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Peter Pitts Director, Center for Medicine in the Public Interest

Has the prodigious American drug development machine started to sputter?

After much hand wringing in the press about there being "too many" new drugs comes a sobering fact: Although pharmaceutical companies poured a record amount of money into drug development in 2005, the Food and Drug Administration approved only 20 new drugs last year, down from 36 in 2004.

Only once in the last 10 years has the number of newly approved drugs been lower than last year's figure.

So what's clogging up the approval pipeline?

According to Dr. Scott Gottlieb, the FDA's deputy commissioner for medical and scientific affairs, "The development process itself is not keeping up at a fast enough pace to match the progress on the discovery end."

In other words, the science hare is outrunning the approval tortoise.

When Thomas Edison was asked why he was so successful, he responded, "Because I fail so much faster than everyone else." Edison didn't face today's massive federal regulation or predatory liability lawyers. And he was working in a technology where failure was often as clear as a short circuit. Pharmaceuticals are infinitely more complex. Success or failure can be a matter of years, if not decades.

But the question remains. Is it possible to apply advanced engineering to the approval process so failure - or success - can be identified faster in the tricky area of medicine?

Not only could there be enormous savings in costs, but helpful drug discoveries could be moved more quickly from bench to bedside, so they actually help the patients who so desperately need them.

Institutional, legal and organizational barriers, of course, remain formidable. But even within the existing structures, there is much that can be done.

Regulators, industry and academia can partner with the goal of improving standardization and automation of clinical research - in effect targeting "cures" for the development process itself. Such a partnership - with a forceful mandate for change - would seek to apply modern engineering and cutting-edge scientific knowledge to medical product manufacturing.

Standard critical path analysis would almost certainly point to innovations in clinical trial design and uniform statistical methodologies that could produce far more efficient evaluation of a drug's safety and effectiveness. The cost savings of these early warnings would more than pay for whatever process redesign was required. Currently, 50% of drugs that undergo large-scale Phase 3 trials turn out to be too unsafe or not effective enough for marketing. That is not a sustainable model for the 21st century.

There are dozens of fairly obvious tools that can speed up the process with little or no risk. Standardized biomarkers, for instance, have been publicly discussed and vetted for years. They can and should be incorporated into the drug approval process.

Consider a few financial implications.

If the FDA were to help companies to "fail faster" by using the lower end of the Tufts drug development number, a 10% improvement in predicting failure before clinical trials could save $100 million in development costs for a single drug.

Shifting just 5% of clinical failures from Phase 3 to Phase 1 would reduce out of pocket costs by $15-$20 million. Moving just 1/4 of failures from Phase 2 to Phase 1 would reduce costs by $12-$21 million.

Such an FDA initiative should not - and need not - conflict with what industry and other regulatory agencies in the U.S. and around the world and are already doing. In fact, coordination and integration are beneficial to everyone. But the FDA's role is pivotal. The agency stands at the crossroads of the translational process.

The FDA is uniquely suited to take a major role in this effort because of its unique broad and deep understanding of the - often predictable - snags companies and products encounter that are causing drug development to fail in late stage clinical trials.

The Agency has the technical expertise that can draw together stakeholders, help prioritize process research, and build partnerships for reform. What's more, since drug development today is in fact global, it's time to push harder for common standards across national approval bodies, private industry, academic institutions and other global translational research groups.

An FDA Critical Path initiative would help American-based pharmaceutical companies as well. Our innovative growth companies would be more efficient in navigating the approval process and could thus compete more effectively against the bigger, better-funded players in the market. That in turn would have distinct benefits both for these emerging growth companies and for public health. The most important tool is collaboration. Regulators must not remain distant, aloof and unpredictable. Rather the FDA should take the lead in embracing all stakeholders as partners in the public health process.

The FDA itself is well aware of these issues, and has already undertaken significant reforms to speed up a number of high-profile critical paths. In the area of cancer therapies, especially, the agency is making innovative therapies available more quickly and at a lower total cost while maintaining high standards of consumer protection.

It has reduced drug development times by avoiding multiple review cycles. It has initiated a quality systems approach to medical product review. It has worked to clarify regulatory uncertainty and increase predictability in product development to stimulate innovation.

The FDA's communication with sponsors has been significantly improved. The agency is now more available and engaged early on in the review process - including interactions at the end of Phase II meetings, prior to NDA meetings, and after the NDA Submission meeting piloted by the Oncology Division.

Even when drugs are given "Fast Track" status, FDA has requested and approved comprehensive development programs in advance of that designation to ensure subsequent clinical trials are properly structured.

With new Special Protocol Assessment guidance, product developers now work more closely than ever before with the FDA to create phase III studies prior to implementation to gather all necessary information.

The agency's emerging Continuous Marketing Application enhances sponsor access to early guidance and feedback for Fast Track drugs or biologics intended to treat serious or life threatening diseases, and provides for FDA-sponsor agreement to engage in frequent scientific interaction.

In addition to early and frequent communication, FDA's quality systems approach to medical product review has also made the whole review process more efficient. The Common Technical Document (CTD) and the electronic CTD (eCTD) uses cutting edge technology and a closer adherence to international public health methodologies to provide better quality, consistency and communication with sponsors.

In priority areas besides cancer (e.g., obesity and diabetes), the agency is stimulating the development of new medicines by creating clearer guidance for product approvals. With its Special Protocol Assessment (SPA) program, the agency now helps product developers design phase III trials so all necessary data is collected.

When there is an anticipation of a Fast Track designation, the FDA now works closely with the sponsor to review and approve the comprehensive development program and the potential filing for Accelerated Approval. This includes the phase III confirmatory studies that are a critical component of application for accelerated approval.

But more needs to be done.

A family has been described as "a parliament of habits." The FDA - with its 10,000 employees - is a unique family with scores of idiosyncrasies. To an outsider, the agency's methods are not always transparent, but there is certainly an internal logic that moves things forward within the organization. Ultimately, that logic is the agency's traditional mandate of protecting public health. That mission is inherently cautious, and conservative.

As the agency enters its second hundred years - a very different medical environment - there are strong arguments that the agency's mission should be expanded to not only protect, but also advance public health.

The stakes are very high. In economic terms alone, the FDA now regulates upwards of 25% of the U.S. economy. And the political implications of changes in health policy are enormous. So different cultures - scientific, business and political - are heavily involved in every proposal for change.

So change is very very difficult and very very political. The FDA remains a government bureaucracy with its own interests and its own byzantine internal politics. When such a bureaucracy is attacked, the wagons are circled. It becomes difficult to accept advice (even good advice) from people viewed as "enemies of the agency." The "current unpleasantness," driven by events ranging from Vioxx to DTC.

Leadership shuffles have brought shifts more attuned to public relations quick fixes in response to ad hoc attacks from politicians and interest groups. And caution replaces fundamental strategic analysis and even science. Because every change hurts someone.

But change there must be if the FDA is to become what it should be in this century. It must become more future-oriented and science-based, able to move down "the critical path" more directly and rapidly and both protect and advance the public health.

To own change, to wrestle the agenda from those who would use it for their own purposes, we must drive change. Rather than being against things we must seize the day and be for something.

There is no question that without core scientific expertise and capacity, it will be difficult to identify problems in product development across products and disciplines, to then identify the real critical path opportunities, to help choose the very best priorities, to identify, support and work with the best partners, to realistically assess the potential of various approaches to do what we want FDA to do (get rid of the barriers and bumps, develop new paradigms, etc.) and to continue to perform science-based review and risk assessment, and provide appropriate guidance, particularly with new/cutting edge technologies, and maintain agency credibility and standing with the scientific and public health communities.

A healthy and sustainable vision would include appropriate support of cooperative agreements, partnerships, targeted infrastructure in specific areas, and joint training programs. There is a need for rigor and expertise even in identifying needs, giving out grants and ongoing evaluation.

As FDA's bioinformatics and biomarker capability increases its scientific abilities will be strengthened by being deeply and consistently engaged in collaborative drug evaluation development work.

Intra and extramural work must become one in the same, must meet and help develop scientific standards and be part of a program of creating support for guidances, endpoints, etc. We must use the mantra of the agency's current antagonists that FDA must be governed by science not politics and use it to our advantage to create a new a gold standard for how evaluation should be conducted.

With respect to the overall critical path matrix, we may wish to also consider how the FDA undertakes the process of identifying relevant public health and medical needs and opportunities. Since we expect the initial list of critical path issues from the FDA shortly, this also gives us a ready-made point of departure.

I recently had the privilege of a private meeting with Nobel Laureate Joshua Lederberg. The topic of conversation was the future of the FDA and the agency's Critical Path initiative.

We talked about the state of applied research and "the texture" of the agency, the prioritization of development science, biomarkers and a host of other future-oriented issues.

He talked. I took a lot of notes.

At the end of the meeting he put everything into perspective in a single sentence. He leaned over the table and said, "The real question should be, is innovation feasible?"

I hope so.