October 15, 2011 (Vol. 31, No. 18)

Gail Dutton

New Commissioner Realigning Programs to Better Support Core Functions and Responsibilities

The FDA must be “a consistent catalyst for innovation,” insisted FDA commissioner Margaret Hamburg, M.D., in a July 13 letter to colleagues. That determination couldn’t come at a more critical time.

The scientific, logistical, and administrative challenges are significant. “Innovative products that are truly transformative create unique scientific and regulatory challenges,” Dr. Hamburg acknowledged. The food, drug, and cosmetic industries have a global reach and a global supply chain, with international regulatory hurdles. Administratively, the FDA faces the challenges of any large organization—providing the resources and training necessary to keep its staff of 12,000 performing at peak efficiency.

Following the April release of its Strategic Priorities 2011–2015 document, the FDA has released several proposals to streamline drug testing, nanotechnology, and low-risk diagnostics, as well as draft companion diagnostics guidance, in an attempt to increase regulatory uncertainty and the speed and accuracy of reviews.

But, as Dr. Hamburg recently wrote to colleagues, “The most obvious change is that the Agency’s programs will be divided into directorates that reflect the core functions and responsibilities of the Agency.” Her goal is to better support core functions and to link programs that share common regulatory and scientific foundations. The seven existing centers, she emphasized, will remain under their current leadership.

To enhance consistency, the position of Deputy Commissioner for Medical Products and Tobacco is being established to oversee the “Special Medical” programs and to provide “high-level coordination and leadership” across the seven centers. The FDA is also establishing the Directorate of Global Regulatory Operations and Policy, to move the FDA from “an organization regulating domestic products to one overseeing a worldwide enterprise.”

The Office of the Chief Scientist will continue its efforts to “improve FDA’s science and address issues of cross-cutting scientific concern.” The National Center for Toxicological Research will report to this office. The FDA is also forming the Office of Foods to implement the Food Safety Modernization Act, and the Office of Operations to oversee administrative functions, including information technology and finance.

This implementation shares some commonalities with the improvements proposed by BIO CEO Jim Greenwood in his keynote speech at this year’s BIO International convention in Washington, D.C. There, he advocated establishing the FDA as an independent agency, updating its mission statement to create a clear mandate to encourage the development of innovative products, creating a chief innovation officer, and developing a progressive approval pathway.

FDA officials say the agency is taking steps to improve its performance, with a special emphasis on streamlining the regulatory review process.[Alexander Raths/Fotolia.com]

FDA Independence

BIO proposes making the FDA an independent agency, like the Environmental Protection Agency, with a fixed term of office for the commissioner. “That would insulate the agency from being second-guessed by external stakeholders and provide additional ability to advocate for funding through the appropriations process,” explained Andrew Emmett, managing director for science and regulatory affairs, BIO.

Allowing a fixed term for the FDA commissioner would increase the likelihood of continuity within the FDA, Emmett continued. Currently, the FDA commissioner is appointed by the Administration so, electing a U.S. President typically triggers the appointment of a new FDA commissioner and a change in FDA priorities.

A fixed appointment—perhaps six years—would insulate the commissioner to some degree from the political gammoning that plagues the position.

Independence could also improve the FDA’s budgetary situation. Currently, the agency submits its proposed budget to the Department of Health and Human Services, which balances FDA requests against those of its sister organizations, and submits a significantly pared down version to the Congressional Office of Management and Budget (OMB). As a separate agency, however, the FDA would submit its budget request directly to the OMB, thus increasing its chances of obtaining the budget it needs. The National Cancer Institute, although not independent, submits its budget this way now, Emmett added.

The products the FDA regulates represent 20% to 25% of every consumer dollar spent in the U.S., Dr. Hamburg pointed out. “That’s a gigantic percent of the country’s gross domestic product,” Tim Rodell, M.D., CEO of GlobeImmune (www.globeimmune.com) and a member of the BIO board of directors, said. “Given the FDA’s importance, it warrants being a cabinet-level agency.”

In the long term, the main issue is how the FDA can facilitate an influx of novel medicines to significantly improve patient outcomes.

21st Century Medicine

Molecular diagnosis and personalized medicine provide opportunities to bring effective therapeutics to patients sooner by allowing biopharma companies to develop faster, more targeted trials that, consequently, require fewer patients.

“Co-development of diagnostics and therapeutics is an area of great interest and concern,” noted Paul Radensky, M.D., J.D., partner with McDermott Will & Emery. Recognizing that, the FDA released the new draft guidance for in vitro companion diagnostic devices on July 14 to resolve issues between the Clinical Laboratory Improvement Amendments of 1988 process and the FDA’s 2007 Draft Guidance for Industry, Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays.

The draft guidance recognizes the importance of co-development, while providing flexibility to accommodate multiple timelines.

Regulating RUO/IUO In Vitro Diagnostics

The agency also recently released initial proposals for IVDs labeled as RUOs/IUOs. The comment period ended August 30, and the agency says the amount of feedback received means changes won’t come anytime soon. Among concerns industry raised:

  • Overly narrow definition of “research only”
  • Provisions inconsistent with applicable law
  • Potential of a shortage of supplies to develop lab tests
  • Lack of clarity for using RUO/IUO tests in drug R&D

For details on these issues as well as suggestions from the industry, check out this story.

“One of the challenges with regulating in vitro diagnostics as medical devices,” Dr. Radensky said, “is that we’re talking about the accuracy, reliability, and reproducibility of the test with respect to the information furnished by the test.” The Coalition for 21st Century Medicine, a group of laboratories, venture capitalists, and patient groups interested in advanced diagnostics, is examining the issues associated with personalized medicine.

The Coalition is working with Senator Orrin Hatch (R-UT), who is considering options for an oversight framework based upon the potential for inaccurate test results to harm patients.

The application of molecular medicine opens a huge opportunity for companion diagnostics, noted Kevin Hrusovsky, president and CEO of Caliper Life Sciences. “So far, 14 drugs have been approved requiring companion diagnostics, and approximately 56 recommend using molecular diagnostic tests. This is a major technology innovation.

“Unfortunately, many drug companies didn’t start their biomarker work early.” Instead, many waited until their therapeutic entered Phase III trials to begin developing a companion diagnostic program. “They didn’t have a diagnostic infrastructure in place and didn’t understand the challenges of diagnostic approval, so were quite frustrated.”

Moreover, they did not have the benefit of stratification to mitigate clinical risks in terms of safety and efficacy, which led to an unnecessarily high failure rate. “Now, pharmaceutical developers are embracing these opportunities and initiating biomarker/companion diagnostics programs much earlier in the discovery process,” he said.

Chief Innovation Officer

Although FDA reviewers typically are trained in scientific research, applying that experience to the regulatory environment is learned on the job. “That’s a significant deficit for the agency,” Dr. Rodell said. “There’s no process to train the kinds of people the FDA needs.” Consequently, “it takes one to two years for new reviewers to get up and running.”

Meanwhile, the FDA, in its determination to do no harm, risks being so cautious that it withholds live-saving therapies. Admittedly, it’s a delicate balance. “Innovation occurs so quickly that FDA staff can’t keep up with new technology,” observed Holli Riebel, president and CEO of Colorado BioScience.

“Patients are waiting and—sometimes—dying, while amazing drugs aren’t released because of fears about potentially adverse reactions. Science isn’t perfect. We can’t push forward without some risks.”

BIO is working with the FDA to reduce the risks of timidity by triaging new technologies by their potential contributions to science and healthcare (such as their ability to reduce false positives and false negatives), and providing the information necessary to help reviewers make informed decisions when they encounter these technologies.

For the future, Greenwood suggested creating the position of “chief innovation officer”. This is different from the chief science officer already in place, Emmett said. “The chief science officer is tasked with enhancing the internal science infrastructure,” he explained.

A chief innovation officer, in contrast, would work with external consortia and public/private/academic partnerships to coordinate and integrate their advances into the FDA as pilot programs. “For example, as new clinical trial designs or new biomarkers or new ways to develop or use electronic medical records are developed, the chief innovation officer would work with their developers to see that they are validated and tested in the FDA’s centers, to increase the FDA’s comfort level with these innovations.”

Despite the significant challenges the FDA is facing, Dr. Rodell said there also are significant opportunities to design an efficient, 21st century agency. “Many of the recommended changes require legislation,” Emmett admitted, “but we want to elevate the FDA’s role to focus on innovation.

“BIO advocates reinvigorating the Regan Udall Foundation as a place for public/private partnerships.” That foundation was created by the Food and Drug Administration Amendments Act of 2007 to support the FDA’s regulatory science priorities, which aim to clarify issues at the intersection of science and regulation.

BIO also supports a progressive approval pathway so that even before final trials are completed, promising therapeutics could be released and monitored. Dr. Rodell suggested that could be accomplished safely and effectively by designing electronic medical records systems to accommodate retrospective, anonymous analysis of drug safety in real time. Therefore, drug developers could track adverse events associated with the commercial release of particular therapies more accurately than under the current system, which depends upon harried physicians taking the time to voluntarily report adverse events. Dr. Rodell added that the FDA is exploring this already with its pilot Sentinel initiative.

That approach can also be used to generate comparative effectiveness data. As Hrusovsky elaborated, “Databases have 10 years of retrospective samples, in which you know the therapies, outcomes, expression levels, etc.” Leveraging that data could yield practice guidelines that address specific details rather than broad generalities, as well as reimbursement guidelines.

Getting Biosimilars on the Market

In an article published in the August issue of the New England Journal of Medicine, Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research (CDER), was one of four agency officials who discussed the challenges associated with reviewing biosimilars. They concluded that science has evolved to the point where the agency can conclude that some biosimilars are similar to the reference product. But that conclusion, the co-authors added, must vary from drug to drug to reflect differences in the composition of those biologic drugs.

“Given the complex nature of biologics, it’s unlikely that a ‘one size fits all’ systematic assessment of biosimilarity can be developed. Instead, FDA scientists will need to integrate various types of information to provide an overall assessment that a biologic is similar to an approved reference product,” the FDA officials wrote.

That “totality of the evidence” approach, as the authors label it, reflects the reality that biosimilars differ by size as well as composition of molecule. They can also differ not just by attribute but by combinations of attributes.

“It’s very hard to fashion rules that govern all biologics because they range from compounds like insulin, which are relatively on the smaller side although still much bigger than traditional small molecule drugs, all the way up to factor 8, which is a very large product, a very sensitive product,” Sara Radcliffe, evp for health at BIO, told GEN. “Fashioning rules that govern all of them is complicated. At the same time, as a regulator they need to provide guidance for biosimilar sponsors so that they can understand what needs to be submitted to the agency.”

In the NEJM article FDA said that their strategies may include a fingerprint-like identification of very similar patterns in a number of different products. Fingerprint studies could reduce the extent of testing required for protein biosimilars, according to FDA. They add, though, that both animal and human testing “will generally be needed for protein biosimilars for the foreseeable future.” But for those studies to be most effective, FDA’s eventual guidance should better define fingerprint tests, both in terms of qualities to be studied and the degree of detail needed. —Alex Philippidis

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