When you read this, it should be about 50 days until 2020. Here are two stats pulled out of 2017 regarding the drug development enterprise for 2020. It is estimated that the majority (72%) of clinical trials will be run by CROs in 2020, and the internal rate of return (IRR) on pharma R&D is predicted to be at 0% in 2020. Since CROs don’t run clinical trials out of the graciousness of their hearts, there looks to be a bit of unsustainability in the market. What future awaits the industry remains to be seen; here are some more uplifting tidbits around innovation that could help change this bleak prospect.

Unified Clinical Operations Survey: Annual CRO Report 

. CROs are initiating change to simplify information exchange with study partners, which they expect to yield significant benefits, including reduction in manual processes (77%), streamlined collaboration (65%), improved study quality (64%), and faster study execution (64%). In addition, the survey found site contracting and budgeting the most cited and fastest growing issue during the study start-up process, with 70% saying it is their top challenge, up 11 percentage points since 2018 and among the primary drivers for change.

 I will be attending KNect 365’s Clinical Trials Europe event this month. Speakers provided their own predictions for the future of clinical trials 

, and I look forward to learning more about the relationship between CROs and sponsors. As stated by Patricia Moenaert, director, portfolio sourcing and relationship management (PSRM) at Celgene, “Sourcing/outsourcing will be supported by more automated systems by 2020 and sponsors will mainly do oversight and less micromanagement since both CROs and sponsors will join the same most common technology. This will allow sponsors to be more efficient in resourcing internally and avoid duplication of task by both CRO and sponsor. Non-core activities will be delegated to CROs who are becoming the experts, while science will stay core at the sponsor.”

 It’s becoming increasingly disingenuous for industry to point fingers at FDA as the block to furthering innovation in drug development. While agency guidances are paramount to following regulatory intent, even when the guidances literally tell industry they can get away from archaic practices, something keeps the CROs and sponsors entrenched. Former FDA Commissioner Scott Gottlieb had been direct in his comments during his tenure around sponsors and CROs that resist change, noting that there needs to be a more concerted effort by leadership across the entire community to lead that change. He did acknowledge that drugmakers need additional contact or reassurance from FDA, that if they are implementing change, they’re going down the right path. But he believes that FDA’s processes are transparent, and often go through a notice and comment period, either rule-making or guidance. And with recent CDER and CBER restructures and a push for the necessary digital transformation, the regulatory future for innovation is bright.

 will highlight Regulatory Updates and include articles around FDA pilots, regulatory information systems, and updated information around China, the EU, and more.

Articles

From the Editor

While the future of the industry is still uncertain, a slew of uplifting ideas around innovation could help turn things around.


2020: The Industry’s Future Awaits

Issue PDF

Click the title above to open the Applied Clinical Trials November 2019 issue in an interactive PDF format.

Applied Clinical Trials, November 2019 Issue (PDF)

Industry-sponsored research (ISR) has been progressively growing within Asia in the last decade. Early phase clinical trials play a crucial role not only in drug development, but also in expanding the clinical trial ecosystem, bringing in scientific knowledge and novel medical technologies and treatments to individual countries. The benefits of conducting early phase trials also extend towards a “spillover” effect of boosting locally conducted later phase trials, leading to access of novel treatments by a large and relatively naïve patient pool and bringing in investments.

	With over 20 years experience in conducting late-phase clinical trials, the Malaysian government realizes the positive impact of encouraging the growth of early phase clinical trials. The country also has an untapped potential that can be used toward delivering high quality early phase clinical trials, such as a naïve and diverse patient pool, established and experienced infrastructure, capabilities and resources, and competitive regulatory timelines compared to its neighboring countries.

	In view of this, there is a strong focus on growing the clinical trial ecosystem in the country by optimizing the already existing resources while expanding and improving them to further facilitate early phase ISRs in the Malaysia. Clinical Research Malaysia (CRM), established for this purpose in 2012, and a Phase 1 Realization Project (P1RP) was launched in 2016. Supported by five pillars ranging from development of guidelines to people and capability development, the goal is to enable Malaysia to cater to early phase drug studies.

	The conduct of ISR in Asia has been gaining momentum for more than a decade.

 states that the contract research organization (CRO) market in Asia-Pacific (APAC) is the fastest-growing in the world with an expected compound annual growth rate (CAGR) of 20% (from 2016-2021) compared to an increase of 11.4% CAGR globally. This follows from estimates of clinical trial volumes increasing from 5.9% of the total global volume between 2005-2007, to 9.7% in 2011 in the APAC region,

showing a steady influx of clinical studies, as it gains a reputation for being a preferred destination for ISRs.

	However, a lack of early phase trials (Phase 0 and I studies) is evident.

 examined the number of ISR Phase I trials between 2007–2009 and found that only 6.8% of them made their way to the APAC region. The early phase clinical trial market in 2013 was valued at approximately $11.9 billion USD with an expected CAGR of 1.5–2%, reaching 4% this year.

 Owing to the important roles of early phase trials that range from their scientific benefits

 to capacity-building and economic advantages, most Asian countries, including Malaysia, have focused initiatives into building adequate infrastructure to attract them.

	As of last summer, there were 16,248 interventional ISRs covering all phases globally; 27.2% (4,424) were in the early phases (Phase 0 and I trials).

 Figures 1 and 2 show the proportion of early phase trials in Asia and Southeast Asia, which are significantly smaller levels compared to North America and Europe.

	There are several benefits in conducting early phase trials in Asia. One is that there are certain diseases that are more prevalent in Asia compared to the West, wherein epidemiology, health services, social determinants, comorbidities, and genetic components of the population can influence how a treatment may be used, as well as differences in genetics and gastrointestinal microbiome effect on the pharmacokinetics and pharmacodynamics of drug molecules.

 There have also been concerns that racial and ethnic minorities, women, and the elderly are often underrepresented in early drug development programs, making Asia an attractive destination for clinical trials.

	The conduct of more early phase trials in regions within Asia, like Southeast Asia, can  play a pivotal role in ensuring that the populations proportional to the potential uses of the product after its registration and approval are performed from the earliest stages.

	Early phase trials: Opportunities for growth in Malaysia

	Malaysia, located in Southeast Asia, is a multi-racial country consisting of Malays, Chinese, Indians, and numerous indigenous people who are mostly treatment naïve. This provides the genetic diversity that is important in every clinical trial. The epidemiology of diseases in an individual country is also a crucial consideration when determining the success of a clinical trial, as it signifies the availability of study subjects and mitigates the risks of poor accrual rates that can cause trials to fail at huge costs.

 Though a strong presence of the disease targeted provides for a rich source of ready patients for later phase clinical trials, it also serves as an important incentive for governments to encourage testing of novel treatments in first-in-human (FIH) trials within the country.

Patient pool with cardiovascular risks-diabetes, hypertension, hypercholesterolemia

	At a global level, the top 20 indications of ISR trials, regardless of phase of study, include cardiovascular disease, diabetes mellitus, hypertension, and hypercholesterolemia.

 Conducting early phase trials targeting these conditions would be doubly beneficial to countries like Malaysia that face major public health concerns with them. Early phase trials would allow access to novel treatments and changing standards of care, and with a ready pool of relatively naïve patients, sponsors and CROs would have easy access to subjects for later phase trials. Being part of the drug development process from its early stages allows investigators and clinical trial staff to become familiar with the treatment, thereby allowing continued progress of clinical study phases to occur more smoothly.

	In Malaysia, the National Health and Morbidity Survey, published in 2015, showed that prevalence of diabetes mellitus among Malaysian adults 18 years old and above was 17.5% (8.3% known and 9.2% undiagnosed).

 The overall prevalence for hypertension and hypercholesterolemia was 30.3% (13.1% known and 17.2% undiagnosed) and 47.7% (9.1% known and 38.6% undiagnosed), respectively.

	In 2016, disease of the circulatory system was among the top five principal causes of hospital admissions (both private and public hospitals), at 7.44% of total admissions, and was among the top five principal causes of mortality.

 With regard to type 2 diabetes mellitus, diagnosis of disease in Malaysia has more than doubled since 1996, and coupled with an overweight and obesity prevalence of 27–31% in school children, the condition poses a major public health concern.

	With the high prevalence of cardiovascular risk factors such as diabetes, hypertension, and hypercholesterolemia, not only has Malaysia a ready, diverse, and relatively naïve patient pool for later phase ISRs that fit into the top 20 clinical trial indications, but it also gives the Malaysian government a strong incentive to encourage early phase trials.

	Studies in the field of oncology treatment are currently the top indication for clinical trials. Using the following search criteria, start date 01/01/2013-12/31/2017, recruiting, not yet recruiting, active-not recruiting, enrolling by invitation, early Phase I and phases I-III, indications for cancer takes up 54.5% of the total industry sponsored interventional studies.

 Additionally, projected distributions of available new active substances in the global market by disease type from 1996–2020 show a projected growth in oncology biopharmaceutical and pharmaceutical products making up 13% of the total new active substances.

 Thirty-three percent of novel drug approvals in 2015 by FDA were for oncology-related products, while 27% were approved in 2017.

 In the U.S. alone, there were 836 drugs and vaccines for cancer in various stages of clinical development or awaiting FDA approvals.

	In Malaysia, cancer is within the top five causes of mortality, and in 2016, the total hospital admissions for neoplasms were 4.2% (based on total admissions of > 3 million).

 Breast cancer is the most common of all cancers (17.7%), followed by colorectal (13.2%) and cancer of the trachea, bronchus, and lung (10.2%).

	FIH oncology trials differ from early phase trials in other therapeutic areas-they are evaluated in patients rather than healthy volunteers. The characteristics of oncology products, mainly their safety profiles, do not allow for testing in healthy volunteers. In the absence of alternative effective treatments, participation in these trials using novel compounds are considered an opportunity to these patients.

	Therefore, with the global pipeline of oncology drugs in clinical development having seen robust growth over the past two decades,

 combined with the strong presence of cancer among Malaysians, not only are sponsors presented an opportunity to tap into the available pool of cancer patients, it is also a considerable push for the Malaysian government to spur the growth of early phase oncology clinical trials within the country.

	The cost of developing a new molecular entity can be over $1 billion USD with an average estimate of $2.6 billion USD.

 Added to that, the development of a new medicine from identification through approval for marketing can take up to or more than 12 years. In view of the extreme financial investments, Asian countries like Malaysia, which provide treatments and medical procedures at a lower cost than in developed countries,

 can be seen by sponsors and CROs as an ideal site for conducting clinical trials with lower investments.

	The 2017 Frost & Sullivan white paper’s

 costing estimates of conducting clinical research per patient, per visit, in all therapeutic areas and in all phases, shows Malaysia as having the second-lowest cost, ahead of India ($350 vs. $330 USD); while costs in Singapore was similar to that in the U.S. ($1,210 vs. $1,380 USD) and that in South Korea ($890 USD).

	One of the complexities of performing clinical trials in Asia is the heterogeneous nature of the regulatory processes and timelines among the countries in the region.

	However, countries in the region have attempted to harmonize these to ensure better data acceptability and reduce trial and drug approval timelines.

 Malaysia is part of the ASEAN Free Trade Area (AFTA) that undertook the ASEAN Common Technical Documents (ACTD) and ASEAN Common Technical Requirements (ACTR) initiatives to standardize drug approval processes.

	In Malaysia, ethics review and regulatory approvals, together with import licensing and contract negotiations, occur concurrently, allowing for faster processing timelines. These are comparable with timelines in South Korea and Singapore (approximately 2-3 months).

 In a recent report, regulatory timelines have been improved to within 30 working days,

 while the centralized ethics committee under the Ministry of Health has shortened its timelines to 51 calendar days.

Established infrastructure, resources, and capabilities

	An established and functioning network of clinical trial centers with advanced equipment and technology, knowledgeable physicians, and available key opinion leaders in different specialties also play an important role in attracting ISRs.

	Malaysia has a well-developed and equipped healthcare system manned by medical doctors that practice and comply with international clinical practice standards.

 ISRs in Malaysia are conducted at government hospitals, teaching institutions, private hospitals, and government health clinics. Government hospitals receive and treat the largest number of patients, thus presenting a unique opportunity for access to the primary care patient pool.

	Developing an ecosystem for early phase clinical research in Malaysia

	The Government of Malaysia, realizing the potential positive impact of early phase trials for patients, scientific advancements, and economic growth, is stepping up its existing clinical trial capabilities by building new initiatives to drive early phase clinical research capacity in-country and develop an attractive early phase clinical trial ecosystem.

	In lieu of this, the Malaysian government included the creation of a supportive ecosystem with the establishment of CRM, a non-profit company, wholly owned by the Ministry of Health,

 to equip the ecosystem of clinical research in the country.

 Its goal is to reach at least 1,000 clinical trials by 2020. Part of the initiatives stated in this section is to set up more clinical research centers, develop more good clinical practice (GCP) certified investigators, and improve existing institutional review board (IRB) and ethics committee (EC) timelines. The Phase 1 Realization Project (P1RP) was aimed at realizing this aspiration of making sure Malaysia is capable in conducting early phase studies.

	The benefits of conducting early phase trials in Malaysia, as laid out by the P1RP, are the increase of Phase II and III trials as a result of a spillover effect from conducting more Phase I trials, contribution to the transfer of knowledge and technologies to Malaysians, creation of new jobs in clinical research, spurring local innovation, prevention of investment outflow, and moving the country as a whole higher up the clinical research value chain. For patients, it increases the opportunity to receive novel medications or treatments that are not yet available in the market, as the majority of ISRs are interventional in nature providing treatment at no cost to patients. It also provides a means for the government to expand its healthcare resources to include more patients and medications, especially oncology treatment that are costly.

	The P1RP stands on five pillars, which are the establishment of guidelines for conducting Phase I clinical trials in the country, people development, capability development, preparation of sites, and risk management. To date, all of the P1RP pillars have been implemented and fulfilled. In the first quarter of 2019, the country’s regulatory authority had indicated that it was ready to review FIH studies.

	The P1RP strategy is multi-pronged wherein regulatory agencies are equipped with the right knowledge to review Phase I clinical trials. Conforming to international standards, local experts are trained with the necessary skills to analyze early phase trials through engagement with international consultants, preparation of clinical trial units at hospitals to conduct Phase I studies, and the development of an action plan to manage and mitigate any given crisis that may occur during the clinical trial process.

Development of Phase I clinical trial guidelines

	The Malaysian Phase I Clinical Trial Guidelines

 was launched in November 2017. Prior to this, the country did not have a specific guideline on Phase I clinical trials. The effort saw the coming together of experts and investigators in the field of clinical trials from the Ministry of Health, Ministry of Higher Education, ethics and regulatory bodies, as well as industry experts. International key opinion leaders on clinical trials were also invited as subject matter experts. The guidelines were based on the Association of the British Pharmaceutical Industry (ABPI) 2012 version of Phase I clinical trial guidelines,

 as this document took into account and expanded its content to reflect the latest changes in conducting FIH trials. The Malaysian guidelines, in turn, considered local regulatory bodies and agencies’ existing procedures, and the local clinical trial environment-adapting relevant areas to facilitate the applicability of the ABPI guidelines in Malaysia.

	To gain knowledge and experience in Phase I clinical trials so as to implement and impart these to relevant agency officers, three regulatory officers were sent to pursue their postgraduate studies at The Christie, Manchester, as well as King’s College London, under a collaborative scholarship between CRM and the Public Service Department. This will allow them to work within a leading Phase I clinical trial unit and gain experience and understanding in the designing and delivering of Phase I studies. This attachment is important, as these regulatory officers will be the ones responsible for reviewing the dossiers of Phase I studies in Malaysia.

	The Ministry of Health has also planned to send local investigators to be attached at reputable Phase I centers, including the Princess Margaret Cancer Center, to be exposed to the experience of conducting FIH studies. The government has also started initiatives to bring back Malaysians from overseas. Experts or specialists from higher-income countries returning home would have an edge due to a global mindset. Coupled with an in-depth knowledge of the country, people, and the culture, it creates a world-class pool of specialists that can support early phase trials.

Initiatives to develop and perform centralized professional training for study coordinators to complement the work of investigators have also began. To attract more specialists to participate in clinical trials, the Ministry of Health now allows for 20% of a work week (or one full day off) for investigators to focus solely on research.

	In a 2011 report presentation of the Health Committee at the 49th Parliament sitting in New Zealand,

 some of the recommendations put forward to increase New Zealand’s presence in the clinical trial industry were to establish a strong intra-governmental collaboration between different ministries, ensure a culture that values research within the public health system, and requiring the Standing Committee on Therapeutic Trials to carry out all scientific reviews within 30 calendar days.

	As part of the capability development pillar of P1RP, a Scientific Review Panel (SRP) for FIH clinical trials was established to support the Medical Research and Ethics Committee (MREC), a centralized ethics committee, in performing scientific evaluations of FIH trials undertaken by and/or conducted in clinical trial sites in Malaysia. The scope of review includes all FIH studies on new chemical, biological, and biosimilar drugs not registered in Malaysia.

	The intensity of early phase clinical trials is more time-consuming requiring increased amounts of physical exams, vital signs monitoring, electrocardiogram (ECG) monitoring, and pharmacokinetic laboratory tests compared to later phase trials.

 The P1RP project and initiatives will harness the available resources and capabilities available within the country’s health system as well as increase its knowledge with international collaborations to ensure that Malaysia is ready to meet with the demands of early phase trials.

	Sarawak General Hospital, located in a major city in East Malaysia, is targeted to be fully equipped to handle early phase clinical trials. It also serves as a template for future units to be developed in other hospitals. This hospital is already a major medical center with ready access to large patient populations, and the clinical trial center is well-equipped and operated by well-trained scientific and medical staff.

	In June 2007, the “Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products” was finalized by the European Medicines Agency (EMA).

 The scope of the guidance, which encompasses both biologics and new chemical entities, was recently updated in 2016 (EMA/CHMP/SWP/28367/07),

and places the focus on the pharmacological characteristics of a new drug.

	The document was created to support the transition from non-clinical to the early phase of clinical development and identifies influencing risk factors of a product, includes consideration of quality aspects, testing strategies, designs for FIH studies, and mitigation strategies such as initial dosing calculation and dose escalation.

	Therefore, part of the P1RP initiative is the preparation and training of risk management guidelines and to manage any crisis in relation to early phase clinical trials. These include creation of a standard operation procedure (SOP) to prepare for and manage all types of crises requiring immediate attention during early phase trials (i.e., unexpected side effects from a clinical trial). The SOP is designed to also ensure that all actions are coordinated, timely, accurate, consistent, and effective in minimizing the potential for confusion, rumor, and misinformation. The overall objective of this effort is to offer support to the sponsor and processes of early phase trials in difficult situations, and to the greatest possible extent, limit potential injury to patients, consumers, or the reputation of the institutions.

	CRM initiated the ACCELERATE project to move Malaysia’s focus further upstream to early phase drug discovery and development, utilizing readily available resources in the country. The project involves converging expertise and collaborations across agencies, clinical research industries, and universities on preclinical projects. Through this initiative, CRM has intensified collaborations with various universities and research institutes in “bench to bedside” projects. The conversion of preclinical studies into early and late-phase trials may spur discovery, local innovation, and eventually manufacturing of innovator drugs in Malaysia. Additionally, it can prevent outflow of investments and move the country higher up the clinical research value chain.

	Malaysia’s effort through the P1RP and ACCELRATE project underlines the government’s commitment to bring the country into a new phase in the clinical trial industry. In the local context, early phase clinical trials play a key role in enhancing the capability of the country in the development of medical science and treatment of disease, as well as placing Malaysia at the cutting edge of research. To this end, the Malaysian government’s goal is to develop the country into becoming the preferred destination for industry-sponsored research.

		Frost & Sullivan (2016) Asia: preferred destination for clinical trials. 

		Frost & Sullivan (2017) The changing face of global clinical trials: Asia-Pacific as an ideal destination for specialty biopharma. 

https://www.cmicgroup.com/files/user/en/solution/pdf/Whitepaper_201710.pdf

		Ilancheran M, Pritchard JF (2015) Is South Korea the next emerging early phase destination?

http://www.appliedclinicaltrialsonline.com/south-korea-next-emerging-early-phase-destination

		Kapiriri L, Lavery J, Singer P, Mshinda H, Babiuk L, et al (2011) The case of conducting first-in-human (phase 0 and phase I) clinical trials in low and middle income countries. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339411/

		Louisa M, Takeuchi M, Setiabudy R, Nafrialdi, Takeuchi M (2012) Current status of phase I clinical trials in Asia: an academic perspectives. 

https://www.ncbi.nlm.nih.gov/pubmed/?term=Current+status+of+phase+I+clinical+trials+in+Asia%3A+an+academic+perspectives

		Rahman S, Majumder M (2012) Managing clinical trials in Asia: issues, threats, opportunities and approaches. 

https://www.banglajol.info/index.php/SEAJPH/article/viewFile/15961/11333

		Yathindranath S, Kureishi A, Singh S, Yeow S, Geng G, et al (2014) Evolution of the clinical trial landscape in Asia Pacific. 

https://www.dovepress.com/evolution-of-the-clinical-trial-landscape-in-asia-pacific-peer-reviewed-fulltext-article-OAJCT

		Mohs R, Greig N (2017) Drug discovery and development: role of basic biological research. 

https://www.ncbi.nlm.nih.gov/pubmed/29255791

		Murthy S, Mandl K, Bourgeois F (2015) Industry-sponsored clinical research outside high-income countries: an empirical analysis of registered clinical trials from 2006-2013. 

 https://health-policy-systems.biomedcentral.com/articles/10.1186/s12961-015-0019-6

https://clinicaltrials.gov/ct2/results/browse?brwse=locn_cat_SE

		Baer A, Bridges K, O’Dwyer M, Ostroff J, Yasko J (2010) Clinical research site infrastructure and efficiency. 

https://www.ncbi.nlm.nih.gov/pubmed/21197190

		Ministry of Health Malaysia (2015) National Health & Morbidity Survey: Non-communicable disease, risk factors and other health problems.

		Ministry of Health Malaysia (2017) Health facts. 

http://www.moh.gov.my/images/gallery/publications/HEALTH%20FACTS%202017.pdf

		Tee E, Yap R (2017) Type 2 diabetes mellitus in Malaysia: current trends and risk factors. 

https://www.ncbi.nlm.nih.gov/pubmed/28513624

		Statista.com. Projected distribution of global available new active substances by disease type between 1996 and 2020. 

https://www.statista.com/statistics/491102/new-active-substance-distribution-projection-by-disease/

Feature Articles

Exploring the nation’s opportunities for growth and the initiatives undertaken to build an attractive clinical trials ecosystem for early stage research.

Establishing Early Phase Capabilities in Malaysia

Participant safety is the clinical trial sector’s top priority-and striving to achieve this laudable aim also makes for more agile, flexible, and efficient studies. That’s what we learned from a second executive roundtable discussion, hosted by the Tufts Center for the Study of Drug Development (CSDD), and supported via an educational grant from CluePoints and PricewaterhouseCoopers, on the progress the industry is making toward implementing the requirements of the ICH E6 (R2) addendum.

	When it was introduced in 2017, ICH E6 (R2) represented the biggest change to international clinical research in two decades. Developed as a response to the rising complexity of studies and the industry’s increasing reliance in electronic data management and reporting systems, the update sought to define good risk management in the modern trial environment. It states that clinical programs should implement risk assessment at both the trial and system levels and that metrics on clinical monitoring and data management should be captured in preparation for clinical study reports.

	Following the addendum’s publication, Tufts CSDD held the first roundtable on the updated guidance and found companies in the early stages of a big change. Kenneth Getz, former director of sponsored research and research associate professor at Tufts CSDD, who was recently promoted to research professor and deputy director, organized and facilitated the event with colleague Yaritza Peña, a research analyst at the center.

	“Two years ago, companies were in the early stages of interpreting the guidance to translate recommendations into tangible operating practices,” said Getz. “Roundtable participants indicated their initial focus was largely on risk-based monitoring (RBM). They were beginning to implement risk assessment procedures to identify which operating practices were most impacted. Although apprehensive about how the addendum would affect their current standard operating procedures (SOPs), the attendees had all agreed that the revised guidance was a step toward more agile, flexible, and efficient clinical trials,” he added.

	These latest discussions, held in Boston in April, found that the organizations had made significant progress on a granular level, and were now taking a more holistic view. A total of 41 participants from organizations including Alkermes, GlaxoSmithKline, Pfizer, Roche-Genentech, Sage Therapeutics, Takeda, the Metrics Champion Consortium (MCC), and FDA took part.

	After a panel discussion about ICH E6 (R2) compliance, the companies offered up their own examples before addressing the barriers and anticipated direction of travel. They found that rather than focusing simply on RBM, the industry has been working toward improving study efficiency overall, by taking a much broader view of risk-based approaches to study execution, or RBx.

	“Company mindset has progressed from 2017,” said Peña. “Since then, many organizations have incorporated a risk-based framework across end-to-end development processes. Companies are refining the quality management plans developed during the planning and execution stage, and using technology to drive pattern identification, machine learning, and study-specific analysis.”

	The discussions found that new regulations had compelled companies to move away from a clinical research associate (CRA)-centric, on-site visit model of monitoring to a data-driven, central statistical approach that improves data quality and contributes to overall trial success. Roundtable participants said that utilizing technological solutions had enabled a risk-based approach, informed by objective data integration, that supported the critical thinking vital to being able to make the right patient safety decision at the right time.

	Amanda Hayden, director of global clinical services at Alkermes, said the industry had experienced “significant maturation” with respect to its response to ICH E6 (R2). “While many companies may have approached the update by addressing each subpart separately, the reality is that many of the processes are interconnected. Advancing clinical processes in a holistic fashion and thinking of risk in all facets of study planning, execution, and analysis creates synergies and efficiencies, and allows for better use of time, resources, and study data.”

	Companies chalking up success in this area are those that have recognized the opportunity and have since worked to reorganize SOPs and pathways to allow for a portfolio, rather than a program-wide view. They are making significant investment in analytical capabilities that not only apply to RBM and oversight, but also to operational outcomes such as enrollment and protocol feasibility. Advanced data visualization, for example, can automatically detect trends and anomalies, and automated query management systems assist with the reconciliation of serious adverse events.

	Study optimization is a natural consequence of utilizing these metrics, which allow companies even more sophisticated ways to distinguish between reliable and potentially unreliable data, and to avoid unnecessary protocol complexity. These opportunities are only set to increase as analytical techniques, including machine learning, natural language processing, and other types of artificial intelligence  (AI) are put to use in the clinical trial space.

	Achieving this holistic approach isn’t without its challenges, and integrating ICH E6 (R2) concepts into study planning and implementation is proving difficult for some sponsors. “Part of the challenge depends on the creation of an efficient interface between a proactive quality planning process and a risk-based monitoring process,” said Getz. “Another daunting task is shifting company culture to adapt to the necessary changes to study processes when anticipating risk and performance issues.”

	Getz further explained: “Since risk management is not currently a core operational competency, employees require training and monitoring to understand concepts such as data quality vs. data integrity, site monitoring vs. trial monitoring, and data reliability vs. trial results reliability.”

	According to the panelists, the companies currently embracing the opportunities of RBx have fundamentally changed the way data are verified, reviewed, analyzed, and managed within their organizations. This has taken commitment from senior leadership and a wholesale change both in company structures and culture. Strategies employed have included robust change management training and the digital upskilling of staff. Clinical study teams, tasked with examining ICH E6 (R2) requirements to ensure the right data quality oversight tools are being used, have also been set up.

	Some industry players have developed teams of subject matter experts (SMEs) with the responsibility to ensure the updated guidance is implemented. These SMEs are able to take an overarching view of risk identification, reporting and evaluation, cross-functional sharing of risk, and the monitoring of risk control measures across studies and protocols.

	“This horizontal view that rises above separate protocols and sites to take in the bigger picture, is the key to realizing the potential of RBx,” said Hayden. “The main drivers in successfully implementing a risk-based approach to study execution is to consider the interconnected nature of risk identification and analysis throughout the entire lifecycle of the clinical program.”

	While many of the companies at the roundtable said the project had increased operating costs, they also said these were offset by the benefits in terms of risk mitigation and proactive decision-making. As clinical trials become ever more complex and fragmented, RBx systems can be used to continue to consolidate and streamline studies while allowing for strategic oversight. In fact, many of the roundtable companies said they believed they were better placed to drive effectiveness and optimize performance in the next three to five years.

 appeared best placed to leverage the rich data that will be generated by ever-advancing analytics. While AI utilization is still in its infant stages, for example, the roundtable participants expect it will soon play a role in efficiently identifying areas of risk and be able to guide stakeholders to the best possible solutions. They are also in the best position to respond to expected regulatory changes-FDA is currently looking at revisions for E8 as well as a proposal regarding the next iteration of E6, for example.

	“Drug development sponsors are being encouraged to partner with regulators, take more innovative risks, and amplify their concerns and ideas in terms of clinical trial quality and compliance,” said Peña. “With more time to process learnings from new technological implementations, the industry will begin to see additional standards for proactive clinical trial planning, execution, and quality-by-design.” In the long-term, companies will save time and expense from identifying anticipated risks early on through the refinement of current processes, she added.

	RBx is about investing in the future by improving quality and effectiveness. Roundtable attendees agreed that while holistic ICH E6 compliance has led to a modest increase in short-term operating costs, they expected to see substantial savings over time.

	Investing in the risk-based approach to the design and conduct of clinical trials is about the intelligent use of data to make informed decisions. It’s not only sponsors and CROs that are adopting risk-based approaches, but regulators are as well.

Roundtable gathers industry experts to discuss the guidance update’s early implementation and the shift toward risk-based study execution approaches.

How ICH E6 (R2) Offers Wins with Risk-Based Study Execution

	Study Will Assess the Effectiveness of Statins in Older Adults

	A $90 million award expected from the National Institute of Aging and the National Heart, Lung, and Blood Institute (NHLBI) will fund the largest pragmatic trial with placebo-controlled drug assignment to date. Building on its success in leading pragmatic approaches for clinical study design, the Duke Clinical Research Institute (DCRI) has been awarded funding to conduct a pragmatic trial studying the effectiveness of statins in older adults without known cardiovascular disease. Funding for the trial is expected to be spread over the next seven years.

	The study, known as Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults (PREVENTABLE), will be funded by NHLBI, of the National Institutes of Health (NIH), and conducted in partnership with Wake Forest School of Medicine. PREVENTABLE also is the first statin trial with a non-cardiovascular primary outcome. Investigators will study whether statins could help prevent dementia or physical disability-the most important outcome for older adults looking to maintain independence. Few statin studies in primary prevention populations have included individuals aged 75 or older, leaving many unanswered questions for older adults.

	PREVENTABLE will partner with PCORnet, the National Patient-Centered Clinical Research Network, and the National VA Network to identify and recruit 20,000 participants 75 years of age or older at 100 U.S. sites, as well as to help identify outcomes via electronic health records. Use of these two national resources is expected to enable investigators to enroll participants and collect health data faster and more efficiently than a traditional trial.

	The acquisition of Medidata Solutions, Inc. by Dassault Systèmes SE was completed late last month. Medidata offers clinical expertise and cloud-based solutions supporting the development and commercialization of treatments.

	The acquisition positions Dassault Systèmes to be a key player in the digital transformation of life sciences in the age of personalized medicine and patient-centric experience through a comprehensive offering that reflects a deep understanding of healthcare, its ecosystem, and market needs. Medidata will operate as a Dassault Systèmes brand powered by the 3DEXPERIENCE platform. The life sciences industry will become Dassault Systèmes’ second-largest core business after transportation and mobility.

	Under the terms of the agreement, first announced in June, Dassault Systèmes acquired all of the issued and outstanding common shares of Medidata for $92.25 per share in cash, representing a total enterprise value of approximately $5.8 billion.

	Pandion Therapeutics, Inc. and Astellas Pharma, Inc. signed a license and collaboration agreement directed toward the research, development, and commercialization of locally acting immunomodulators for autoimmune diseases of the pancreas. The collaboration will allow the parties to combine Pandion’s modular biologics and functional immunology expertise with Astellas’ advanced therapeutics development and global commercialization capabilities for the treatment of autoimmune diseases.

	Under the terms of the deal, Pandion will be responsible for design and discovery of bispecific drug candidates based on Pandion’s proprietary modular immune effector and tissue tether platform and Astellas will be responsible for conducting preclinical, clinical, and commercialization activities for the selected candidates developed during the collaboration.  

	Parexel announced the expansion of its collaboration with the Society for Clinical Research Sites (SCRS), the first and only global organization fully dedicated to representing the interests of clinical research sites. Parexel will participate as a Site Engagement Partner and lead a number of key initiatives focused on improving the patient experience in clinical trials. The company’s global site solutions team maintains a site alliance network of more than 500 sites and 17,100 investigators across the globe.

	One initiative Parexel will work on with SCRS will be leading a site advocacy group (SAG) on diminishing patient burden in clinical trials, bringing sites and patients together to discuss patient perceptions of methods of reduction of patient encumbrance to participate in clinical trials.

	The Cystic Fibrosis Foundation unveiled its “Path to a Cure” last month, an ambitious research agenda to deliver treatments for the underlying cause of the disease and a cure for every person with cystic fibrosis (CF). The Foundation is challenging potential collaborators to submit proposals that will accelerate the pace of progress in CF drug discovery and development and intends to allocate $500 million to the effort through 2025.

	The Foundation offers partners a range of resources to de-risk CF drug discovery and development, including the world’s largest network of CF clinical trial sites and a dedicated laboratory to support translational research for potential therapeutic programs.

	The European Medicines Agency (EMA) announced its conditional marketing authorization of a vaccine used to prevent the spread of the Ebola virus. University of Florida researchers played an integral role in the design and analysis of trials testing the effectiveness of the vaccine, manufactured by Merck & Co. Conditional authorization brings the vaccine a major step closer to licensing, which will eventually make the vaccine more widely available to protect people who are at risk of contracting Ebola.

	Alexion Pharmaceuticals, Inc. and Achillion Pharmaceuticals, Inc. have entered into a definitive agreement for Alexion to acquire Achillion, a clinical-stage biopharma company focused on the development of oral small molecule factor D inhibitors to treat people with complement alternative pathway-mediated rare diseases, such as paroxysmal nocturnal hemoglobinuria (PNH) and C3 glomerulopathy (C3G).

News

A compilation of recently released news briefs that pertain to the clinical trials industry.


News Notes

Precision oncology promises a new model of cancer care where medical decisions are based on a holistic view of the patient, including their genes, environment, and lifestyle, and tailored to the molecular profile of their tumor. To date, great strides toward the paradigm of precision oncology have been made in the area of cancer immunotherapy, which boosts a patient’s own immunity to combat tumor cells. Immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapies have dramatically improved outcomes for a select number of patients, but widespread use of these treatments remains elusive.

	To make personalized cancer treatment a reality for all patients, we need to reimagine the biopharmaceutical business model and drug development process, both of which have traditionally been focused on broad drug development and blockbuster medicines. New regulatory, technical, clinical, and economic frameworks are needed to ensure that the right patient can access the right therapy in a meaningful timeframe. In this article, I discuss three key challenges that must be addressed to fulfill the promise of precision oncology.

	#1: Understanding and addressing mechanisms of resistance

	The ultimate goal of cancer immunotherapy is to stimulate the immune system to launch a sustained attack against tumor cells.

 Given the complex and dynamic interactions between tumors and the immune system, achieving this is complicated.

	The challenge lies in managing the delicate balance between autoimmunity and the immune system’s ability to recognize non-self. In some cases, the immune system may fail to recognize tumor cells as non-self and may develop a tolerance to them. Moreover, tumors have myriad methods for evading the immune system (see Figure 1 below).

	Resistance to cancer immunotherapy can be categorized as primary (i.e., failure to respond) or secondary (i.e., relapse after successful treatment). Approaches for optimizing response and minimizing resistance to cancer immunotherapies include developing biomarkers to assist with patient selection or treatment monitoring, altering the tumor microenvironment, and educating healthcare practitioners on the potential for delayed response with these types of treatments. With CAR-T therapies, resistance may be due to poor persistence of CAR T-cells after infusion or due to antigen loss of the target receptor.

	Given the elaborate interplay between cancer and immunity, combination therapies may be a rational approach to addressing resistance. For example:

		Combining two immunotherapies targeting distinct immune checkpoints (see Figure 1).

		Combining an immunotherapy with chemotherapy, which directly kills tumor cells and may help activate the immune system to boost the response to immunotherapy.

		Combining an immunotherapy with targeted therapy to create a possible synergistic effect.

	#2: Solving the logistics of manufacturing

	Whereas the conventional manufacturing process is typically confined to a single facility, manufacturing of cell therapies requires multiple hand-offs. While the process begins and ends at the bedside, the process of genetic modification involves a complex chain of custody that blends manufacturing and administration (see Figure 2).

 The manufacturing process is further complicated by the fact that, unlike traditional manufacturing where the starting materials are standardized, the starting materials for cell therapies are highly variable because they are derived from patients.

As evidenced by the highly publicized manufacturing hurdles surrounding the launch of Kymriah (tisagenlecleucel), meeting label specifications for commercial use is challenging, even for industry leaders.

 Sponsors must consider how manufacturing will evolve from a single center or investigator-initiated trial to a multi-site commercial endeavor. Proactive planning around logistics is also critical, and the sponsor will need to create an infrastructure for tackling and managing all aspects of chain of custody in a highly controlled manner.

	#3: Developing innovative pricing models

	Targeted therapies are quite costly in comparison to their traditional counterparts, and existing health insurance models have not been structured to reimburse for these types of treatments.

 The pricing model for CAR-T therapies may be especially challenging for commercial insurers, which typically have higher turnover and shorter coverage windows than national health insurance programs. Value- or outcomes-based pricing models represent one approach to addressing the challenge of reimbursement. These new pricing models will rely heavily on patient selection, and sponsors will need to develop tools for identifying those patients who are most likely to respond to particular precision medicines.

	Notably, the Centers for Medicare & Medicaid Services (CMS) recently finalized their decision to cover FDA-approved CAR-T therapies when provided in healthcare facilities enrolled in FDA risk evaluation and mitigation strategies (REMS) for FDA-approved indications. Medicare will also cover FDA-approved CAR-T treatments for off-label uses that are recommended by CMS-approved compendia.

	Realizing the promise of precision oncology

	The precision medicine market is expected to exceed $96 billion by 2024, with the oncology segment leading the way.

 Patients, providers, and advocacy groups are pushing for innovation, but precision oncology is still in its infancy and significant challenges remain. As advanced technologies and data analytic techniques are increasingly incorporated into the drug discovery and development process, the hope is that precision oncology will not only enable the personalization of cancer drugs, but also improve population health as new genetic and molecular insights enhance our understanding of the mechanisms of disease.

		Ventola CL. Cancer Immunotherapy, Part 1: Current Strategies and Agents. 

		Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. 

		Genetic Engineering & Biotechnology News. Cell Therapy Manufacturing: The Supply Chain Challenge. Available at 

https://www.genengnews.com/insights/cell-therapy-manufacturing-the-supply-chain-challenge/

		Hucks G, Rheingold SR. The journey to CAR T cell therapy: the pediatric and young adult experience with relapsed or refractory B-ALL. 

		Biopharma Dive. In CAR-T, manufacturing a hurdle Novartis has yet to clear. Available at 

https://www.biopharmadive.com/news/in-car-t-manufacturing-a-hurdle-novartis-has-yet-to-clear/543624/

		Blue Latitude Health. Precision Medicine from Concept to Clinic. Available at 

https://www.bluelatitude.com/how-we-think/precision-medicine-from-concept-to-clinic/

		Centers for Medicare & Medicaid Services. Trump Administration Makes CAR T-Cell Cancer Therapy Available to Medicare Beneficiaries Nationwide. Available at 

https://www.cms.gov/newsroom/press-releases/trump-administration-makes-car-t-cell-cancer-therapy-available-medicare-beneficiaries-nationwide

		Reuters. At 10.7% growth, Precision Medicine Market will cross $96.6 billion by 2024. Available at 

https://www.reuters.com/brandfeatures/venture-capital/article?id=65658

 MD, PhD, is the Executive Medical Director, Oncology at Premier Research

Outlining the three critical challenges that need to be addressed to make personalized cancer treatment a reality.

Applied Clinical Trials-11-01-2019

2020: The Industry’s Future Awaits

Applied Clinical Trials, November 2019 Issue (PDF)

Establishing Early Phase Capabilities in Malaysia

How ICH E6 (R2) Offers Wins with Risk-Based Study Execution

News Notes

The Challenges in Fulfilling the Promise of Precision Oncology

Sponsors Struggle with Trial Disclosure, Patient Privacy Requirements

The ‘Quest’ For an Effective Partner in Pharma And Biotech

China: A New Era of Drug Development and Innovation

Who’s Going to Be Disrupted by Shifts in European Health Strategy?