Brian D. Bollwage, JD

Although the FDA has always been focused on improving drug and device instructions for the safe and effective use of drugs and devices in children, this issue has a confusing history, which has led to industry misunderstandings about the FDA’s desires regarding pediatric labeling. This blog will clarify some of these misimpressions. 	 	

	 	Since the early 1990s, the FDA has encouraged using data extrapolation to provide more comprehensive labeling for use of drugs in pediatric patients. The 1994 Pediatric Labeling Rule created a pediatric use subsection in drug package inserts and encouraged the use of data extrapolation.	 	However, the FDA’s 1998 Pediatric Rule required drug manufacturers to study efficacy and safety of drugs in children or risk FDA denial. Somewhat concurrently, Congress provided incentives to encourage pediatric drug testing in the FDA Modernization Act (FDAMA) of 1997. Both encouraged pediatric clinical trials, while the FDAMA’s promise of extended exclusivity and the Pediatric Rule’s threat of NDA rejection captured much attention.	 	After a federal court in 2000 vacated the Pediatric Rule, Congress responded in 2003 by incorporating its relevant provisions into the Pediatric Research Equity Act (PREA) and went much further to require the conduct of clinical trials in pediatric populations. The resulting confusion led the industry to conclude, incorrectly, that efficacy trials in pediatric patients were required in order to incorporate a claim for pediatric use into product labeling.	 	

	 	However, included in the PREA of 2003 is language that permits the FDA to accept data extrapolation in creating pediatric labeling:	

		“Where the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, FDA may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults usually supplemented with other information obtained in pediatric patients, such as pharmacokinetic studies. Studies may not be needed in each pediatric age group, if data from one age group can be extrapolated to another.”

	The FDA can and does grant pediatric labeling claims for drugs based on extrapolated data. In a 2011 study looking at 166 products approved for pediatric use between 1998-2008 (Dunne J et al. Pediatrics 2011; 128; e1242), 29 used no data extrapolation, 113 relied on partial data extrapolation and 24 relied completely on extrapolated data.	 	It is important to note that for drugs, extrapolation is appropriate only to support a determination of efficacy. In most cases, the FDA will not accept extrapolated adult safety data.	 	

	 	The FDA’s three-part test indicates that extrapolation of efficacy must be based on evidence-based assumptions:	

		Is the course of the disease sufficiently similar in adults and children?

		Is the response to treatment sufficiently similar in adults and children?

		Do adults and children have a sufficiently similar exposure-response relationship OR can the pediatric dose to match the adult exposure be determined in cases when certainty already exists on response?

Extrapolating Adult Data for Medical Devices

	 	In 2007, the Pediatric Medical Device Safety and Improvement Act, Title III of the Food and Drug Administration Amendments Act (FDAAA), authorized the use of adult data to demonstrate pediatric effectiveness. In June 2016, CDRH issued a draft guidance, 

“Leveraging Existing Clinical Data for Extrapolation to Pediatric Uses of Medical Devices,”

 which espouses similar principles as expressed for drugs in determining whether extrapolation is appropriate. CDRH cites three main factors to consider:	

		The similarity of the existing adult response data and/or population characteristics to the intended pediatric population

		The quality of the adult data in terms of study design, data collection and measurement

		Whether extrapolated data may be used to fairly and responsibly decide whether there is reasonable assurance of the safety and effectiveness (or probable benefits for humanitarian device exemptions) of a medical device

	What is important is the comparison in regard to disease and response to treatment and the quality of the data relied upon. Also, extrapolation of efficacy data can only be used to support a PMA, HDE or de novo premarket application but not a 510(k).	 	

	 	The FDA’s ultimate objective, providing safe and effective treatments to patients, is supported by data extrapolation where the requisite conditions are met. There is no single approach to fit all circumstances. The FDA strongly advises researchers to consult early with the agency to determine the appropriateness and degree to which data extrapolation may be leveraged.

Articles

The FDA’s objectives regarding pediatric labeling have been misunderstood due to a confusing history on the matter. Data extrapolation can leverage an avenue for providing more comprehensive labeling for pediatric drugs.

Data Extrapolation to Support Pediatric Labeling

	Regulatory science is the science of developing new tools, standards, methods, and approaches with the goal to assess the safety, efficacy, quality, and performance of all FDA-regulated products. By leveraging regulatory science, the FDA’s Center for Devices and Radiological Health (CDRH) intends to facilitate medical device innovation and to improve decision making in the areas of premarket evaluation, post-market surveillance, and compliance under a total life cycle framework.

	To this end, CDRH created a Regulatory Science Subcommittee in 2013, an advisory group of CDRH leaders and staff charged with proactively enhancing medical device innovation, development, safety, quality, and effectiveness through the development of policies and practices to incorporate new science and technological innovation into regulatory decision making. The end objective is to achieve a positive overall impact on public health. Regulatory science embraces many fields, including engineering, medicine, chemistry, toxicology, epidemiology, statistics, and social sciences.

	CDRH has set upon a cyclical approach to setting regulatory science priorities involving first a phase of critical review and assessment followed by an announcement of priorities and then finally implementation.

	Its most recent action in this approach occurred in October 2015, when CDRH announced its top 10 Regulatory Science Priorities for Fiscal Year 2016. CDRH has stated that these priorities are more than a mere philosophical statement of topics of interest; rather, these priorities are expected to influence CDRH intramural funding decisions. This means that sponsors should take note of the strong message intended by these priorities. Sponsors can learn important lessons and should be able to leverage these lessons into program enhancements that will lead to greater success in the areas of premarket review, post-market product surveillance, and overall total life cycle management of their medical devices. This article will examine CDRH’s top 10 priority regulatory science initiatives and offer some suggestions of how to leverage regulatory science.

	CDRH Top 10 Regulatory Science Priorities for 2016

	CDRH’s top 10 list of regulatory science priorities, all assigned equal importance by CDRH, follow.

	The existence of Big Data warehouses like the human genome sequence data base, clinical trials databases, and insurance databases means that a wealth of scientific and clinical information, potentially relevant to the safety and performance of medical devices, is available to be mined for those willing to expend the effort. The development of informatics capabilities and information technology that can harvest, validate, organize, and disseminate these data will likely pay dividends in both the premarket review process and the post-market surveillance of newly approved medical devices.

	In a related fashion to the Big Data priority, CDRH believes that while most regulatory decisions are based on information provided solely by a device’s manufacturer, opportunities exist to synthesize data from numerous evidence sources to improve the quality of regulatory decision making. Observational data on device use in the marketplace available from health care databases as well as data from the scientific literature are readily available and minimal effort could result in the development of data enabling better insights into both the device approval process and safety signal identification in a post-market setting.

	Since the 1976 enactment of the Medical Device Amendments, CDRH has, to say the least, not been a fan of medical device reprocessing and reuse. Reuse of devices introduces risks not intended by the original manufacturer such as the risk of infection transmission between patients and compromise of performance and safety characteristics.

	Balancing these concerns against the practical reality that device reprocessing and reuse is driven by the marketplace and efforts to constrain costs, CDRH is requesting a more comprehensive approach to assess the use of reprocessing techniques. Recognizing that safety , effectiveness, performance, and quality can only be assured through such a comprehensive approach, CDRH is challenging advocates of reprocessing to begin their evaluation at the design consideration phase employing human factors considerations along with reprocessing methodology development and validation for reprocessing, cleaning, and disinfection. Validated release testing, analogous to the initial “original” release, is considered a critical element as well. 

	Given the practical experience in the marketplace with the transmission of infectious agents via reusable endoscopic equipment, as reported broadly in the news media in January 2015,  CDRH’s demands seem not only reasonable, but just basic good sense. Manufacturers of reusable equipment and medical device reprocessors should be paying close attention to this priority statement.

	While the trend for using computational modeling and simulations for device development is on the upswing, CDRH recognizes that it has not yet leveraged these data effectively for regulatory decision making. CRDH is expressing a willingness, in harmony with the FDA’s Least Burdensome approach,

 to evaluate data from such methodologies to assess their credibility and use in supporting device reviews.

	This area would appear to be a true green field open to leveraging by a sponsor willing to validate alternate evaluation methodologies and educate CDRH on their merits.

			Enhanced Digital Health & Cybersecurity

	Recognizing that digital health is perhaps the fastest growing area impacting medical device development, CDRH is concerned that technology development is outpacing its ability to ensure that the intended public health benefit is achieved without negative consequences. As devices increasingly use networked environments relying on secure and accurate communication between system modules, it is critical to ensure that these technologies and the environments in which they perform are properly designed from a security perspective as well as from an operational perspective. Increasingly, software modifications thought to be inconsequential have led to performance problems resulting in device recalls or repairs. FDA scrutiny and challenges in this regard are expected to increase.

	For those in the medical device industry who hoped that Human Factors Principles

 were merely a flavor of the month that would run its course and disappear, they’ll be disappointed to hear that CDRH’s interest in this area continues to increase as evidence mounts that many recalls and a significant number of device-related adverse events can be traced directly to the failure of underlying human factors engineering problems. Stated more directly, avoidable user error can be reduced substantially through examination of device usability issues earlier in the development process. Preventable design problems can often only be uncovered through a robust human factors evaluation program. This will become increasingly important as CDRH relies more heavily on alternate data sources and grants approvals based on the Least Burdensome approach, which may, at times, eliminate or reduce the requirement for actual clinical trial data.

			Modernize Biocompatibility Evaluations

	The typical battery of preclinical testing employed for medical devices has not changed significantly in more than 35 years, which is the limit of this author’s observation. By including this as one of its top 10 priorities, CDRH is inviting the industry to step up and innovate, to develop alternate approaches to the standard battery of tests. CDRH speculates that computational or 

 modeling might result in advancements that, while not eliminating the need for animal testing, might indeed reduce the dependence on animal testing.

			Evaluation of Medical Device Materials

	In November 2015, the FDA issued a summary of its observations over several years suggesting that numerous product recalls, some including patient deaths, were directly related to the failure of both hydrophilic and hydrophobic surface coatings for a number of devices including catheters and guide wires.  This finding reinforces CDRH’s belief that there is a large gap in our collective understanding of surface coating technology and the role of nanotechnology in selecting material types as well in our understanding of what impact they may have on quality, performance, and safety of medical devices. The current state of the art involves the modification of a product’s surface with the ultimate test being the actual implantation, for example, of the modified device to determine what impact the coating or nanomaterial may cause in patients. CDRH believes there is a critical need to improve the nonclinical assessment tools for the physicochemical and mechanical performance of devices and no longer rely predominantly on human subject exposure to develop this insight.

			Patient Reported Outcome Measures (PROMs)

	While there is an increasing use of PROMs in medical device trials, CDRH observes that the quality and reliability of the data of PROMs are very variable. Increasing the systematic development and validation of PROMs will pay dividends for medical device manufacturers that want to propose the use of alternate data tools consistent with the Least Burdensome approach.  The experience of the Center for Drug Evaluation and Research (CDER), which has employed patient reported outcome data for a number of years, can provide a road map for interested parties. CDER guidances on development and validation of PROs exist and will inform device developers’ efforts.

	The FDA in general recognizes the potential value of a patient-centric approach to product development including both drugs and devices. With patients increasingly interested in expressing their views, e.g., via social media, CDRH is welcoming ideas on how to better leverage the wealth of experiential data that exist and incorporate high-quality patient experience data into its regulatory decision-making process.

	Clearly CDRH is open to, and even hungry for, innovation in regulatory science. Its self-proclaimed mission to make the best possible decisions, both in premarket review and post-market surveillance, based on sound regulatory science speaks to an atmosphere where a forward-thinking sponsor can benefit from this open-minded atmosphere at CDRH. A sponsor’s willingness to invest time and resources into answering questions, sometimes in a departure from convention, might be expected to result in significant leveraging opportunities via the FDA’s Least Burdensome approach. A creative mind set towards marshalling data from unique sources can contribute to the overall success of a sponsor’s 510(k) or premarket approval application.

	Brian D. Bollwage, JD, is Vice President, Global Regulatory Affairs at Chiltern.

 “The Least Burdensome Provisions - Activities Related to Implementation,” U.S. Food and Drug Administration, 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/MedicalDeviceProvisionsofFDAModernizationAct/ucm136685.htm

 “CDRH’s Approach to Providing Human Factors Information,” U.S. Food and Drug Administration, 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HumanFactors/ucm128192.htm

CDRH announced its top 10 Regulatory Science Priorities for Fiscal Year 2016, and stated that these priorities are more than a mere philosophical statement of topics of interest; rather, these priorities are expected to influence CDRH intramural funding decisions.

Leveraging Regulatory Science to Succeed at CDRH

	The Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Devices and Radiological Health (CDER, CBER and CDRH) will review all new investigational new drugs (INDs) or investigational device exemptions (IDEs) within 30 calendar days of receipt and determine whether the application supports commencement of the planned clinical trial(s) or whether a clinical hold should be imposed. The Food and Drug Administration (FDA) may impose either a complete clinical hold, in which case a delay or suspension of all clinical work requested under an IND or IDE is invoked, or a partial clinical hold preventing only part of the proposed clinical work requested under the IND or IDE from being conducted.

	The distinction between complete and partial clinical holds, while administratively significant, may be even more important in illustrating the FDA’s underlying philosophical basis for IND and IDE decision making. The FDA will generally permit clinical trials to proceed where they do not present unreasonable and significant risk of illness or injury to human subjects. The evaluative criteria establish a risk/benefit weighing calculus that involves balancing the available safety data submitted in the investigational application against the magnitude, scope and duration of the proposed clinical trial. Stated simply, basic safety data that might be deemed insufficient to support conduct of a large clinical trial may be sufficient to support a more modest trial plan. This risk/benefit calculus should be considered carefully in proposing clinical trial plans in any new IDE or IND.

	The grounds for imposing a clinical hold for investigational drugs or medical devices are to be found respectively at 21 CFR 312.42(b) and 21 CFR 312.30(b

. The language of these two regulations is markedly different, but a single underlying and unifying principle is shared for both drugs and medical devices: Human subjects should not be exposed to undue risk in comparison to the potential benefit of the investigational treatment. This principle is stated somewhat differently for drugs, as a prohibition against exposing patients to “unreasonable or significant risks of illness or injury,” compared to medical devices, which require the determination that the risks to subjects “must be outweighed by the potential benefit to the subjects and the importance of the knowledge to be obtained.” In either case, the importance of the risk/benefit analysis can easily be appreciated.

	For drugs and medical devices, some of the broader categories for invoking a clinical hold include:

		Untrue statements of material fact in an application

		A scientifically unsound investigational plan

		Inadequate data provided in the IDE or IND

	The FDA lists criteria that can be invoked in supporting a clinical hold decision. The CDER 

Manual of Policies & Procedures MAPP 6030.1

 speaks to 10 separate categories of clinical hold deficiencies, any one of which alone can justify a clinical hold decision. The 10 clinical hold categories are:

Some Examples of Typical Reasons for Clinical Hold Decisions

		Data from animal studies is insufficient to support the planned human exposure (dose, duration, route, frequency). See 

		Selected starting dose is too high or inadequately justified. See the FDA’s 

Estimating the Safe Starting Dose Guidance

		Toxicology studies were not conducted in compliance with good laboratory practice (GLP) regulations. Even “clean” toxicology studies can expect to be discounted if non-compliant with GLP regulations.

		Safety signals observed in animal studies have not been adequately investigated/followed up.

		Observed toxicities have not been incorporated as safety assessments in the clinical protocol/plan.

		Treatment plan is imprudent, e.g., too many subjects, patient population too broad, dose escalation too aggressive, absence of safety oversight (data and safety monitoring board), enrollment is not staggered.

		Impurity profile is either ill-defined or indicative of potential health hazard.

		Product stability is inadequately demonstrated.

		Evidence of final product quality is inadequate.

	The above lists are not exhaustive but do provide examples of the most frequently cited deficiencies that cause IDEs or INDs to be placed on clinical hold. It is important to note that there is no single predominant discipline responsible for clinical hold decisions. Factors relating to product quality, preclinical testing and clinical trial design all can play a part in the clinical hold decision. Therefore, a multidisciplinary approach to developing the investigational application is considered essential to success. This multidisciplinary approach, combined with a pre-IND or pre-IDE meeting, will go a long way to streamlining the IND/IDE process and preventing a clinical hold.

Value of the Pre-IND or Pre-Submission Meeting

	Establishing an early and ongoing dialogue with the FDA may be the most important step a sponsor can take to ensure the successful development of its drug or medical device. The FDA is, without question, the greatest repository of intelligence regarding drugs and medical devices in development. While the agency may not have all the answers to a sponsor’s questions and will not share proprietary data, it will steer a product’s development course, leveraging the data available. Sponsors are often surprised to find out later in the course of a development program why the FDA appeared to channel a product down a certain pathway, relying on the benefit of insights it would not be able to share explicitly. With an investment in time of typically 10-12 weeks, a sponsor can tap into this regulatory intelligence gold mine.

	An open discussion with the FDA can enable a sponsor to identify and skip unnecessary studies, verify that studies are appropriately designed, gain the FDA’s support for the proposed regulatory and clinical strategy and eliminate or minimize clinical hold issues. In addition, the intangible benefit of establishing a collaborative working relationship with the FDA can be expected to pay significant dividends throughout a product’s development life cycle.

	The contents of an IND or IDE are described in their respective regulations at 21 CFR 312 and 21 CFR 812. While the terminology used for each submission type may differ, the basic elements of each application are similar. The sponsor is expected to “tell a story” in presenting its product idea to the FDA. While the terminology for individual submission components may bear different names, the critical elements of a sponsor’s story include demonstrating that the 1) product has a sound basis in science and medicine, 2) target indication is rational, 3) product’s safety profile has been adequately studied, 4) product can be reliably produced and 5) clinical trial design is reasonable and does not place subjects at undue risk.

	Several parts of the IND and IDE that often receive little attention from the sponsor are actually quite important in telling the product’s story. For medical devices, the report of prior investigations and the design history file provide the background information needed by the FDA to frame a medical device in the proper context, and later become the basis for communicating this information to investigators. Likewise, the introductory statement and the investigator’s brochure frame the context of the drug’s development and the near-term plans for further development, providing the basis for the FDA’s appreciation of a new drug candidate. These sections of the IND or IDE should be given adequate emphasis by sponsors in presenting their new products to the FDA for consideration.
	 

	Transparency in communication of sponsors’ plans for their drug or medical device development is a critical component of success with the FDA and other competent authorities. Whether leveraging the available opportunities for formal meetings or emphasizing the importance of detailed communications regarding a product’s development history to-date and intended future plans, sponsors can improve their chances of success dramatically by communicating effectively.

Brian Bollwage is Vice President, Global Regulatory Affairs at Chiltern.

Characteristics of the Successful IND or IDE

	The era of personalized medicine is fast approaching and, in many therapeutic areas such as oncology, is already underway. Now a topic of public discussion, the drive for precision medicine is being pushed from behind as a response to the lack of widespread efficacy many existing drugs offer, and pulled from ahead by recent advancements in technology and capabilities in pharmacogenomics. Moreover, the FDA has reprioritized and implemented significant changes to its infrastructure to leverage the progress, for example, of the human genome project. In the past few years, the research community has experienced a rapid upswing in the number of companion diagnostics being developed and approved. As we look to the future of precision medicine, we must first understand and actualize the role of companion diagnostics in clinical research, product development, and, ultimately, drug administration.

	In his 2015 State of the Union Address, President Barack Obama introduced the American people to the concept of personalized medicine when he announced his new precision medicine initiative intended to “lead a new era of medicine, one that delivers the right treatment at the right time.” The president urged Congress to increase research funding to support investment in precision medicine “to bring us closer to curing diseases like cancer and diabetes - and to give all of us access to the personalized information we need to keep ourselves and our families healthier.” The successful sequencing of the human genome was actually accomplished more than a decade before, and though much progress was made, it went with little public notice until now.

	What’s driving this new initiative? There has long been a recognition that many drugs are ineffective in a large proportion of the patient populations they intend to treat. In 2001, 

 published survey results demonstrating the percentages of patients for whom drugs are ineffective.

 These startling numbers suggest a lack of efficacy exceeding 40 percent associated with drugs intended to treat conditions including diabetes, migraines, cancer, asthma, arthritis, Alzheimer’s disease, and many more. If these drugs fail to benefit large proportions of their intended target population, shouldn’t we be able to do better? With the completion of the human genome mapping project in 2004, the tools needed to forge a new era of progress have become available.
	 

A Busy Decade at the U.S. Food and Drug Administration (FDA)

	Since the 1998 approval of Herceptin - the first product approved by the FDA that relied on its unique pharmacogenomics characteristics - the FDA has approved more than a hundred drugs that reference their own unique pharmacogenomics attributes in their labeling. In 2013, four of the twenty-seven new molecular entities approved were co-developed with a companion diagnostic, and, in the two-year period covering 2013 and 2014, a quarter of the sixty-eight new drug approvals were for such uniquely targeted therapies. These figures demonstrate not only progress, but also a strong FDA bias in favor of these targeted therapies. Targeted therapies often qualify for special FDA consideration and are good candidates for programs like breakthrough designation, fast track, accelerated approval, and priority review. In 2014, two-thirds of the new drugs approved were designated under one or more of these special programs, demonstrating the clear value of these designations.

	Without much fanfare, a shift in the FDA’s prioritization has brought greater attention to targeted therapies. But how has this shift occurred? In response to the completion of the human genome project, the FDA began to implement significant changes to infrastructure to better leverage the progress of the human genome project. At the heart of this effort was the creation of many new FDA programs and offices, including:

		The Voluntary Exploratory Data Submission Program, which handles genetic target reviews offline from the product review divisions

 Diagnostics and Radiological Health (OIR)

		The Center for Devices and Radiological Health (CDRH) Personalized Medicine staff in OIR

		The Genomics and Targeted Therapy Group in the Office of Clinical Pharmacology within the Center for Drug Evaluation and Research (CDER)

		The National Center for Toxicological Research’s Center of Excellence for Bioinformatics, Functional Genomics, and Structural Genomics

		The Center for Biologics Evaluation and Research (CBER) Genomic Evaluation Team for Safety

	As a result of these efforts, targeted therapies have begun to reach mainstream medicine. The ability to optimize efficacy while potentially minimizing risks makes for a more attractive benefit-to-risk balance in many cases. The most significant breakthroughs have been in the areas of cancer, genetic diseases, and infectious diseases, but significant potential awaits in many other areas. A partial list of drugs approved by the FDA that have relied on pharmacogenomics data to target these therapies includes drugs like: trastuzumab, valproic acid, citalopram, pimozide, aripiprazole, tetrabenazine, capecitabine, ivacaftor, and others.

	Companion diagnostics will be an integral part of the personalized medicine program. To target the right patients, for whom the benefit-to-risk profile may be favorably influenced, we need to know who these patients are. Companion diagnostics may tell which patient 

 receive a particular medication. The FDA has stated it may require a companion diagnostic when a drug works on a specific genetic or biological target present in only some patients. The first such use of a companion diagnostic occurred with Herceptin; the HER2 diagnostic test helps identify the approximate third of breast cancer patients with high HER2 expression as the best candidates for treatment. In August 2014, the FDA issued its guidance on companion diagnostics, which provides important insights to developers of targeted therapeutics along with their associated companion diagnostic devices.

 Companion diagnostics for targeted therapeutics are considered by the FDA to be essential to the safe and effective use of their corresponding therapeutic because they help 1) identify patients most likely to benefit, 2) identify patients that run at increased risk of adverse events, and/or 3) permit monitoring of patient response to inform treatment or dosage adjustments.

	Developers of personalized therapeutics and companion diagnostics are advised that close cooperation and early collaboration with the FDA will be required to streamline the development process. In the FDA’s experience, the process works best when diagnostic development begins before the companion drug enters clinical trials, in which case drug and diagnostic development can occur in parallel. While the Office of Combination Products can be a strong ally in your development program, the responsibility of managing the dialogues needed with personnel at CDER or CBER and CDRH remain with the product sponsor. It’s recommended that a sponsor always ask for a consultation with the Office of Investigational Diagnostics when potentially developing a companion diagnostic in a drug trial. In addition, pre-investigational device exemption (IDE) and pre-investigational new drug (IND) meetings for both new and aftermarket diagnostics are highly recommended.

	Because companion diagnostics are usually considered critical to the safe use of the corresponding personalized therapeutic, they are considered to be high-risk devices, and, therefore, clinical trials require submission of an IDE application, contrary to the situation with most standard diagnostic products. At present, companion diagnostics are treated as Class 3 medical devices, therefore requiring submission as either an NDA, biologics license application (BLA) or an original premarket approval (PMA) for approval.

	More than a hundred drug products have already used genetic information to improve or enhance therapeutic use. Genomic science will continue to provide many new clues leading to improved treatments, and the FDA has already invested significant resources in creating the necessary infrastructure to facilitate development of targeted therapeutics. The FDA is not only philosophically inclined, but has taken a role of leadership globally to promote the personalized medicine movement. The FDA’s early approval record reinforces the dramatic potential for patients, and abundant development opportunities exist. The possibility of a distinct paradigm shift to smaller patient populations with faster approvals is considered very likely, as demonstrated by the FDA’s 2014 approval record in which approximately two-thirds of the forty-one new molecular entities approved had either fast track status, breakthrough designation, priority review, or orphan designation.

	___________________________________________

	1.    Brian Spear, Margo Heath-Chiozzi, and Jeffrey Huff. 

In Vitro Companion Diagnostic Devices - Guidance for Industry and Food and Drug Administration Staff, 

US Food and Drug Administration, August 6, 2014.

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.pdf

The era of personalized medicine is fast approaching and, in many therapeutic areas such as oncology, is already underway.

Personalized Medicine and Companion Diagnostics

Vice President of Global Regulatory Affairs, Theorem Clinical Research

	Just two years ago there were more than 100,000 health-related apps available for download just from Apple’s iTunes Store and Google’s Play Store. This year, it is estimated that more than a third or 500 million of the estimated 1.4 billion global smartphone users will have installed some type of mobile medical application. These numbers are expected to continue their explosive growth with more than 50 percent of the 2018 projected smartphone population of 3.4 billion expected to have downloaded at least one mobile health application. While most of the early health-related apps were educational in nature, were intended to track exercise or weight loss, or provided motivation/instruction for weight loss or smoking cessation, the kinds of apps also have expanded.

	More recently, application designers have begun to take advantage of the enhanced computing power of later model smartphones, tablets and other devices and their improved visual displays to create new categories of portable medical devices. Not surprisingly, with the burgeoning advancement of technology and the growing patient trend for self-diagnosis and treatment, regulators have begun to scrutinize mobile medical apps. The approach taken by regulators in the U.S. and the EU show striking similarities. This article will focus principally on the FDA’s Mobile Medical Application Guidance initially issued in Sept. 2013 and was recently updated and re-released on February 9, 2015 to be consistent with FDA’s related Guidance on Medical Device Data Systems, Medical Image Storage Devices and Medical Image Communication Devices. While an equivalent formal guidance has not been published by EU regulators, comparisons of the regulatory controls for mobile medical apps between the two regions will be discussed.

The FDA Guidance and EU Corollary Approach

	FDA and European regulators recognize the potential benefits that mobile medical applications can provide to help patients gain access to useful information and manage their own health and wellness.

	The mobile medical app industry is moving very quickly with new tools being adopted almost as quickly as they can be developed. The FDA’s guidance is intended to provide a framework without unduly restricting medical application development.

	FDA and EU regulatory authorities will exert their oversight of mobile medical apps consistent with their respective legislative and regulatory frameworks covering medical devices. That is to say, a mobile medical app will first need to fall under the relevant statutory definition of a medical device before the authorities will exercise oversight. For the purposes of this white paper, I will paraphrase and create a sort of “straw man” definition of a medical device to facilitate our review. A medical device is generally an instrument, apparatus, appliance, machine or contrivance intended for use in the diagnosis, cure, treatment, mitigation or prevention of disease. This is a narrowly constructed definition for a medical device that admittedly ignores certain finer distinctions of both EU and U.S. law, which are unnecessary to, and would only complicate, our further examination of this topic in this white paper.

	The FDA has decided to implement a three-tiered approach in considering mobile medical applications: medical devices that the FDA will regulate; medical devices for which the FDA will exert enforcement discretion; and apps that do not meet the definition of a medical device.

	Given the immensity of the present mobile app marketplace and the explosive growth projected in the short term, it appears prudent that the FDA is taking a tailored, risk-based approach to focus its regulatory attention on those mobile medical apps that meet the statutory definition of a medical device and are also intended to be used as an accessory to a regulated medical device or transform a mobile platform into a regulated device. Some notable examples include: mobile apps that connect to a medical device for the purpose of controlling the operation of the device (e.g., an app that alters infusion pump settings), apps that display, transfer, convert or store patient-specific data from a connected device (e.g., apps that transmit patient data to a central nursing station), and apps that transform a mobile platform into a medical device (e.g., apps that use a sensor or lead to measure ECG). 

 of the FDA’s guidance provides a lengthy and detailed list of many such devices that will draw the greatest oversight from the FDA.

	In choosing this approach, the FDA will focus its limited resources on apps whose functionality could pose a risk to patients if they were to fail to operate as intended. The FDA urges manufacturers of mobile apps that might fit the definition of a device to follow the Quality System Regulation (QSR) in designing and developing their mobile apps. QSR includes the requirement for good manufacturing practices. In addition, the requirements for a relevant premarket submission, depending upon device classification, would also apply. The FDA’s guidance 

 provides a very nice overview of the relevant regulatory requirements for medical devices including medical device facility and device listing requirements, investigational device exemption requirements, labeling requirements, adverse event reporting, QSR and others.

Apps as Devices but FDA Will Exert Enforcement Discretion

	Many mobile apps that may meet the regulatory definition of a device but pose minimal risk to patients will be afforded FDA enforcement discretion, meaning that the FDA will not expect manufacturers to submit premarket review applications or to register and list their apps with the agency. The FDA will exert enforcement discretion for apps, among others, that organize and track a patient’s health information or that help patients self-manage their disease without providing treatment suggestions, apps that automate simple tasks for health care providers or apps that provide access to personal health records or electronic health record systems. A comprehensive list of detailed examples can be found in 

	Mobile medical apps that do not meet the statutory definition of a medical device will not be regulated by the FDA. Apps that merely provide access to electronic copies of medical texts or reference materials or general patient education materials are not considered devices and therefore not subject to FDA regulation. Likewise, educational tools for use by health care providers for medical training purposes are not considered medical devices. Mobile apps that automate general office procedures and are not intended for the diagnosis or treatment of disease would also not be considered medical devices. From an EU perspective, these types of apps do not achieve a therapeutic or diagnostic effect “in or on the human body” as required by the medical device definition under the EU Medical Device Directive.

	Therefore, these apps that solely log, record or track general health and wellness information, even though related to maintaining general health and wellness, are not considered to be devices in either the EU or the U.S.

	Finally, the FDA’s mobile medical app policy and the EU’s directive do not apply to mobile apps that function merely as an electronic health record.

	FDA and EU regulators have expressed their interest in directly regulating only those mobile medical apps that meet their respective statutory definitions of a medical device AND present potential risks to patients. This tempered approach will allow for a focused oversight on a very small subset of the ever-growing mobile medical app marketplace. The FDA’s guidance provides a framework for answering most questions that a manufacturer might have regarding the level of regulatory control that will be applied to mobile medical apps. The FDA recognizes that its guidance does not expressly discuss every possible mobile medical app and has provided for multiple contact points - phone, email, online, letter, etc. - for manufacturers to inquire further about their specific app and the regulatory controls that will be applied.

Vice President of Global Regulatory Affairs, Theorem Clinical ResearchIntroduction

How Will the FDA and the EU Regulate my Mobile Medical App?


The 505(b)(2) new drug application (NDA) provides a potentially streamlined path for sponsors who have developed improvements to drug products that have previously received FDA approval. Successfully navigating the process requires close communication with the FDA, but, for those who do so the potential benefits can be significant. 

The 505(b)(2) process was established at the same time that Congress created the generic drug industry with passage of the Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman) in 1984. This legislation included section 505(b)(2) to encourage further innovation for drugs that have already received FDA approval. Specifically, this section permits submission of a new drug application containing one or more investigations necessary to approval that were not conducted by the applicant and for which the applicant has no right of reference. Innovations that may qualify for 505(b)(2) treatment include modifications to: dosage form, formulation, strength, route of administration, dosing regimen, indication for use, active ingredient and others. What makes this section unique is that it opens up the door to data leveraging, which may include both non-clinical and clinical studies as well as a resource that is often overlooked: the published scientific literature. And, unlike the case with generic drugs, section 505(b)(2) also provides for potential approval exclusivity of three to five years if clinical trial data is a requirement for approval. When a 505(b)(2) NDA qualifies for orphan drug designation, the award of exclusivity may be as much as seven years.


The standard for approval of a 505(b)(2) NDA is the same as a traditional NDA. Both applications require inclusion of data demonstrating substantial evidence of safety and effectiveness. However, the source of the data is different. In a traditional NDA, you own all the data. In a 505(b)(2) NDA, you rely upon data that you don’t own or have a right of reference to, including published literature. For example, you can rely on general, non-product-specific published literature, the FDA’s previous finding of safety and effectiveness (i.e., previous NDA approval). In order to leverage this data, the 505(b)(2) sponsor needs to build a bridge back to the approved product, which may require bioavailability, bioequivalence or efficacy trials, for example.


Sponsors can begin to navigate the 505(b)(2) process by researching available FDA guidance’s and performing a thorough literature search on the active ingredient. The FDA has assembled a wealth of reference tools for sponsors to help them navigate the 505(b)(2) process. The most relevant of these FDA guidance’s are:

Applications Covered by Section 505(b)(2)

. This guidance, issued October 1999, describes the type of information that can be relied upon from a reference listed drug and what can and can’t be submitted in a 505(b)(2) application.
  


Listed Drugs, 30-Month Stays and Approval of ANDAs and 505(b)(2) Applications Under Hatch-Waxman, as Amended by the Medicare Prescription Drug, Improvement and Modernization Act of 2003, Questions and Answers.

 This guidance, issued October 2004, defines the concept of a listed drug as it applies to follow on NDAs, both ANDAs and 505(b)(2)s. 

Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications.

 This guidance, issued January 2013, describes the substance and format of the data submission requirements for traditional NDAs, ANDAs and 505(b)(2) applications.

Formal Meetings Between the FDA and Sponsors or Applicants

. This guidance, issued May 2009, provides basic information for requesting and conducting meetings with the FDA to seek its input on product development plans.


Establishing a dialogue with the FDA is critical to the success of any 505(b)(2) development plan. Typically, in a mere 10 weeks’ time, a sponsor can schedule a meeting with the relevant FDA review division, compile the necessary briefing information, hold the meeting and reach agreement with the FDA on the development objectives for its product. In just a short time, sponsors can build the necessary foundation to ensure a successful development pathway. But it all starts with a discussion with the FDA.

First and most important is the need to confirm that 505(b)(2) is a suitable path. The FDA can and will refuse to file an NDA for a drug that is a duplicate and therefore eligible for approval as an ANDA (505(j)).  During pre-IND discussions, sponsors can also establish the product’s value and define the target label. Having the FDA’s buy-in to the proposed development strategy or at least having the agency’s input into the plan can save time and money and significantly accelerate the development process.

Additionally, the FDA can provide valuable input on your plans to leverage data from the approved drug. The FDA’s guidance “Formal Meetings Between the FDA and Sponsors” provides an excellent road map for beginning the necessary dialogue with the FDA to streamline your development path. The data needed in a 505(b)(2) NDA can usually be limited to demonstrating the value of the particular innovation or variation of the already approved product. The data needed can range anywhere from a simple demonstration of bioequivalence to a full verification of clinical safety and efficacy. Additionally, an objective assessment of available data in respect to how this data supports proposed labeling claims is imperative.

Also by meeting with the FDA, any significant objections or data gaps can be identified and addressed, thereby facilitating development or making any early go/no-go decision much more apparent. Unfortunately, data gaps are sometimes not terribly obvious. Take, for example, a product improvement made to an “old” NDA — that is, one approved prior to the enactment of the GLP regulations. A 505(b)(2) applicant wanting to rely on such an “old” reference listed drug will likely be asked to fill even non-clinical data gaps if a complete line of GLP toxicology data is not available for reference from the precursor NDA. The FDA must apply today’s approval standard when approving a product modification in a 505(b)(2), and this may require backfilling data that was not required at the time of the original NDA approval. 

While data leveraging should be considered an opportunity, it needs to be realistically balanced against any data gaps identified. It pays to be optimistic but optimism should be tempered with a realistic assessment of probability of success. Your meeting with the FDA should clarify your assessment.


The 505(b)(2) process offers quite a few potential advantages by providing a method to obtain FDA approval of your product sooner, with fewer costly studies and yet still with the possibility of an award of exclusivity. Likewise, there are quite a few potential pitfalls in the 505(b)(2) process. With careful planning and with early consultation with the FDA, sponsors can maximize their chances of success.


Brian Bollwage, JD, is vice president of global regulatory affairs for Theorem Clinical Services, a leading, global provider of comprehensive clinical research and development services. In a career spanning more than 30 years with almost all of it focused on regulatory affairs, Bollwage is a leading authority on regulatory law.

The 505(b)(2) new drug application (NDA) provides a potentially streamlined path for sponsors who have developed improvements to drug products that have previously received FDA approval.