Precision medicine, also known as personalized medicine, is transforming drug development due to its growth over the last five years. The definition of precision medicine or personalized medicine is “tailoring medical treatment to the individual characteristics of each patient. It does not literally mean the creation of drugs that are unique to each patient, but rather the ability to classify individuals into sub-populations that differ in their susceptibility to a particular disease or their response to a specific treatment.”¹ A precision drug is one shown to be effective for specific sub-populations. In the coming five years, the number of precision medicine drugs is expected to increase by 69% and investment in precision medicine is expected to expand by 33%.² The industry is also expected to see two to three times the number of drugs with companion diagnostics—a subset of precision medicine drugs.³ Currently, oncology is the therapeutic area where precision medicine is most commonly utilized, followed by the neurology and cardiovascular areas.^2,3

Growth in precision medicine can be viewed within two areas: the number of drugs with companion diagnostics and the use of advanced diagnostic techniques for screening and risk identification.The industry has already seen the growing adoption of next generation sequencing in clinical diagnostics and diminished costs of whole genomic sequencing and advances in technology, resulting in a greater potential for genomic data to be combined with electronic health record data.⁴

Over the past 10 years contract research organizations (CROs) have expanded their range of services for conducting clinical trials including technology solutions and contributing to the development of new medicines.⁵ Sponsors have developed greater reliance on CROs to support drug development and estimates of the global CRO market could reach as high as $45 billion by 2022.^6,7 CROs are now collaborating with sponsors as they develop new strategies and discover innovative approaches to drug development. The main areas associated with precision medicine are biomarkers, assays, genomics, diagnostics, regulatory and technology. For CROs, these areas are characterized by varying levels of complexity in implementation and opportunities for growth. All of the major CROs view biomarker research services as a growth area and have integrated these capabilities into their service offerings.³ Some CROs are choosing to expand their services through mergers and acquisitions or by developing partnerships and working in collaboration with other organizations. Gathering insight into CRO preparedness or the development of those capabilities in order to expand into the precision medicine market is critical in order for CROs to be able to expand their collaboration with sponsors in this area.

There are, however, many challenges in advancing precision medicine. Biomarker identification and diagnostic test development are key challenges.² The regulatory environment is also challenging. In 2014, the FDA released draft guidance of its LTD oversight (laboratory-developed tests) and LDT regulations.⁹  The FDA has also proposed the use of standards to help establish the safety and efficacy of next-generation sequencing (NGS) based tests, and has recently issued two draft guidances on NGS sequencing.^10,11 Reimbursement challenges from third party payers are also significant hurdles, with skepticism by physicians and payers regarding whether molecular diagnostic tests are clinically useful or will improve the standard of care.¹² 

Data management and analytics are also challenging areas, as there have been surges in the quantity of clinical data being collected, including biomarker and genomic data. There is a need for sophisticated analytics, or “big data analytics” that can provide greater insights into the field.³ Ownership of data presents an additional issue, as patients participating in clinical trials contribute personal biological information, especially for genomics or biomarker research, but currently have very few rights to determine its usage. Privacy issues associated with biomarker samples have also emerged. Recently, there has been a great deal of discussion among stakeholders regarding the use of data and where it ultimately resides.¹³

Despite the challenges, by 2020 the companion diagnostics market is projected to grow by 20% globally.¹⁴ In addition to the growth of drug and diagnostic treatments within oncology, other therapeutic areas such as neurology and cardiovascular have also developed such treatments. The growth of precision medicine has impacted the clinical research process, and capabilities and infrastructure need to be redefined to be successful. This is especially true for CROs conducting trials in many different therapeutic and disease areas. As CROs evaluate their operational approaches and strategies needed to meet precision medicine growth and determine areas that may change, it is essential to examine this process. Therefore, in order to explore and assess the capabilities and readiness of CROs for precision medicine, Tufts CSDD spearheaded a research study on this topic. This research was funded by a grant from IBM Watson Health.

Methodology
The research was conducted in three phases: conducting an on-line survey; interviews with senior executives at CROs; and an evaluation of published company information with the goal of gathering insights into overall industry trends. The evaluation focused on developing a list of key CRO services and capabilities in the field of precision medicine.

Tufts CSDD developed a web survey in collaboration with industry thought leaders to assess CRO precision medicine capacity and readiness. Precision medicine was defined as an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.¹⁵ The survey examined the type of precision services currently offered as well as future plans for each of these services.  In addition, therapeutic areas of focus, level of investment in knowledge sharing, areas of opportunity and challenges for precision medicine development were also evaluated. Tufts CSDD identified potential respondents using accumulated contact lists. The survey was sent out to senior-level contacts at contract research organizations, pharmaceutical, and biotechnology companies through a Qualtrics e-mail invitation with a survey link. The survey was conducted from late December 2016 to early March 2017.

To gather insights into CRO industry trends, Tufts CSDD conducted interviews with eleven senior executives at four of the top 10 CROs by revenue. All interviewees had expertise in precision medicine and were experienced in a number of areas including oncology, corporate/business strategy and genomic medicine. The interviews focused on current company capabilities, precision medicine investments, and perceptions of gaps and opportunities within precision medicine. Two groups of interviews were conducted: one at the onset of the study (3 interviews) and the second to corroborate data gathered from the survey and industry evaluation (8 interviews). The interviews were coded using Nvivo, a software designed to analyze qualitative data.

Finally, researchers gathered on-line and published company information to develop evaluative criteria to measure the capacity of the CRO industry to support precision medicine. The landscape scan consisted of a literature review comprised of more than 50 sources including press releases and published articles in journals, trade magazines, on websites, and in company blogs and profiles. Commercially available print and online directories of contract service providers were used to identify individual contract research organizations of varying sizes. A total of 43 CROs were identified and assessed for the landscape scan and stratified by size—27 small, 5 mid-sized, and 27 large CROs—based on number of employees (10000= large).15 Information on the CROs was gathered primarily through online searches.

Results
For the survey portion of the study, a total of 54 responses were gathered from pharmaceutical, biotechnology and contract research organization industry professionals. E-mails were sent to 636 contacts; 74 surveys were opened and 54 were completed, representing an 8.5% completion rate.

Nearly 70% (n=37) indicated that their position directly involved precision medicine. Respondents were employed in their current role an average of 6.6 years and primarily worked in research and development (28%) or clinical departments (20%). Other respondents worked in medical affairs (16%), biomarkers (12%), or other functions (24%).

Key CRO services and capabilities
Based on the findings from the survey and interviews a list of key CRO services and capabilities in the field of precision medicine was developed. Six areas were identified consisting of access to and interpretation of data, statistics and modeling, clinical development and operations, companion/ complementary diagnostics, collaboration and partnerships, and patient engagement (Table 1).

Access to and interpretation of data was associated with the context of real world data, patient databases, and data as currency in which an organization derives value from data. Real world data, when matched with publicly available data, was seen as essential to genomic research. Respondents revealed that searchable patient databases that recorded specific biomarker information were beneficial to patient recruitment. Finally, data handling and secure transferring were seen as top challenges in the future.

Statistics and modeling was identified as a growth area. Quantum computing and statistical modeling and simulation of clinical trials were the primary areas of development.

Clinical development and operations was discussed in a number of applications including clinical and genomic strategy, operational planning and complexity, and protocol design. These were seen as areas where CROs are already devoting time and resources, but where adapting these techniques to precision trials would require additional investment.

Companion and complementary diagnostics were identified as areas where too few CROs are providing services. These focused on research into the need for a diagnostic test in a trial, diagnostic development and validation, and regulatory support for trials involving diagnostics.

Collaborations and partnerships were incorporated into some organizational strategies.  CROs with this business model typically acquire organizations with existing capabilities rather than developing capabilities in-house. Others reported using collaborations and partnerships with biomarker labs and sites, for example, to gather the necessary expertise to support precision medicine.

Patient engagement was viewed as an improvement area for CROs. Precision trials require a very specific set of patients, so recruitment issues were a concern. In addition, patient access to data was identified as an area of future contention between patient advocacy groups and sponsors.

Service area evaluation results
From the six capability areas, a list of services that adequately covered precision offerings was developed incorporating the survey results and published data. Technology was a seventh area included given its overall relevance to the practice of precision medicine (Table 2). Technology focused on concepts and techniques commonly associated with precision medicine.

Company websites and other published information from 47 CROs were used to determine the prevalence of service area offerings in the overall CRO market. Tufts CSDD then developed a visual display of an estimate of overall market service area capabilities, grading each area as a proportion of the companies in the sample offering these services (Table 3). Capability scores were assessed by company size—small, mid-sized and large—and graded on the level of maturity in the industry—nascent, established or strong.

Overall, the assessment uncovered vast differences in CRO service area offerings despite supporting research in all areas. Two areas, however, received nascent ratings: statistics and modeling, and collaboration and partnerships. These services and strategies were found in only 12.5%-37.4% of the total companies evaluated. Access to and interpretation of data, companion/complementary diagnostics, patient engagement, and technology were all rated “established” and for 37.5%-62.4% of the companies sampled. Clinical development and operations was the only category that received a “strong” rating, indicating the presence of these services among 62.5%-87.4% of the companies assessed. No service area had complete coverage of all areas identified.

Large CROs were the most diversified and received “strong” ratings in nearly all areas except collaboration and partnerships. Mid-sized CROs scored strong in some areas but nascent in others and the only group with a “complete” assessment within clinical development and operations. They were “strong” in terms of their technology offerings, “established” in statistics and modeling and patient engagement, and “nascent” in access to and interpretation of data, companion/complementary diagnostics, and collaboration and partnerships. Small CROs lagged in the most areas and received a “strong” rating only in clinical development and operations, “established” ratings in patient engagement and technology, and were “nascent” in three areas: access to and interpretation of data, statistics and modeling, companion/complementary diagnostics, and collaboration and partnerships.

CRO precision medicine preparedness
Both interviewees and survey respondents were asked for their perceptions on their organization’s precision medicine competitiveness. They were also asked for their company’s precision medicine preparedness and overall industry preparedness to support precision medicine. The majority of survey respondents perceived that their company was competitive rather than market leading or market lagging, while most interviewees thought their company was market leading. More than half of survey respondents (52%, N=15) believed that they offered competitive solutions, while 28% (N=8) indicated that they were leading and 21% (N=6) reported that they were lagging. Two of four interviewees thought that their organization was market leading, one indicated that it was competitive and one that they were market lagging (Figure 1). 

The majority of survey respondents reported that their company was “not at all prepared” (5/13) to support precision medicine. This finding contrasts with their perceptions about the industry overall, with the majority believing that it is “somewhat prepared” (7/13) (Figure 2). Interviewees, however, rated their companies and the overall industry’s preparedness—on a scale from 1-5)—with average company preparedness a 4/5 and average industry preparedness a 2.9/5. This result most likely reflects the differences in company size and type across the methodology. All interviewees belonged to large CROs while most survey respondents belonged to either small or large companies other than CROs (Figure 3).

Discussion
The findings of this study regarding CRO preparedness are mixed. However, one of the strongest areas for CRO services are clinical development and operations. Given a traditional customer and operational focus, CROs have been able to leverage their expertise in this area.  Gaps in service offerings were found within collaboration and partnerships, statistics and modeling and companion/complementary diagnostics. CROs are continually exploring new partnerships, while statistics and modeling continue to be niche areas. Companion and complementary diagnostics are typically dominated by large companies. Lastly, CROs have made major investments in the following areas: patient engagement, access to and interpretation of data, and technology. Investments in real world data and evidence and using technology to expand such areas are recognized by CROs as critical areas to inform drug development. Also, as organizations become more patient focused, the industry is seeing more investment in areas that capture patient insights and data. Top CROs are consistently the strongest investors given their financial capital and resources and potentially have the greatest strategic advantages within the field of precision medicine.

The study also suggested that sponsors perceive that their core competencies outweigh CRO service offerings and are therefore investing in growing their internal capabilities in precision medicine. The perceptions from CRO staff are that sponsor investment is hindering CRO precision medicine growth and prevents these organizations from building capacity. However, large CROs have the capital and resources to invest in multiple areas and are subsequently able to bolster their capacity.
As a result, small and mid-sized CROs do not seem to be making greater investments even though they perceive the market is ‘somewhat prepared.’

Another finding from this study is that CROs do not offer services throughout the entire value chain, from discovery through clinical trials to licensing and post approval marketing and sales. Additionally, CROs encounter a number of hurdles in the growth of companion and complementary diagnostics, including the changing regulatory space, the evolving use of real world data and evidence, and the strategies and approaches CROs adopt to leverage information to drive the science. Other areas such as late or delayed decision-making or the timing of decisions come into play and can limit development. Moving forward, CROs will need precision medicine capabilities given the growth in the number of smaller sponsor companies and industry downsizing resulting in increasing in outsourcing demand.

The limitations of the study include a low survey response and interviews limited to executives from large CROs. These areas warrant future research and could potentially involve broadening the survey reach and conducting interviews to include representatives from small and mid-sized companies, as well as stratifying the overall results by global region. In addition, re-examining the service areas to assess any changes over time by area or capabilities could also be included in future studies. 

References

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Table 2

Table 3

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FIGURE 2

FIGURE 3