FDA’s multi-pronged approach helps meet the challenge of bringing new and innovative antibiotics to patients who need them

By: Edward M. Cox, MD, MPH

With a growing number of infections becoming increasingly resistant to our current arsenal of antibiotics, developing new antibiotics to treat serious or life-threatening infections has become a key priority.

Edward Cox interview

There are significant scientific and economic challenges inherent to the development of new antibiotics. From a scientific standpoint, many patients with bacterial infections are often very sick and need to begin antibiotic therapy immediately, without further complications that enrollment in a clinical trial might involve. Moreover, it can be difficult to conduct a clinical trial involving very sick patients.

From an economic standpoint, antibiotics may be perceived as less potentially profitable for a company because they are generally taken only for a short period of time and often only for one course of treatment, by any given patient. Compare this to the long, dependable income stream from a diabetes medicine or a blood pressure medicine that a patient takes indefinitely, often for the rest of their life. These economic realities, which are rooted in the biology of acute bacterial infections, can make it challenging for a company to justify large expenditures for the development of drugs in this area, as a recent report by Eastern Research Group (ERG) affirms.

Provisions in a law passed a little over two years ago, commonly known as the GAIN Act, or the Generating Antibiotics Incentives Now Act, is helping to stimulate the development of new antibiotics. Under GAIN, certain antibacterial or antifungal drugs intended to treat serious or life-threatening infections can be designated “Qualified Infectious Disease Products” (QIDPs). As part of its QIDP designation, a drug receives priority review and can also receive fast track designation at the sponsor’s request. At the time of approval, a product with QIDP designation may be eligible for an additional five years of marketing exclusivity, exclusive marketing rights without competing with a generic drug product. To date FDA has granted 52 QIDP designations to 35 different unique molecules. We are already beginning to approve new antibacterial drugs with this beneficial QIDP designation.

FDA is working hard to streamline requirements for clinical trials for studying new antibacterial drugs and the provisions of the GAIN act are being actively implemented, but more is needed. There are still significant economic and scientific challenges in the development of new antibacterial drugs that need to be addressed. Additional financial incentives as well as new approaches for studying antibacterial drugs such as common clinical trial protocols could provide other important means to stimulate antibacterial drug development. We also need cutting-edge science to stimulate the development of new and innovative antibacterial drugs. To help drive this effort, FDA has assembled our Antibacterial Drug Development Task Force, a group of expert scientists and clinicians from within FDA, to consider opportunities to promote antibacterial drug development.

To advance this field, our Task Force is working with many leaders including those drawn from academia, regulated industry, professional societies, patient advocacy groups and government agencies. For example, FDA has contributed to the efforts of the Biomarkers Consortium of the Foundation for the National Institutes of Health to develop new endpoints for studying antibacterial drugs. FDA also works closely with the Clinical Trials Transformation Initiative (CTTI), a key group of dedicated scientists focused on advancing clinical trials for more efficient drug development. As a result, FDA and CTTI have helped convene a variety of important scientific meetings and activities on vital topics related to efficient clinical trial designs for testing new antibiotics. Our Task Force has also helped FDA team up with colleagues at the Brookings Institution’s Engelberg Center for Health Care Reform to help galvanize the scientific community’s efforts in new antibiotic drug development. August, 2012 began the first Brookings Council for Antibacterial Drug Development (BCADD) meeting, with meetings that occur approximately twice a year.

FDA and our Task Force members have also been busy on our own.  In February of 2013 we held a public meeting focused on creating an alternative approval pathway for certain drugs, such as antibacterial drugs, that are intended to address unmet medical need. We have also asked the public for their thoughts; in March of 2013, we issued a Federal Register Notice seeking input from the public on a wide range of topics related to antibacterial drug development. FDA has generated a number of guidance documents for industry, in draft and final form, that describe FDA’s scientific thinking with regard to developing new antibacterial drugs.

As part of our Task Force’s collaborative efforts, FDA is working closely with The National Institutes of Health (NIH) to further advance the development of new antibacterial drugs. Together, we are hosting a two-day Public Workshop to identify strategies for promoting clinical trials for antibacterial drugs and encouraging partnerships to accelerate their development. The ERG report will be presented at the workshop and other specific issues will be discussed including:

  • Priorities and strategic approaches to conducting clinical trials for antibacterial drugs
  • Regulatory pathways—including streamlined development programs for antibacterial drugs for patients with limited or no treatment options
  • Clinical trial design issues such as the development of common clinical protocols; using common control groups; statistical analysis issues; sharing data across trials (and data standards); appropriate clinical trial endpoints; and lessons learned from other therapeutic areas
  • The role of public-private partnerships in advancing the scientific and clinical trials enterprises

The work of the FDA Task Force as well as the GAIN Act have provided good first steps toward strengthening the antibacterial drug pipeline, but as the findings from the ERG report indicate, the forecast for antibacterial drug development likely will include a less than robust pipeline. Thus, additional attention on both financial incentives, new approaches for studying antibacterial drugs such as common protocols, as well as streamlined development pathways, likely will be needed to improve the climate.

Edward M. Cox, MD, MPH, is Director, Office of Antimicrobial Products, in FDA’s Center for Drug Evaluation and Research

As nanotechnology is being used to develop new drugs, FDA is working to ensure quality, safety, and effectiveness

By: Celia N. Cruz, Ph.D. 

Nanotechnology is a new and exciting field that offers scientists the opportunity to control matter at very small dimensions, opening many possibilities for making all kinds of new products. This technology operates on an incredibly small scale that measures things in units called nanometers. One nanometer is one billionth of a meter. It’s hard to even imagine how small that is, but here’s one way to do it: A human hair is about 100,000 nanometers wide. 

Wow, that’s small! But nanotechnology promises big things! There are already many products made using materials at the nanoscale, including new kinds of clothing, packaging materials, and light-weight, but strong, building materials. 

Why are we at FDA’s Center for Drug Evaluation and Research (CDER) writing about it? Because medical products can also be made using materials at the nanoscale. In fact some are already available, including certain sunscreens, in which the nanomaterials are used to provide UV protection while remaining transparent on the skin, and in drugs to treat cancer, including Doxil and Abraxane. Use of nanomaterials can enhance delivery of drugs to their biological target or help scientists customize them for a particular type of patient. 

Materials at the nanoscale can have different chemical, physical, or biological properties compared to their conventionally-scaled counterparts. Scientists can use these features to enhance the properties or the quality of a drug. But because such properties can affect the quality, safety, or effectiveness of a drug, FDA is studying these issues related the use of this powerful new technology in medical products. 

Recently, to help us better understand the potential impact nanotechnology could have on a drug’s quality, safety, or effectiveness, CDER’s Nanotechnology Risk Assessment Working Group (Nano Group) finalized a series of risk assessment and risk management exercises to identify potential risks associated with a drug product that contains nanomaterials. A key goal was to determine if our current regulatory processes are adequate to identify any potential risks and reduce those risks. 

Some members of the Nanotechnology Working Group in the CDER labs where characterization of gold nanoparticles is underway. Left to right, front row: Katherine Tyner, Ph.D. Office of Clinical Pharmacology; Celia N. Cruz, Ph.D. Office of New Drug Quality Assessment; middle row: Olen Stephens, Ph.D. Office of New Drug Quality Assessment: Don Henry, Office of Pharmaceutical Science; Abigail Jacobs, Ph.D. Office of New Drugs; back: Paul Brown, Ph.D. Office of New Drugs.

The CDER Nano Group consisted of a multidisciplinary team of scientists that could provide a complete evaluation of the use of nanomaterials in the types of drugs regulated in the Center. We first performed a thorough risk assessment of all stages in the lifecycle of a drug containing nanomaterials to capture any real or perceived hazards related to the nanomaterials. To complete the exercise, we evaluated the common ways a person could be exposed to nanomaterial in a drug product ― swallowing a drug, having it injected, applied to the skin, or inhaled. In addition, we evaluated unintentional and accidental exposure. 

Once all the potential risks were identified, we undertook a risk management exercise to examine the regulatory process we use to evaluate drugs. We then considered whether the identified potential risks in the first exercise could be sufficiently managed by the existing review processes we use to help protect patients from harm. 

Our risk management exercise determined that our current regulatory review processes indeed can adequately protect the public from potential risks associated with the use of nanomaterials in drug products. We also identified areas that could benefit from improvement. These areas include increased nanotechnology regulatory science research and up-to-date training of the review staff who evaluate marketing applications for drug products developed using nanomaterials. FDA does not make a categorical judgment that nanotechnology is intrinsically safe or harmful. Rather, for nanotechnology-derived and conventionally-manufactured products alike, FDA considers the characteristics of the finished product and, as applicable, its safety, effectiveness, or other product attributes. 

Historically, FDA has successfully adapted to novel technologies, and the robust review process we use will continue to capture the potential risks associated with this new technology. To share the findings of the nanotechnology risk assessment and management exercises, in January 2014, FDA will co-sponsor a workshop with the US Pharmacopeia, the International Society for Pharmaceutical Engineering, the American Association for Pharmaceutical Scientists, and the Society of Toxicology to review and share experience gained during the development and review of medical products containing nanomaterials. With these and other activities, FDA will continue to work to ensure that safe, effective drugs are available to the American public. 

Celia N. Cruz, Ph.D. is Senior Reviewer, Chemistry, Manufacturing and Controls, at FDA’s Center for Drug Evaluation and Research

“Breakthrough” Designation … Another Powerful Tool in FDA’s Toolbox for Expediting the Development and Review of Promising New Drugs for Serious Conditions

By: Janet Woodcock, M.D.

Janet Woodcock, M.D. is the Director of FDA’s Center for Drug Evaluation and Research

In fiscal year 2012, FDA approved 35 novel new drugs, also known as “new molecular entities.” Among these new products were drugs to treat patients with unmet medical needs, such as a groundbreaking treatment for a form of cystic fibrosis, the first FDA-approved human cord blood product for hematopoietic reconstitution, used to help patients with blood forming disorders, and the first drug to treat advanced basal cell carcinoma (a form of the most common skin cancer).

To enable our ongoing efforts to bring innovative drug products to the public as efficiently as possible, FDA relies heavily on several expedited development and review tools such as fast track designation, the accelerated approval pathway and priority review designation. For instance, 56 percent of the novel drugs approved by the Center for Drug Evaluation and Research in calendar year 2012 used some combination of these tools to speed promising therapies to patients with serious conditions. And any given drug may have received multiple expedited program designations. (See a brief summary of how each of these tools helps FDA shorten the development and review of promising new therapies.)

In July 2012, a provision in the new law called the Food and Drug Administration Safety and Innovation Act, or FDASIA for short, gave FDA another powerful expedited development tool, known as the “breakthrough therapy” designation. This new designation is now helping FDA assist drug developers expedite the development of new drugs with preliminary clinical evidence that indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases. Although the designation is not yet even a year old, FDA has received 62 requests to grant this new designation to products under development. We have been very active on this subject, meeting with companies and discussing ways to expedite the drug development process for drugs that show striking early results. We have already granted the breakthrough designation to 20 potential innovative new drugs that have shown encouraging early clinical results.

Drug developers should have a clear understanding of all of FDA’s expedited development and review tools. To help industry better understand each tool, including when the tools can be used and the features of each, we have just published an industry draft guidance titled Expedited Programs for Serious Conditions — Drugs and BiologicsAmong other important information, the draft guidance describes FDA’s policies and the threshold criteria for each expedited program, defines and discusses important concepts, including serious condition, unmet medical need, and available therapy, and provides some general considerations for products utilizing an expedited program, such as manufacturing and product quality, nonclinical considerations, and clinical inspection considerations.

The breakthrough therapy designation gives us another tool in our “toolbox” to help expedite the development and review of new drugs to treat patients with serious medical conditions and little or no treatment options. We’ll continue to use the new breakthrough therapy designation and our existing tools to help make our expedited programs even more effective.

We’ve said it before — and I believe it’s worth repeating — our decision-making on whether to approve a drug always involves an evaluation of many factors, such as the seriousness of the disease.  However, ultimately any drug approved must show that its benefits outweigh its risks and regardless of which expedited development or review program or programs are used, FDA does not compromise its safety or efficacy standards in exchange for rapid approval. Like all drugs we approve, those approved after having been designated as breakthrough therapies will meet our usual rigorous standards for safety and effectiveness.

Janet Woodcock, M.D. is the Director of FDA’s Center for Drug Evaluation and Research