fibrosis and the multiple different gene mutations leading to the disease was another critical factor. Researchers discovered that a mutation of the CFTR gene produces a protein that causes the chloride channels, which regulate the flow of salt and water out of cells, to snap shut. Kalydeco keeps the chloride channels open. The gene mutation occurs in only about 4% of people with cystic fibrosis.

Investigators also had a biomarker to measure chloride in the skin, Spielberg said, “so that Phase II became almost a non-doer; with a couple of patients you had your answer.”

The sponsor then worked with FDA “on a clinical trial so small, so efficient, so fast that we got the answer unequivocally in barely 200 patients,” Spielberg stated.

“If you took the old approach to drug development” and enrolled 7,000 patients with cystic fibrosis regardless of their genetic mutation, “you would have ended up with a negative study because only the patients with this mutation could benefit from this drug,” Spielberg noted.

“If you took the old approach to drug development” and enrolled 7,000 patients with cystic fibrosis regardless of their genetic mutation, “you would have ended up with a negative study because only the patients with this mutation could benefit from this drug,” he said.

Under the new approach FDA approved Kalydeco in less than three months, half the time of standard priority approval Also see "Vertex Gets Quick FDA Approval Of Kalydeco; Prices New CF Drug At $294,000 Per Year" - Pink Sheet, 31 January, 2012..

Center for Drug Evaluation and Research Director Janet Woodcock also highlighted the Kalydeco experience as a new way of finding effective therapies in small patient subgroups in a blog posting on the approval.

“The unique and mutually beneficial partnership that led to the approval of this new therapy for some CF patients serves as a great model for future drug development and patient group collaboration moving forward,” the center director said.

She also stressed the personalized medicine angle as a factor that tipped the regulatory scales, and cited two other recent examples of targeted medicines cleared with companion diagnostics for patient identification – Pfizer Inc.’s Xalkori (crizotinib) and Roche’s Zelboraf (vemurafenib). All three drugs were approved well in advance of their user fee deadlines.

FDA Seeks To Be At Cutting Edge Of Diagnostics, Clinical Trial Designs

Spielberg, who joined FDA three months ago, was previously Director of the Center for Personalized Medicine and Therapeutic Innovation at Children’s Mercy Hospital in Kansas. His choice to head one of the agency’s new directorates was seen as a boost to the agency’s efforts to encourage personalized medicine Also see "FDA Reorganization Creates Prominent Roles For Mercy Hospital's Spielberg, CDER's Autor" - Pink Sheet, 13 July, 2011..

At the BIO meeting Spielberg also voiced support for creativity and innovation at FDA. He indicated that the agency is reviewing internal data to determine best practices, and provide better advice to companies.

“We need to be at the cutting edge, and I hope leading the biologic revolution in thinking about the problems that sponsors large and small are going to face with respect to using diagnostics – validation and clinical utility of those diagnostics in predicting outcomes – and novel clinical trial designs,” he stated.

He noted that Robert Temple, deputy center director for clinical science in CDER, Woodcock and others are working actively now on innovative study designs based on the data that FDA has, looking at what works and what doesn’t. Similarly, on the diagnostic side, he said the agency is assessing what aspects of diagnostics have been successful and what aspects have been failures.

“When a company says we want to do X, we can say you could except for Y,” Spielberg said. The agency can then suggest that the sponsor do something different that “leads to a faster, more efficient development process.”

Other panelists emphasized the need for innovation at FDA to reduce the time and cost of drug development and encourage investment.

Jonathan Leff, managing director of healthcare at Warburg Pincus, cited a survey in which venture capitalists said they were pulling out of the biopharmaceutical space primarily because of the regulatory environment.

But while he pointed out that only 10% of compounds put into the clinic ultimately get on the market, Leff said one cannot blame FDA. “We have to recognize that there’s a problem and then recognize that it is nobody’s fault but it is everybody’s problem,” he stated.

Safety And Efficacy Must Be Balanced With Innovation, Investor Says

When venture capitalists talk about the regulatory environment they mean that the cost and time of drug development has escalated, Leff said. Noting that there has been an emphasis on the need for safety and certainty about new drugs over the past decade, he asserted that safety and efficacy must be balanced with promoting innovation. Venture capitalists made this argument last year in proposals for improving the approval process Also see "FDA Approval Standards Need To Be Relaxed, Venture Capitalists Say" - Pink Sheet, 11 July, 2011..

Leff recently gave a presentation to CDER staff on the state of emerging companies and how they perceive the regulatory environment, at the invitation of FDA’s Woodcock. He said he showed them an illustration of a triangle with safety, efficacy and innovation at each point.

These are the goals “that need to be balanced in the regulatory process and in the policy decisions that get made at FDA,” he said. “It may sound like a radical notion to some people within FDA to put innovation on the same slide with safety and efficacy. I tried to challenge people to think about that more broadly and that these three things have to be together.”

Innovative Drug Development: Kalydeco Provides A Paradigm, FDA’s Spielberg Says

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