December 30 2017 M. Alexandra Rohall

A single review of the past year within the biopharmaceutical industry cannot comprehensively cover all developments. In 2017, FDA issued 226 draft and final guidance documents addressing its current thinking with regard to food, laboratory, blood banking, drug, and device regulations. With respect to the research of drugs and biologics, some of these guidances covered topics in drug and biologic technology, product classification (drug, device, or combination), pediatric rare and serious diseases, and software as a medical device (SaMD). In the following segments, a few of these topics are addressed, particularly as they pertain to areas of heightened activity in the industry. Under new FDA leadership, the industry looks forward to further support of innovation in clinical research.



For the past 25 years, the US Congress has sought to incentivize the biopharmaceutical industry to undertake the complex and expensive task of research and development of treatments for small markets. The Orphan Drug Act (ODA)1 of 1983 identified rare diseases and conditions as those with a prevalence of < 200,000 patients in the US, or with a prevalence of ≥ 200,000 but for which the cost of drug development could not reasonably be expected to be recovered by US sales. Incentives included tax credits to defray research costs, seven years of market exclusivity, and waiver of the marketing application user fee. Since 1983, annual orphan drug approvals have increased more than 10-fold.2

Over the ensuing years, there has been greater recognition of the need to develop treatments particularly for children with rare diseases. The 1997 FDA Modernization Act3 gave sponsors another six months of market exclusivity when pediatric studies were included in a submission. And the Pediatric Research Equity Act(PREA)4 of 2003 required that certain applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration include safety and effectiveness data for the proposed indication in relevant pediatric populations.

This year, FDA has taken two steps to advance the development of treatments for rare pediatric disorders. The FDA Reauthorization Act(2017) extended the scope of PREA to require pediatric studies of certain adult oncology drugs aimed at a molecular target substantially relevant to the growth or progression of pediatric cancer. In addition, the Draft Guidance for Industry: Clarification of Orphan Designation of Drugs and Biologics for Pediatric Subpopulations of Common Diseases (December 2017)5 indicates that FDA will no longer grant orphan drug designation to drugs for pediatric subpopulations of non-rare diseases, unless the pediatric subpopulation meets other regulatory criteria for orphan status or the disease in the pediatric subpopulation is considered a different disease than that in the adult population. This clarification closes a loophole by which sponsors could obtain pediatric-subpopulation orphan status, which carries no obligation to do pediatric trials, and thereby avoid PREA requirements. With these two actions, FDA aims to increase drug development for pediatric rare and serious diseases.

Also released at the end of 2017, FDA’s Draft Guidance for Industry: Drug Products, Including Biological Products, that Contain Nanomaterials (December 2017)6 represents FDA’s commitment to addressing new technological developments that will lead to precision treatments and, thereby, benefit patients. The guidance outlines FDA’s approach to examining products containing nanomaterials by providing working definitions of these materials, and by indicating the research, at each phase of development, that sponsors may need to perform to have their new nanomaterial products considered for approval.

From the standpoint of clinical development, this guidance pertains to nanomaterial products developed using comparisons to a reference product; i.e., along the 505(b)(2), 505(j), or 351(k) pathways. Using definitions and examples, the guidance categorizes nanomaterials along the lines of their low, medium, or high risk for exhibiting clinically significant changes in exposure, safety, and/or effectiveness relative to the reference product. Especially with regard to new products considered to have a medium or high risk of clinically significant differences, FDA indicates that studies beyond the standard bioequivalence study, i.e., beyond comparative plasma PK, may be needed to provide the necessary bridging data. Nanomaterials, which can act as therapeutics, carriers of therapeutics, or inactive ingredients, can alter delivery targets, delivered doses, and clearance pathways of drug products, to name a few effects. Therefore, careful elucidation of the similarities and differences between the new and reference products is necessary when pursuing approval along reference product pathways. FDA hopes that providing this guidance will help sponsors prepare efficient clinical development plans for products containing nanomaterials.



Advances in data science over the past decade have increased the focus on data collection in clinical trials. Developments in clinical data management are rising to the challenges. One such challenge is the desire of independent endpoint adjudicators to have access to nearly real-time data, whether or not blinded. For trials involving multiple sites that may have differing standards of care, or medical or cultural biases, endpoint adjudication is aimed at standardizing endpoint data interpretation, and allows sponsors to correct data interpretation and quality issues while a trial is in progress. To this end, having trial data on integrated platforms is one focus of clinical database software providers.

Clinical and laboratory data have been integrated in electronic data capture (EDC) systems for a number of years. In the past year or two, several vendors of these sophisticated clinical databases have been introducing add-on modules for randomization, drug supply management, mobile device data collection, and clinical trial management functions. These utilities, residing on a single platform, allow data visualization and data mining that can enhance a sponsor’s ability to optimize trial efficiency and data quality.

There is rapidly growing interest in mobile device and wearable device data collection, known as mHealth or digital health. There are hopes that mHealth data can be collected through web applications directly linked to clinical databases. But questions remain about the security and integrity of these data.

One aspect of digital health technology is SaMD. Since 2013, the International Medical Device Regulators Forum (IMDRF) has been developing a framework for SaMD and converged principles for global regulators to adopt in their respective jurisdictions. The Working Group’s most recent document, Software as a Medical Device: Clinical Evaluation, released in June of 2017, has been issued as a Guidance for Industry and FDA Staff (December 2017).7 FDA prefaces the guidance by noting that the IMDRF document provides FDA with an initial framework on which to develop FDA’s specific regulatory approaches and expectations for regulatory oversight of SaMD.

SaMD: Clinical Evaluation builds on the three previous reports that covered definitions, risk categorization, and quality management systems for SaMD. The clinical evaluation of SaMD should be an iterative and continuous process that answers the questions of a valid clinical association between the SaMD output and the target condition; the correct processing of input data to generate accurate, reliable, and precise output data; and whether the output data achieves the intended purpose with regard to clinical care in the target population. As mHealth grows in popularity with the medical profession, payers, and consumers, technical and clinical evaluation of SaMD will be incorporated into the clinical research process by FDA and agencies around the world.

In recent years, there has been much discussion of innovative ways to control the cost of clinical development. One of the most costly areas within the industry is clinical operations, the function that handles the logistics, conduct, and data collection of a trial. As traditionally conducted, clinical monitoring is one of the most costly functions within clinical operations. The industry has been examining the elimination of 100% source document verification (SDV) of trail data and a move to risk-based monitoring (RBM), which includes off-site monitoring methods.

In June 2017, the European Medicines Agency became the first regulatory authority to put into effect the ICH E6 addendum (R2). In recognition of the spiraling costs associated with traditional on-site monitoring, including 100% SDV, ICH expanded the acceptable methods for trial monitoring. Sponsors are encouraged to assess trial risks and develop appropriate monitoring strategies during the protocol development phase. Through recent technological advances, such as wearable devices and EDC, sponsors can get a real-time view of data, thereby increasing surveillance of subject safety and of data integrity. These technologies lend themselves to central trial monitoring, which leads to more efficient data cleaning and reduced onsite monitoring costs. Central monitors have a broader view of the data across all subjects and can address data integrity issues more swiftly than is common in traditional monitoring models.

The flexibility of the monitoring model allowed by E6 (R2) lends itself particularly well to the study of rare diseases. The small numbers of subjects, and commensurate limited quantity of data, requires closer, more frequent examination to ensure data integrity and patient safety. Central monitoring and real-time data collection can allow sponsors to monitor and identify risks much more quickly than onsite monitoring alone. This allows for faster mitigation actions that improve data integrity and ensure subject safety.



Five years ago, a consortium of data scientists took up the challenge of developing the technology to facilitate a learning healthcare system (LHS) using the data collected in electronic health records (EHRs) in European countries. The aim of the project, known as TRANSFoRm,8 was to develop a “rapid LHS,” driven by advanced computational infrastructure, that could improve patient safety, and the conduct and volume of clinical research in Europe. The hope was that this standardized, minable database would speed differential diagnosis for patients and would provide clinical researchers, through standard electronic case report forms within EHRs, with rapid access to eligibility information, data points, timelines, and interventions in trial subjects.

A few of the many challenges included: management of privacy laws; terminology mapping in light of semantic variations across countries and languages; assessing data quality; creating clinical prediction rules based on ontological representation of clinical cues and differential diagnoses; and developing software and testing models to ensure that data were of sufficient quality to be used in research.

The scientists used Clinical Data Interchange Standards Consortium (CDISC) standards in the development of the many necessary platforms and services. Their achievements in meeting the challenges led to the successful development, validation, and evaluation of the first real-world clinical trial using primary care EHRs. In this trial, patient reported outcome measures (PROMs), captured on a mobile device, were analyzed for 600 subjects in four countries, with four different languages, and using four different EHR systems. The successes of the TRANSFoRm project and the first trial of TRANSFoRm’s technologies open the door to enhanced and timely international clinical trials.

In the current environment of rapid technological advancement, drug product development often includes emerging technologies not yet familiar to FDA scientists. In September 2017, the Center for Drug Evaluation and Research (CDER) finalized its Guidance for Industry: Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization.9 In this guidance, FDA encourages sponsors whose drug production includes emerging technology to ask for guidance from FDA’s Emerging Technology Team (ETT), a group of scientists representing each FDA pharmaceutical quality function. The ETT answers the sponsor’s questions about the types of information FDA expects to see in an upcoming submission (e.g., IND, NDA), evaluates the technology with regard to legal and regulatory standards, guidances, and policy, and provides leadership during FDA’s assessment of the Chemistry, Manufacturing, and Controls (CMC) section of a submission.

Through this Emerging Technology Program, which allows early engagement and meeting opportunities for sponsors planning to use novel technologies, FDA intends to encourage innovative approaches to pharmaceutical manufacturing, which will ultimately improve product quality and availability.

Thank You


PROMETRIKA is excited to be part of the evolving clinical research landscape. Thanks to the many biopharmaceutical industry sponsors who put their trust in our expertise, PROMETRIKA has been involved in many of the year’s most interesting trials and technological advances. We look forward to participating in the operational and scientific advances to come in 2018.




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