	Treatments for rare conditions account for a large and growing proportion of new drugs and biotech therapies in the U.S., encouraged by favorable FDA regulatory policies for developing, approving and marketing promising therapies. More than 40% of new molecular entities in 2015 and 2016 were orphans, a level reflecting the success of the orphan drug designation program and

 expedited review pathways for breakthroughs and other innovative medicines. 

	Yet, high prices on important new therapies and complaints about drugmakers exploiting loopholes in the Orphan Drug Act have led to push-back from policymakers and payers. A firestorm erupted following FDA’s controversial approval in September 2016 of Sarepta’s Exondys 51 for Duchenne muscular dystrophy (DMD), despite limited evidence of efficacy and a $300,000-a-year price tag for initial treatment. More recently, Biogen set a launch price of $750,000 for first-year treatment with its drug Spinraza for spinal muscular atrophy. And Marathon Pharmaceuticals raised eyebrows when it launched Emflaza for DMD at $89,000 a year, even though the drug was already available at low cost in Europe and the sponsor had to conduct only one fairly small study for U.S. approval. 

	A recent analysis by Kaiser Health News cited biopharma companies for manipulating the rules to gain added exclusivity for drugs with mass market sales able to document an orphan indication. Congress is investigating  whether sponsors develop some orphans with an eye to expanding use to much broader indications, or “evergreening” exclusivity. Leading senators want the Government Accountability Office (GAO) to examine whether the program is working as intended, while others back legislation that codifies such exclusivity extensions. 

	Meanwhile, orphan drugs will account for more than 21% of worldwide brand-name prescription drug sales in 2022, up from 6% in 2000, according to an analysis by EvaluatePharma. Sales reached $114 billion last year, but will grow to $209 billion in five years, as FDA’s Office of Orphan Products Development processed nearly 600 designation requests in 2016 and granted  more than half. Such promise has attracted major pharma companies to the field, replacing the many small biotech firms that initially focused on developing these highly targeted therapies. And contract research organizations (CROs) are looking to tap the rare disease development business. In February, PPD formed a new center to oversee development programs for orphans and pediatric therapies. 

	President Trump highlighted the importance of “miracle” rare disease treatments in his address to Congress in February, which coincided with Rare Disease Day. Trump stated that the discovery of orphan drugs, as for Pompe disease, required significant reform of FDA’s “slow and burdensome approval process…. so more lives can be saved.” The National Organization for Rare Disorders (NORD) fired back that FDA is doing a terrific job of speeding rare disease treatments through the approval process and of supporting flexible R&D approaches in evaluating those therapies. 

	In fact, more than three-fourths of orphan drugs developed between 2008-2015 benefitted from “flexible development approaches,” which consist of less than two well-controlled studies or novel endpoints, explained Richard Moscicki, deputy director for science operations at the Center for Drug Evaluation and Research (CDER), in a February address to the World Symposium on Science. He noted that it takes three years less to develop a drug with a breakthrough designation.

	At the same time, Moscicki and others emphasize that randomized clinical trials often provide valuable evidence for developing rare disease drugs. At NORD’s summit last October, Moscicki advised sponsors that including well-controlled studies in protocols can provide FDA with “good scientific information to make good regulatory decisions.” Rigorous collection of natural history data can help researchers understand the disease, and qualification of important assays and biomarkers prior to use can support efficient development and avoid the waste of clinical specimens.

	More collaboration on orphan drug designations and clinical trial design by FDA and the European Medicines Agency (EMA) also promises to streamline rare disease research and approvals. The regulators have formed a formal “cluster” for sharing information on orphan drug designation, exclusivity and regulatory flexibility, including selection of trial endpoints and design of postmarketing studies. What is really needed to expedite orphan drug development, said NORD in response to Trump’s February comments, is adequate FDA funding to expand rare disease office staff expertise.

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The rise of new drugs targeting rare disease ignites increased push for flexible R&D approaches and more collaboration on orphan drug designation and clinical trial design between global regulators.

Orphan Drug Surge Raises Regulatory and Development Challenges

	The European Forum for Good Clinical Practice (EFGCP) has unveiled plans to boost quality and innovation in so-called complex studies, which it defines as being more difficult to develop and design, to recruit for, and to evaluate once the clinical trial has been completed.

	“The subjects are from populations that are typically vulnerable because of the potentially complex interventions required, the lack of treatment options, the use of more novel compounds, the difficult choice of comparators/use of placebo, or it could be that the outcomes are more difficult to measure,” notes a statement issued by the EFGCP. “These types of studies include rare diseases/orphan indications, trials in pediatric populations and oncology studies.”

	At EFGCP’s workshop, to be held June 12 at University College London, the focus will be on innovation, but also speakers will look at current regulations and their impact in complex studies, the use of big data, and the impact of technological advances, as well as gene profiling in oncology studies and requirements for laboratories taking part in clinical research. The other central theme will be quality management, including the challenges of remote audits and preparation and management of research units who will run complex studies.

	According to the organizers, “Quality and innovation may not always go ‘hand in hand’; while they may be related, they are not always complimentary. Innovation is today’s ‘buzz’ word but this needs to be carefully considered and systemically incorporated for it to be successful. Quality and quality improvement practices continue to play a significant role in clinical research ensuring subject safety and data integrity.”

	The campaign is being organized by the Education Working Party (EDWP), which has around six active members and is chaired by Nicky Dodsworth, vice president of global quality assurance at Premier Research, a CRO based in Reading, U.K.

	The role of EDWP is to identify priority needs and primary challenges in the education and training of good clinical practice (GCP) among those involved in preparing and carrying out clinical trials. Its aim is the coordination and harmonization of educational and training programs in GCP, while appreciating that different traditions in medical and scientific education across Europe are considered when developing GCP practices. The group seeks to develop cross-national understanding through ‘train-the-trainer’ schemes.

	Additionally, EFGCP is working hard to increase its membership. The group’s latest annual report showed that 142 members joined EFGCP or renewed their membership in 2016, compared with 141 members in 2015 and 237 members in 2012. Staff in Brussels contacted everybody whose membership expired in 2015 and 2016 and who had not renewed, and now it insists that each member of a working party is also an EFGCP member.

	“Potential organizations that would benefit from joining EFGCP (medical societies, companies, academic institutions, etc.) were also approached to better understand the current needs of these different audiences and what the role of EFGCP could be to interact better with its members and provide the right format of services,” wrote the authors of the annual report.

	In the future, the Policy and Strategy Working Party will help to achieve this goal at a larger strategic level for EFGCP. Staff have also developed a set of “elevator pitches” to present and promote EFGCP in a clear and proactive manner, and the goal for 2017 is to continue such a recruitment strategy with the support of the new website designed to reposition the EFGCP identity.

	In other EFGCP news, the Ethics Working Party met in Brussels in February to discuss several topics, including the ethical aspects of development and implementation of lay summaries, as requested by the upcoming Clinical Trial Regulation.

The European Forum for Good Clinical Practice to examine the impact of current regulations and areas such as big data and quality management on so-called complex studies.

EFGCP Puts Renewed Emphasis on Complex Studies

	You’ve waited long enough for this … the European Union (EU)-led attempt to move decisively ahead at the international level on personalized medicine has just published its action plan. Now decide if it was worth the wait.

	The wait has lasted for more than a decade. The 

, released in late March by the ICPerMed consortium, notes “previous initiatives in personalized medicine at EU and national level” going back to before 2007, and even including a 2015 agenda calling for “a different approach” to research. That emphasized the need for collaboration “across the entire healthcare value chain,” and listed some of the desiderata: research cooperation with regulators, healthcare providers, policymakers, ethical, legal and social experts and patients; extending research funding to communication, training, outreach and non-research cross-sectoral projects; and new transnational networking structures.

	What this EU-sponsored international consortium presents us with this spring is an action plan-but not yet any action. And in line with the plan’s own acknowledgement that plenty of work has already been done in identifying the challenges of personalized medicine, what we get is a lot of confirmation of what was already agreed in 2015-and, indeed, what has been also been repeatedly pointed out by other organizations working in this field over recent years. “In order to develop and use the full potential of personalized medicine, truly interdisciplinary research and inter-sectoral collaboration is needed,” says the 2017 action plan. “Knowledge, research activities and best practices need to be shared and where appropriate, aligned.”

	The ICPerMed plan goes on to offer the now-familiar lists of areas requiring attention: generation of best available evidence, attention to ethical aspects, information for citizens and patients, healthcare professionals and providers, payers and researchers. It calls for comprehensive, validated, accessible and interoperable datasets, harmonized and with quality data that also takes account of data protection and ownership. And it genuflects to the need for “patient-centred, strategic approaches” that are nonetheless cost-effective and capable of “ensuring the sustainability of national health systems.” It also sets out the requirements for an effective context for personalized medicine: infrastructures, resources and frameworks for education and training, and empowering citizens to manage their own datasets.

	In concrete terms, there is an attempt to set some specific goals, and some indicative timelines for achieving them. Data features prominently in the most urgent needs. Two immediate objectives-defined as needing action over the next two to four years-include research projects at the European level to ensure the quality, completeness, validity and analysis of datasets, and studies on data integration and interpretation of multifactorial diseases-work which should be shared at European, regional and national levels.

	Up to seven years is the medium-term timeframe set for other actions, such as support for research on enabling the extraction of structured data from unstructured sources, pilot projects to assess the impact of sharing data for researchers and others, research projects to optimize data security, privacy and ownership within personalized medicine approaches, and research projects to develop innovative decision support tools for healthcare providers. It isn’t all about data, either. The same medium-term timeframe is indicated for development and implementation of high-throughput preclinical models, and translational programs with shared access to genetically defined patient populations.

	Seven years is seen as a reasonable window for integrated research into clinical validation of pharmacogenomics, research into "adequate regulatory structures and pathways in personalized medicine" and clinical trials methodology, as well as longitudinal cohort studies of disease outcomes. A similarly soft deadline applies to action to engage patients, to conduct research into postmarketing surveillance methodologies for accessing patient outcomes, developing tools to enhance digital health literacy, and sharing best practices in conducting and evaluating the impact of public and patient engagement.

	Work should start immediately on some longer-term infrastructure preparations, such as "development and maintenance of biobanks and population/disease cohorts," but less urgency applies to "supporting interdisciplinary research in challenges and drivers that influence bringing PM innovation to the market, from ethical, legal, and societal perspectives."

	Another area where ICPerMed claims to be innovative is in ordering the often fragmented approaches to personalized medicine. It is, it boasts, “the first time that such an impressive number of research funders and policymakers have identified and published a consensus view on the R&D needed in order to further advance personalized medicine.” It certainly meets its claim on numbers, because it does bring together 30 European and global research and health ministries and funding agencies, including such big hitters as the UK’s Medical Research Council, France’s Agence Nationale de la Recherche, and Germany’s Federal Ministry of Education and Research.

	The plan also offers what it calls a chance for "enhanced coordination and alignment of research activities," with its "work program for ICPerMed member organizations," and engagement in a European research area network, which it aims to have up and running by the end of 2017. The plan talks of having created "a blueprint for a coordinated approach for personalized medicine research and reasonable implementation."

	Its "blueprint" does contain some view of how detailed interlocking of many distinct strands could promote progress. For instance, data harmonization requires a prior definition of minimal datasets for clinical and general population databases, since "only then can all available and relevant datasets such as from medical/clinical, lifestyle and other sources be utilized." Similarly, "it would be of great benefit if existing information, for example, within text documents, could be edited in a way that would ensure that these sources could also be utilized." Or it proposes a three-stage approach to integrating research for clinical validation of pharmacogenomics: "promoting clinical trials of new diagnostic systems; innovative technological platforms for clinical validation and standardization, and dissemination in order to facilitate the implementation in ordinary clinical practice."

	The plan also proposes a three-level process for standardizing clinical trial designs to demonstrate the feasibility of personalized medicine: new clinical trial design methodology and guidelines for approval and reimbursement, clinical and cohort pilot studies and new stratification strategies based on biomarkers, and combination trials on companion diagnostics and therapeutics.

	It would be churlish to dismiss the work that ICPerMed has put into developing this action plan-and I declare a marginal interest, in that I moderated the closing session of the Personalized Medicine Conference in 2016 that contributed to the process. ICPerMed makes much of the collaboration this has entailed. "Reaching this shared understanding was a worthwhile process in itself," says the action plan. But credibility for this exercise will depend on a lot more than "worthwhile" collaboration. To be taken seriously, the effort will need to show that it is delivering on some of its goals in a way that has not been done before. Otherwise, the risk is that it will come to be seen as just one more in a long series of European talking shops that have talked and talked, but done nothing.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium

Is the much anticipated Europe action plan on personalized medicines, unveiled recently by an EU-sponsored international consortium, worth paying a close eye on?

What’s New in the 'New’ EU Personalized Medicines Bid?

	A new regulatory framework for the authorization, conduct and supervision of clinical trials across the European Union (EU)/European Economic Area (EEA) was published on May 25, 2014. The regulation is expected to go into effect by October 2018, following confirmation that the IT infrastructure underpinning its implementation (the EU portal and database) is fully functional. 

	The new Regulation aims to streamline the submissions and authorization procedures for clinical trials by the creation of a single submissions portal and coordinated assessment between EU member states concerned with the trial. 

	Decisions on a clinical study will be made on a member-state basis, rather than separate competent authority and ethics committee (EC) decisions as is currently the case under Directive 2001/20/EC; however, the Regulation does not dictate how a member state should be organized to reach its decision: 

“It should be left to the member state concerned to determine the appropriate body or bodies to be involved in the assessment of the application to conduct a clinical trial and to organize the involvement of ethics committees within the timelines for the authorization of that clinical trial as set out in this Regulation.”

	The review of an application will involve drafting of a “Part I” and a “Part II” assessment report. Part I will focus mainly on benefit-risk considerations and will be assessed in cooperation with all concerned member states (CMS) with a “reporting member state (RMS)” taking the lead. 

	Part II will involve only national considerations such as informed consent and suitability of investigators and sites. In most (if not all) member states, ECs will exclusively assess Part II aspects and will have input into the Part I assessment report, with competent authorities taking the lead. 

	The timelines involved in reaching an assessment conclusion are 45 days for both Part I and Part II assessment. A maximum of an additional 31 days can be added to the overall time frame if the member state needs to obtain further information from the sponsor organization. ECs will need to consider how they will deal with the review of responses from the sponsor, which will be submitted via the EU portal any time up to 12 days following the request for information. This review may also require interaction with the competent authority to reach an agreed member state position. 

	An additional challenge for ECs arises when their member state is acting as RMS. In these cases, the draft Part I assessment report needs to be circulated to the CMS by day 26, who then have 12 days to provide their considerations. The RMS then has seven days to consolidate these considerations and finalize the assessment report. These time frames raise challenges for ECs involved in the Part 1 assessment. For example, will they be able to meet and review the documentation by day 26? Will they meet again to consolidate the considerations from CMS 12 days later, convene a subgroup, take chairman’s action, or leave it to the competent authority? 

	The single member state decision on the trial will be submitted to the sponsor via the EU portal within five days of the conclusion of the Part I and/or II assessments (whichever is later). 

	It is not only the assessment of applications that will require closer cooperation between ECs and competent authorities under the new Regulation. Activities such as validation of the application, declaring willingness to act as RMS, provision of considerations to the RMS (or consolidation of the considerations if your member state has the RMS role), and submission of information to the EU portal are all done on a member-state basis and need to be performed under a defined timeline. In addition, any appeal to a decision for an application will need to be organized on a member-state level rather than being submitted to the individual organizations involved. 

	These activities present new opportunities and challenges to both competent authorities and ECs, particularly in light of the fact that review of trials of investigational medicinal products (IMPs) may only be a small proportion of an ECs total workload. In the UK, it is estimated that approximately 15% to 20% of research reviewed by ECs is for IMP studies. 

	In order to meet the requirements of the new Regulation, many member states have needed to reorganize their ECs system. In practice, this has involved reducing the number of committees and the introduction of a form of centralized coordination in the member state. In the UK, this central coordination is carried out by the Health Research Authority (HRA). 

	Many member states are considering, or have already begun, piloting new ways of working under the Regulation. This is arguably the most efficient way to prepare for the exciting future that lies ahead in order to provide consistent and timely decisions on trials for the benefit of public health.

Martin O’Kane is Head, Clinical Trials Unit, Medicines and Healthcare Products Regulatory Agency (MHRA), UK

Application review will require closer cooperation between ethics committees and competent authorities in several areas.

Collaboration On EU’s New Clinical Trials Rule Brings Opportunity, Challenges

	Despite best intentions, drug development operations remain highly inefficient and unpredictable. There are a number of fundamental factors driving these conditions, including complex protocol designs, poorly executed operating strategies and the failure to engage study volunteer and healthcare provider communities. I’ve touched on these factors in past Clinical Trial Insights. This

 column presents updated data characterizing protocol design and collaboration execution practices.  

	Let’s begin at the macro level looking at the high and rising financial and time-based cost of innovation. In 2017, close to $160 billion will be spent globally on R&D-a 4% average annual increase during the past decade. The out-of-pocket (direct) costs-adjusted for inflation-to develop a single approved drug is approaching $1 billion; 2.5 times the out-of-pocket R&D cost to develop a single approved drug 10 years ago.   

	The ever-increasing use of contract service providers and the implementation of new technologies and practices have had little-to-no impact accelerating development timelines. Clinical and regulatory durations-averaging 6.8 years and 1.6 years, respectively-are slower than those observed in the mid-1990s. 

	A key contributor to longer timelines is patient recruitment and retention. This is an extremely difficult task for clinical operations to execute effectively, efficiently and predictably. Based on company reports of thousands of clinical trial cycle times, across all therapeutic areas, actual recruitment timelines end up nearly double in duration than planned timelines. This reality is a function of the growing challenge of identifying, finding and attracting study volunteers, particularly in specific disease conditions where very targeted patient subpopulations are sought and in crowded disease conditions where the competition for study volunteers has intensified. The wide variances between actual and planned enrollment timelines are also a function of overly ambitious timelines set by clinical teams.   

	Even after planned timelines have been doubled, we see widely disparate enrollment achievement rates across participating investigative sites involved in a given clinical study.  During the past decade, research from the Tufts Center for the Study of Drug Development (Tufts CSDD) shows that approximately 10% of all investigative sites will fail to enroll a single patient in a global multi-centered Phase III clinical trial. Approximately 40% of sites will be activated-requiring investment in monitoring, relationship and data management throughout the study-yet they will under-enroll, failing to recruit and retain the requisite number of patients. In the aggregate, the high cost of identifying, recruiting and managing non- and under-enrolling investigative sites represents a significant portion of overall study budgets.

	Site management and performance is one of the most inefficient and unpredictable areas in clinical development. Study start-up timelines have increased by approximately 40% during the past 10 years. Tufts CSDD research shows very wide variability in cycle times for all study start-up activities-from site identification through to study completion. These variances are unprecedented given the volume of clinical trials initiated by mid-sized and major pharmaceutical and biotechnology companies each year. Budgeting and contracting, contract execution to site initiation, and site initiation to site activation processes are the most variable and unpredictable. 

	Without a doubt, protocol design complexity is the most fundamental driver of development operating conditions. Tufts CSDD studies conducted over the past two decades show high growth in the number of protocol endpoints, eligibility criteria and procedures performed overall and per study visit. Although the cost for many individual procedure has declined over time (e.g., ECG assessments; imaging), the overall direct and indirect cost per study volunteer visit has increased due to the larger number of procedures performed each visit.

	To lower clinical trial costs and to reach large untapped patient populations and well-trained personnel, companies are placing their Phase II and III studies in more countries. At the same time, companies are engaging a larger number of investigative sites to each recruit a smaller number of patients. Taken together, sites have more difficulty achieving familiarity with the protocol and operating efficiency when they are only enrolling a few patients during the treatment duration of the study. This problem will grow as R&D pipelines increasingly focus on rare and specialty diseases.

	Protocol complexity is positively correlated with longer cycle times and higher costs. Complexity is also associated with a higher incidence of amendments and change orders.  The typical Phase III study has an average of 2.3 unplanned and unbudgeted amendments.  Each amendment requires three months and  $500,000 in direct cost to implement. The primary reason 

for amending a protocol is to relax the eligibility criteria. And half of all amendments occur before the first patient has received the first dose, indicating that in our haste to put the protocol into the clinic we’re not spending enough time challenging the protocol’s executional feasibility. The number of reported change orders has also increased as protocol designs have become more complex (see chart).  

	A number of studies in the literature have shown that protocol complexity is associated with poorer data quality and integrity. The number of complaints that the FDA receives for investigative site non-compliance and fraud has also risen substantially since the mid-2000s. Protocol violations are the number one reason why complaints are filed against clinical investigators and may reflect the high execution burden that study staff must bear.

	This past year, of the nearly $148 billion spent on R&D, 55%, or approximately $80 billion, was spent globally on all forms of contract R&D services, including personnel, consultants, contract research organizations (CROs), contract manufacturing and investigative sites. During the past several years, pharmaceutical and biotechnology companies in the aggregate have spent more on contract R&D services than on their own internal staff and infrastructure. There is no indication that this trend will reverse.

	Clinical operations activities are deeply dependent on collaborative effectiveness.  Approximately $26 billion was spent on CROs in 2016 largely to execute clinical trial activity worldwide. And about $14 billion was spent on study grants to investigative sites. It is widely acknowledged that these two markets are integral to the success of clinical development activity. Yet our research and that of others continues to show that site and CRO performance remains mixed, inefficient and unpredictable.

	Although the CRO market has been consolidating during the past decade with the largest 10 CROs now capturing 60% market share, it is the middle full-service CRO market that has been vanishing. A vibrant and growing market exists for niche and specialty service providers.  

	The investigative site market remains highly fragmented and nascent. As a result, we have seen virtually no scale economies or efficiencies. The number of private community-based physicians involved in conducting clinical trials continues to grow each year. Fragmentation-particularly on complex development programs-introduces project coordination and management inefficiencies, system and process integration and compatibility challenges.  

	Inconsistent collaboration is another fundamental driver of operating inefficiency.  This area has much to do with the failure of sponsor companies to translate and enforce strategic intent into executional practice. Despite the fact that nearly all major sponsor companies have entered into at least one

 strategic alliance, a very small percentage of CROs participate in development planning and protocol design. Sponsors also report that-although they are expected to work with preferred providers-they routinely mix and match the use of niche and full-service CROs to meet the needs of each individual study. And sponsors typically evaluate CRO performance and relationship effectiveness on measures that are at best joint responsibilities or that fall squarely in the sponsor’s camp.

	Although advanced data- and evidence-based solutions are available, a large percentage of sponsor companies continue to rely on very unsophisticated approaches to identify and engage investigative sites. Competition for experienced sites in crowded, rare and stratified disease conditions is forcing sponsors to increasingly turn to physicians and healthcare providers new to the clinical research enterprise. 

	Sponsor companies are keenly aware of fundamental factors contributing to perennial operating conditions. Drug developers are actively evaluating, piloting and implementing new strategies and tactics (e.g., standardized and novel practices, technologies and collaboration models). And there has been a proliferation of solutions providers-and investors -focusing on new standalone and combined offerings designed to inform, enhance and accelerate drug development activity.

	To name but a few areas: collective efforts to elevate the level of patient engagement in clinical trials holds promise in helping to simplify protocol designs; to target research activity on clinically meaningful benefits as defined by patients; to minimize participation burden and inconvenience; and to enlist stronger support from prospective study volunteers. 

	The use of advanced analytics of large structured and unstructured data-patient reports and real-time clinical and behavioral metrics-to better understand the course and impact of disease, how to treat it and to collect more comprehensive and meaningful insights into the safety and efficacy of investigational therapies is another promising area. 

	Lastly, perhaps the most transformative landscape development is the integration of clinical care and clinical research, supported by flexible and mobile technologies (e.g., smart phones and wearable devices), to bring clinical trials to wherever patients wish to and are best able to participate. This integration leverages healthcare infrastructure, telemedicine and the growing volume of electronic health information to identify patients quickly, recruit patients while they are receiving medical care and engage them seamlessly and conveniently. 

	All of these areas hold the potential to dramatically change the economics and duration of traditional drug development operations.  

Ken Getz, MBA, is the Director of Sponsored Research at the Tufts CSDD and Chairman of CISCRP, both based in Boston, MA. email: 

Clinical Trial Insights

Examining the evolution of protocol design and collaboration executing strategies.

The Elusive Goal of Optimizing Development Operations

	Pharmaceutical regulation is a data-driven environment; it has been undergoing a data revolution due to the speed at which innovative technologies have be applied within the life sciences sector. However, the pace at which innovation can be transitioned into the regulatory framework and applied as regulatory science and technology across the global product lifecycle to support more efficient and effective decision-making requires a rigorous level of assessment and analysis. Some of this process is untested due to lack of precedent. More specifically, the regulatory framework operates at a different speed for a variety of reasons, such as acquiring the appropriate level of intellectual capital within the pharma industry and regulatory agencies, fully understanding the technology in question for applicability and use, and the development and implementation of policy to guide and support implementation.

	Although there are several efforts underway to bridge this divide, ranging from something as basic as mandating the submission of regulatory data in an electronic format to the more complex such as the incorporation of tools to support the submission and use of next-generation sequencing (NGS) data (e.g., FDA-CBER’s High-Performance Integrated Virtual Environment-HIVE). True convergence between the two will not be possible without the introduction of a more agile process for regulatory policy and guidance development and the utilization of data standards to ensure that received data to be analyzed is of the highest quality with minimal data integrity loss. It is important to ensure what is being applied is fit-for-purpose for its intended application while mitigating any risk that would outweigh the potential benefit to better inform regulatory decisions.

	Though it may appear to be fairly straightforward at a strategic level, the complexities of regulatory data are vast and comprehensive given that the global regulatory product lifecycle covers a broad spectrum-from clinical trials through to marketing authorization and postmarketing activities. A logical and foundational starting point would be the ability to uniquely identify medicinal products on a global scale throughout their lifecycle, from the origin of the substance through to unique identification at the individual package level. Currently, Industry and regulatory authorities have their own distinct processes for identifying a medicinal product to support their activities. Then there is the matter of how product information is identified and used downstream by external stakeholders for electronic health and medical records, prescribing, dispensing, supply chain, clinical decision support, and patient registries, among other areas.  For example, the are ongoing initiatives to publicly release vast amounts of clinical and safety data to support better evidence generation on regulated products. The most significant item of importance is robust data quality and integrity, but poor data quality  can cripple even the best analytical techniques and methods, thus limiting utility.

	The International Organization for Standardization (ISO) identification of medicinal products (IDMP) is a suite of standards and corresponding technical specifications for improved identification, data quality, and integrity of medicines throughout the product lifecycle. The implementation of data standards such as IDMP is simply one key step to ensuring that product information is identified and captured accurately within the regulatory framework and beyond. It is not limited to finished products, as it can be applied early in R&D prior to the initiation of the regulatory lifecycle. While the original intent of IDMP as a global standard was to primarily support pharmacovigilance, the concept of uniquely identifying a medicinal product on a global scale has multiple utility to support a variety of regulatory initiatives. Those include establishment identification, product to establishment relationships, lot distribution, supply chain integrity, falsified medicines, and clinical trial registration and results reporting.

	IDMP consists of the five following data standards: 

		ISO 11615, health informatics-Identification of medicinal products-data elements and structures for the unique identification and exchange of regulated medicinal product information.

		ISO 11616, health informatics-Identification of medicinal products-data elements and structures for the unique identification and exchange of regulated pharmaceutical product information.

		ISO 11238, health informatics-Identification of medicinal products-data elements and structures for the unique identification and exchange of regulated information on substances.

		ISO 11239, health informatics-Identification of medicinal products-data elements and structures for the unique identification and exchange of regulated information on pharmaceutical dose forms, units of presentation, routes of administration and packaging.

		ISO 11240, health informatics-Identification of medicinal products-data elements and structures for unique identification and exchange of units of measurement.

		505(b)(2) applications accounted for 63% of 451 original new drug applications approved by the FDA during 2009-15.

	There are four corresponding technical specifications to these standards (see 

). The primary purpose for the development of these standards was in response to a worldwide demand for internationally harmonized specifications for medicinal product identification. IDMP specifies data elements, structures, and relationships, in addition to required terms and definitions. There is a vast amount of information required in a dossier and IDMP is not intended to be the complete solution for all regulatory data represented. However, the ability to uniquely identify a medicinal product and structure this information per these standards allows for consistent implementation throughout the international regulatory framework-to achieve regulatory harmonization and ultimately convergence.  

Vada A. Perkins, Founder and Managing Principal of IDENTIFICA, a global regulatory intelligence and life sciences IT firm specializing in global product lifecycle data management

The implementation of the International Organization for Standardization identification of medicinal products (IDMP) is a key step to ensuring that information on new innovations are identified and captured accurately within the regulatory framework and beyond.

IDMP: An International Standard for Lifecycle Data Management

	To get a feeling of how much emphasis is put on ethical review in the Regulation (EU) 536/2014 (CTR), a simple comparison was performed with the current legal document regulating clinical trials, known as the Directive 2001/20/EC (CTD). Searching for the character string “e t h i c” results in 62 hits on 19 pages of the CTD, whereas in the CTR the result is 18 hits on 76 pages (a drop from 3.26 hits per page to 0.24). This finding may indicate that ethics committees (ECs) were not among the most prominent concerns when the Regulation was written.

	However, another, and much more serious, indication that this may be so is the wording of Article 4 of the Regulation, addressing the authorization procedure. Here it reads: “The review by the ethics committee may encompass aspects addressed in Part I of the assessment report…“

 to do so, which is in sharp contrast to what can be found on this topic in several internationally accepted documents, including Good Clinical Practice (ICH-E6(R2); article 1.31) and the Declaration of Helsinki (current version Fortaleza 2013, article 23). Both documents state quite explicitly that it is the obligation of an EC to review the protocol and its amendments. 

	A further aspect to be considered is the impact of the CTR on the workflow of ECs. The following analysis applies to Austria, but is most likely applicable to other European Union member states. From all projects handled by the EC of the Medical University of Vienna (MUV), only 17% represent trials on medicinal products. Ten percent represent trials on medical devices and the remaining 73% are clinical studies addressing issues such as new methods, basic science questions and retrospective and other non-interventional research. All these projects have a monthly application deadline, followed by a monthly session (12 sessions per year). The four weeks before the session are dedicated to intense-and in great part written-review, thus allowing the time in the session to be used for discussion of open issues. All necessary members for voting on a particular study are present at one time in one place. The applicant receives a reasoned opinion from the EC within 35 days of receipt of a valid application. This timeline is CTD-driven and kept for all types of studies. 

	The described procedure is no longer feasible under the terms of the CTR, because there is no application deadline. As a consequence, the EC will continue to assess 83% of the applications following its current procedure, but will have to implement a new one for the 17% of studies falling under the 

scope of the CTR. It is obvious that such a situation will not facilitate competent ethical review. The feeling remains that the CTR has been written neglecting the fact that there exists clinical research outside of what’s conducted on medicinal products. 

	The issue of timelines of the CTR deserves special consideration. The CTR allows for the assessment of a clinical study a period of 45 days (after a 10-day validation period). The reporting member state can request additional information (RFI) from the sponsor, who must respond within 12 days, otherwise the application will lapse. The member states, in turn, have 12 days for review of the additional information and seven days for consolidation. Thus, the entire procedure of issuing and handling a RFI is 31 days.

	In  2011, under the Directive, the EC of MUV had performed an analysis of all RFIs handled in that year. The median times found to resolve an RFI were 59, 73 and 45 days for trials on medicinal products, medical devices and other studies, respectively. Based on these results, it is conceivable to assume that under CTR a substantial number of applications will lapse.

	The CTR represents an important step toward facilitating clinical research on medicines in the EU. However, there are some issues regarding ethical review. The wording of Article 4 is not acceptable; ethical review of the study protocol must be mandatory. And the imposed timelines represent a formidable challenge for maintaining the current standard of ethical review.

Ernst A. Singer, MD, is Professor of Pharmacology Ethics Committee, the Medical University of Vienna

A Closing Thought

The language in Europe's Regulation (EU) 536/2014 regarding ethical review of protocols is concerning.

Ethics Under the Clinical Trials Regulation

	Consistency is a theme that ran through the expert panel discussion on successful partnerships, the resultant article from which can be found here. Consistency in outsourcing models, consistency in communications, and consistency in trial management were all discussed as cornerstones to a fruitful business relationship. 

	Without consistency, outsourcing partnerships suffer. Inconsistency leads to

 chaos, dysfunction, micromanagement, dissension and, ultimately, failed processes. To ensure consistency, our panel experts recommend a playbook. Simply put, it is the guide for how clinical trials will be managed in their respective company’s. The guide is updated, and all parties are updated and trained on changes.

	Well, you might say, “I’ve managed trials all my life, I don’t need a guide.” You may be able to run a trial blindfolded. But the ah-ha moment I had was when one expert said, “Everyone has a different philosophy on how to manage a study.” This industry has undergone a lot of change, mergers and acquisitions in the 30-odd years of wholesale clinical trial conduct and outsourcing. What you learned at, say, the former PharmaNet or Kendle may not be how the former Sandoz would run a trial. 

	How trials are run at your company may be a mish-mosh of all of your managers previous jobs. It’s like driving on the New Jersey Turnpike on a Sunday. You’re all from another state, going to another state, and you all know how to drive, but you don’t drive like, say, how a New Jerseyan would drive at rush hour. It just doesn’t work well and it’s chaotic. 

	In conferences, I have heard how one study team will try a new technology in a trial, never to realize a team in their same company was also using it. That one team chooses one type of software and another team picks something else. It is also entirely possible that both teams work with the same CRO, so now you have two teams using the same CRO but on different software. This is also true of an example shared in the article of using different outsourcing models in the same therapeutic area. Maybe 40% of the trials get one model and 60% another model. The experts say, “Just don’t do it.” If you want consistency-internally or with your external partners-just pick one. 

 in our April/May issue, he details the macro issues that are hindering collaborative effectiveness between CROs and sites and sponsors. And many of these were touched on in our panel. But put in a financial context, he states, “Clinical operations activities are deeply dependent on collaborative effectiveness. Approximately $26 billion was spent on CROs in 2016 largely to execute clinical trial activity worldwide.” And, he also emphasized, there is no indication that this trend will reverse. 

	This is the way drug development is structured, and the more effective the partnership, the more potential for efficiencies that save money, bring drugs to market faster, and support the advances in technology. I know we tend to want to believe our way is best, but sometimes when your company is following one playbook in one direction, you can focus on consistent excellence rather than inconsistent chaos. 

From the Editor

Why following one consistent playbook for trial management should be at the core of outsourcing partnerships in drug development.

Choose Consistency Over Chaos

The FDA and other regulatory bodies have issued multiple guidance documents addressing technology tools that are used in clinical trials. FDA guidance documents include Computerized Systems;

 is also available online. In 2010, the European Medicines Agency (EMA) issued a Reflection Paper on electronic source records in clinical trials,

 and recently, the Medicines and Healthcare Products Regulatory Agency (MHRA)

 issued a document on data integrity. In 2016, the Chinese FDA issued Technical Guidelines on Electronic Data Capture for Clinical Trials.

 issued a document addressing the use of CDISC standards to facilitate the use of electronic source data in clinical trials.
	
	The regulatory push to the paperless clinical trial has occurred despite a pharmaceutical industry that has been risk-averse in adopting modern-day technology tools that could support clinical trials. This risk aversion is in part due to fear by sites and sponsors of receiving a FDA Form 483.

 What if the FDA turns down an application if it discovers that, for example, a patient was born in 1982, when in the study database it is recorded as 1983, even when there is no impact on the study results? The clinical sites are also fearful of losing business as a result of any FDA Form 483 finding, however minor.
	
	The major stakeholders in the clinical trial enterprise include study subjects/patients, sponsors, clinical researchers, regulators and the public at large. Now that the electronic world has entered the clinical trials space, as part of routine pre-approval inspections there will be an assessment of the impact of

 electronic systems on 1) informed consent; 2) data integrity and accountability; 3) protocol compliance; 4) monitoring of the study by the sponsor, including risk-based monitoring; 5) patient safety by assuring that all safety events are accurately collected and reported, and 6) drug/device accountability.
	
	The following are examples of regulated clinical trial software currently being used:

		Electronic patient reported outcomes (ePRO)

		Electronic clinical outcome assessments (eCOA)

		Dedicated tablets collecting and storing data in real time and transmitting data on a schedule to the study database

		Web-based systems collecting data in real time which transmit the data to the study database only after the source record is securely received and stored in an independent eSource storage location under control of the study site

		Mobile-based medical apps whose functionality could pose a risk to a patient’s safety if the app were to not function as intended


	
	It is strongly recommended that a risk-based approach to software validation be assessed for any medical software/app, even those not being used in clinical trials, as there are moral and ethical issues if any software used for medical decision-making does not act as intended.
	
	For software to be “reliable,” it needs to validated. Therefore, assuring that software is in a validated state is a key factor when regulators look at software products used in clinical trials. Fortunately, in 2002, FDA provided validation guidelines for software supporting regulated products.


	
	The following sections address some of the needed steps to assure that software used in clinical trials will be adequate to support regulatory scrutiny during pre-approval inspections and the review of marketing applications.
	
	


	
	Here are some critical questions to be asked concerning the “intended use” of the software, and depending on the answers, appropriate steps must be put in place.
	
	1. Why am I using the software?
	2. How is it being used?
	3. Will the data be used to support decision-making such as:

	4. Will the data be used to support primary and secondary outcomes?
	5. Will the data be used to support subject’s safety?
	6. How will patient privacy and confidentiality be maintained?
	
	


	
	A software product used in clinical trials must be validated and compliant with the Code of Federal Regulations (CFR) incorporated in Title 21 (Food and Drugs), Chapter I, Subchapter A, Part 11.

 21CFR Part 11, as it is commonly referred to, sets forth the criteria under which the FDA considers electronic records, electronic signatures, and handwritten signatures executed to electronic records to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper.
	
	There is a distinction between validation and compliance. Validation is objective evidence which demonstrates that a given piece of software performs as intended against the user needs and the documented specifications and requirements.

	While it is true that software requirements and resulting features within the software can support compliance with 21 CFR Part 11, it is also true that no software or hardware system can be 21 CFR Part 11 compliant on its own. The software implementation, including processes and procedures for use of the system, are what constitute 21 CFR Part 11 compliance.
	
	And validation of the software goes beyond just the software requirements and resulting features necessary for Part 11 compliance. Validation is necessary for the entire software application and should be a defined part of the Software Life Cycle (SLC).
	
	


	
	There should be very clear SLC management documentation that contains the software development process from cradle to grave. In fact, many SLCs can go beyond the development process, to include ongoing support and even consideration for end-of-life for the software.
	
	In terms of popular development methodology choices, there is the Agile development methodology versus the traditional Waterfall approach. For the former, when it is very clear what the deliverable will be, one makes a detailed plan and then implements the plan. In contrast, the Agile approach accepts that there will be changes during software development and has built in flexibility to change direction at a moment’s notice.
	
	The first validation element is the software concept/requirements, or in other words, what is the problem we are trying to solve and why do we need this software? Usually an executive or the person driving the software writes the concept document to convey the mission and rationale of this new endeavor. Next, the “requirements” phase must clearly document what the software intends to do. For example, the software should allow for study subjects to enter study outcome data over the web using any device and any browser.
	
	Once the requirements are buttoned down, there needs to be clarity on how the requirements will be executed, which comes under the heading of “functional specifications.” For example, if the requirement is that “changes to the data base need to tracked,” then the functional specification could say that there needs to be an audit trail which must display the original value, the new value, why the change was made, who made the change, and what was the reason for the change.
	
	The next phase is left to the programmers and architects who create the very technical “design document.” This document basically is in “geek-speak” and we leave that document to the specialists. Once programming begins, the programmers work closely with the “testers” to test and debug the program until at some point the development team says the software is ready for a formal user acceptance test (UAT). In an Agile methodology, the design document, test plan and test scripts are written concurrently with development, iterating as features are refined. In a Waterfall methodology, the test plan and test scripts are often written with the design document, all of which is completed before development even begins.
	
	Once the “test plan and test scripts” are written and signed off, formal testing can usually begin right away. During testing, the testers document the “errors, bugs and fixes,” and when all that is completed, the software is “released” and signed off by those responsible and accountable. Post-release, “version control and change management” kick in. A plan is also put in place for the retirement of the software when it will no longer be supported or commercially available.
	
	


	
	A quality by design (QbD) methodology, which includes a risk assessment and risk mitigation strategies, is a critical exercise when building software. Using a Boeing 787 analogy, a plane has several electrical systems that control the engine and the coffee machine. We should not assign the same risk to the coffee machine not delivering hot coffee as we do to the engine failing on takeoff. Therefore, in a clinical trial, we propose the following for each risk:

		Assign a value of the risk to the study participant if a software failure happens

		Assign a value of the risk to the study itself if a software failure happens

		Assign a severity score if a software failure happens

		Assign a likelihood of detecting the software failure

		Then create a score and a risk-mitigation strategy for each risk


	
	A well-designed and well-written protocol can be viewed as one approach to an ideal quality manual. Therefore, in addition to standard protocol elements that we are all familiar with, the protocol should identify where and when electronic systems will be used, and then explicitly describe at a minimum, 1) all electronic systems being used; 2) the reason for their use; 3) how the systems will be used; 4) how the software will be controlled; 5) the basic elements of the risk assessment and risk mitigation strategies and; 6) data ownership and access controls.

	The inspectors will not usually do an assessment of the protocol design, as that was already done by the clinical team at the regulatory agencies. What the inspectors will do is attempt to determine whether 1) the protocol was followed; 2) there are SOPs supporting the protocol; 3) the site and sponsor followed what was stated in the protocol and SOPs; 4) the electronic case report form (eCRF) was intelligently designed to support protocol compliance; 5) there were system-generated management reports of site communications and protocol deviations/violations; 6) there was an integrated risk management plan and risk mitigation strategy; 7) there was a substantiated and complete root cause analysis of observed issues/events; and 8) there were follow-up corrective and preventative action plans (CAPAs) and that the follow-up actions were resolved as planned.
	
	From the safety perspective, the inspectors will want assurances that there was accurate reporting of safety events by evaluating 1) how safety data were collected; 2) the process for determining the source of original safety data based on a data source agreements; 3) a sample of source data from disparate sources, including review of source records written on pieces of paper, if relevant, and; 4) subject records maintained at the study site.
	
	

Are electronic source data reliable and fit for purpose?


	
	We are asked many times by those committed to paper records-sponsors or regulators-that if the system is fully electronic, how do we know that the data are real if there are no source records with which to compare the electronic record? Ironically, you can ask the same question about paper records; unless there are major controls of paper, notebooks, etc., nothing prevents a piece of paper from being destroyed and replaced by a new one. Bottom line, as some suspicious data trends are impossible to spot through manual review of records, 

fraud and dishonesty can usually only be identified through adaptable, validated checks and the use of informatics and multidisciplinary expertise. Clearly then, misconduct is not dependent of the collection medium of the original record (paper vs. electronic). Consequently, in a double-blind, randomized trial, one effect of fraud, if it occurs, could affect the study results by demonstrating that a potentially effective drug is ineffective from a statistical perspective (Type 2 error). This is where study monitoring techniques and fraud detection programs become vital.
	
	Therefore, when using off-the-shelf or proprietary software systems, the following are some of the quality questions that should be considered:

		Can the software provide any assurances that the study subjects are real?

		Are there validated systems to assure user authentication and control?

		Did the sponsor perform installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ)?

		How was access to the original data controlled?

		Were there date and time stamps for all transactions?

		Were there audit trails that can’t be overwritten?

		How was the data transferred to the study database?

		Can patient privacy and confidentiality be maintained?

Pre-approval inspections of an eSource program


	
	Based on our experience and the experience of others, when the regulators/inspectors arrive, they will need to review:

		Your organizational chart as it relates to the clinical trial

		Copies of relevant contracts/agreements

		Documents supporting vendor qualifications

		Documents supporting software validation/testing

		Corrective actions taken, reasons for actions taken, and the results of any actions

	As of this publication, two regulatory marketing applications have been submitted to FDA where direct data entry at the time of the office visit took place in lieu of maintaining paper source records. From the perspective of the pre-approval inspections at the clinical research sites, there were no Form FDA 483 findings related to study monitoring oversight and any of the electronic systems that were used for data collection. The inspections occurred at three of the five major medical centers that were inspected for the first application, and at five of the 20 outpatient clinical research sites that were inspected for the second application.
	
	The following are the redacted excerpts of the FDA inspection of the CRO (Target Health Inc.) for the first program that received marketing approval where the clinical research sites entered the majority of the data directly into the EDC system at the time of the clinic visit, and all documents were maintained in an electronic Trial Master File (eTMF; target document).
	
	

		This FY 2015 CDRH High-Priority Class II Device Application Inspection was conducted.

		This inspection was limited to the areas of compliance program 7348.810, “Sponsors, clinical research organizations and monitors.”

		Data line listings were provided with the background package, for comparison to the site eCRFs.

		An FDA 483 inspectional observation was not issued to management during this inspection.

 The clinical project manager develops a clinical data monitoring plan and safety monitoring plan for each study, using a company-specific template; these plans are approved by the sponsor before any site monitoring takes place.

Feature Article

How to assure that software used in clinical trials will support regulatory scrutiny during pre-approval inspections and application review.

Regulatory Considerations for 21st Century Paperless Trials

The impact of globalization resulted in the shift of industry-sponsored clinical research (ISR) from high economic countries to Eastern European, Latin American and Asian countries. Since 2008, Asia has shown significant growth in interventional studies with an average of 8% growth. Asian countries offer two main benefits for conducting clinical trials: their large and diverse patient pools, and the relatively lower cost of clinical trial conduct. Malaysia, in particular, has many inherent qualities that make it an ideal country for conducting clinical trials. Those include a multi-ethnic population, which is relatively treatment naïve, competitive costs and an established healthcare infrastructure. Additionally, for over 20 years, Malaysia has had existing experience, facilities, processes, regulations and manpower in conducting clinical trials. The current Malaysian Economic Transformation Program (ETP) targets clinical research as one of its main drivers in economic growth. Therefore, the government of Malaysia, with an aim to promote and increase the number of clinical studies in the country, established Clinical Research Malaysia (CRM) in 2012 with the objectives of effectively increasing the speed, reliability and delivery of outcomes for all stakeholders involved. This review outlines the role of CRM, its achievements, future endeavors and the opportunities it provides for sponsors to carry out clinical trials in Malaysia.

	Traditionally, industry-sponsored research has been conducted in high-income countries in Europe and in the U.S. due to the established research infrastructure and presence of major pharmaceutical companies in these countries.

 However, globalization resulted in shifting this research outside high income countries. The major beneficiaries of this shift have been Eastern European, Latin American and Asian countries. This change in the clinical research landscape has substantially increased the number of registered clinical trials globally, as evidenced by two separate studies analyzing the number of clinical trial registrations based on various global clinical trial registries. Viergever and Li analyzed the number of registered clinical trials in the International Clinical Trial Registry Platform (ICTRP), which was established by the World Health Organization (WHO) in 2006. The database was mined to include all studies registered up to December 31, 2013. After excluding all observational studies, a total of 186,523 clinical trials from 16 clinical study registries were included in the analysis. The number of registered clinical trials showed a substantial increase, constituting a seven-fold rise between 2004-2013.

 In another study conducted by Yathindranath et al, 15 online databases that contained registration for clinical trials globally were used, along with clinical trial registries in Asia. In Asia-Pacific, clinical trial volumes have been steadily growing from 5.9% of the total global volume in 2005–2007 to 9.7% in 2011.

 This shows that during these time periods, this region has become an important one for the clinical trial industry.

	 Asia, specifically, has shown significant growth in registered interventional clinical studies from 2008–2012, with an average growth rate of 8%,

 while North America showed a decline of 2% during the same time frame.

 Sixty percent of the world population reside in Asia.

 Therefore, as potential clinical trial hubs, Asian countries offer large and genetically diverse patient pools that are mostly treatment naïve, and a lower cost in conducting clinical trials in the face of limited patient pools and rising costs in the U.S. and Europe. Countries in Asia also offer varying disease epidemiology

 in both infectious and chronic diseases. This is reflected in the rise of lifestyle diseases such as diabetes, obesity, hypertension and various cancers due to urbanization.

 Factors such as government interest in expanding clinical research, large hospital infrastructures and an increasing number of clinical researchers, growth in the pharmaceutical sector and an increase in investment in research and development by pharmaceutical companies also contribute to Asia being an attractive destination to conduct these studies.

	The government of Malaysia, with an aim to provide sustained growth in various economic sectors, initiated the ETP, which comprises 12 National Key Economic Areas (NKEA). Clinical research is listed under the Healthcare NKEA, the second among the Entry Point Projects. Through this project, the Malaysian government intends to promote clinical research in the country and aims to increase the number of clinical trials from about 200 per year to at least 1,000 new and ongoing studies by 2020.

	Malaysia comprises 13 states: 11 in Peninsular Malaysia and two, Sabah and Sarawak, in the northern part of Borneo Island.

 Peninsular Malaysia is neighbored by Singapore in the south and Thailand to the north.

	The Ministry of Tourism tagline for Malaysia, “Malaysia truly Asia,” depicts the diversity of races in this culturally rich land. The population estimates for 2016 stood at 31.7 million people (107 males per 100 females), out of which 89.7% are Malaysian citizens. Three major races and a minority of other races make up the Malaysian population (68.7% Bumiputera, consisting mainly of the Malay race; 23.4% Chinese; 7.0% Indians; and 1% other races).

The median age is 28 years and the largest age group, between 15-64 years, makes up 69.4% of the population. The proportion of the elderly is also increasing due to better access to healthcare. Malaysia has a growing urban population. In 2016, it was estimated at 75% of the total population (compared to 57% in the East Asia and Pacific region).

	The healthcare system in Malaysia is two-pronged with a major contribution from the public health sector. Both public and private healthcare systems are closely monitored by the government under the Ministry of Health, and share a similar system that offers primary health and specialist care. The public health system is far-reaching, with presence in the rural and urban settings, while private healthcare is mainly found in the urban areas.

	Malaysia’s public health system is based on the WHO’s district health system model.

 The larger district health clinics are managed by family medicine specialists and are self-contained with their own basic laboratories, x-ray and ultrasound facilities. These district health clinics are capable of attending to both acute surgical and medical cases, as well as patients with stable chronic diseases, and providing maternal and child healthcare services. The smaller community clinics that are under the purview of these district health clinics are most often run exclusively by registered nurses and midwives who are trained to provide preventive maternal and child services, including home visits.

	Primary care in the private healthcare system is provided by privately-owned general practice (GP) clinics, stand-alone specialist clinics and outpatient specialist clinics in private hospitals. In 2008, there were an estimated 6,000 to 7,000 GP clinics and for every 10 primary care visits, six were to GP clinics. Some GP clinics, especially those that belong to a group practice, have added facilities such as portable blood analyzers, x-ray and ultrasound services.

Examining the role of Clinical Research Malaysia in advancing industry-sponsored drug development in the country.

Applied Clinical Trials-04-01-2017

Orphan Drug Surge Raises Regulatory and Development Challenges

EFGCP Puts Renewed Emphasis on Complex Studies

What’s New in the 'New’ EU Personalized Medicines Bid?

Collaboration On EU’s New Clinical Trials Rule Brings Opportunity, Challenges

The Elusive Goal of Optimizing Development Operations

IDMP: An International Standard for Lifecycle Data Management

Ethics Under the Clinical Trials Regulation

Choose Consistency Over Chaos

Regulatory Considerations for 21st Century Paperless Trials

Malaysia’s Clinical Research Ecosystem

The Regulatory Debate Around Pre-approval Product Access

Outsourcing in 2017: Playing to Win

Applied Clinical Trials, April/May 2017 Issue (PDF)