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As the popularity of personalized medicine grows the role of the CRO continues to evolve.
Personalized medicine is the tailoring of medical treatment to a specific subset of patients who are usually identified by genetic markers or other molecular profiling strategies. There is an increasing interest in this therapeutic strategy on the part of pharmaceutical and bio-pharmaceutical companies, consumers, and third-party payers. Consequently, the level of clinical trial activity surrounding personalized medicines is intensifying as sponsors seek ways to target their therapies to patient populations that would most benefit from them. The personalized medicine landscape, however, is still evolving. While some pharmaceutical and biotechnology companies are currently exploring this field, others may lack the expertise or the inclination to do so. Fortunately, clinical research organizations (CROs) can provide valuable assistance in this area. This article will discuss the rationale and scientific basis for personalized medicine, while also providing an overview of some of the services CROs can provide in assisting sponsors of personalized medicine clinical trials.
The growing interest in personalized medicine has been driven by major advancements over the past decade or so in genomics (including toxicogenomics), proteomics, imaging, and diagnostics (predictive/prognostic testing). These advances have spurred efforts within pharmaceutical and biotechnology companies to prospectively identify and develop medicines that are designed to work in individual patients based on their genetic makeup and the specific molecular characteristics of their disease.
Expanded efforts to develop medicines aimed at discrete groups of patients appear to be particularly timely, given that an estimated 55 percent of drugs consumed in the United States—including as many as 80 percent of approved anticancer therapies—are thought to be ineffective in the patients who receive them.1 The estimated annual cost for such unwarranted or "wasted" care ranges from $250 billion to $325 billion.2
The personalization of therapeutics is being driven by an enhanced understanding of how human genetic variation affects an individual's response to treatment. As described in a recent report from Business Insights Ltd.,3 this understanding largely results from the advent of sophisticated genomics capabilities and the expanding use of biobanks that allow researchers to link data from genetic studies to disease outcomes. Recent advances in genomics have facilitated the development of predictive tests that stratify patients by response to therapy, usually by identifying patients who have the best chance to benefit from a particular treatment or who may be prone to particularly toxic effects of a treatment. An example of the former is the human epidermal growth factor receptor-2 (HER2) gene, which is amplified in roughly 25 percent of breast cancers and predicts a particularly poor prognosis in untreated patients. By developing predictive testing for HER2, scientists can identify patients who are most likely to respond to targeted therapy. Predictive testing for HER2 led to development of Genentech's Herceptin® (trastuzumab), a monoclonal antibody targeted specifically to breast cancer cells that overexpress HER2, but which does not produce a response in tumors that do not overexpress HER2. Predictive tests for additional genetic biomarkers (e.g., BCR/ABL tyrosine kinase, PML/RAR alpha fusion protein, and EGFR/KRAS) have been similarly co-developed with other targeted anticancer therapies, such as Novartis' Gleevec® (imatinib mesylate), Bristol-Myers Squibb's Sprycel® (dasatinib), Cephalon's Trisenox® (arsenic trioxide), AstraZeneca's Iressa® (gefitinib), ImClone's Erbitux® (cetuximab), and Amgen's Vectibix® (panitumumab).
Another application of personalized medicine is the development of prognostic tests that stratify patients by disease outcome to guide clinical decision-making. As with predictive tests, the use of prognostic tests has thus far been mostly limited to the oncology setting. Recent examples include Genomic Health's Oncotype DX® 21-gene breast cancer assay and Agendia's MammaPrint® assay, both of which predict the risk of disease recurrence in certain women with early-stage, node-negative breast cancer.3
Advances in genomics have also given rise to toxicogenomic testing, which identifies patients who may experience treatment-related adverse events due to hypersensitivity reactions or variations in metabolism. Myriad Genetics' TheraGuide® 5-FU test, which predicts toxicity to the chemotherapeutic agents fluorouracil and capecitabine, is a notable example in oncology.3 Toxicogenomic information can also inform clinical decision-making in other disease areas. For example, patients with glucose-6-phosphate dehydrogenase deficiency are at an elevated risk of toxicity and can be counseled to avoid anti-malarial drugs, certain analgesics, and some non-sulfa antibiotics.4 Another example is that of irinotecan (Camptosar®, Pfizer) and the UGT1A1*28 allele. Patients who are homozygous for this allele are at increased risk for neutropenia.
In some cases, pharmacogenetic or toxicogenomic information is incorporated into product labeling, as has been done recently for Bristol-Myers Squibb/Sanofi Pharmaceuticals partnership's Plavix® (clopidogrel), the label of which warns of an increased risk of cardiovascular events in patients who have mutations in CYP2C19, the enzyme that converts Plavix into its active metabolite.3 Tests are now available to determine a patient's CYP2C19 genotype and to directly assess platelet function in treated patients.5
Despite the early successes of personalized medicine, its incorporation into routine clinical practice has been slow, and its scientific basis does not currently impact the care of the vast majority of patients. The adoption of personalized medicine has been hampered by the lack of reimbursement for many genomic-based tests, the dearth of targeted therapies in companies' development pipelines, and few examples of clinical benefit from identification of novel biomarkers.3 Proponents of personalized medicine would thus do well to demonstrate its promise in terms of return on investment (ROI).6 Consumers can theoretically reap an almost immediate ROI in personalized medicine due to a decrease in adverse events (based on avoidance of unnecessary treatment) and the potential for enhanced therapeutic response. Although consumers may end up paying more for personalized treatments in the short term, they may enjoy a longer-term benefit based upon improved quality of life and decreased mortality. For biotechnology companies, it is likely that continued advances in personalized medicine will shift the industry paradigm away from blockbuster products to one of "more therapies, smaller markets." Companies that enter the personalized medicines market early can potentially earn significant ROI as traditional therapies are replaced by highly effective targeted treatments. Companies can also increase their ROI through enhanced patient recruitment and streamlined R&D processes that make drug development less costly, in particular by shortening the time to drug approval. Application of the principles of personalized medicine may be particularly valuable in early-phase drug development, as it can allow companies to more quickly identify whether a drug will or will not work in certain populations (e.g., proof of concept studies), thereby facilitating later-stage "go/no-go" decisions. On the other hand, companies that are slower to adopt personalized medicine may find it more difficult to gain share when they do enter the market. While some companies may not feel there are adequate returns to pursue personalized medicine, choosing instead to focus on more broadly targeted therapies, they may miss the opportunity to increase their potential patient base by developing a suite of personalized medicines with enhanced efficacy, safety, and adherence.
Signaling its support of the concept of personalized medicine, the US government has made development and use of personalized medicine a high priority in its efforts to reform the nation's healthcare system and reduce healthcare-related costs. In a recent commentary in The New England Journal of Medicine,7 FDA Commissioner Margaret A. Hamburg and National Institutes of Health Director Francis S. Collins describe how their respective institutions are working together to "develop a more integrated pathway that connects all the steps between the identification of a potential therapeutic target and the approval of a therapy for clinical use." They liken these efforts to building "a national highway system for personalized medicine, with substantial investments in infrastructure and standards."
To use Hamburg and Collins's metaphor, the personalized medicine highway is still under construction. As noted at the beginning of this article, while some biopharmaceutical companies may be inclined to explore it, navigating the highway remains a significant challenge for many. That is largely due to the lack of adequately designed studies to assess the clinical utility of genomic testing and other personalized approaches.8 Fortunately, CROs are well-equipped to provide sponsors with a viable navigation system for the design, conduct, and coordination of personalized medicine clinical trials.
For pharmaceutical and biotechnology companies, outsourcing clinical trials to CROs can yield significant financial and human resource benefits. According to the Tufts Center for the Study of Drug Development, working with CROs has enabled companies to keep R&D head counts stable over the last decade even as the number of active clinical projects around the world increased by 80 percent. Moreover, trials managed by CROs are, on average, completed 30 percent sooner than those conducted in-house, providing an average time-savings of four to five months.9
Specifically, CROs offer a variety of services that may benefit companies developing personalized medicines. Although some or all of these services can be provided by the sponsoring companies themselves, many sponsors recognize that their core competencies lie elsewhere and choose to delegate these responsibilities to organizations that specialize in the processes and logistics of managing clinical trials:
Protocol design. A number of CROs employ physicians and statisticians with extensive experience in protocol design, including knowledge of genomic tests and expertise in adaptive study design and related strategies that may be important in the design and interpretation of specialized trials of personalized medicines.
Patient identification/recruitment. Difficulties in patient enrollment contribute to delays in most clinical trials, thereby increasing trial costs. CROs, with their access to investigator and, in some instances patient databases, can use analytic techniques to screen large numbers of electronic records to help sponsors identify potential candidates for personalized therapies, based on certain diagnostic criteria. Such capabilities can expedite trial initiation and reduce the costs of patient recruitment. In a recent survey of 84 sponsor companies, Cutting Edge Information concluded that CROs can determine the likelihood of strong recruitment by using tools such as dedicated patient recruitment groups and databases with site-specific demographic information.10
Biomarker identification/validation. Some CROs can provide assistance in identifying and validating biomarkers that are correlated with therapeutic response, resistance, and toxicity. This knowledge can be leveraged in both preclinical and clinical testing of drug candidates.
Diagnostic co-development. The Accumetrics VerifyNow® test for platelet function5 is an example of a diagnostic test that can be paired with a specific agent. Many CROs have experience in and can assist companies in designing and executing trials for diagnostic tests that are being developed along with drug compounds.
Regulatory support. Regulations that address the testing and eventual approval of personalized medicine have lagged behind the rapidly developing science. The co-development of companion diagnostics and the use of biomarkers in early and perhaps later-phase testing are examples of topics that should be addressed with the FDA and other regulatory agencies. In addition, and under circumstances defined by FDA, the agency is open to receiving and discussing pharmacogenomic information as it may relate to a drug under development separate from the product review process itself. A number of CROs have sophisticated regulatory affairs departments that can facilitate productive interactions between sponsors and government agencies on various topics, including the evolving personalized medicine landscape.
Data Monitoring Committees (DMCs). With their ties to experts in a wide range of medical and scientific disciplines, CROs can facilitate assembly of DMCs, provide guidance on the development of DMC charters, and provide unblinded staff support to these committees.
Biospecimen storage. Biobanks, which collect and store human biospecimens (e.g., whole organs, tissue, blood, plasma, and urine, as well as DNA and RNA), play an important role in personalized medicine, as they facilitate testing of medicinal compounds on preserved samples. Not many small pharmaceutical or biotech companies have their own biobanks. Furthermore, storage of biologic samples is deceivingly complex and must take into account the collection, transportation, storage (under a variety of different and tightly monitored thermal conditions), and reliable retrieval of such samples. Some full-service CROs and a number of stand-alone facilities can provide this critical service.
While CROs can offer the above array of services a la carte to clients or integrate them for individual trials, many national and international CROs are well-positioned to provide these services as an integrated package for an entire development program. Combining regulatory and medical/scientific expertise and follow-through and having a single dataset can be a big advantage to expediting a development program. Securing the services of a single CRO for the entire development program can also foster more expeditious biomarker identification/validation and diagnostic testing co-development, which generally occur throughout the development program.
Furthermore, CROs, with their broad clinical and regulatory development experience and expertise across numerous therapeutic areas, are in an excellent position to offer strategic regulatory and clinical program development advice at the earliest stages of development planning. This process could begin as early as the IND-consideration stage.
There are many CROs and identifying the right one can be a challenge for sponsors. CROs are generally classified by size, national/international, therapeutic focus, and overall capabilities. Most large CROs offer a broad array of therapeutic expertise and are full-service as well as international in operations. These CROs can often provide the best "one-stop shopping," especially for consideration of full development program outsourcing. CROs, in general, are always willing to provide potential clients with a capability presentation at no cost to the sponsor and to provide proposals/bids for solicited work. Choosing the right CRO then becomes a matter of personal preference, comfort "fit," CRO capabilities/history, and cost.
The promise of personalized medicine can potentially open up vast horizons for patients and industry alike. By providing their specialized expertise in conducting clinical trials, as well as critical expertise throughout all stages of the drug development process, CROs can help developers of personalized medicines, and the patients who would benefit from them, reach these goals.
Thomas J. Newman,* MD, is President, e-mail: [email protected], and Jeffrey J. Freitag, MD, FACP, is Chief Medical Officer, PharmaNet Development Group, Inc., 504 Carnegie Center, Princeton, NJ.
1. C. Mintz, "What's Next? (The Answer May Surprise You)," Life Science Leader, June 2009, http://www.lifescienceleader.com/index.php?option=com_jambozine&layout=article&view=page&aid=3827&Itemid=68.
2. L. Henderson, "Personalized Medicine For Now and the Future," Applied Clinical Trials, June 1, 2010, http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/News/Personalized-Medicine-for-Now-and-the-Future/ArticleStandard/Article/detail/671477?contextCategoryId=3300.
3. S. Falkingbridge, "Expanding Applications of Personalized Medicine: Use of Biomarkers in Prognostic, Predictive, and Pharmacogenetic Tests in a Targeted Approach," (Business Insights Ltd, London, 2009).
4. Wikipedia, "Glucose-6-phosphate Dehydrogenase Deficiency," (2010), http://en.wikipedia.org/wiki/Glucose-6-phosphate_dehydrogenase_deficiency.
5. VerifyNow® System, "P2Y12 Inhibitors: Plavix® (Clopidogrel), Effient® (Prasugrel), Ticlid® (Ticlopidine)," Accumetrics, Inc., (2011), http://www.accumetrics.com/products/verifynow-p2y12/p2y12-inhibitors/.
6. "The ROI for Targeted Therapies: A Strategic Perspective: Assessing the Barriers and Incentives for Adopting Personalized Medicine," Deloitte Center for Health Solutions, (Washington, DC, 2009), http://www.deloitte.com/assets/Dcom-UnitedStates/Local%20Assets/Documents/us_chs_ROIforTargetedTherapies_January2009%281%29.pdf.
7. M. A. Hamburg and F. S. Collins, "The Path to Personalized Medicine," New England Journal of Medicine, 363 (4) 301-304 (2010).
8. A. M. Garber and S. R. Tunis, "Does Comparative-Effectiveness Research Threaten Personalized Medicine?" New England Journal of Medicine, 360 (19) 1925-1927 (2009).
9. E. Lipp, "CRO Relationships Get More Serious: Pharma Downsizing Results in Increased Reliance on Outsourcing Partners," Genetic Engineering & Biotechnology News, July 1, 2010, http://www.genengnews.com/gen-articles/cro-relationships-get-more-serious/3346/?page=1.
10. N. Taylor, "Strategic Partnerships with CROs Key to Patient Recruitment," Outsourcing-Pharma.com, August 31, 2010, http://www.outsourcing-pharma.com/Clinical-Development/Strategic-partnerships-with-CROs-key-to-patient-recruitment.