ENGAGING PATIENTS FOR CLINICAL RESEARCH

CLINICAL RESEARCH AND PATIENT ENGAGEMENT IN PERSONALIZED MEDICINE

It is largely accepted now that we are in the midst of a major transformation in drug discovery, clinical development and clinical care, one that has the potential to deliver substantial health, social and economic benefi ts.

By integrating molecular information with an individual’s medical or personal information, personalized medicine (PM) is a key factor in this transformation. Innovations like Pfi zer’s Xalkori, Roche’s Zelboraf, and Vertex’s Kalydeco demonstrate the types of impacts that this transformation provides.

PM can shorten approval times and speed drugs to market. For example, Zelboraf and the companion BRAF V600E test were approved ahead of their goal dates, and the FDA PMA review was less than four months compared to the standard of nine to 18 months. Xalkori was on the market only four years after the discovery of its target and companion diagnostic (ALK) and reviewed and approved by the FDA in less than fi ve months. Furthermore, these drugs have been welcomed by patients, physicians and payors, despite their high cost. They have also provided unprecedented advances in treating two deadly cancers, metastatic melanoma (Zelboraf) and non-small cell lung cancer (Xalkori).

Developing drugs that target small populations in partnership with patient organizations can be a recipe for success in PM. Kalydeco, launched late in 2012, proved effective in individuals who carry a G551D mutation in cystic fi brosis (CF) gene, which accounts for only four to fi ve per cent of CF cases. Although the CF gene was discovered in 1989, by a team that included Lap-Chee Tsui from Toronto’s Hospital for Sick Children and Francis Collins (now director of the NHI and a prominent advocate for PM), Kalydeco is the fi rst drug to target the defects caused by mutations in the CF gene. The early development of the cystic fi brosis drug Kalydeco by Vertex was funded and supported by the CF Foundation in exchange for a royalty on future sales.1 This was critical for the success of Kalydeco and has set a model for similar partnerships between other foundations/patient groups and drug developers.

In all of this, what is the role of patients, or even the general public? How can they participate in this transformation? What contributions can patients make to accelerate progress?

Co-creating value with patients, healthcare consumers, tapping into their knowledge of disease and healthcare, is increasingly a potential driver of clinical innovation. In

the digitized world, individuals have an unprecedented capacity to create, share and manage valuable personal data.2

Online communities of patients with a ‘Citizen Science’ research objective are beginning to demonstrate the benefi ts of engaging patients more broadly (see Figure 1 for examples).

The examples in Figure 1 rely on an interactive IT interface to engage, communicate and share with participants. The success and growth of this new paradigm refl ects important changes in attitudes toward privacy, individual involvement and the value of broader patient participation in research.16 Engaging patients through an interactive IT interface, where the patient has a level of data control, allows for new types of interactions and more effective mobilization of knowledge between patients and researchers, faster recruitment of participants and longitudinal research. This approach can streamline consent and reduce the need for anonymized data while facilitating patient participation. This type of engagement transforms research subjects into research partners through matching, dynamic negotiation and citizen science.17

High content clinical research addresses real-world clinical problems defi ned by patient experience and knowledge. It requires biological samples provided by patients and clinical outcomes data measured based on patient experiences. Patient recruitment is a time consuming and expensive part of most clinical studies and widely recognized as a barrier to translational research in PM. In contrast, patients have traditionally been engaged largely as a donor or a subject, not as a participant. They are often hesitant to act as a ‘research subject’ and may feel not well informed as to the objectives, outcomes and impacts of the study to which they will contribute. Patients are in fact the most important contributor to clinical research. Unfortunately, less than fi ve per cent of Canadians participate.

Robust, diverse patient registries and detailed patient data are needed for innovation in PM. We now know that different diseases often share molecular features; registries and information that enable crossdisease studies, such as Reg4all, are likely to be fundamental going forward. To date patient groups have been instrumental in creating disease registries and biobanks. Patient groups are a trusted source patient information and have a direct and altruistic relationship with patients and can act to mediate and enable patient participation and facilitate researchers’ access to patient data and registries. As in the Kalydeco example, foundations associated with patient groups can effectively partner with companies to accelerate progress. For these reasons, patient groups are well positioned to capture and mobilize patient knowledge, create resources for research and interact with various stakeholders, while representing the best interests of patients. Considering the potential public benefi ts, it is unfortunate how little funding and support patient groups receive from federal and provincial governmental bodies.

Another area where patient engagement can enable progress is in real-world research. Demonstrating the clinical utility and value of PM products in real-world practice is essential for realizing key elements of the PM paradigm - improved outcomes, fewer adverse reactions and cost-effectiveness. Traditional Randomized Controlled Trials (RCTs) often do not accurately refl ect or inform real-world use where the population treated is more heterogeneous and practice is less controlled. This is particularly the case for PM as narrower populations are targeted and interventions comprise patient stratifi cation/molecular testing and a treatment steps.

Post-approval research is increasingly mandated by regulatory agencies. Adaptive licensing and early access programs are more and more common; allowing earlier patient access to innovations in highly defi ned populations while requiring a continuous stream of realworld data to inform licensing extensions.18 Pharmaceutical companies’ interests and investments in this area are also increasing and in fact pharmaceutical companies often work closely with patient groups to execute real-world studies. However, better collaboration, interactions and alignment of incentives between health care systems, research institutions, patient groups and companies in this area could help to make the most of these investments/studies and maximize the benefi ts for all concerned.

Real-world studies including: market access, pharmacoeconomic, comparative

Figure 1:

PatientsLikeMe3 23&Me5 The Genetic Alliance13 CuraRata15

• provides a robust method for patients to record and share data online • engaged a community of 190,000 patients covering more than 1,000 conditions • performs observational studies to assess the real-world effectiveness of treatments • one observational study provided the same conclusion as a clinical trial ongoing in parallel4 (with much less time and expense) • showing how this approach compliments clinical trials • controversial operations as a direct to consumer genetic testing company • created a cohort of more than 100,000 participants for genetic research (probably the largest in the world) • numerous research contributions6 and peer-reviewed publica-

tions7,8,9,10,11

• developing and validating methods and best practices for ‘Citizen

Science’12 • in partnership with fi ve US patient groups launched Registries for

All Diseases (Reg4ALL)14 a crowd-sourced crossdisease registry • allows patients to contribute personal data, control access to these data and engage directly with clinical researchers • uses privacy and online consent methods that are fully compliant with U.S. laws and regulation • Reg4ALL aims to reach over 9,000 research organizations and 1,200 disease advocacy groups • a data-sharing partnership between eight hospitals in the

Netherlands • partners pool clinical information and biomaterials for research • provides an online interface for patient to access and manage their health care data and preferences for data sharing • supports dynamic negotiation between researchers and participants

effectiveness and implementation studies can uncover unmet medical needs, burden of disease, optimal clinical decision making and treatment practices as and best practices for health care system implementation. In this way, it provides a rich source of information for pre-clinical research and health services research, can enable patient access and guide the adoption of new practices by physicians and health care systems. Clearly better integration of real-world studies with publically funded research efforts could have a major positive impact. Again, patients and patient groups could play a key role in this type of integration.

Patient and patient groups should be systematically engaged in: • Setting priorities for research, • Collecting patient reported data, • Bridging patient populations nationally and internationally, • Engaging and pre-characterizing potential participants, • Defining patient populations and capturing longitudinal data, • Developing patient-centric outcomes measure, and • Mediating or facilitating the recruitment and participation of individuals.

There are numerous examples of this type of approach developing internationally including CuraRata and Reg4All mentioned above. Additionally, in the UK, the Clinical Practice Datalink19 has been launched to support sharing anonymous National Health Service (NHS) patient data with private healthcare firms, enabling all patients to become research participants and accelerating innovation. In Canada, the BC Health Agency launched an initiative called ‘Patients as Partners’ in 2008.20 This initiative aims to increase patients’ engagement in their own health care as well as in system design and research. As part of this project a network of BC patients was created and a measurement strategy for patient engagement with the health care system was created.

The role of patients, their contributions and participation in clinical research are rapidly increasing and evolving with the shift toward PM. However, we have a long way to go before the participation of patients in clinical research can be fully harnessed and its benefits realized. To start with, we need to educate the stakeholders (including patients and the public) as well as build strategies, networks, resources and tools for patient engagement, stakeholder interactions and information sharing. At Cepmed, we are eager to create and participate in initiatives that can address these needs and promote patient engagement in clinical research in Canada.

References:

1. http://www.forbes.com/sites/matthewherper/2012/12/27/the-mostimportant-new-drug-of-2012/ 2. FORA. New nature of innovation: understanding policy implications of new forms of innovation. Copenhagen: FORA, 2009. 3. www.patientslikeme.com 4. Wicks, P., Vaughan, T., Massagli, M. & Heywood, J. Accelerated clinical discovery using self-reported patient data collected online and a patient-matching algorithm.

Nature biotechnology 29, 411–4 (2011). 5. https://www.23andme.com/ 6. http://blog.23andme.com/articles/ 7. Eriksson, N. et al. Genetic variants associated with breast size also influence breast cancer risk. BMC medical genetics 13, 53

(2011). Henn, B. et al. Cryptic distant relatives are common in both isolated and cosmopolitan genetic samples. PloS one 7, e34267 (2011). Eriksson, N. et al. Novel associations for hypothyroidism include known autoimmune risk loci. PloS one 7, e34442 (2011). Eriksson, N. et al. Webbased, participant-driven studies yield novel genetic 8. Lill, C. M., et al. “23andMe Genetic

Epidemiology of Parkinson’s Disease

Consortium; International Parkinson’s

Disease Genomics Consortium; Parkinson’s Disease GWAS Consortium; Wellcome Trust Case Control Consortium 2.

Comprehensive research synopsis and systematic meta-analyses in Parkinson’s disease genetics: the PDGene database.”

PLoS Genet 8.3 (2012): e1002548. 9. Kiefer, A. et al. Genome-wide analysis points to roles for extracellular matrix remodeling, the visual cycle, and neuronal development in myopia. PLoS genetics 9, e1003299 (2013). 10. Do, C., Hinds, D., Francke, U. & Eriksson,

N. Comparison of family history and SNPs for predicting risk of complex disease.

PLoS genetics 8, e1002973 (2011). 11. Eriksson, N. et al. Novel associations for hypothyroidism include known autoimmune risk loci. PloS one 7, e34442 (2011). 12. Eriksson, N. et al. Web-based, participantdriven studies yield novel genetic associations for common traits. PLoS genetics 6, e1000993 (2010). 13. http://www.geneticalliance.org/ 14. www.reg4all.org/ 15. http://www.curarata.nl/uk/3/patients/ home.html 16. Kaye, J. et al. From patients to partners: participant-centric initiatives in biomedical research. Nature reviews. Genetics 13, 371–6 (2012). 17. Kaye, J. et al. From patients to partners: participant-centric initiatives in biomedical research. Nature reviews. Genetics 13, 371–6 (2012). 18. Eichler H-G et al. Adaptive Licensing:

Taking the Next Step in the Evolution of

Drug Approval, Clinical Pharmacology & Therapeutics (2012); 91 3, 426–437. doi:10.1038/clpt.2011.345 19. http://www.cprd.com/intro.asp 20. http://www.impactbc.ca/patientsas-partners

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