Speech by Margaret A. Hamburg, M.D.
Commissioner of Food and Drugs
Second Annual Pediatric Surgical Innovation Symposium, "Lessons from Drugs to Devices: A Pediatric Perspective"
October 24, 2014
Thank you, Dr. Kim, for your kind introduction. It is an honor to participate in the 2nd Annual Pediatric Surgical Innovation Symposium and provide some final thoughts about today’s conversation on this very important topic.
I also want to applaud the Children’s National Health System’s Sheikh Zayed Institute for Pediatric Surgical Innovation because it lays out a set of ambitious goals for making pediatric surgery more precise, less invasive and pain free.
Certainly how you’ve gone about trying to achieve this goal is a model to emulate. Besides bringing together a critical mass of talented experts, you’ve recognized that significant health care advances also require creative connections with patients and families, clinical, academic, government and corporate partners in Washington, the nation, and the world.
In short you’ve been carefully and deliberately building just the sort of ecosystem that can support the goals of advancing pediatric surgical innovation. A model that will really help best leverage the opportunities in science and technology today for the benefit of patients and ensure that we link unmet medical needs with what can be done in terms of new research and development and product availability and deployment.
And the need for pediatric surgical innovation is great. Children represent our future – it’s trite but true – and any of us who are parents go to any lengths to ensure our children’s health. And yet I think we have to say our health care system has really not, been able to provide the surgical tools and implantable devices that are so critically needed to treat and sustain some of our young people who require surgical intervention.
We’ve all heard the anecdotal stories about surgeons who have no choice but to use oversized endoscopes, electrosurgical devices, staplers and gastrojejunal tubes and other tools when operating on newborns.
Even as a medical student, I remember struggling with oversized IVs and catheters for our younger patients.
And of course, the need doesn’t end there. It continues across the age spectrum of the pediatric population.
There have been some important exceptions to this trend. In the 1950s, the medical device company Medtronic developed its first significant product—the battery-powered pacemaker. This device was developed to address a pediatric need identified by the open heart surgeon Dr. C. Walton Lillehei, who would wire his patients up to a pacemaker connected to an electrical outlet while they healed.
When a young patient died following a power failure at the hospital, he contacted Medtronic, then a fledging local company. Of course, advanced iterations of this device would go on and be translated into products for adults as well as children, demonstrating how developing products that are good for kids can be good for adults as well.
More recently, there have been some truly noteworthy devices approved for pediatric patients such as the Berlin Heart EXCOR Pediatric Ventricular Assist Device (VAD), the first FDA-approved pulsatile mechanical circulatory support device specifically designed for children.
And infants and children born with pulmonary insufficiency from fused ribs and congenital scoliosis have lived more normal lives because of the Vertical Expandable Prosthetic Titanium Rib (VEPTR), to treat Thoracic Insufficiency Syndrome (TIS). Importantly, the rib adjusts as the child grows.
I am also aware of some recent start-up companies that are specifically focused on developing devices for children – and that some of you are here in the room today. That is wonderful. Thank you for your presence and your work. We want to work with you.
But if you look at the data, it’s clear that too few device companies are stepping up to address the needs of pediatric patients, and we are not seeing the activity and applications we would like.
In fiscal year 2013, FDA approved one device under the Humanitarian Device Exemption, a pathway to market for devices intended for rare diseases or conditions which can often include the pediatric population but this product didn’t include a pediatric indication. In the same fiscal year, FDA approved 38 premarket approval applications, either PMAs or panel-track PMA supplements. Eleven of those 38 PMAs, were approved for a treatment, diagnosis or cure of a disease or condition that occurs in children, yet only 8 were indicated for a pediatric population, defined by the Center for Devices and Radiological Health as up to age 21.
Only one of the PMAs—the Minimed insulin pump – was approved for a pediatric patient under the age 18, and it is indicated for patients aged 16 and older.
Given these trends, pediatric surgeons have responded out of necessity by getting creative, jury rigging surgical tools and implantable devices in order to care for their young patients. This has made a difference in care, but such use can bring with it patient risks that could be avoided if there were more FDA-approved pediatric devices.
For example, we have become aware of harm from the off-label use of implants to treat pediatric patients with congenital dental and cranial-facial abnormalities and in the school age pediatric population where gastric stimulating devices are being used off-label. So we must address these critical challenges.
Moreover, there are a host of engineering issues related to designing a pediatric device.
It requires taking into account such factors as unpredictable growth and development, hormonal influences, anatomic and physiologic differences, and activity level. And scaling down an adult-size device for use in children brings potential mechanical challenges as well because thinner or shorter devices could change the product’s compositional properties.
So what can be done to encourage medical device manufacturers to enter the pediatric surgical and implantable space? In some areas of unmet medical need we can point to lack of understanding of the underlying biology and natural history of a disease, or even a lack of technological prowess, as the major drags to progress.
But we DO know what needs to be done to encourage devices for pediatric surgical innovation.
It requires a comprehensive approach that includes enhanced pediatric incentives and requirements, more information about the specific needs of pediatric patients, creative approaches to device development and regulation, advances in regulatory science, support for young companies, and a collective will to get things done.
I know this morning you began with a look at the policies in place that encourage pediatric and orphan drug development to help inform your discussions. And indeed what has happened in pediatric drugs can be a useful model – at least to a certain extent.
As you know, drugs that treat a small patient population, including many for pediatric patients, can fall under the umbrella of the Orphan Drug Act.
That act, as amended and supplemented by other laws, provides a range of incentives including tax credits to offset the cost of clinical trials, the waiver of marketing application user fees, and potential eligibility for seven years of marketing exclusivity upon approval of the drug.
And there are specific incentives and requirements designed especially for the pediatric population including the Best Pharmaceuticals for Children Act (BPCA), which grants an additional six months of marketing exclusivity for the entire drug moiety to companies that develop drugs for children in response to a Written Request from FDA; the Pediatric Research Equity Act (PREA), which requires drug companies to study their products in children under certain circumstances; and finally the recent Rare Pediatric Disease Priority Review Voucher (PRV) program, which allows sponsors of a drug approved for a rare disease that primarily affects the pediatric population to receive a voucher for a Priority Review which they can sell to another company to use to obtain faster review for another drug that wouldn’t otherwise qualify for priority review.
Additionally, companies interested in developing pediatric drugs often can take advantage of the expedited development and approval programs available for those drugs that meet unmet needs – programs that include fast track, accelerated approval, priority review, and the more recent breakthrough therapy designation. Indeed, products developed for pediatric use under BPCA or PREA typically have 6 month review cycles.
These various inducements, requirements and incentives, combined with the increase in the number of targeted therapies that take advantage of our growing knowledge in areas such as genomics and biomarkers, are having a beneficial effect on rare disease drug development, including development of drugs for pediatric diseases.
Over 500 drug products now have new pediatric labeling because of participation in either BPCA or PREA or both programs. And as a result, many drug companies increasingly view rare disease drug development as an attractive investment.
In contrast, there are far fewer incentives available as either carrots or sticks to prod investment in devices for pediatric surgery.
There are no vouchers, no clinical tax credits or opportunities for patent extensions specifically for pediatric devices. Indeed, any patent-related incentives are especially challenging given the iterative nature of devices. And the primary path to market for pediatric devices is subject to the device tax.
In addition, devices have nothing comparable to PREA; there is no requirement that device companies study their product in children.
This doesn’t mean there are no incentives available, there just aren’t as many. FDA does have limited money available to provide grants to fund clinical development of either drugs or medical devices for rare diseases through the Orphan Product Grants Program. About 10 to 15 grants are funded through this competitive program every year. In fact, the Berlin Heart took advantage of this funding mechanism.
And as you’ve discussed today, there are inducements in the Humanitarian Device Exemption (HDE) path to market for a pediatric surgical device or implant. This pathway is available to devices that are designed to treat or diagnose a disease or condition that affects or is manifested in fewer than 4,000 persons in the United States every year.
For one thing, companies do not have to pay user fees for an HDE application. Second, while, an application for an HDE is similar in both form and content to a premarket approval application (PMA), a device under the HDE pathway is actually exempt from the effectiveness requirements of a PMA. Instead, sponsors need only demonstrate, among other things, that the product will not expose patients to an unreasonable or significant risk of illness or injury and that the probable benefit outweighs the risk of injury or illness.
This exemption is in place in part because there are often too few patients who can be studied in small rare disease populations to conclusively establish statistical efficacy. This different evidentiary standard is intended to encourage companies to develop devices for rare diseases or conditions but we understand that some companies feel that they need more guidance on this approach.
Perhaps the biggest incentive is that HDE-approved devices intended for use in pediatric patients and labeled for the pediatric population are allowed to make a profit.
This exemption from the profit restriction for HDE-approved devices was first authorized under the 2007 Pediatric Medical Device Safety and Improvement Act and then was further expanded under the 2012 Food and Drug Administration Safety and Innovation Act or FDASIA.
As a safeguard, pediatric medical devices approved under the HDE pathway and exempt from the profit prohibition are required to undergo annual reviews by the FDA’s external Pediatric Advisory Committee to ensure that the HDE for the devices remains appropriate for the pediatric population(s).
I know that some insurers – including CMS – have viewed HDEs as experimental because an investigational review board must approve the use of the device after its marketing approval. FDA is doing what it can to dispel this impression. In early 2013 we issued explicit guidance pointing out that devices approved under the HDE pathway should not be deemed experimental.
Given the small number of HDE applications we see for children, some have argued additional incentives may be necessary to spur pediatric device development. We have heard from various stakeholders that one way to do so is to increase the 4,000 patient statutory threshold for the HDE. It is unclear whether doing so would best serve the pediatric population.
But regardless of whether the patient limit is increased, we believe more needs to be done. There could be other options such as working with CMS to encourage reimbursement.
And of course not all pediatric devices can be expected to reach the market as an HDE, nor should they. We’re currently looking at ways to further encourage product development for unmet medical needs through the premarket approval pathway
A draft guidance issued earlier this year calls for the expedited access PMA program, a voluntary program that would speed to market certain devices that address unmet needs for life-threatening or irreversibly debilitating diseases or conditions and are subject to PMAs. Under the expedited access PMA program, FDA may accept less certainty regarding the benefit-risk profile of a device at the time of premarket approval, as long as the data supports a reasonable assurance of safety and effectiveness.
Both HDEs and PMAs require clinical trials which are always expensive but when they involve children they can be even more challenging for many reasons, and made even more so because we lack a national pediatric device trial infrastructure. This is an important area for further work and has been much discussed inside government and out. Help us think about how to address this.
In addition, to make device development easier, the Pediatric Medical Device Safety and Improvement Act of 2007 also explicitly allowed companies to extrapolate the results of adult effectiveness data for approved devices, where there was scientific data to support such an approach, in order to extend claims to pediatric patients. And apart from this statute, we may also be willing to consider other sources of valid scientific evidence from “real-world” clinical experience, registries and other sources.
There is one other pathway worth noting – FDASIA included provisions to streamline the de novo classification pathway for novel devices of low-to-moderate risk.
Also, FDA has implemented process improvements to increase the efficiency, transparency, and accountability of the Agency’s de novo review process, resulting in a more than 70 percent reduction in total time to market for these products from submission to approval since 2010.
And there are other steps underway that could encourage pediatric device innovation.
The Center for Devices and Radiological Health’s Patient Preference Initiative is intended to better incorporate the voice of patients on the benefit-risk trade-offs of medical devices into the full spectrum of regulatory decision making. For rare or serious diseases or conditions, FDA understands that a patient or caregiver may have a higher acceptance of risk associated with a given therapy.
The Initiative began with a series of meetings sponsored by the National Organization for Rare Diseases and resulted in a 2012 guidance document, for “Factors to Consider” when making benefit-risk determinations in medical device premarket approvals and de novo classifications. It created a systematic patient-centric benefit risk framework which includes a template for reviewers to further assure decisions are consistent across premarket submissions.
The Patient Initiative is one of the action items in the FDA’s strategic plan for encouraging pediatric drug and medical device development that was issued earlier this year. That plan also calls for conducting a needs assessment for patients with rare diseases sin order to document the compelling need for devices for these patients, including pediatric patients.
Toward this end, FDA has begun working with the National Institutes of Health’s National Center for Advancing Translational Sciences’ Office of Rare Diseases Research on a medical device needs assessment for rare diseases that will also address the needs of the pediatric population. The project will include a survey of physicians, researchers, patients, and industry.
We also will take advantage of another source of information as we assess this problem. Under a final rule issued in January, device manufacturers must now describe any pediatric subpopulation that suffers from the disease or condition that the device is intended to treat, diagnose, or cure when they submit a marketing application.
Also highlighted in the strategic plan are a few steps to advance regulatory science – that is, the knowledge, tools, strategies, and approaches that will enable us to more efficiently and meaningfully assess product safety, efficacy, quality and performance.
We intend to further refine and expand our use of computational modeling, which can predict how a device will perform before a single prototype is produced. Computational modeling is being used to predict the best ways to defibrillate children since existing defibrillation devices have only been optimized and studied for use in adults.
Using such models can speed the design and testing of new and improved devices and can provide enriched information when widespread clinical trials aren’t feasible.
Computational modeling, in vitro tests and animal models, including juvenile animal models for pediatrics, are all examples of Nonclinical Assessment Models that can potentially streamline the preclinical phase of device development.
In November 2013, FDA published a draft guidance on Medical Device Development tools. It describes how both nonclinical models as well as various biomarkers and clinical outcomes assessments can be validated and used in studies.
The strategic plan also acknowledges the importance of collaboration in advancing pediatric device product innovation.
As you all well know, knowledge isn’t confined to FDA or academic medical centers or industry. Success can be achieved much more quickly and effectively when different communities with the same goals work together.
One example of what collaboration can achieve was the new paradigm for obtaining marketing approval for prosthetic heart valves for children. Recognizing there were no FDA-approved heart valves available for the pediatric population and the pressing need to develop them, in January 2010, heart valve manufacturers and pediatric clinicians collaborated with academicians and FDA staff in a workshop to suggest ways to successfully evaluate pediatric prosthetic valves and conduct pediatric clinical trials to provide acceptable heart valve replacement options for this patient population.
This effort is already paying dividends. Earlier this year St Jude Medical publicly disclosed that it had filed an investigational device exemption with FDA to study a tiny mitral valve that is right-sized for a newborn.
There are other important collaborations that will ultimately benefit the development of pediatric devices. FDA is one of the partners in the Medical Device Innovation Consortium, a public private partnership working to advance medical device regulatory science.
Its members include government, industry, academia, and patient and consumer groups. Two of its current projects are focused on patient benefit risk assessments and computational modeling.
But certainly the highest profile collaboration for pediatric devices is administered by our own Office of Orphan Products Development - the Pediatric Device Consortia Grant Program, another by-product of the 2007 Pediatric Act.
A total of $14.6 million has been awarded since the program became operational in 2009. In FDASIA, Congress reauthorized FDA to distribute $5.25 million every year through 2017, but the program is currently appropriated for less than that - $3 million a year.
Each funded consortia is expected to bring together teams with excellence and expertise in delivering business, regulatory, legal, scientific, engineering, and clinical services for children.
In addition to business and regulatory advising, the consortia’s device development services include intellectual property consultation, prototyping, engineering, laboratory and animal testing, grant writing, and clinical trial design with the goal of supporting pediatric medical device progression through all stages of development—concept formation, prototyping, preclinical, clinical, manufacturing, marketing, and commercialization.
Collectively, the consortia have advised innovators on over 400 potential pediatric medical devices; there are over 125 of these projects on which the consortia remain actively engaged. Funding advice on some of these projects has resulted in more than $30 million dollars being raised to fund and advance pediatric medical device research.
The work of the Consortia has already brought to market a device to treat pain with childhood injections, a brace for pectus carnatum and a computer-based asthma management program that now incorporates pediatric parameters.
If these activities seem to embody the collaborative vision of the Zayed Institute, that’s not accidental because your organization is part of the National Capital Consortium for Pediatric Device Innovation, which received $700,000 in grants from FDA in 2013 and 2014.
With enhanced pathways to market, improved information about the unmet medical need, greater understanding of a patient’s benefits and risks, advances in regulatory science, and funding that supports collaboration, we have begun to put in place the mechanisms that will drive innovation in pediatric devices for surgical applications. Now we must ensure action and the continuing will to do so.
Thank you for all the important work you do and your commitment to our greatest and most precious assets, our children.