The transfer of oversight of most biologic medications to the FDA’s Center for Drug Evaluation generally garners praise. Will the efficiencies expected to result in the review process ultimately reduce drug-review times and costs?
Abstract
The transfer of oversight of most biologic medications to the FDA’s drug-evaluation center gains praise. Time will tell if it ultimately cuts review times and costs.
To most observers, outgoing U.S. Food and Drug Administration Commissioner Mark McClellan, MD, PhD, wasted little time carrying out his vision of a more progressive FDA. Implementation of one of McClellan’s objectives — to streamline the review process for drugs and biologic products — began last October when review responsibilities for many biotechnology therapies were transferred from the FDA’s Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER). Although specifically reducing approval times for biologics was not the stated intention, the change ultimately may cut product-review time and costs.
The move affects the review of monoclonal antibodies; cytokines, growth factors, enzymes, immunomodulators, and thrombolytics; proteins intended for therapeutic use that are extracted from microorganisms or animals (including recombinant versions), and non-vaccine therapeutic immunotherapeutics (see “What’s Affected,” on page 29). Vaccines, including those used for therapeutic purposes; gene therapies; antitoxins, antivenins, and venoms; and some in vitro diagnostics, such as HIV test kits, remain the domain of CBER. Biologic products transferred to CDER will continue to be regulated as licensed biologics.
What’s affected?
Oversight for the following currently approved biologics has been transferred to CDER:
| Product name | Trade name |
|---|---|
| Abciximab | ReoPro |
| Adalimumab | Humira |
| Agalsidase beta | Fabrazyme |
| Aldesleukin | Proleukin |
| Alefacept | Amevive |
| Alemtuzumab | Campath |
| Alteplase | Activase |
| Anakinra | Kineret |
| Anistreplase | Eminase |
| Arcitumomab | CEA-Scan |
| Asparaginase | Elspar |
| Basiliximab | Simulect |
| Becaplermin | Regranex |
| Becaplermin Concentrate | (none) |
| Botulinum Toxin Type A | Botox; Botox Cosmetic |
| Botulinum Toxin Type B | Myobloc |
| Capromab Pendetide | ProstaScint |
| Collagenase | Santyl |
| Daclizumab | Zenapax |
| Darbepoetin alfa | Aranesp |
| Denileukin diftitox | Ontak |
| Dornase alfa | Pulmozyme |
| Drotrecogin alfa (Activated) | Xigris |
| Epoetin alfa | Epogen |
| Epoetin alfa | Eprex |
| Etanercept | Enbrel |
| Filgrastim | Neupogen |
| Ibritumomab tiuxetan | Zevalin |
| Indium In-111 Chloride Sterile Solution | Indium In-111 Chloride Sterile Solution |
| Indium In-111 Chloride Sterile Solution | Indiclor |
| Infliximab | Remicade |
| Interferon alfa-2a | Roferon A |
| Interferon alfa-2b | Intron A |
| Interferon alfacon-1 | Infergen |
| Interferon alfa-n3 (Human Leukocyte Derived) | Alferon N |
| Interferon beta-1a | Avonex |
| Interferon beta-1a | Rebif |
| Interferon beta-1b | Betaseron |
| Interferon gamma-1b | Actimmune |
| Laronidase | Aldurazyme |
| Muromonab-CD3 | Orthoclone OKT3 |
| Nofetumomab | Verluma |
| Omalizumab | Xolair |
| Oprelvekin | Neumega |
| Palivizumab | Synagis |
| Pegaspargase | Oncaspar |
| Pegfilgrastim | Neulasta |
| Peginterferon alfa-2a | Pegasys |
| Peginterferon alfa-2b | PEG-Intron |
| Rasburicase | Elitek |
| Reteplase | Retavase |
| Rituximab | Rituxan |
| Rituximab Formulated Bulk | (For further manufacturing use) |
| Sargramostim | Leukine |
| Satumomab Concentrate | (For further manufacturing use) |
| Satumomab Pendetide | OncoScint CR/OV |
| Streptokinase | Streptase |
| Tenecteplase | TNKase |
| Tositumomab and Iodine I 131 Tositumomab | Bexxar |
| Trastuzumab | Herceptin |
| Urokinase | Abbokinase |
SOURCE: FDA 2003
Until the transfer of oversight responsibilities last October, mass-market drugs and biologic products had moved through separate regulatory pathways. They still will — the biologic pathway hasn’t changed with the transition from CBER to CDER — but dealing with a single center for most products is something most drug makers welcome. To them, the two-pathway, two-center system is slow, expensive, and cumbersome — even if it works as advertised.
“Most of the review goals, which are the same for drugs and biologics, are set by the Prescription Drug User Fee Act, and both centers have been meeting those goals,” explains Sharon Risso, senior adviser to the CDER director. “The pharmaceutical industry has been focused on the length of time it takes to approve a new drug application, which includes both the agency review time and the applicant’s response time.”
Relocating hundreds of CBER people to CDER poses some disruption for two vital parts of a very busy agency and may take years to be completed
Indeed, manufacturers have been vocal about what they view as unpredictable and sometimes relatively lengthy approval times. If this phenomenon feels to drug makers like salt in a wound, consider that it coincides with a steady drop-off in approvals of new molecular entities. In 1999, the FDA approved 35 NMEs; in 2002, 17. The FDA approved 21 last year, and the line is expected to trend upward in coming years as innovation returns to the market, according to Doug Long, vice president for industry relations at IMS Health.
As approvals were declining, the situation was compounded by a handful of high-profile withdrawals of drugs from the market. This, says Long, has effectively made the FDA more risk averse — even as it began to fast-track novel therapies, including many biotech medications. In 2003, the FDA approved 25 new biotechnology drugs (up from 20 in 2002), plus 12 new indications for existing products.
Under McClellan’s leadership, the FDA has demonstrated that it can get novel treatments approved rapidly. Imatinib mesylate (Gleevec), indicated for chronic myeloid leukemia; enfuvirtide (Fuzeon), for HIV); and oxaliplatin (Elozatin), for colorectal cancer, all got to market relatively quickly.
At press time, the Bush administration tapped McClellan to head the Centers for Medicare and Medicaid Services. If the Senate confirms McClellan’s nomination, FDA Deputy Commissioner Lester Crawford will become acting commissioner. It is expected that Crawford, who worked side by side with McClellan to implement faster drug approvals, would continue the approach McClellan instituted at the FDA.
GOOD, BAD, OR INDIFFERENT?
The transfer of oversight responsibilities for most biologic products is one of a series of steps the FDA is taking to try to streamline product reviews. Other such tactics include root-cause analyses to dissect the reasons behind numerous multiple-cycle drug reviews. The FDA believes that earlier collaboration with the pharmaceutical industry can lead to fewer multiple-cycle reviews and thus allow safe and effective products to reach the market sooner.
Risso thinks the switch from CBER to CDER may help biotech and pharmaceutical manufacturers in several ways. For one thing, CDER is a much larger organization (with about twice as many employees as CBER had); handles a much larger number of products; conducts more industry outreach via training seminars, workshops, and trade association meetings; and issues many more guidance documents to help applicants understand exactly what the FDA requires. All of these are potentially significant advantages — if the transfer works out as planned — considering the importance of intense, interactive, and ongoing communication between the agency and applicants in the rapidly evolving biotech sector.
CDER has more employees but also more applications — so the resources dedicated to biotech products won’t necessarily increase, nor will review goals change. Yet, applicants for a biologics license can expect to save time, administrative work and, ultimately, expense by dealing exclusively with CDER, as opposed to separate IT systems, application processes, and secure e-mail systems at CBER and CDER.
“I don’t think we know if it’s good, bad, or indifferent at this point, but the idea of a certain level of consistency between CBER and CDER is no bad thing,” says Gillian Woollett, vice president of science and regulatory affairs at the Biotechnology Industry Organization. “There are increasing requirements of the agency, and it makes sense for the two centers not to learn the same thing twice.”
But Woollett worries that the reorganization may prompt some experienced CBER staffers to jump ship. CBER is on the National Institutes of Health campus in Bethesda, Md., while most CDER people work in Rockville, Md. — only five Metro stops apart, but perhaps a bigger change than some CBER people will want to make. In an industry where product development — according to the Tufts Center for the Study of Drug Development — can take 15 years and cost an average of almost $900 million per entity, staff turnover at the FDA only increases the potential for expensive and time-consuming changes in the agency’s requirements in the period between early development and submission of an application. Relocating hundreds of CBER people to CDER also poses some disruption for two vital parts of an extremely busy agency and may take years to be completed.
According to the FDA, the staff that had made up CBER’s Office of Therapeutics Research and Review will maintain responsibility for review of therapeutic biologics through two new offices at CDER. One of those is the Office of New Drugs: Office of Drug Evaluation VI, which includes the divisions of Therapeutic Biological Oncology Products, Therapeutic Biological Internal Medicine Products, and Review Management and Policy. The second new entity at CDER is the Office of Pharmaceutical Science: Office of Biotechnology Products, which includes two divisions, Monoclonal Antibodies and Therapeutic Proteins.
A steady and entirely manageable volume of applications may eventually be what reaches FDA reviewers
Part of the rationale for the transfer was that many of the affected biologic products are used to treat some of the same illnesses as conventional drugs. The feeling on the street is that as the nature of biotech medications diversifies — from being largely an oncological arena to an armamentarium for combating psoriasis, asthma, rheumatoid arthritis, pain, and even dental disease — the FDA will want biotech companies to bear in mind CDER’s philosophy on safety evaluation when developing products.
In Woollett’s view, the transfer is partially a response to a quandary with which the FDA might always struggle: Do you assign review responsibilities to teams with expertise in a specific clinical condition, or to teams with expertise in certain types of products, such as biologics?
“Of course, the answer is that you want both — so maybe there’s no perfect way to do this,” she says. “Biologics raise case-by-case questions. The manufacturing component also is a consideration, because biologics are so difficult to make.”
She adds, “There’s nothing but support for what the FDA is doing, but there’s also a recognition that it takes a while to see the impact of such a major reorganization.”
Well, almost everyone seems supportive of the transfer, but as they say, you can’t please all of the people all of the time. The Cancer Leadership Council, a coalition of patient-advocacy organizations, thinks that while the transfer itself is well and good, it doesn’t necessarily go far enough.
In an open letter to McClellan, the CLC called on the FDA to establish a review office at CDER specifically for cancer therapies and led by cancer specialists. In addition, CLC requested that cancer vaccine products also move to CDER oversight, noting that unlike traditional vaccines remaining under CBER’s purview, cancer vaccines “are therapeutic rather than preventative and are designed to treat cancer through manipulation of the immune system.” Presently, the transfer does not include cancer vaccine products.
NOT YOUR FATHER’S FDA
This reorganization followed the Aug. 20, 2003 release of “Protecting and Advancing America’s Health: A Strategic Action Plan for the 21st Century,” by McClellan. Among other goals in this report, the Commissioner aims “to maximize the public health impact of every FDA dollar and of our greatest resource, the thousands of dedicated professionals at the FDA.”
In telegraphing the release of his strategic plan, McClellan told attendees at BIO’s annual meeting last June that the FDA hopes to cut product-review times by at least 10 percent, and cut a collective $12 million annually from review costs, according to BNA’s Health Policy Report.
“I’ve been very impressed with him and the people who work for him,” says Long, at IMS Health, who met McClellan several times when they were both on the lecture circuit. As for the CBER/CDER reorganization, Long agrees that “As you see more biologics, it would make sense to have one streamlined process to go through, instead of two separate ones.”
Presumably, streamlined processes will pay off in a big way by the time hundreds of biotech products now in development are being submitted for review. But Woollett actually downplays the perception that a “tidal wave” of products will ultimately inundate the FDA review machinery. Because of the lengthy development cycles for these products, a steady and entirely manageable volume of applications may eventually be what reaches FDA reviewers.
The transfer does not mean that a single approval pathway for all drugs and biologics is coming or is even being contemplated. For now, though, most believe the scope of the transfer will at least bring efficiencies and consistency to FDA reviews.