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Accelerating the Development of Pediatric Drugs for Rare Diseases

Keynote Speech, Alexandria Summit on Oncology 2013
Margaret A. Hamburg, M.D.
Commissioner of Food and Drugs
New York City, NY
June 27, 2013

Thank you, Joel for that kind introduction.  And thank you Nancy, for all your hard work on this issue. Your efforts not only have inspired us, but also influenced productive discussions within the Agency that are leading to faster access to safe and effective new drugs for children with cancer. And perhaps most important, each day you give new and enduring meaning to your son Jacob’s life as you make a difference in the lives of the many children who will face cancer.

Today, I want to discuss the issues you have raised about research and drug development for pediatric cancer, what FDA is doing to address these challenges, and the significant progress and potential for future success we see in this area.

We are in the midst of some exciting advances in the development of improved and better treatments for cancer that we expect can and will translate into new treatments for pediatric cancer.
This success depends on the science and on new ways of thinking and acting, how well we adjust and reinvent processes and procedures, expand cooperative efforts, and eliminate barriers that have prevented us from maximizing innovation and efficiency. And it means taking risks.

Greater coordination among regulators, researchers, and industry, as well as the growing role of patients and advocacy groups, is helping us improve efficiency and strengthen productivity in how we address clinical trial designs, share research findings, and avoid duplication. This has allowed us to speed up processes and make earlier decisions that will allow us to increase our progress against some pediatric cancers and, we hope someday lead to cures for more children. 

We have long faced historic obstacles in pediatric medicine generally, and more specifically in efforts to develop treatments and cures for pediatric cancers.  This is the result of the tension between our eagerness to respond as quickly as possible to find new therapies for children, and our desire to protect children from potentially dangerous side effects, particularly in the early stages of research when effectiveness is not fully known.
Children with cancer have unique needs requiring specialized medical treatments, drugs, and dosages.  Differences in the types, sites, causes, and biology of the tumors that occur in children and adults make it impossible to prescribe drugs to children simply based on adult data.  Many drugs approved for adult diseases, particularly in the area of cancer, are not designed or intended for, not always effective on, and could cause grave harm to pediatric patients. Even in those limited cases where pediatric and adult cancers are similar, adjustments in dosing from adults to children requires understanding of many different factors, including rates of absorption, distribution, metabolism, and clearance of the drug. This is a real challenge we must address.

The challenges are further complicated by the lack of economic incentive for drug companies to explore these issues because of what they view as the relatively small size of the market. The outlook for cancer drugs for children in particular contrasts sharply with many other larger market areas of pediatric product research, such as antibiotics, asthma-related products, some vaccines, and cough and cold medicines, where the same clinical conditions occur in both adults and children. 

If the story ended there, it would be largely one of disappointment and frustration.  Happily, it does not. We are at a point where we are rethinking how we deal with and treat specialized pediatric illnesses, including cancer. Over the past 20 years we have evolved from a view that we must protect children from research, to a view that we must protect children through research, in order to assure their access to new and effective medications.

We understand more clearly than ever that the performance of research studies to evaluate drugs for children is the only way to truly determine the safety and efficacy of medication in children and to avoid possible harm when children are given drugs approved only for adults. This recognition is why the FDA has expanded its efforts and focus in the area of pediatric drug development.

Recent legislative changes have created both voluntary and mandatory mechanisms to prioritize drug research and development for children, which has resulted in a dramatic increase in pediatric drug trials.  Beginning with the Food and Drug Modernization Act (FDAMA) of 1997 -- renewed as the Best Pharmaceuticals for Children Act (or BPCA) -- Congress created a reward for pharmaceutical sponsors for evaluating molecular entities in children by providing for an additional 6-month exclusivity period that attaches to existing patent and exclusivity protections when an industry sponsor conducts studies in pediatric patients under a Written Request from FDA.

The added exclusivity provision has played a major role in spurring pediatric studies. Under this incentive, four cancer drugs have been approved for use in children and information about pediatric studies has been added to the labeling of another 12 cancer-specific drugs. In 2010, with the passage of the Affordable Care Act, the pediatric exclusivity provision was extended to biological products. As a result, those biologic products developed for cancer indications are also being studied in children.

Just as important was Congress’s passage of the Pediatric Research Equity Act (or “PREA”) in 2003. PREA requires sponsors who submit applications for new active ingredients, indications, dosage forms, dosing regimens, or routes of administration to conduct pediatric studies in the indication in which adult approval is sought unless the studies are waived because they are impossible, impracticable, the drug will be unsafe or ineffective  in pediatric populations, or the product provides no meaningful benefit over existing therapies and  is not  likely to be used in a substantial number of pediatric patients.  So far, PREA’s significance for pediatric cancer patients primarily has involved drugs developed to treat or prevent the side effects of chemotherapy, since PREA requires studies in the same indication in which adult approval is sought and most adult cancer types for which most oncology drugs are developed do not occur in children.

What is especially important, however, is how BPCA and PREA work in tandem to encourage pediatric product development and support both industry’s and FDA’s ability to meet the unique needs of children. For instance, when a sponsor submits a new drug application and is required under PREA to conduct pediatric studies, we explain that they may also qualify for pediatric exclusivity.  Similarly, when the mechanism of action of a new drug developed for a specific adult cancer type might be also be relevant to the treatment of a pediatric cancer, providing incentives for pharmaceutical sponsors such as the exclusivity provided for in BPCA can assure that potentially promising drugs are evaluated in children.

FDA’s Office of Hematology and Oncology is focusing efforts on optimizing use of the regulatory authority provided by BPCA and PREA. One important way it has done this is through earlier consideration of Written Requests, which were developed to implement the pediatric exclusivity provision. Once issued by the FDA and agreed upon by the pharmaceutical sponsor, the Written Request describes the pediatric studies that the sponsor must complete. I’ll speak a little more about this significant development in a moment.

We are also working to strengthen the laws in this area.  One important advance has been the result of your remarkable efforts, Nancy, in getting the Creating Hope Act signed into law last year. Providing a transferable priority review voucher to companies who develop drugs for rare pediatric diseases allows us to offer drug developers even more incentive to develop drugs for such rare conditions.  The law has the potential for real impact, particularly in smaller markets like pediatric cancer, where special incentives can make all the differences.   This is still a very new program, of course, but we already have several requests in the pipeline for these vouchers, including one for a pediatric cancer indication. 

These legislative changes reveal the growing understanding among many different communities – Congress, industry, regulators, and of course families -- of the need to focus on pediatric cancer. I can assure you that FDA is playing a key role in moving this agenda forward, by working to increase flexibility, broaden cooperative efforts and information-sharing, strengthening sponsor interest, and coordinating engagement with clinical investigators. We want to ensure that the right research is being done as early as possible, and encourage industry to focus more attention on pediatric development plans when their primary marketing strategies or objectives are oriented to specific adult cancers.

We already are seeing progress. More and more drug companies today are hiring pediatric experts, and some large pharmaceutical companies have developed pediatric centers of excellence.  Monthly Pediatric Cluster teleconferences coordinated by the FDA’s Office of Pediatric Therapeutics helping us work more closely with our European regulatory counterparts on various drugs and trial designs and better align pediatric investigation plans. The result is accelerated drug development in specific types of childhood cancer. 

We are also promoting earlier and more coordinated communications between the FDA and the National Cancer Institute, with clinical investigators and clinical research networks, including the Children’s Oncology Group, the Pediatric Brain Tumor Consortium, and others, as well as with commercial sponsors, and with patients and their families and advocates. We are trying to “lean in.” Indeed, our entire infrastructure increasingly is aimed at promoting earlier consideration and approval of these treatments. On a more personal level, we are working to build a system that assures parents that their children are being treated appropriately, safely, and effectively.

There already have been some very substantive and important changes in the treatment of a number of pediatric cancers. For example, although no new drugs have been developed to treat a form of brain cancer known as medulloblastoma, several approved drugs have been introduced as part of current treatment strategies. In fact, a sponsor is in the very early development of a promising molecularly targeted compound for medulloblastoma in children and adults.

We also have seen a number of drugs approved for pediatric cancer, some more recently, some a number of years ago. But as you know, approval is just the last part of the process. When FDA is asked to review new drugs we act quickly and generally favorably. Unfortunately, most oncology products studied in pediatrics have simply not gotten to the review stage -- because they have not worked.

This highlights a bigger problem – that we do not receive enough applications for new oncology drugs for children. Approval is the last step in the development process.  In most cases, there is simply nothing to approve.  That is why we need to join forces and put our emphasis on the discovery and development of these drugs, which comes from the industry and the academic research community.  And we are hopeful that initiatives like the Creating Hope Act may provide incentives to change the landscape.

One promising opportunity for speeding up the development process is a 2012 change to PREA requiring all sponsors to put forth proposed pediatric study plans early in the development timeline.  In addition, our Pediatric Subcommittee of the Oncologic Drugs Advisory Committee now assembles sponsors, investigators, and advocates to consider Written Requests for promising compounds of interest long before sponsors submit applications for approval of these new drugs. And we routinely initiate early discussions about possible pediatric investigations, even when these cancer drugs are being developed for adult tumor conditions that do not occur in children. In fact, we review mechanisms of action and/or molecular targets for their potential applicability or relevance to a childhood cancer and, when warranted, advise sponsors to consider an investigation and development plan for one or more relevant pediatric cancers.

What this new approach has the potential to do is chop 8-10 years off the investigation and pediatric development process.  And we already have nearly doubled, in the last two years alone, the number of Written Requests under development and provided to sponsors. This means sponsors have incentives to move through the pipeline more and potentially better options for children with cancer. We want to build on this broad input from all of our partners. That’s why, as part of our commitment to the law, we are preparing to hold a public meeting to ensure that we hear from all parties on ways to accelerate therapies for pediatric rare diseases.

As I said at the outset, we are in the midst of some exciting advances. Let me summarize the three key areas of focus. 

First, the importance of flexibility in terms of regulatory requirements and the design and analysis of clinical studies.  Increased flexibility does not mean abandoning science. Just the opposite. We need to employ the best science in ways that will increase our efficiency, productivity, and ability to find creative solutions to the challenges that confront us.

Second, partnerships matter.  Success can be achieved much more quickly and effectively when different communities with the same goals work together. So whether it is FDA sharing information with our regulatory counterparts in Europe, or building relationships with the community of patients and their families, or finding new and creative ways to connect with and encourage the research community and the industry, we must be ready to engage.

Third, engagement in the research and development process must be early and frequent. As our new Written Request process confirms, we can improve traditional methods and processes. At FDA we have a unique ability to achieve this, through our understanding of unmet medical needs, the ability to bring together parties productively, provide incentives to get the work done, and help turn projects in the pipeline into real developments.
I think we can all recognize that the opportunities for progress have never been greater. The science has never been more exciting and promising.  But we must continually be asking ourselves and others – and here I quote Deeda Blair – “how do we do science better?” And how can we truly leverage all of the opportunities before us so as to expand treatments, make available new drugs and hopefully develop new cures?  That is the duty we have to patients, families, the nation, and the world. And by working together we will meet this obligation and achieve these vital goals.