FDA Approves a Vaccine to Address a Critical Public Health Need – Trumenba– for Prevention of Serogroup B Meningococcal Disease

By: Karen Midthun, M.D.

Over the last year and a half, there have been numerous reports about outbreaks of bacterial meningitis on several college campuses. Invasive meningococcal disease is a life-threatening illness caused by the bacterium Neisseria meningitidis that infects the bloodstream (sepsis) and the lining that surrounds the brain and spinal cord (meningitis). N. meningitidis is a leading cause of bacterial meningitis, which can have devastating consequences. Between 10 and 15 percent of people who develop meningococcal disease die from the infection, and another 10 to 20 percent suffer permanent complications, such as brain damage or limb loss.

Dr. Karen MidthunThere are five main serogroups of meningococcal bacteria that cause illness: A, B, C, Y and W. FDA has previously approved other vaccines to prevent invasive disease caused by serogroups A, C, Y and W, but they do not protect against meningococcal disease caused by serogroup B, which is the serogroup responsible for the recent outbreaks.  These outbreaks underscore why it’s so important to have vaccines that can prevent meningococcal disease.

FDA recently used several strategies to approve Trumenba, the first vaccine licensed in the United States to prevent invasive meningococcal disease caused by serogroup B. This included use of the accelerated approval regulatory pathway, which allows the agency to approve products that provide meaningful therapeutic benefit to patients over existing treatments for serious or life-threatening diseases, based on evidence that the product has an effect that is reasonably likely to predict clinical benefit. The use of this pathway reduces the time it takes for needed medical products to become available to patients.

Trumenba also received breakthrough therapy designation. This designation facilitated the development, scientific evaluation, and approval of the vaccine. In particular, it provided the manufacturer with more intensive FDA guidance on an efficient vaccine development program, and an organizational commitment involving senior FDA managers. It also provided for a “rolling” submission of the Biologics License Application, which allows for sections of the application to be submitted to FDA for review as they are completed, without waiting to submit the complete application at one time.

FDA also designated this application to receive priority review. I am very proud of the extraordinary effort by FDA review staff to thoroughly evaluate the safety and effectiveness of Trumenba and approve it in record time. Our scientific staff worked tirelessly to complete their evaluation in well under the usual six-months timeframe for priority reviews. My colleagues worked closely with Pfizer, the manufacturer, to address this critical public health need.

We are committed to making important medical products available to people who need them. The approval of Trumenba is just one example of the outstanding work by dedicated FDA staff.

Karen Midthun, M.D., is the Director of FDA’s Center for Biologics Evaluation and Research

Early communication: A key to reduced drug development and approval times

By: Anne Pariser, M.D.

From “test tube” to market typically takes a new drug more than 10 years.  FDA has been working hard at many points along a drug’s developmental path to reduce this time and bring safe and effective new therapies to Americans as efficiently as possible. 

Much has been said about FDA’s success in using its “expedited approval” tools, specifically Priority Review and Accelerated Approval, to support innovative new drugs. These are important tools that FDA can use once a marketing application is submitted. For instance, last year, FDA’s Center for Drug Evaluation and Research (CDER) approved 39 novel medications, almost half of which benefited from one (or both) of these expedited approval tools. According to a recent FDA report, this is a 63% increase over the average number of annual approvals since 2002. 

But less has been said about FDA’s “expedited development” tools, which help foster new drug innovation during the investigational phases of drug research and development, well before a marketing application for a new drug is even submitted to FDA. Among these tools are more frequent and earlier opportunities for communication between FDA and drug developers. FDA’s Fast Track designation for drugs with the potential to address unmet medical needs is an example. For many years, Fast Track has helped speed new drug development by encouraging more communication early in the development process. In 2012, about 40% of CDER’s novel new drug approvals were drugs that were given this Fast Track designation.     

Just this past year, the Food and Drug Administration Safety and Innovation Act (FDASIA) authorized FDA to use a new Breakthrough designation for investigational new drugs when preliminary clinical data suggest that the drug may provide a substantial improvement over existing therapies for patients with serious or life-threatening diseases. The concept behind Breakthrough is that, with increased communication, FDA will work with new drug developers to help design efficient ways to study the safety and effectiveness of their drug. This early assistance can help ensure that the results of clinical trials provide the evidence that FDA must have to determine whether or not a drug is safe and effective for approval. A growing number of drug developers are already taking advantage of Breakthrough.

But even before Breakthrough had been authorized by FDASIA, FDA was working to encourage communication opportunities for drug developers to meet with FDA to help make sure their clinical trial designs and development plans offered the best chances of efficient, safe, and timely development and approval. These opportunities are available at the start of a drug’s clinical development cycle: right before the earliest phases of human testing known as the “pre-investigational new drug (IND) phase” (fittingly called pre-IND meetings) and continue throughout drug development.

Early communication in action

Recently, FDA has taken a look at the development times of new drugs that were approved with the benefit of pre-IND meetings and compared them to the development times for drugs that were approved without such meetings. The findings underscore the value of early communication. For those new drugs for which a pre-IND meeting between the drug developer and FDA was held, average clinical development times were substantially shorter than when a meeting was not held. For instance, for all new drugs approved between 2010 and 2012, the average clinical development time was more than 3 years faster when a pre-IND meeting was held than it was for drugs approved without a pre-IND meeting.

For orphan drugs used to treat rare diseases, the development time for products with a pre-IND meeting was 6 years shorter on average or about half of what it was for those orphan drugs that did not have such a meeting. Early communication is especially important for orphan drugs because these products require special attention and thus early talks can be especially beneficial.

Many factors can influence the speed and efficiency of a drug development program. Nevertheless, FDA strongly believes in the value of effective communication during the drug development and approval process, especially for novel development programs when established regulatory pathways do not exist. FDA is committed to working with drug developers to ensure efficient and effective drug development programs whenever possible.

Thirty-nine novel new drug approvals last year is encouraging – one third of which are indicated to treat rare diseases – and many of these new drugs are now making valuable contributions to public health inAmerica. FDA will continue to do its part to help bring safe and effective new drugs to market as soon as possible. We will continue efforts to enhance communication as a critical part of the drug research, development, and regulatory process – especially since it is so clear that communications can make a big difference.

Anne Pariser, M.D., is Associate Director for Rare Diseases, Office of New Drugs, Rare Diseases Program at FDA’s Center for Drug Evaluation and Research

Cancer Care in the U.S. – Looking Back, Looking Forward

By: Richard Pazdur, M.D.

2012. A milestone in my professional career marking the 30th anniversary since I finished my medical oncology fellowship and started practicing in the field. Oncology is a much different place today than in the late 1970’s when I was an oncology fellow in Chicago and when I took my first faculty position at Wayne State University in Detroit in 1982.  In 1988, I assumed a faculty position at The University of Texas M.D. Anderson Cancer Center and left Houston in 1999 to join FDA.

I remember a time when the only drug we had to treat advanced kidney cancer was the hormone, Megace… a time when the only drug to treatment metastatic colorectal cancer was 5-fluorouracil… a time when the only drugs to treat chronic myelogenous leukemia (CML) were hydroxyurea and Busulfan… a time when adjuvant therapy in breast cancer was just beginning to be investigated.

Today is a very different picture. Since 2005 FDA has approved seven drugs for advanced kidney cancer. Oncologists now have multiple options for the treatment of metastatic colon cancer, including the combinations of Camptosar (irinotecan), Xeloda (capecitabine), Eloxatin (oxaliplatin), Avastin (bevacizumab), Erbitux (cetuximab), and Vectibix (panitumumab). Patients with CML have been greatly helped with the introduction of tyrosine kinase inhibitors. Adjuvant therapy, both for breast and colorectal cancers, now has an established role in medical oncology practice and we have moved the early use of anti-cancer drugs a step further into the neoadjuvant setting in breast cancer.

There have been many advances during this 30-year period, including the development of curative therapies in childhood malignancies and great strides in supportive care products. I did not intend to prioritize these advances and I apologize for missing the one you feel most important.

“Cancer” is a multitude of diseases and our current classification of cancer based on organ location (“breast cancer”, “colon cancer”, lung cancer”) will be transformed based on the “molecular fingerprints” of an individual’s tumor. The increased understanding of cancer biology will have profound positive implications for all stakeholders with the development of drugs with greater efficacy and less toxicity.  

The future therapeutic advances in oncology will be based on our enhanced understanding of the biology of cancers. The identification of specific mutations in the BRAF gene in melanoma and mutations in BCR/ABL genes led to the development of therapeutic breakthroughs in melanomas and CML, respectively. Herceptin (trastuzumab) for the treatment of HER-2 positive breast cancer and the anti-CD-20 antibody, Rituxan (rituximab), to treat B-cell lymphomas are examples of using enhanced understanding of cancer biology to discover and develop targeted therapies.  In 2011, FDA approved two drugs – Xalkori (crizotinib) and Zelboraf (vemurafenib) – with concurrent approvals of in vitro diagnostic tests for patient selection providing a clear regulatory pathway for co-development of a drug and a diagnostic test. This year we also saw the approval of Jakafi (ruxolitinib), the first drug approved for myelofibrosis, whose development was based on our understanding of the JAK 1 and 2 pathways in the disease.

In a two-part appearance on Biocentury TV starting Sunday, January 29, I discuss what I see as the changing landscape of oncology (check your local listings). One point I discuss is the need for companies to take a more strategic approach to cancer drug development and to begin thinking of their business as a “disease” company vs. a “drug” company. Successful drug development will only occur with an in-depth understanding of basic disease mechanisms. This “disease orientation” will require greater collaboration between pharmaceutical sponsors, the academic community, government agencies, and patient groups.

The following week (February 5), three reviewers from FDA’s oncology office join me for a roundtable discussion about what they see as the future of oncology and what they encounter as practicing oncologists.

I have been fortunate to work with a talented team of oncologists, pharmacists, toxicologists, nurses, safety and public health experts to evaluate cancer drugs. Our staff understands that there are many diverse opinions in the oncology community regarding approval of oncology drugs. The balance between the immediate needs of an individual patient and the assurance of a drug’s safety and efficacy for approval will always exist. When appropriate, we have permitted the use of single patient INDs, exemptions to existing protocols, and expanded access programs to allow patient access to promising, yet unapproved, drugs.

To expedite drug development and our review of applications, FDA has approved oncology drugs on the basis of a single trial and used a variety of clinical trial endpoints — including overall survival (the time a patient lives before death), progression-free survival (the time a patient lives without their cancer progressing), and response rates (tumor size reduction). FDA has taken advantage of regulatory initiatives for serious and life-threatening diseases, such as fast-track, priority review, and accelerated approval.

When aspiring physicians ask me what it takes to become a medical oncologist I tell them – you must be an optimistic person. It’s demonstrated in the care of patients and a vision for the future of cancer care. Thirty years from now, our success won’t be measured by the number of cancer drugs approved, but by the number of patients living and functioning longer and feeling better.

This year also marks my 30th wedding anniversary to an oncology nurse who I met while we were mixing a chemotherapy drug in Chicago. My wife Mary would clobber me if I didn’t acknowledge the role of the dedicated oncology nurses who kept us all in line—past, present, and future.

Richard Pazdur, M.D., is the Director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research