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.
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.
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.
Interview with Janet Woodcock, Deputy Commissioner and Chief Medical Officer
PM: Congratulations on your new appointment as Chief Medical Officer. What are your goals, both short- and long-term? After years of dealing, at CDER, with engineering science concepts like statistical process control, do you feel that you’re returning to your roots in medicine?
JW: I’ll be working in the area where medicine comes together with those concepts, and I really look forward to that. Now is the time when medicine can become more of a science and less of an art. We’re at the forefront of [driving] that at FDA.
Short-term, we’ll have a research and science review to see whether we’re organizing and utilizing scientific information in the best way possible. Next, we’ll focus on our bioinformatics process. I want to develop an enterprise-wide planning process for IT use at the Agency. The bioinformatics initiative has been going on for a year, and I’d like to see some very substantive accomplishments come out of that initiative over the next year.
In the long term, we want to utilize the emerging science in the most effective way to modernize FDA regulation across all regulatory areas.
PM: What do you see as the top challenges to realizing your vision?
JW: The hardest part with any change is getting people to embrace that change and to put in the effort needed. It takes a lot of work on everyone’s part, but the reasons for it are so compelling. For example, in the clinical world, we won’t just improve regulation, but we can improve how medicine is used; we can improve the safety of medicine and its utility for the population. The opportunities are tremendous and well worth the effort.
PM: What are your top goals for the Agency this year?
JW: The Commissioner has articulated that his number-one priority will be readying the Agency for the new science that’s coming, so that we can be a bridge to better health for the American people. I will be working on that.
My second priority will be strengthening FDA’s manage-ment and organization so that scientists can be supported and so we’ll be a stronger organization. We want to establish a good scientific culture of openness and transparency [that facilitates open] discussion of science at the Agency.
PM: We hear, anecdotally, of a “disconnect” at FDA between goals and some of the actions of individual change-averse inspectors and reviewers. Is it possible that the Agency might apply performance standards like those used in industry, and dismiss those who aren’t on board with the new concepts?
JW: It’s not a question of dismissing anyone. It’s more that we need to have vigorous internal debate and decide on a direction in concordance with our leader. Those who really can’t get on board with that will have many options available to them after we’ve had complete opportunity for internal discussion and debate.
I know that in the product quality initiative, for example, there may be some folks who do not agree or cannot put in the effort required to adjust to the change in the new way of doing business. That’s okay, but perhaps it will just be time for them to contribute in some other way.
PM: What concrete and positive changes have you seen since your days at CDER, when 21st century GMPs and quality guidance documents were first issued?
JW: We expected that changes on the shop floor would be slow. There’s a lot of capital sunk into the current systems and approaches, equipment and everything.
What we’re doing is to invite and enable that change, without forcing it. We’re changing the way that we review, to help drive change on the outside. We’re institutionalizing Quality by Design in how we review and regulate in the Chemistry Manufacturing and Control (CMC) area. That is not a trivial task — it’s very important — but we’re well along the way in doing that. The field and the Office of Compliance are all on board with this.
We have a three-pronged strategy. First, we’re trying to advance the science in different ways with academia and with various consortia that have been formed. Then, we’re changing the way we regulate, and finally, we’re harmonizing internationally.
I’m surprised by how much progress we’ve made in ICH in the quality area. Industry has been perfectly clear that unless we can [harmonize regulations] internationally, it’s not going to work for them. Right now, the same production line is regulated by many regulators, and there’s a situation where different people are coming in and interpreting things differently. That approach sets up [a potential for] errors and problems.
PM: But doesn’t ICH provide the 6,000-foot view? Closer to the ground, which standard-setting groups will be most important in advancing ICH’s goals on a day-to-day basis within the industry?
JW: We’re working with all the key standard-setting organizations: USP, ASTM, and we’ve applied to join PIC/S [the Geneva, Switzerland-based Pharmaceutical Inspection Cooperation Scheme, www.picscheme.org/index.php]. We’re also working with professional organizations such as ISPE. We need to do this because we’re attempting a whole culture change. We’ve been doing things virtually the same way for over 30 years.
We know that it’s going to take a while. I’m actually surprised by the vigor with which people have introduced and adopted [ICH], even within the industry. Not so much on the shop floor, perhaps, where people have invested so much [in existing systems], but in new drug development. That’s where I think we’ll see a lot of the transition happen because they haven’t sunk costs into it yet.
Interview with Joseph Famulare, Deputy Director, Enforcement
PM: Has the industry made progress so far in applying the advanced concepts behind 21st Century GMPs — i.e., risk management and process understanding? Do you see a lot of room for improvement?
JF: This is a continuum. You’re not going to see an immediate switchover from conventional to more advanced ways of doing business, but we’ve been impressed by the application of some of our Quality Systems guidelines. We’ve had some companies come to us and explain how they’ve done it. They’ve already seen savings in the costs of manufacturing and in greater efficiencies, and can even show trends in areas such as less deviation follow-up. We’re encouraged by what we’re seeing so far.
PM: What will be the key to changing the industry’s motivation for improvement, so that patients are seen as the key driver, rather than fear of regulatory agencies?
JF: We’re trying to get industry to take into its own hands the control over quality, advancement of technology, science and continual improvement, so that it moves from a reactive to a proactive mode. We’re hoping that, as firms invest more up front and learn about their quality systems over the life cycle of their products, they’ll be able to take this information, use it, and improve themselves [not only from a compliance but] from a business perspective, to put them in a place where they can really help the patient, as Dr. Woodcock has said.
PM: Is there still a trust gap between industry and FDA? Some companies are somewhat cynical about PAT or QbD being the latest “flavor of the month” from FDA. Is that starting to change?
JF: I don’t know if I’d categorize it as cynicism, but it takes time to change, to communicate and establish trust. And it’s not only a question of trust between industry and FDA, but trust within each company’s own internal organization. Each company may have its own way of doing things… how they deal with each other between development, tech transfer, manufacturing and regulatory affairs. Certain parties may not be communicating with each other, internally, as to what may best help them. Some may be more conservative about making changes and communicating with FDA.
By using our QS guideline, you should expect to have less interaction with FDA, once you’ve identified your critical factors and applied risk management principles. When this knowledge is evident during an FDA inspection, it should make that inspection quicker and much more focused. And if you’ve done that work, your knowledge of your process or “design space” will be [advanced enough] that you should not need to file additional regulatory submissions such as supplements.
PM: We sense some confusion about PAT and QbD. Isn’t manufacturing really about “Quality by Redesign?” How can you redesign existing processes or do continuous improvement given current validation requirements and batch definition?
JF: First of all, cGMPs, in terms of validation and batch definition, are quite flexible. A batch is defined as a period of time. There is no impediment whatsoever to continuous manufacturing or real-time release based on existing cGMP regulations, parts 210 and 211.
Regarding process validation, we have already changed our internal guidelines for compliance policy, instructions to field staff, investigators and compliance officers, and it’s all available on the Web. We need to get out of this “three-batch” thinking for validation, because modern development, risk management and QS will put in place continuous quality verification methods. We’ve already unshackled that thinking in the guide that we issued in 2003. We’re further revising the guidance documents to reflect what we’re already saying.
PM: Please recap the progress and goals for the risk-based site selection program.
JF: The risk-based site selection program has run, in its current model, two or three complete years. We have shared those risk factors that we’re looking at. Of course, how we score things individually is internal to FDA, but what we see is a way to accomplish those inspections at those sites that really represent the most important risk factors to us in any given year.
We have enhanced the data we’re using to determine risk. We use our adverse drug experience and drug quality reporting experience. This year, we’re also using our recall database. There are other factors, too. Facility size and type, whether it’s a manufacturer or a repackager, the last three district decisions, field alert reports, recalls and time since last inspection.
PM: How is the Pharma Inspectorate training program progressing and what are your plans for the program next year?
JF: The first class of 45 investigators is in the process of being certified. The second class has taken place and they’re doing what they need to do to be certified. There will probably be plans for a third class. We’ve already seen the benefit of their knowledge and understanding in the inspection work that we’ve seen done, their participation in the Office of New Drugs quality pilot, and their input on the ICH Q10 document.