By Wayne Koberstein, executive editor
New mandates, new user fees, and new uncertainties occupy the FDA’s drug center in 2014.
Speaking in whole sentences may become an everrarer practice in this, the Abbreviated Age of texts and tweets — but Janet Woodcock, head of the FDA’s Center for Drug Evaluation and Research (CDER), is someone who speaks in whole paragraphs. She is not reading from a script; she spontaneously composes succinct, lucid, and informative statements based on logic and knowledge, requiring none of the editing we usually expect with extemporaneous speech. Woodcock speaks with the perspective of a builder, not an observer. Over many years, she has helped shape and construct the agency as it is today. Consequently, she has become the most consistent, reliable voice of the FDA for most people in the life sciences industry.
In general, the political and economic environment for the world’s largest drug regulator has grown even more difficult since we last spoke with Woodcock for the cover story of our November 2011 issue. Broad austerity in the federal budget has largely replaced the targeted anti-regulatory assaults of two years ago, but the agency still faces the challenges of doing more with less, perhaps for many years ahead.
With new responsibilities covering more regulatory and geographical territory, the FDA cannot simply add resources. Although it stands to gain new income from industry user fees, the agency carries a backlog of work and needed expenditures. Its only other option is to reorganize and redeploy the resources it has. Most of the FDA’s recent assignments are mandated by law, specifically the Food and Drug Administration Safety and Innovation Act (FDASIA), the Generic Drug User Fee Act (GDUFA) and similar user-fee legislation for biosimilars, and the Drug Quality and Security Act, which amends FD&C Section 503A to establish registration and fees for certain compounded drugs, as well as track-and-trace provisions for FDA-regulated drugs.
CDER’s responsibility includes the bulk of items driven by the mandates: implementing the new user-fee programs, an accelerated review process for new drugs, and pushing overall improvements in drug manufacturing and quality. To those ends, Woodcock has overseen an extensive reorganization of the drug center, including elevation of the new Office of Generic Drugs (OGD) and creation of the Office of Pharmaceutical Quality (OPQ). The changes involve shuffling existing duties and adding new ones wherever needed — sometimes to the chagrin of affected personnel. At the same time, Woodcock prefers to emphasize continuity.
“We are continuing a balanced-portfolio approach across drug development, post-marketing surveillance, drug safety, scientific innovation, and controlling illegal activities,” she says. “We regulate everything from drug advertising down to INDs (investigational new drugs) and first-in-human studies, and I work to make sure we have all those covered at a strong level — along with our communications office and other functions necessary for us to communicate and work with our diversity of stakeholders.”
GDUFA: An Opportunity For Balance
But Woodcock then proceeds to describe how the “balance” in CDER’s portfolio has profoundly shifted: in this case, toward a more even-handed system for regulating the majority of prescription medicines consumed by U.S. patients — generics. “The success of the generics program had outrun its resources. We now get about a thousand ANDAs (abbreviated new drug application) every year, compared to about 200 in 1990,” she says. “The staffing has increased somewhat, but not at all proportionately, and we have developed a huge stack of pending applications. So GDUFA is an opportunity to get all that back into balance.”
Partly because of GDUFA, but also affecting the pharma industry as a whole, CDER’s reach is extending across the globe. “Our inspectional forces were always a domestically based group,” says Woodcock. “But one hallmark of GDUFA is that we will now have the same regulatory scrutiny of all manufacturers, regardless of where drugs are produced around the world.” For example, non-U.S. drug manufacturers, which have typically received only one inspection per plant every five years, will see the inspection rate increase to one every 18 months, the average for U.S. producers.
Meanwhile, CDER has been on the educational offensive with programs to help industry streamline trials, improve clinical data quality, and share outcomes and lessons from drug development. Although relations with industry remain a mix of positive and negative, Woodcock believes a net gain has resulted from changes inside the industry itself.
“On the new-drug side, the industry is emerging from a transition. It is now focusing on real innovation and less on getting me-too drugs on the market with market penetration through advertising and so forth. Under FDASIA, we have the breakthrough drug provisions which enable us to designate very promising drugs early on and facilitate their development. We also negotiated a more transparent NDA review process. Such changes are very popular in the industry.”
The generics sector is still in wait-and-see mode, she says. “They put their money down, they made commitments, and the agreement cannot be amended in the first two years of the GDUFA program. We are doing our best to get the whole program organized so it can operate on a much larger scale. OGD must work through all the backlog and start operating in a steady state as PDUFA does.”
QUALITY — CAN’T GET AROUND IT, SO GET ON BOARD
If Woodcock has made any single issue the hallmark of her tenure at CDER, that issue would be quality in pharmaceutical and biopharmaceutical manufacturing. When we visited her in 2011, her group was working to develop an industry-wide consensus on defining quality above and beyond minimum GMP or product standards. Such a definition is still at the heart of current CDER initiatives, including OPQ.
“I think you would do a great service if you could explain how we think about this,” Woodcock says. “Actually, we defined the quality of a pharmaceutical product a long time ago: fitness for use. It delivers the properties described on the label and is not contaminated. But the other piece is, what is quality in manufacturing? And that’s really what we are focusing on. Right now, a lot of the industry delivers quality products by throwing away, by wasting, up to 35 percent of what’s produced, and we don’t believe that amounts to quality manufacturing. We’ve been exploring this question extensively with industry in a very open process: ‘What metrics might we use that would measure the quality of your manufacturing processes?’”
An April 2013 article in our web portal, Pharmaceutical Online, quoted Woodcock as saying that the FDA has no way of measuring drug-manufacturing quality, putting the agency in the same predicament as manufacturers. Here, she elaborates: “What is the inventory of facilities we regulate today? We are now conducting an extensive IT effort to create the inventory and then define the state of that inventory. How many API manufacturers earn a Six Sigma rating or have a very high level of defect-free products, no recalls, no problems? Which ones are in the bottom 10 percent?”
Manufacturing quality — or a lack thereof — has received much of the blame for drug shortages, though some suppliers have faulted low-margin or below-cost reimbursement and puny contract prices for driving good manufacturers away from producing essential off-patent drugs. Claiming no expertise in economics, Woodcock seems to see some common sense in the argument.
“You might pay $3.50 for a cup of coffee, but only 45¢ for a vial of propofol. Yet sterile injectables, in particular, are very hard to make right. They are very hard to make consistently sterile, without any particles or endotoxin in them, which they must be because they’re given intravenously.”
Still, she stresses quality as the underlying issue, citing the inefficiencies built into manufacturers’ legacy systems and technology. Besides coaxing industry to update and upgrade its facilities, she believes the FDA can also help widen payers’ perspective. “We are trying to make quality of manufacturing more transparent to purchasers. Quality of manufacturing predicts reliability of supply.” Internally, with no intent to impose or even publish the results, CDER is establishing a “framework” of quality metrics to help it characterize the variations among facilities in its database, she says.
“Someday we might publish an annual report on the spread of performances, without identifying the companies. It would then be up to purchasers, in their due diligence, to go beyond the issue of cost. I don’t think they’ve ever taken reliability of supply into account before now, because it has not been an issue. But shifts in the industry, probably including pricing structure, have consolidated suppliers and limited the sources for essential drugs.”
As the objective expression of a quality-promoting agenda, Woodcock has championed the creation of the new Office of Pharmaceutical Quality. Still in its infancy, the OPQ now consists of a “reorganization package,” essentially a proposal that CDER must formally submit to all concerned parties for their review and sign-off. “We know how we want to work in the future, and this organization will reflect that, and it’s going to be quite different, but we’re very happy with it. I think most people are pretty happy with it and excited about what’s going to happen now, which is good.”
Creation of the OPQ is a key part of the larger reorganization of CDER. In mid-December 2013, the center announced its plans to “elevate” the Office of Generic Drugs (OGD) to report directly to CDER’s director. Although movement of new people into positions at the OPQ cannot begin until its plan is approved, Woodcock says the process of recruitment and reassignments has already begun.
Another announced change is that all drug chemistry and microbiology review, including that formerly conducted by the OGD, will move to the OPQ. Woodcock says OPQ will also assume facilities review from the compliance office and set up a new surveillance function, which will develop the manufacturing quality metrics and conduct the related assessments. “The Surveillance Office will be the owner of a large database of manufacturing facilities, where we will house all the quality information.”
Woodcock has publicly criticized the agency’s traditional inspection procedure, which concentrates on individual steps and components in the process rather than an overall view of manufacturing quality at any given site. “We will be changing how we do the surveillance inspections,” she says. “We want our investigators to go in armed with the history of the company, including recalls, field alerts, or anything that affected the performance of the facility. We can also examine and verify any metrics that manufacturers send us.”
CDER is collaborating with industry on the metrics development; in late 2013, for example, it participated with industry leaders in a PDA (Parenteral Drug Association) meeting devoted to the topic of measuring manufacturing performance. “Companies are learning they can save money with quality,” says Woodcock. “Most other industries, when they adopted high-level quality, found they could reduce waste, customer complaints, and recalls while improving scale-up and safety.”
A FAIR HAND FOR THE FAST TRACK
Possibly because of fewer NDA submissions in 2013, the FDA approved only 27 new medicines last year compared to 39 in 2012. But one new issue drew even more attention than drug approvals during the year: expedited development. Of 120 applicants for breakthrough status, the agency awarded it to only 36 candidates. A separate, accelerated-approval program also disappointed some companies, as well as patients and their families.
A case in point was Sarepta’s drug eteplirsen for Duchenne muscular dystrophy (DMD). In the opinion of its supporters, the drug caused significant improvement in patients’ walking ability along with boosting the levels of dystrophin, a putative biomarker for DMD symptoms. When the FDA asked the company for more information from its dataset on eteplirsen to support its request for accelerated approval, the head of the main DMD patient group sent a long, petulant email to Woodcock in response.
No one expects Woodcock to comment specifically on the eteplirsen case, but she has this to say: “Sometimes people do pitch their case to me, and they’re just so convinced they have a breakthrough. They may come in with incredible clinical data, but we say, ‘Well, just repeat it, open label; take another 30 people and show you get the same results, and then we’ll talk about accelerated review. It depends on what the results are and how convincing the data are.”
Woodcock says she identifies with the patient-community advocates and could even see herself joining them if she faced a disease such as ALS or AIDS. “HIV was the instigation for accelerated approval; we said we were going to approve drugs based on a surrogate marker if it was reasonably likely to predict clinical benefit. And we’ve done a large number of accelerated approvals since then, many of them for orphan or rare diseases but also for cancer and so forth. But the data, even if it’s Phase 2, must be convincing.”
Data quality in general needs industry’s attention, Woodcock says. Academic data is especially problematic, with some estimates that up to 50 percent of it cannot be reproduced. She believes pharma companies are much more careful about validating the research data they generate, considering the money at stake in selecting development candidates.
Yet, she says, strange as it may seem, companies still routinely fall short with clinical research data, often because of poor practices by individual investigators. But poor trial design, rather than poorly run trials, may compromise trial results as well, she believes. A solution? More data transparency, ideally shared through a “trusted third party” or custodian as proposed by GSK and others, would allow companies to learn from past errors and successes, according to Woodcock.
GHOST OF THE SEQUESTER
The ability of the FDA and CDER to conduct industry-friendly policies and services ultimately rests on the federal budget. Although the endof- year budget deal restored some level of stability to the process, the same political powers that forced sequestration and shutdown on the U.S. government continue to promise more confrontation than compromise. Uncertain funding in the future can be more intimidating than sure scarcity in the present.
“We would like to receive a budget each year at the beginning of the fiscal year that we can execute with confidence,” says Woodcock. “That hasn’t happened in a very long time. When we do get the money, we don’t know how much of it we will get because of the various cutbacks, sequestration, and so on. All this uncertainty makes it very difficult to manage a program as complicated as a drug regulatory program. So, the situation is very suboptimal. But we just do the best we can because we have an important mission.”
Framing the budget as just another problem, among many to be solved, seems like a sensible solution for an absurd predicament. For example, Woodcock says the funds from the PDUFA programs were sequestered last year, “So we didn’t get the increase that we negotiated very carefully with the industry for additional services we would provide. Now we can’t provide services at the level we promised.”
As always, however, and in all our conversations with Woodcock through the years, she remains not only optimistic but also sincerely excited about her job and the agency she has helped shape in that time. “The science now can’t be any better for developing new medicines and for improving manufacturing. We are hopefully on the verge of revolutions in both those areas, which will create great benefits for the public, and the industry you see today will not be the industry you see in 10 years.” It is a safe bet that, during most of the changes she foresees, Janet Woodcock will be there to help them along.
FDA’S FUTURE-INDUSTRY VISION: CONTINUOUS PRODUCTION
As payers recognize the problem of reliability in the drug supply chain, they will gravitate toward the most reliable suppliers — and ultimately, perhaps, to an entirely different supply-chain model. That is the view of Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research (CDER). Are you ready for the concept of continuous drug production? Get ready, advises Woodcock:
“A number of companies are on the verge of adopting continuous manufacturing and other advanced manufacturing techniques which are not susceptible to many of the problems of traditional manufacturing models. Continuous manufacturing can transpire in a single small room, starting with raw materials on one end and finishing with tablets on the other. We believe the new technologies are highly superior. They have a very small environmental footprint and they require high-tech workers experienced with advanced technologies.
“Continuous drug manufacturing creates opportunities that haven’t existed before. It will help personalized medicine, because it’s very flexible, unlike traditional operations where everything has to be rigidly validated and so on. There are many new dosage forms that could be made with the new techniques. It is also perfect for clinical trials because you don’t have to scale-up — you just run your machine longer. Bioprocessing also has some promising alternatives on the horizon. Plant-based protein production and single-use manufacturing equipment parallel the advancements with small-molecules.
“In the United States, we lost our industrial base of drug manufacturing, and we ought to seize the day to bring it back. We ought to support academia in drug manufacturing innovation; states or other organizations could set up high-tech drug manufacturing centers; and the federal government should do its share of funding and incentives. It’s a brave new world, and our nation would be welladvised to foster this new drug manufacturing paradigm. CDER will continue to take a progressive stance, doing our best to enable and actually stimulate the new methods of manufacturing.”