	Regulators and sponsors increasingly are looking at the experiences and recommendations of individuals suffering from a disease or condition in developing and testing new therapies, and new legislation and user fee initiatives are poised to further this approach. A more formal patient-focused drug development (PFDD) framework was established by the 2012 FDA Safety & Innovation Act (FDASIA), and the Prescription Drug User Fee Act (PDUFA V) has provided support for incorporating patient viewpoints into a clearly articulated benefit-risk assessment of emerging treatments. Sponsors applaud this model, in that clear patient acceptance of greater risks of adverse events or limited efficacy in a new therapy can support greater leniency in FDA approval decisions.

	The role of patients in shaping clinical research may be strengthened further by the “21st Century Cures” legislation, which gained House approval last month due to strong support from some 250 patient groups, as well as hundreds of research organizations, medical societies, and biopharma companies. The bill establishes a “structured framework” to more fully incorporate patient experiences in considering a drug’s benefits and risks, while also aiming to expedite new drug approvals through biomarker qualification, incentives for developing antibiotics and treatments for rare diseases, and speedy designation of breakthrough drugs. The Association of Clinical Research Organizations (ACRO) also cites specific provisions in the bill to modernize clinical trials, namely, enhancements in the clinicaltrials.gov website, streamlined institutional review board processes, and support for data sharing.

	The House measure now will be debated and revised in the Senate, a process that could extend to next year and become enmeshed in efforts to renew FDA user fees in 2017. FDA launched the PDUFA VI negotiating process with a public meeting in July; regular discussions with industry begin this fall, along with monthly meetings with patient, consumer, and health professional groups to hear their views on relevant issues.

	A main topic on the PDUFA VI agenda is to more systematically incorporate patient views into drug development from early discovery through clinical testing and regulatory approval. FDA expects to discuss strategies for advancing the science of patient input and methodologically sound approaches for shifting from PFDD meetings to a more systematic collection of the experiences of people living with a disease, said Theresa Mullin, director of the Office of Strategic Programs (OSI) in the Center for Drug Evaluation and Research (CDER), at the June annual meeting of the Drug Information Association (DIA). Mullin noted interest from sponsors and disease groups in devising new approaches for capturing and communicating patients’ experiences on disease burden over time.

	Meanwhile, FDA is continuing to hold PFDD meetings with patient groups to discuss disease burden and treatment options for specific conditions. The agency has held 14 PFDD meetings since 2013, addressing conditions ranging from lung and breast cancer to hemophilia and Chagas disease; three more sessions are scheduled for this fall, and seven more in 2016-2017. FDA announced last month that those final meetings will consider autism, alopecia areata, hereditary angioedema, organ transplant patients, psoriasis, neuropathic pain, and sarcopenia.

	FDA looks to these sessions to ask patients about which symptoms have the greatest impact on daily life, how well current therapies treat significant symptoms, what an ideal treatment would look like, and what most spurs individuals to use a treatment or to participate in a clinical trial. PFDD meetings have been relatively small, Mullins commented, but have led to revisions in CDER policies and to new FDA guidance on developing treatments for certain diseases and to new patient-reported outcomes (PRO) tools. A compendium of PROs is scheduled for publication by FDA in September; it will list PROs that have been identified as important to patients and whether these have been used to support labeling claims.

	Sponsors find that the PFDD program have encouraged earlier interactions with patient groups, which can facilitate subject enrollment in clinical trials and help identify relevant clinical endpoints, noted Mary O’Donovan, executive director of BioMarin Pharmaceuticals, at the DIA conference. Pre-FDASIA, sponsors often did not hear patient viewpoints until advisory committee meetings; now such engagement occurs well before those sessions.

	Looking ahead, O’Donovan expects PDUFA VI to further industry engagement with patients and to provide more resources to support PFDD meetings and better systems for identifying suitable patient representatives for advisory committees and other FDA programs. A white paper from the Biotechnology Industry Organization (which is changing its middle name to “Innovation”) describes the value of PFDD meetings. It (see 

) advises sponsors to start a dialogue with patient representatives early in development in order to establish a complete benefit/risk framework by the end-of-Phase II meeting with FDA that can help shape Phase III studies.

Articles

News

The "Cures" bill and PDUFA IV are the latest measures pushing for more systematic inclusion of patient views into drug development.

Patients Gain Added Prominence in Shaping R&D

	After almost a decade of the European Union’s pediatric regulation and nearly 2,000 submitted pediatric investigation plans (PIPs), attention must now shift to the continued problems that can result in delayed access by children to innovative medicines, according to the Drug Information Association (DIA), European Forum for Good Clinical Practice (EFGCP), and European Medicines Agency (EMA).

	“Pediatric needs are recognized as an integral part of drug development, with the inclusion of children now accepted as standard procedure. However, challenges remain,” the three groups noted in a joint statement in advance of their annual pediatric conference, to be held in London October 1-2.

	To overcome these challenges, the groups believe more international collaboration is vital, particularly between the EMA and FDA. They call for more discussion about convergence on timing between EU and the U.S., as well as the greater use of extrapolation, modeling, and simulation techniques and the implementation of adaptive pathways.

	The main goal of the London conference is to promote interaction between the EMA’s pediatric coordinators and members of the Paediatric Committee (PDCO), plus other stakeholders interested in pediatric drug development. The views of patients and healthcare professionals will be presented, along with reports based on practical experience. In addition, attendees will be able to send a question before the meeting to ensure that the topic is addressed during the event.

	Other objectives are to update delegates on current pediatric regulatory requirements, scientific and operational success and challenges, to share experiences with regulatory authorities, academia, and industry, and to discuss the long-term vision, challenges with implementation, and potential ways to move forward and further improve processes for pediatric drug development.

	There will be an update on PDCO/EMA initiatives and a Q&A session on regulatory issues. Also, the perspective of a contract research organization (CRO) will be provided on the feasibility of, and hurdles facing, pediatric clinical trials. A panel discussion will elaborate on the need for early pediatric interaction and look back at a decade of pediatric legislation, and plenary lectures will concentrate on innovative pediatric plan design and facilitating data sharing, extrapolation, and clinical trial design/modeling and simulation, looking at new approaches in ICH E11.

	Small group discussions will tackle complex questions such as age-adapted formulations (European Paediatric Formulation Initiative [EuPFI], a consortium comprising representatives from academia, hospital pharmacies, and the pharmaceutical industry), preclinical research for medicines for children, how to address contraception in pediatric trials, and post-marketing studies, registries, and long-term safety. The EuPFI is holding its own annual meeting September 16-17 in Antwerp, Belgium.

	At the DIA/EFGCP/EMA meeting, further elaboration is likely on EudraCT. This European database contains information on all trials performed anywhere in the world with children, if the trial is part of an agreed PIP or is sponsored by a marketing authorization holder and involves the pediatric use of a medicine that has an EU marketing authorization. This requirement is set out in Article 46 of the Paediatric Regulation. EudraCT covers all clinical trials in the EEA from May 2004 onwards, and it was established in accordance with Directive 2001/20/EC and is managed by the EMA.

More Collaboration Sought in Pediatric Drug Development

	By now there are few individuals remaining in the clinical research enterprise who are not familiar with the concept of patient-centric drug development and the many tactics and initiatives to support it. The mission is to engage patients and the healthcare community as partners and to engender in them a sense of connection and ownership in the success of new medical treatments. There are four core principles that frame the growing arsenal of patient centric initiatives:

 Patient-centric research targets unmet medical needs identified in collaboration with, and based on input from patients and their healthcare support network.

Patient-centric research agendas and clinical trial designs recognize and accommodate real-life patient and healthcare community needs and experiences.

Patient-centric clinical trials minimize the burden of study participation and are supported by initiatives that improve convenience.

 Patient-centric research planning and execution amplifies and responds to the patient’s voice, receives support from the patient community, and gives the patient community an opportunity to be actively involved and respected partners throughout the research process.

Through adherence to these core principles, patient-centric drug development strives to minimize non-critical research activity and support the sharing of precompetitive information and drug development risk among a broader community of external partners (e.g., academic and basic research groups, co-development sponsors, development operations alliances, and patient advocacy groups). 

	Clinical research professionals look to conduct not only great science, but also more feasible clinical trials that enhance study volunteer participation experiences and reduce the burden of participation. In this approach, contract research organizations (CROs), investigative sites, healthcare providers, and payers each play important roles as R&D partners and supporters helping to ensure that the four core principles are upheld.

	During the past 24 months, a large and growing number of organizations have turned their attention to planning and piloting initiatives that touch all areas of the drug development continuum of activity. Regulatory agencies and quasi-regulatory groups such as the Clinical Trials Transformation Initiative (CTTI) and the Patient-Centered Outcomes Research Institute (PCORI) have been involved in soliciting patient input to define meaningful study endpoints and in establishing broad guidelines for patient engagement respectively. 

	A growing number of pharmaceutical and biotechnology companies are beginning to solicit patient input into specific study designs through the use of patient advisory boards, one-on-one interviews, crowdsourcing, and social media. Sponsors and CROs are evaluating and piloting approaches designed to make study participation more convenient, including the use of telemedicine, home nursing networks, direct-to-patient platforms, and the use of wearable technologies. Sponsors are also routinely disseminating lay language non-technical clinical trial results summaries to volunteers at the completion of clinical studies.

	As clinical teams begin implementing patient-centric initiatives across multiple studies, it will be beneficial to centrally monitor and coordinate activity. Doing so will promote greater awareness and coordination within the organization and will better assist in communicating lessons learned from earlier implementations and from peer companies. This central function or mechanism, with the assistance of internal patient-centricity champions, can also play a key role in deriving consensus metrics to evaluate the impact of various initiatives on organizational and study-level processes and performance.

	Return on investment (ROI) expectations need to take a reasonably long-term view. Clinical teams and their collaborative partners need time to gain experience with patient-centric initiatives, learn from mistakes, and continuously refine their use. As such, benchmark measures from multiple representative studies should be gathered two to three years pre- and post-implementation of initiatives. Stakeholders have been using a number of key implementation and ROI metrics to measure three broad areas: reach; patient/study volunteer feedback; and performance.

	Reach measures are typically quantitative. Their primary purpose is to assess the extent of adoption and usage within organizations and the number of patients and study volunteers who have participated in a given initiative. Internal reach measures include:

		The total number of initiatives being piloted or implemented within a particular time frame.

		The number of studies for which a specific initiative has been piloted or implemented.

		The total number of initiatives in planning stages within a particular time frame.

		The total number of studies for which a specific initiative is planned within a particular time frame.

		The total number of studies for which all patient centric initiatives have been completed within a particular time frame.

		The total number of studies for which a specific initiative has been completed within a particular time frame.

		The total number of patients/study volunteers reached by all patient-centric initiatives within a particular time frame.

		The total number of patients/study volunteers reached by a specific initiative across all studies in which it was implemented within a particular time frame.

		The total number of patients/study volunteers reached by each specific initiative in a given study.

	Primarily qualitative in nature, several organizations have added a few quantitative feedback measures into the mix. Their primary purposes are to assess subjective reports of satisfaction; sense of involvement in a given study or in association with a specific initiative; and the perceived relevance of specific clinical trials. Quantitative measures have sought to demonstrate how well patient/study volunteer participation is facilitating change. Patient/study volunteer feedback measures include:

		Ratings (e.g., "Very, "Somewhat," "Not Very," "Not at All") of overall satisfaction among participants in a particular study.

		Aggregate ratings (e.g., "Very," "Somewhat," "Not Very," "Not at All") of overall volunteer satisfaction across multiple studies in which patient-centric initiatives have been implemented.

		Comparison of pre- and post ratings of volunteer satisfaction between multiple studies that did, and did not, implement patient-centric initiatives.

		Ratings (e.g., "Very," "Somewhat," "Not Very," "Not at All") of the impact that specific patient centric initiatives had on study volunteer attitudes about aspects of the participation process (e.g., ease of understanding the informed consent form; convenience of study visits and procedures) compared with those studies that have not implemented initiatives.

		Ratings of perceived relevance or importance of studies that have, and have not solicited patient input into study design, to understanding disease conditions and addressing unmet medical needs.

		Total number of protocol design and schedule of assessment changes that have been made as a result of patient/study volunteer feedback.

		Total number of changes that have been made to clinical trial communications as a result of patient/study volunteer feedback.

	Performance measures are quantitative and they largely compare studies that do, and do not, include use of patient-centric initiatives. Many organizations are using consensus metric definitions developed and compiled by the Metrics Champion Consortium (

). The primary objectives of these measures are to gather hard outcomes data demonstrating improvements in feasibility and convenience. Performance metrics include:

		Number of study volunteers who drop out prematurely for reasons other than. adverse/serious adverse reactions.

		Number of study volunteers completing participation as a percentage of those who enrolled.

	Some professionals are already discounting patient centricity as simply a "buzz-worthy" label for practices that certain professionals have long embraced. There is some basis for this view. However, the major difference is that this is the first time where broad consensus has been reached among stakeholders throughout the clinical research enterprise and where there is widely shared motivation to change.

	Some have raised concern that the patient-centricity movement will result in clinical research professionals incrementally adding new practices and solutions onto already overburdened and demanding scientific and operating processes. In order for patient centricity to succeed, clinical research professionals will need to challenge, rethink, and redo certain conventional processes using the four-core principles as a guide. 

	Critics fear that the patient-centricity movement is inviting too many cooks. Some professionals are reluctant to invite yet another voice to the table for fear that patients, healthcare payers, and providers will be hard to accommodate and will introduce more complexity. Others hold the traditional view that physicians and scientists know what is best for their patients and study subjects. Sponsors and CROs will need to set expectations among all stakeholders that all input is valued but that scientific integrity and safe and ethical principles must be met. Sponsors and CROs will also need to establish new processes that enable them to solicit and prioritize ideas and input.

	A number of clinical research professionals fear that patient centricity is pushing them to discard traditional practices, including the use of blinded, randomized controlled clinical trials. This fear is particularly pronounced in the absence of regulatory guidance on acceptable and encouraged patient-centric practices. If patient centricity is to successfully transform R&D, it must be widely adopted and integrated into all aspects of R&D while preserving the strengths and value of traditional approaches.

	Several stakeholders have raised concerns that involved and engaged patients will want to see their clinical trials succeed and, as a result, these patients will bias the study findings. The gravitas of conducting medical research to treat serious and life-threatening illnesses, and deep study volunteer motivation to search for real answers about disease and how to treat it are too strong to allow this effect to occur. Patients and their healthcare support network want accessible, safe, and effective treatments for themselves and future patients. They will not compromise on scientific integrity. They will demand the highest quality research results based on clinical and patient-reported outcomes.

	It is still in the early days and there is limited data demonstrating the extent and impact of patient-centric initiatives. As more is learned, select initiatives will take hold and many will not. At a minimum, the patient-centricity movement is inspiring the drug development enterprise to challenge and transform the traditional drug development paradigm by putting the patient at its core.

, MBA, is the Director of Sponsored Research at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, e-mail: 

Clinical Trial Insights

While still early days, key metrics can be collected in three broad areas

ROI for Patient-Centric Drug Development

	With Europe’s chief architect of health policy approaching his first anniversary in office, it is a good time for assessing performance and refining the definition of objectives. And that is just what the European health commissioner, Vytenis Andriukaitis, did as the Brussels summer rose to a brief peak in July. 

	Outlining his “aspirations and hopes” for the four years that he is due to remain in post, the commissioner placed most of his emphasis on prevention in a set-piece speech he delivered to a Brussels think tank. At first glance that may not appear to throw much light on his ambitions for the activities that preoccupy most readers of this publication-clinical trials, research and development, diagnosis and treatment, product authorization, and, arguably, pricing and reimbursement.

	Perhaps not so surprising. Because although Andriukaitis is titular head of health policy, his role is circumscribed by the underlying constitution of the EU: its treaty. Healthcare system reform is, he admitted openly, “a responsibility of the member states.”

	But the commissioner is determined to maximize his role-and that could have a positive impact, too, on those whose job is designing, developing, and delivering care. “I want to see real results at the end of my mandate, not only talk,” he said, citing his tangible achievements as a practicing physician for 27 years, as a member of the Lithuanian parliament, and as his country’s health minister. “I produced practical solutions, and I want to believe that I have an added value at the EU level,” he insisted. So he has committed himself to “striving for health to be included in all policy areas, and ensuring that the European Commission puts the health of European citizens first.”

	Andriukaitis’ focus was on “healthy citizens, efficient and equitable health systems, and a thriving health sector.” And he did not shy away from the recognition that this needs expenditure-but he made it clear that he regards health expenditure not as a cost but as an investment. It is time, he said, for “a serious discussion about economic language.”

	It is also time, he said, for governments to pay more attention to early access to screening, diagnosis and treatment, and vaccination, he said. He has already launched an expert study assessing health systems performance across the member states, which is developing tools to influence policy-making at national and European levels, with a focus this year on quality of care.

	The commissioner is also responding to what he sees as “an increasing interest among member states to reflect jointly on how to increase patient access to innovative medicines and foster discussion on pricing.” That is almost certainly good news for drug developers dismayed at Europe’s increasingly evident confusion over pricing and reimbursement. And the good news is further embellished by his commitment to “promote cooperation among member states on health technology assessment.” The situation won’t change dramatically tomorrow, but a start to some more coordinated thinking on these most thorny of issues is long overdue. And it cannot do any harm that Andriukaitis is-as he says-“ready to support such reflections.”

	There is also some potentially good news in the commissioner’s attachment to creating a series of centers of excellence for highly-specialized healthcare providers-known as European Reference Networks. A major conference in Lisbon in October will spell out just where progress is being made, and an invitation will be issued early next year for organizations to sign up to the scheme. Ultimately, this could provide some top-level treatment centers combining the best of Europe’s often scattered expertise, with a positive impact on drug development and delivery. “Cooperation across national borders will serve to spur innovation in healthcare,” he predicted.

	The commissioner’s forthright commitment to tackling antimicrobial resistance also bodes well for drug developers. He promised to review what the EU can do to remedy the deficiencies in antibiotics, and undertook to continue the Commission’s active involvement on the issue “internationally, including through G-7, WHO, and other organizations.”

	For the record, he also noted what he had been doing over the past year-notably helping tackle Ebola virus in Africa, confronting the health challenges raised by migration, and exploring the health dimension of the EU’s new strategy to create a digital single market-including e-health, telemedicine, electronic prescriptions, and mobile health applications. And for this, he added, the EU dilemma over data protection “must be addressed without delay.”

	But Andriukaitis concluded with a plea-one that the clinical trial community might like to take account of: “I am here to drive the issues at a European level, but the discussions have to make their way through you as well. ... I am here to steer the policy but I cannot do it alone.”

	There were some further signals of things to come-although over a shorter time-frame-when the newly-appointed president of the EU council of health ministers (regular readers will recall the bizarre EU custom of rotating the council presidency every six months-it is Luxembourg until December) briefed the European Parliament just days later on plans for the rest of this year. Lydia Mutsch, the Luxembourg health minister, emphasized the importance of innovation, and particularly patient-centred innovation.

	She focused on personalized medicine; the presidency already held a conference on this at the start of the month, and Mutsch said the aim is to build on the messages from that meeting to produce formal conclusions at the meeting of health ministers in December. Innovation, she said, should be integrated into clinical practice so everyone can obtain access to advanced personalized medicine. Prospects for this are enhanced by the fact that the Dutch presidency-which will follow the Luxembourgers for the first half of 2016-also plans to focus on innovation in medicines.

	The conference was entitled "Making Access to Personalized Medicine a Reality for Patients," and its avowed aim was to assess the obstacles to integrating personalized medicine into Europe’s healthcare systems.

	The Luxembourg initiative has won praise and support from the European Alliance for Personalized Medicine, which has already scheduled another conference on the theme for next spring-during the Dutch presidency of the council. Mary Baker, of the European Brain Council and a leading figure in EAPM, underlined the need for collaboration "to help speed a process that currently takes a medicine around 13-and-a-half years to get from bench to bedside.”

	Maggie de Block, Belgium's Minister of Public Health, added her support, too. She said that developing personalized medicine is not only a challenge for scientists and innovators, but also a call for creative policymakers to introduce more effective early diagnoses, and safer and better tailored treatments for patients.

	As the saying goes, one swallow does not make a summer. But there is some consolation to be derived from the readiness of at least some of the EU's top people on health to look ahead at medicines development.

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.

View from Brussels

Officials tackle such areas as early diagnosis and treatment, patient access, and personalized medicine

Europe's Health Chiefs Look Ahead on Drug R&D

	Patient-reported outcome (PRO) questionnaires can be used to collect subjective clinical and psychosocial outcome data directly from patients in clinical trials, in order to describe their perception of a disease and its treatment(s), without the interpretation of responses by a physician or others. They are the only systematic quantitative way to ask  patients directly about how they feel or function. 

	In looking at the newer classes of drugs for type 2 diabetes mellitus (T2DM), such as DPP-4 inhibitors, GLP-1 receptor analogues, novel insulins, and SGLT-2 inhibitors, PRO questionnaires have been used to

 inform endpoints in most of the pivotal programs. As with the concept of blood glucose, a PRO can contain many related but distinct concepts, including symptoms of diabetes, side-effects of treatment, health-related quality of life, psychological well-being, and treatment satisfaction. Each concept captures a different aspect of a person’s experiences, thoughts, and feelings about T2DM and/or its treatment. All of these have been measured as endpoints across the pivotal trials of the newer classes of T2DM drugs. 

	This PRO data has the potential to offer insights into the subjective experience of therapy and provide an informed perspective of the associated patient-perceived benefit-to-risk ratio of the medication. Historically, PRO data has not been held in high esteem in T2DM, partly due to the traditional glucose-centric model of care, and partly due to variable scientific credibility in their measurement and lack of clarity in their interpretation.

	However, in recent years the science of PROs has progressed considerably, with U.S. and European regulators releasing guidance clarifying their expectations of the scientific rigor that should be applied to the development and selection of PRO endpoints. A recent PRO extension to the CONSORT statement highlights that well-developed PRO instruments can provide reliable and valid data in a manner which is meaningful to clinicians and patients alike. Despite this, the only PRO data to be reflected in product labelling for any anti-hyperglycemic medication for T2DM is blood glucose (based on patient self-recording of objective data). That was, until the 2014 European approval of Trulicity (dulaglutide).

	In the efficacy and safety section of the summary of product characteristics for Trulicity, the European Medicines Agency (EMA) included the following text: “Dulaglutide significantly improved total treatment satisfaction compared to exenatide twice daily. In addition, there was significantly lower perceived frequency of hyperglycaemia and hypoglycaemia compared to exenatide twice daily.” 

	Demonstrating improvements from baseline in treatment satisfaction with Trulicity, and showing that this improvement was greater with Trulicity when compared to exenatide twice daily, allows the developer of Trulicity (Eli Lilly & Co.) to summarize with one metric the patient’s appraisal of his or her experience with treatment (i.e., both processes and outcomes), their perception of the relative balance between positive clinical outcomes and negative side-effects, and their perceived benefit of improved clinical efficacy and reduced injection frequency versus an efficacious comparator. Perhaps most importantly for translational researchers, the data is important for clinical feasibility. 

	Such PRO data, taken together with clinical efficacy and safety data, can assist HCPs in providing holistic care in T2DM that is in line with patient preferences, needs, and values per the principles of evidence-based medicine. The inclusion of PRO data in the product label demonstrates a regulatory acknowledgement of the relevance of the patient perspective as it pertains to the saturated market of antihyperglycemic medication for T2DM, and gives HCPs confidence in the scientific credibility of the PRO endpoint.

A Closing Thought

Combining PRO data with clinical feasibility data can make a difference in diabetes care.

Patient’s Voice Finally Being Heard in Diabetes Drug Research

		An increasing amount of public data on clinical trial research has become available, including ClinicalTrials.gov and Open Payments. In addition, Europe has developed equivalent databases, or is in the process of developing them. The FDA has made its global site audit results available for some time to the public. The number of audits increased substantially, growing from 1,185 in 2008 to 10,264 in 2013, the last full year available. The summary results do indicate that up to 2010, the FDA increased the number of audits outside the U.S. However, since 2011, the percentage of sites audited outside the U.S. has remained stable at 26% to 28%.

		The FDA reports results in three categories: no action indicated (NAI), official action indicated (OAI), and voluntary action indicated (VAI). Since 2008, there has been virtually no change in the audit results. 

The number of site audits performed has grown significantly.

FDA Audits and Protocol Complexity

	As the biopharmaceutical industry continues to move down an outsourcing path, it is essential that logical sourcing strategies and operational processes exist and align with corporate strategy. This alignment will ensure desired outcomes are realized, such as shorter timelines, enhanced trial enrollment, and reduced overall costs while maintaining quality. Sponsors are often so focused on specific clinical deliverables that they often overlook the essential need for sourcing strategies, detailed deliverable specifications along with robust operational and oversight processes. In a report by Booz & Company based on interviews with top-20 pharmaceutical companies, it found that while sponsor companies have expanded their level of outsourcing and embraced deeper and more integrated third party organization (TPO) relationships, sponsors have done so without carefully thinking through the necessary support mechanisms and without aligning their outsourcing and corporate strategies.

 This lack of proper planning and oversight can often lead to operational efficiency, quality, and regulatory issues as regulatory bodies are now heavily focused on TPO oversight. This article discusses the essential steps for developing and implementing a logical sourcing strategy.

Step 1: Developing a logical sourcing strategy (what is needed and when)

	In order to have a truly logical and effective sourcing strategy, the sponsor must first have a clear understanding of its current and near future portfolio. This includes not only understanding therapeutic area needs, but also understanding the portfolio at the compound and trial levels, including trial volume and design. A logical sourcing strategy must be developed that provides flexibility in order to meet a variety of therapeutic study designs and compound-development needs while also ensuring consistency, quality, and timeliness of data and clinical processes, ultimately ensuring patient safety, data integrity, and the on-time delivery of the portfolio while controlling developmental costs. 

	A portfolio analysis is needed initially to develop the initial strategy, and then periodically in order to proactively plan and adjust the sourcing strategy as the portfolio changes. The analysis should be conducted over a suggested three-year time span in order to proactively set the sourcing plan and to ensure that the proper number and types of vendors are selected to meet the projected work volume. Contingency plans may easily be added to the overall strategy to buffer for any sudden portfolio shift. Critical trial criteria for successfully conducting the study need to be determined in order to fully understand the true clinical and sourcing needs for each trial type making up the portfolio. Trial types might include trial phase (IA, IB, IIA, III, etc.), trial size, complexity, specialty design needs (i.e., adaptive design) and registration needs. 

	The critical trial criteria might include clinical expertise, operational expertise, access to patients, investigator connectivity, site interface, recognized areas of therapeutic expertise, geographical presence, service capacity, timeliness, and strategic advantage. See Table 1 for an example of a critical trial criteria table.

Vendor and sourcing model analyses are now needed to align with the previously determined portfolio needs. Vendor models would include the larger, full-service contract research organization (CRO), the smaller specialized niche CRO, and the full-service clinical network. Sourcing models such as full (or project), functional (or process), and role-based sourcing also should be compared and aligned to the portfolio needs. The detailed analysis information needs to be collected using a request for information (RFI) process. It is crucial that a well-designed RFI document with specific questions measuring for critical trial criteria, cross-functional services, vendor capability, and capacity is utilized to ensure an accurate vendor and sourcing model analysis is performed.

	Questions seeking the same information should also be placed in multiple sections of the RFI document to serve as an accuracy check. The RFI document should also include standardized definitions and data collection templates to ensure data entry consistency. The RFI data collection process should be a completely web-based process with data aggregation, filtering, and reporting functionality. The RFI should be reviewed by a cross-functional analysis team to ensure that an accurate vendor model analysis occurs in order to ensure optimal trial-model alignment within the overall strategy summary. See Table 2 for an example of a vendor capability table.

Analysis of the detailed portfolio and critical trial criteria data compared to the vendor capability data will allow for the preparation of a sourcing strategy summary including optimal vendor model types and target vendor pool numbers used to finalize the vendor pool. The vendor pool numbers are extremely important, ensuring that there are not too many vendors not allowing for steady stream utilization, but not too few in order to allow for portfolio/trial-need flexibility.

	A Phase I/II adaptive design trial has very different needs compared to a large, global, Phase III registration trial. The summary should also be written in a user-friendly manner listing out the primary and secondary options or models by therapeutic area (if applicable) and trial type, along with a brief justification explaining the benefits and reasoning of the suggested options. To optimize use, the strategy summary needs to be converted into a very simple, user-friendly tool. Figures 1 and 2 below illustrate examples of a user-friendly, logical decision tree and a vendor selection consideration tree, respectively. 

Step 2: Implementing using logical operational processes (how to make it happen)

	In order to optimize the benefit of the sourcing strategy and ensure delivery of the portfolio, a logical operational process flow must be developed and implemented consistently across all study teams within the sponsor organization. The first key step in the process is the selection of an optimal TPO from the TPO pool based on the trial design or program needs. It is recommended that both a primary and secondary TPO choice be made in case the primary TPO choice has capacity issues or competing trials at that time. The selected TPO must be checked and verified for proper qualification dependent on which services are being outsourced. It is highly recommended that all TPOs or at least the core set of primary TPOs within the overall pool be periodically reviewed and qualified prior to being assigned a project in order to minimize trial startup delays. Periodic portfolio reviews are recommended and as the portfolio and sourcing strategy shifts, the TPO pool and qualifications may need to adjust as well.

	Next, a request for proposal (RFP) packet must be compiled for the project. The RFP packet must include a draft or final protocol, detailed specifications and operational plan(s) dependent on the services being outsourced. These detailed documents are critical to ensure optimal TPO comprehension of service expectations, compliance, and ultimately delivery of the key deliverables. This includes the development of an accurate service budget/proposal to avoid future trial delays, issues, and change orders. Once the final contract and budget are negotiated and executed, the project kick off meeting may occur where the operational plan is further discussed along with the development of mutually agreed upon communication and risk plans. Communication flow is extremely important to ensure that the trials are implemented and managed in an effective and streamlined manner. Optimal flow would need to flow from function to function, sponsor to vendor, and from vendor to vendor, especially if functional/process sourcing is being utilized to ensure compliance with functional process requirements and to avoid duplication and other issues. The flow must also be coordinated and facilitated by one primary function (i.e., project management or external sourcing), though all functional areas will have partial ownership.

	Recent publications have reported on a lot of dialogue and activity on many fronts on how to improve overall efficiencies in clinical trials and how sponsors may engage properly with their outsourcing partner(s) so that efficiencies and cost containment are a priority on both sides. Collaborative clinical/technical interactions between the select vendor pool and the sponsor need to occur. These interactions optimally need to occur at the portfolio, compound, and trial levels in order to ensure logical trial designs and trial placements occur for each compound that makes up the overall sponsor portfolio and to ensure a priority exists on both sides. Most sponsors only interact with their vendors at the trial level. In order to allow for proactive resource planning, the vendor-sponsor interactions need to occur at the portfolio and compound level. 

Step 3: Measuring and maintaining through efficient control processes (how to ensure it truly happens and continues to happen)

	Once the project services have been implemented, effective control processes must be put into place to ensure the deliverables are consistently delivered as specified in the contract.  The first control process is efficient TPO oversight implemented in a manner to maximize quality while also minimizing sponsor and TPO staff impact to help control costs. An oversight plan will be needed to ensure consistent implementation across the sponsor staff.

	Functional areas may need to develop separate oversight plans or a separate section within an overall plan to ensure their unique deliverable requirements are being met. Effective oversight needs to include both lagging and leading indicators. Lagging indicators would be used to measure historical results telling the sponsor how well the TPO has performed, while leading indicators would tell the sponsor if its sourcing strategy is effective and logical. Lagging indicators may include enrollment-to-plan and data-transfers-to-plan, while corresponding leading indicators might be number of initiated sites, countries with FPV, or outstanding monitoring visits (backlog).

	Clinical processes can start to go wrong well before the TPO performance turns the lagging indicator red. It is crucial that the right indicators be measured, paired, and analyzed or investigated to tell an accurate performance story-and then acted upon in a timely manner by the sponsor to ensure the TPO is performing at a level to deliver the trial and justify continued inclusion into the select vendor pool. In addition, positive trends need to be continued through shared learning and negative trends mitigated through corrective action preventative action (CAPA) development.  

	Indicators must be standardized across all TPOs governed by the strategy in order to have fair and accurate cross-TPO performance analyses. Indicator categories might include site selection, regulatory readiness, enrollment to plan, financial,

 dataflow, and compliance. In addition, it is recommended that an overall value model be developed and tracked along with the performance indicators looking at not only TPO performance, but TPO service fees and sponsor staff oversight that impact the overall value to the sponsor. The actual TPO service fees may be easily monitored by tracking the TPO invoices, while the actual sponsor staff oversight may be tracked using a time entry process (i.e., database, excel sheet) by service categories. The goal of the value model analysis is not to pick the least expensive TPOs, but rather the TPOs with the best overall value. Figure 3 above illustrates the typical vendor value model.

	Two additional areas important to the overall oversight plan are quality/compliance management and TPO governance. Quality /compliance management would include ensuring that all TPOs within the TPO pool have been properly assessed prior to use for proper procedures being in place, staff qualifications, system validations, security, privacy, and other key requirements.

	In order to ensure timely project initiations, the TPO pool must be qualified at all times and ready for use. To ensure this “state of readiness,” periodic reviews of the TPO pool, TPO services, service locations, and staffing must occur. These reviews could be incorporated into a periodic portfolio review, since the portfolio needs are directly correlated to the TPO pool needs. Thus, as the portfolio needs shift, the TPO pool would be reviewed, including TPO services, service locations, performance indicators, and need for additional assessments. Periodic checks for TPO service changes and needs for additional assessment could also be incorporated into the TPO audit cycle, which the sponsor’s quality department would periodically conduct usually based upon a risk-based approach. Quality indicators could also be added to the periodic performance reviews as an alert mechanism to the sponsor. 

	These alerts could be discussed at the TPO governance meetings, which are also part of the oversight plan. The key to having effective TPO governance is having the “right size” governance. Similar to performance indicators, excessive governance can be counter-productive, where the resource costs outweigh the benefit to the TPO and the sponsor. The key to determine the optimal level of governance is to have a risk management plan in place to determine the TPO’s relationship impact on the sponsor’s portfolio. Key risk factors to consider include work/project volume, service/project complexity and impact, safety and quality impact, budgetary impacts, and competitive advantages.

	Typical TPO governance levels start at the project team operational level, focused on a specific project, and then escalating to the enterprise operational level, focused on multiple projects, and, finally, to the executive operational level, focused on strategic development and efficiency. All of the levels focus to some degree on relationship development. The level and intensity of governance (i.e., meeting frequency, length, committees, communication channels, etc.) all depends on the risk determination so that the “right size” is applied.

	In order to have effective uptake and compliance to the oversight plan and control processes, it is crucial that a positive TPO relationship be maintained throughout the entire process. TPO relationship management is not easy, especially when managing multiple TPOs within the TPO pool. The key to a positive relationship is to create and maintain a collaborative environment between the sponsor and TPO staff. An effective communication plan and open channels are the first step to creating a collaborative environment, ensuring that both the TPO and sponsor staff is kept updated at all times, making them feel like an actual team member.

	A collaborative approach should be utilized for the development of the final, standardized indicators, so that the TPOs feel they contributed to the development of logical and fair indicators. These indicators will allow for cross-TPO performance analysis in a de-identified, confidential format, and all trial or project work with the sponsor will be measured and analyzed in one standardized manner. 

	Not all TPO specific indicator suggestions or requests will be met; this point needs to be stressed during the collaborative development process. The performance indicators must be reviewed on a periodic basis (i.e., annually, biannually) and user feedback collected for definition and analysis criteria enhancements based on the actual cross-TPO performance trends from the previous performance period. In addition, as business processes change, performance indicators may require additional modifications to remain applicable and effective. A final point to stress on performance expectations and indicator development is that a sponsor should never expect more from a TPO’s performance than it would expect from their own performance.

Step 4: Replication using a logical document architecture (how to ensure it is all properly documented to allow for compliance and replication)

	A logical, streamlined third party management (TPM) document architecture is essential to ensure optimal process and deliverable specification comprehension and, ultimately, efficient service delivery. All too often the sponsor will create very detailed, function-specific operational plans and other TPM governing documents in silos (i.e., in a specific functional areas like data management or statistical services) without consideration of other functional area impacts.

	This cross-function oversight omission will often lead to conflicting process and specification conflicts. Excessive, duplicative details and content will often be included in the TPM document(s). Over time, as regulations, business processes, and requirements change-leading to needed document revisions-conflicting content will often arise as different functional areas update at different times and in different manners. These issues clearly illustrate the difference between having TPM documents versus a true TPM document architecture. A true architecture will consist of multiple standardized documents that are written in a manner to clearly define, govern, and manage both the work and relationship between the sponsor and the TPO. Each document that makes up the overall architecture must have a clear purpose and proper connectivity among the other documents. This will then allow for a logical hierarchy and standardized content landscape, helping to ensure optimal content comprehension and management.

	So, how many TPM documents make up a logical architecture? The first step to developing a logical architecture hierarchy is listing out the key content categories such as privacy, confidentiality, escalation, governance, onboarding, training, and records management, as well as several other categories that need to be covered within the hierarchy. The category listing needs to be developed by a cross-functional team ensuring all functional needs are considered and based upon all TPM regulations, requirements, and applicable business processes to ensure overall compliance. Once the list is reviewed and confirmed by the functions, the next step is to determine the logical combinations and overall placement of the content categories to ensure wide accessibility and optimal user comprehension.

	The overarching content landscape and hierarchy, including the logical number of documents, will then be finalized, always keeping accessibility, comprehension, and compliance in mind. Though architecture consistency across the TPOs is extremely important for optimal-user comprehension, not all TPO architectures may be exactly alike. Lower-volume TPOs may not require an extensive architecture, such as a high-volume TPO, and thus the sponsor needs to determine what approach is optimal for each TPO category, always keeping accessibility, comprehension, and compliance in mind.

	Using the content landscape as a guide or road map, the cross-functional team would then need to focus on the development of logical architecture templates. It is essential that key instructions are written in a manner that is user-friendly and allows TPO relationship managers and study teams to convert the templates to TPO-specific and trial-specific documents. The standardized templates would be developed by functional area subject matter experts (SME). Once approved, a template owner would be assigned to each template in order to ensure the templates are periodically reviewed and the content maintained as regulations, requirements, and business processes change. 

	To help ensure proper architecture utilization, and maintenance, a content maintenance and change-control process must be implemented as the architecture is developed. These processes are crucial to ensure the architecture content does not gradually drift back into silos, ultimately leading to duplicative, conflicting, and ambiguous content. In addition, a TPO conversion checklist tool or process flow mapping all of the conversion tasks is highly recommended to help ensure consistent and compliant implementation. Once TPO-specific and trial-specific documents have been created and finalized, the TPO relationship manager (enterprise level) and study team (operational level) would be responsible for document content maintenance and periodic reviews. It is highly recommend that all periodic reviews and document content decisions are recorded and filed in the trial master file showing a complete decision trail and oversight, in case of future audits or inspections.

	Centralized storage, maintenance, and accessibility are extremely important to ensure optimal architecture utilization and compliance across the sponsor and TPO staff. If staff is not able to easily access the key documents, then compliance will be negatively impacted, as well as inspection readiness. The end-user needs to know where to quickly obtain the most current version of the architecture documents and who to contact for assistance. Proper archival of previous document versions is also extremely important in order to have the ability to show the full document and oversight history. A centralized website with document management functionality, including proper metadata, which meets 21CFR Part11 requirements, is highly recommended. Proper account management and, thus, access to the site and site folders will also be important, so that sponsor staff may access all applicable documents while TPO staff may only access their TPO-specific documents for proper confidentiality. Site development and validation will be an important step to ensure all access and functionality is properly functioning.

	During these changing times as the biopharmaceutical industry is facing increasing healthcare reform challenges, sponsors are quickly focusing on the development of a more efficient clinical research model, where sourcing is an essential and strategic component. Use of a strategic, collaborative approach, including management of a pre-qualified TPO pool all based upon the true portfolio needs, is essential. Sponsors must conduct ongoing portfolio and performance indicator reviews to adjust the strategy and TPO pool accordingly, while also enforcing the utilization of the strategy across the study teams and functions. Development and maintenance of proper control and oversight processes clearly defined in a logical document architecture will help to ensure ongoing utilization of the overall strategy. 

		1. Getz, K. “Peril and Promise of Risk Imbalance,” INSIDE Outsourcing - Guide to Strategic Outsourcing - Trends, Surveys, Analysis (10-16) (Dec., 2012).      

 is an External Sourcing Relationship Manager (at the time of research); 

, PhD, is a Senior Director of External Sourcing; 

 is a Director of External Sourcing (at the time of research); all with the Development Center of Excellence, Eli Lilly and Co. 

Feature Article

The four essential steps to ensuring optimal clinical deliverable specifications and process controls.

Developing a Logical Sourcing Strategy

There has been a recent thrust within the pharmaceutical industry to promote the transformation of the clinical trial process. In 2008, the Clinical Trial Transformational Initiative (CTTI), a public-private partnership with the FDA, and Duke University, was established to identify practices that, through broad adoption, will increase the quality and efficiency of clinical trials. A major publication by CTTI of monitoring practices has helped to transform the monitoring of clinical trials.

	According to the Food and Drug Administration (FDA) eSource Guidance of 2013: “Electronic source data are data initially recorded in electronic format. They can include information in original records and certified copies of original records of clinical findings, observations, or other activities captured prior to or during a clinical investigation used for reconstructing and evaluating the investigation.”

 Saying it differently, eSource data are original subject data that are collected digitally without having to record the data on a piece of paper first, and then transcribe it to an electronic data capture (EDC) system.

	It has been shown by many that changes made to the study database as a result of source document verification (SDV) affect neither study results nor the interpretation of those results.

 Therefore, despite the support of regulators, including the FDA

, it is difficult to explain 1) why many of those managing clinical research operations they still respond to a perceived risk, instead of adopting systematic and scientifically substantiated approaches for data management and cleaning, and 2) why there has been tepid adoption of eSource solutions coupled with “intelligent” monitoring of clinical trials. Perhaps failure to appreciate the wisdom contained in the quotes below explains why those doing clinical research spend a lot of their time on non-productive activities.

“Life is really simple, but we insist on making it complicated”

“Simplicity is the ultimate sophistication”

“The art of being wise is the art of knowing what to overlook”

	There is broad agreement across the pharmaceutical industry that it no longer makes sense to collect clinical trial data by writing results and observations first on a piece of paper, then to transcribe those data into an EDC system, and then to save that paper so that a clinical research associate (CRA) can check how precisely a person transcribed information from a piece of paper into the EDC system. Sadly, we continue to see residual, frequent emphasis on checking these transcription activities when electronic systems can easily eliminate this highly inefficient process. Doing the math, moving to electronic systems can provide a dramatic return on investment by 1) reducing labor costs at the clinical research sites and sponsoring companies, 2) reducing travel costs, and 3) providing improvements in data quality.

	In 2006, the Electronic Source Data Interchange (eSDI) Group within CDISC issued a paper entitled “Leveraging the CDISC Standards to Facilitate the use of Electronic Source Data within Clinical Trials.”

 The eSDI document was the product of the CDISC eSDI Initiative, the purpose 

of which was “to investigate the use of electronic technology in the context of existing regulations for the collection of eSource data (including that from eDiaries, EHR, EDC) in clinical trials for regulatory submission by leveraging the power of the CDISC standards, in particular the Operational Data Model (ODM)." The overall goal of the initiative was to make it easier to collect data once in an industry standard format.

	Eight years later, on Jan. 29, 2014, FDA addressed these issues in a webinar reviewing the final guidance for industry titled “Electronic Source Data in Clinical Investigations."

Leonard V. Sacks, associate director, Office of Medical Policy (CDER), Ron Fitzmartin, Office of Strategic Programs (CBER), and Jonathan S. Helfgott, associate director for risk science (acting), Office of Scientific Investigations (CDER).  Clearly, FDA is supporting efforts by industry to adopt eSource solutions.

	Even earlier, however, in 2010, the EMA GCP Inspectors Working Group eSource subteam released the “EMA Reflection Paper On Expectations for Electronic Source Data and Data Transcribed to Electronic Data Collection Tools in Clinical Trials.”

 The reflection paper-which is very similar in nature to an FDA guidance-was followed up by direct exchanges with industry representatives (the Society for Clinical Data Management and the eClinical Forum, among others). Those discussions are captured in a series of questions and answers that are frequently updated on the EMA website.

 of an independent contemporaneous investigator copy (ICIC) of the case report form (CRF) has led to numerous and passionate debates among the professional and industry associations. The basic concept of the ICIC is still far from being consistently understood and implemented in the different geographies; regardless, ICIC has had a considerable impact and has brought about an extension of the concept of ALCOA, that source data should not only be

attributable; legible; contemporaneous; original; and accurate, but also complete; consistent; enduring and available, when needed

As a result of this lack of consensus of the regulatory understanding of how to optimally generate and review electronic source records, apprehension and uncertainty among solutions vendors, contract research operatives, and pharmaceutical company sponsor remains.

 Good Clinical practice states that “The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s) by providing direct access to source data/documents.” There are no statements that paper records must be kept, just that there needs to be direct access to source data/documents.

	The FDA, in September 2013, issued a final “Guidance for Industry: Electronic Source Data in Clinical Investigations.”

 This guidance is consistent with the EMA “Reflection Paper on Expectations for Electronic Source Data and Data Transcribed to Electronic Data Collection Tools in Clinical Trials.”

	Regulators seem ahead of the game in supporting the transformation of how the pharmaceutical industry manages the performance of clinical trials. The following summarizes aspects of the perspectives of FDA and EMA.

	According to the FDA Guidance, source data include all findings, observations, or other activities in original and certified copies of original records, which are used by regulators to reconstruct and evaluate a clinical trial. All interested parties need to review source data and ensure adequate protection of human clinical trial subjects and the quality and integrity of the clinical data. Source data should be ALCOA and must meet the regulatory requirements for recordkeeping. FDA has proposed that electronically capturing and transmitting source data to the eCRF should:

		Encourage entering source data during a subject’s visit, where appropriate

		Eliminate unnecessary duplication of data entry and transcription errors

		Facilitate remote monitoring of data and promote real-time access for data review

		Facilitate the collection of accurate and complete data

	According to the FDA, data can be entered into the eCRF either manually or electronically using “direct entry of data into the eCRF.”  For example, there are many data elements in a clinical investigation, such as blood pressure, that can be entered directly into the eCRF at the time of the office visit. FDA also indicated that “data elements originating in an electronic medical record (EMR) can be automatically transmitted directly into the eCRF.  Unlike a direct transmission to an eCRF from instruments or medical devices, EMRs can use intervening processes (e.g., algorithms for the selection of the appropriate data elements).” In cases where the EMR serves as the source, the pertinent data for the subjects in the clinical study should be made available for review during regulatory inspections and monitoring visits.

	And although many may know this, the FDA added that the eCRF should be capable of recording metadata (e.g., data about the data identifying who entered or generated the data and when the data were entered or generated).  Also, changes to the data must not obscure the original entry, and must record who made the change, when, and why. Data element identifiers should be attached to each data element as it is entered or transmitted by the originator into the eCRF. Data element identifiers for each subject should identify the:

		Originators of the data element (including those entered manually (e.g., by the clinical investigator(s)) or automatically by devices

		Date and time that the data element was entered into the eCRF

	These data element identifiers allow sponsors, FDA, and other authorized parties to examine the audit trail of the eCRF data and to provide information that will allow FDA to reconstruct and evaluate the clinical investigation.

	The following are from the EMA Reflection Paper

In order to meet the requirements of maintenance of an independent contemporaneous copy of source records, a certified copy of the data should be created before the transfer to the sponsor and retained at the investigator site. The method of transfer should be validated. 

The recording of a clinical observation is made at the same time as when the observation occurred. If this is not possible the chronology of events should be recorded. An acceptable amount of delay should be defined and justified prior to trial recruitment.

The source data and their respective capture methods should be clearly defined prior to trial recruitment (i.e., in the protocol or study-specific source data agreement). The sponsor should describe which data will be transferred, the origin and destination of the data, the parties with access to the transferred data, the timing of the transfer, and any actions that may be triggered by real-time review of those data. There should only be one source defined at any time for any data element.

	According to the EMA, the source data and their respective capture methods should be clearly defined prior to trial recruitment (i.e. in the protocol or study specific source data agreement). The sponsor should describe which data will be transferred, the origin and destination of the data, the parties with access to the transferred data, the timing of the transfer, and any actions that may be triggered by real-time review of those data. There should only be one source defined at any time for any data element. The EMA has focused on the issue of source data control and specifically stated that “the investigator should maintain the original source document or a certified copy (Requirement 5, ICH GCP 2.11, 5.15.1); that source data should only be modified with the knowledge or approval of the investigator (Requirement 6, ICH GCP 4.9.3, 4.9.4 and chapter 8); and the sponsor should not have exclusive control of a source document. (Requirement 10, ICH GCP 8.3.13).”

	The EMA also requires that “all data generated in a clinical trial relevant to patient care must be made available to the investigator at all times during and after the trial, and all data held by the sponsor that has been generated in a clinical trial should be verifiable to a copy not held by the sponsor.”  The EMA also stated that “the requirements above are not met if data are captured in an electronic system and the data are stored on a central server under the sole control of the sponsor.” The EMA requires that a “contemporaneous certified copy of the data should be retained at the investigator site in addition to the record maintained on a central server.”

	In addition, the business requirement of any electronic system can be summarized to include:

		To be a separate legal entity from the sponsor and from the investigator, with a detailed contract defining duties and responsibilities of each party

		An assured mechanism for investigators to be informed about and/or approves of modifications to the data should be clearly established, and this control by the investigator should be demonstrable 

		Any changes to the data should be captured by the audit trail

	The variations in regulatory understanding have confounded many stakeholders. In order to find a practical way forward, industry and professional associations should concentrate efforts on identifying and addressing concerns around clinical data quality. Specific provisions associated with quality assurance and the transparency of data flow should be present in the protocol, protocol-associated plans, and any contractual agreements with the vendors and study sites. Failure to create, implement, and document such risk mitigation associated with source data would be a major shortcoming, as it could:

		Hinder the scientific interpretability of the data-and renders any clinical decision support impossible

	Not surprising, the EMA has directly warned sponsors and contract research organizations (CROs) that documentation, procedural, and systemic shortcomings will compromise (or even block) application package submission to the Committee for Medicinal Products for Human Use (CHMP). Similar reactions in presence of blatant lack of compliance are to be expected in the case of NDAs (CDER), BLAs (CBER) and PMAs (CDRH).

Source records during development process

	Despite the philosophical and historical differences explained earlier, it is possible to implement a clinical data acquisition environment that meets all recognized regulatory expectations. Source records, for example, can be maintained in many formats, including but not limited to paper records (e.g., data files, XML files, and PDF files). Regardless of the medium or the format, compliant maintenance of source records:

		Assures the ability of independent auditors to confirm the accuracy of data presented to regulatory agencies by pharmaceutical and device companies

		Allows for the reconstruction of study data in the event of catastrophic loss of data by the sponsor

	Source data should not be the same “version” of the data that the sponsor (or CRO) “controls.” Confirmation of the accuracy of the data submitted to regulatory agencies can be accomplished by review of the validation of electronic systems used as original data sources, manually reviewing paper records and comparing results submitted by sponsoring companies and/or performing “data compare” of electronic source records to data stored in locked databases. Ideally, evaluating extracts of, or entire datasets against CRF data elements could provide corroborating evidence, and ultimately a measure of confidence, as to the accuracy of reported assessments and endpoints. This, however, would require access to the electronic source data from EMRs, machines used in the clinical trial process (e.g., raw MRI records) and EDC databases prior to transfer to the sponsor of the clinical trial. While all of these tasks can be used to assure precise data (i.e., data elements agree between databases), these processes do not holistically address data accuracy. Sensitivity analyses done on real clinical trial datasets have repeatedly shown that database changes, as a result of SDV and SDR, have little or no impact on final means and standard deviations (SD).

	Therefore, key areas of focus during monitoring, audits or inspections are the following:

		Were the clinical site personnel qualified, as documented by education and experience, to perform the activities for which they were responsible?

		Were the clinical site personnel properly trained on the protocol and the electronic systems used for the trial (e.g., EDC, eSource storage, etc.)?

		Did the clinical site understand and follow the protocol?

		Were there any differences in outcomes between sites, suggesting lack of understanding of the protocol or possible fraud?

How to satisfy regulatory concerns about EDC data integrity and site controls over its source records.

Applied Clinical Trials-08-01-2015