FDA Sets Its House in Order

Agency leaders are redefining science, moving away from early 20th century empiricism and toward a mechanistic understanding of processes, in everything from manufacturing to R&D and clinical trials.

By Agnes Shanley, Editor in Chief

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FDA, like the pharmaceutical industry it oversees, is at a turning point in its history. Criticized by the media and politicians, and challenged by tight budgets, the Agency is rebuilding its public image and taking decisive steps to ensure that science is guiding its decisions.

It is also redefining that science, in efforts such as the Critical Path initiative. As Dr. Janet Woodcock, FDA’s Deputy Commissioner, reiterated at the recent IFPAC conference in Baltimore, “The drug development process is becoming a serious bottleneck. We’re using the evaluation tools and infrastructure of the last century, and in some cases, tools from very early in the last century, to develop this century’s medical advances, and FDA would like to change that.” In her new role as Chief Medical Officer, charged with raising the level of scientific quality and effectiveness at FDA, Dr. Woodcock is optimistic. “We want to establish a culture of openness and transparency,” she said.

March 2007 Cover ImageThe Agency has already addressed its most obvious vulnerability: lack of a dedicated, full-time “CEO.” Years of tentative leadership came to an end last December, when Dr. Andrew von Eschenbach was confirmed as the new FDA Commissioner, with final closure in February, when former Commissioner Lester Crawford was fined and sentenced to three years’ probation for conflicts of interest. He had been Commissioner for all of two months.

In addition to conflicts of interest, concerns about drug safety and the politicization of the Agency took shape during Dr. Crawford’s term. These issues came to a roiling boil in late 2004, when Merck withdrew its anti-inflammatory drug, Vioxx, from the market and FDA reviewer Dr. David Graham testified to the Senate about problems with FDA’s new drug review process.

Earlier that year, Dr. Crawford and senior FDA leadership appeared to make a sudden reversal in position over Plan B, the emergency contraceptive that an FDA advisory panel had suggested would be appropriate for over-the-counter sales. Critics charged that the Agency was driven more by politics than by science.

Also problematic have been user fees, which the Agency has been charging industry since 1992, for reviewing new drug applications and inspecting facilities. The fees make up for chronic shortfalls in the Agency’s funding, and FDA has requested an $87 million increase in these fees to strengthen its post-marketing safety system and help it improve its IT infrastructure. However, these user fees have led to criticism that the Agency is in industry’s pocket and is stymieing innovation by smaller companies.

Two important bills have been proposed in Congress recently that would strengthen FDA’s enforcement ability. One would increase its authority for addressing post-approval marketing and clinical trials, while the other would create a separate center within FDA to oversee the safety of drugs on the market.

Continuous improvement

Even during the most challenging years, FDA had begun to dig into some of its own shortcomings, in an evaluation of the regulatory process and the industry that began when Mark B. McClelland was Commissioner, and continued during Dr. Crawford’s tenuous term. Leading these efforts was Dr. Woodcock, then Director of FDA’s Center for Drug Evaluation and Research (CDER), along with a core group that began to evaluate processes. They invited experts to present the latest findings at advisory committee and Science Board meetings. Some were asked to evaluate FDA operations, all in the quest to improve the Agency and the industry.

It was an “eye-opening journey,” recalled Ajaz Hussain, former Deputy Director of CDER’s Office of Pharmaceutical Science and now vice president of drug development at Sandoz Corp. (Princeton, N.J.), at the IFPAC meeting. It resulted in something of a renaissance, and new thinking demonstrated by 21st Century GMPs, the Agency’s risk-based approach to regulation and compliance, the Process Analytical Technologies initiative, Quality Systems guidance and Quality by Design framework.

FDA is encouraging the industry to become more open to using new manufacturing technologies, and some established conventions are due to change, explained Moheb Nasr, Director of FDA’s Office of Drug Quality, who discussed these issues at IFPAC with Contributing Editor Emil Ciurczak. “With new technologies [such as continuous manufacturing], there will be some associated regulatory challenges,” Dr. Nasr said. “So, we at the Agency are currently revisiting our process validation guidance where the traditional ‘three batches’ approach may not be appropriate.” FDA is looking into different ways to verify the quality of the batch, using continuous process verification and the level of validation and verification that is proportional to process understanding, he added.

“If you have fully developed your design space and you have full knowledge and good predictability of the batch, the validation requirement that will be expected of you will be considerably less than if you’re using empirical techniques to assess quality of the batch,” he said. In addition, the whole concept of the batch is changing, he said, and new technologies may even make compliance easier. “With continuous monitoring, traceability will be much easier than it is today,” he said.

But, as it encourages industry to explore new technologies, FDA also plans to use new tools. To help it achieve these goals, the Agency has just appointed a new CIO and is gradually building laboratory capacity at its new central campus in Silver Spring, Md., at the White Oak facility formerly owned by the Naval Ordnance Laboratory.

FDA has articulated some ambitious goals — nothing less than transforming itself and the industry, and nudging pharma away from the blockbuster and toward a whole new model. Can it succeed? We interviewed two of the Agency’s key leaders for their perspectives.

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