Implementing Patient-Centric Strategies in a Natural History Trial: A Case Study
San Diego Clinical Research Network and Greater San Diego Chapter of ACRP
June 21, 2016
Contributed Blog by Roberta Alexander, Ph.D.
The San Diego Clinical Research Network (SDCRN) (Clinical Research News, Developments, Resources & More) and the San Diego Chapter of the Association of Clinical Research Professionals (ACRP) (http://www.acrpnet.org/) co-organized an event on June 21st, 2016 at the Scripps Green Hospital in San Diego to discuss patient-centric strategies in clinical research.
The speaker was Jacqui Blem, Senior Director of Clinical Operations at Regulus Therapeutics (http://regulusrx.com/).
Regulus’s technology focuses on microRNA, which are short, non-coding RNA sequences which interfere with RNA translation and, ultimately, regulate protein synthesis. Regulus’s approach aims at modulating the function of microRNAs that are altered in human disease; this technology may be helpful in treating diseases caused by abnormal gene expression. Regulus has several clinical programs in hepatitis C and in Alport Syndrome. Jacqui shared with the audience her experience in conducting a natural history study in Alport syndrome, highlighting the patient-centricity of the study.
What is Alport Syndrome?
Alport Syndrome is an orphan genetic disease affecting approximately 5,000 patients in the USA. Three mutations in the gene that codes for collagen type IV have been identified in these patients. The disease manifests itself at a very early age with kidney disease, hematuria and proteinuria and, eventually, end-stage renal disease (ESRD). Dialysis and kidney transplant are common in Alport Syndrome patients in their 20s and 30s. Hearing loss and eye disease occur early in life as well. The disease is usually diagnosed by pediatric nephrologists; however, diagnosis is difficult – especially if no family history exists – because of the low incidence and slow progression of the disease. Regulus is developing a microRNA therapy for Alport Syndrome, RG012, which gained orphan drug designation by the FDA and the EMeA. Given the rarity of the disease and the paucity of clinical trials, Regulus recognized the importance of better understanding the disease and its progression before testing RG012; this led to the initiation of the natural history study which was the focal point of Jacqui’s talk.
What is a natural history study?
A natural history study, as the name suggests, is designed to study the history of a disease. It is not an interventional study and there is no investigational treatment administered to the patient. Rather, patient visits are conducted to measure clinical parameters and biomarkers over time. The study Regulus is carrying out follows patients with Alport Syndrome every 12 weeks for a period of 2 years; kidney function is measured over time, and biomarkers are measured to better understand the disease and the possible response to therapy.
How do you make this natural history study patient-centric?
Especially when working on orphan diseases, you need to put the patient at the center of your activities, because there are not many patients to begin with. The first hurdle in a study like this is, indeed, patient recruitment. To increase patient participation, Regulus tried to make the study visits as easy as possible for the patient.
Regulus has 15 sites all over the globe to recruit just 150 patients, and is working closely with the Alport Syndrome Foundation to promote awareness via social media and other outlets. Flexibility of diagnosis is important for proper recruitment in an orphan study: although Alport Syndrome is a genetic disease that can be diagnosed with a genetic test, Regulus allows also the inclusion of patients diagnosed clinically or because of disease history. They also offer free genetic testing – which may not be covered by insurance in the USA – to the participants! Although recruitment challenges are to be expected, the global nature of this study posed additional, unexpected, challenges.
Regulus decided to have frequent visits (12 weeks is a short period of time, especially for a slow progressing disease…) and measure glomerular filtration rate, which is a lengthy and cumbersome test: this can be quite an inconvenience for many patients! On the other hand, the 24 hour urine collection turned out not to be a big challenge: patients were given nice insulated backpacks to carry their urine from home to hospital, and they did not mind it!
Because there are only a few specialized centers for Alport Syndrome, in-person visits every 12 weeks are inconvenient, time consuming, and costly for most patients. The cost issue was solved by Regulus reimbursing the patients and their caregivers for travel expenses. Payments and travel arrangements are done by an independent agency to safeguard patient privacy and comply with HIPAA regulations. Different countries have different rules for patient reimbursement, which creates a challenge in a global study; in addition, in some countries, debit cards are widely used, while in others, they are not, adding to the difficulty of the reimbursement program.
To increase compliance and decrease travel, Regulus implemented a home nursing system via a global company. Nurses visit patients at home, perform routine test and physical exams, as well as collect clinical information.
This program did, however, present some challenges. For example, China does not have a home nursing service; thus, Chinese patients need to live relatively close to the site if they wish to participate in the study. In some countries, nurses cannot perform what in the USA is called a physical exam, so the study terminology needed to be changed. In other countries, nurses cannot manipulate dry ice; an arrangement with a courier had to be put in place to circumvent this problem. One key opinion leader did not want their patients to be visited at home by an outside nurse, while a certain hospital wanted to use their own nursing service instead of the global service contracted by Regulus.
Challenges notwithstanding, the study is going well, and the Alport Syndrome patients are excited to participate in a study that furthers the knowledge and understanding of their disease. For us, listening to Jacqui was definitively a great learning experience, and we look forward to the other activities organized by SDCRN and ACRP!
May 9, 2016
San Diego Clinical Research Network + San Diego Regulatory Affairs Network
Clinical Trials in the Future. How Mobile Technologies and Telemedicine are Transforming Clinical Research
Report by Roberta Alexander, Ph.D.
San Diego Clinical Research Network (SDCRN) and San Diego Regulatory Affairs Network (SDRAN) came together to discuss ways to utilize telemedicine and mobile technologies in clinical research. The speakers were Kevin Bruhn, Ph.D., VP Strategic Development at Science 37, and Kim Tyrrell-Knott, Partner, Epstein, Becker & Green Law Firm. The event was moderated by Brad Pruitt, M.D., Executive Director and Chief Medical Officer, Parallel 6, and took place at BD (formerly Carefusion) in San Diego. Many members of SDCRN and SDRAN attended, in addition to others interested in clinical research and digital medicine.
Unlocking Access: How Mobile Technology Accelerates Discovery
Kevin Bruhn, VP, Strategic Development, Science 37
Science 37 was the winner of The Most Disruptive Innovation in Clinical Trials award by dPharm in 2015, and Clinical Informatics News Best Practices Award in 2016. Their CEO and Co-Founder, Noah Craft, M.D., Ph.D., was recently named as one of the top 40 healthcare transformers.
It is definitively an exciting time to use mobile technology in clinical research to reach more patients and keep them engaged. In fact, although 90% of patients say that they would like to participate in a clinical trial, only 3% actually do. Many patients live too far away from a site, don’t know that a study is even going on, or maybe they lack trust and education about clinical research. Patient recruitment suffers, and time and costs go up.
It takes 6 to 9 years to do the necessary trials to get a new drug approved, and clinical trials account for approximately 40% of the total budget of drug development. In addition, lengthy clinical studies leave less and less time for patent protection.
Science 37 aims to streamline clinical trials by decentralizing them and facilitating virtual interactions between the patient and the investigator. Science 37 uses a unique platform called NORA (Network Oriented Research Assistant) that functions as electronic medical record storage and database for data collection and management. Patients can interact with NORA via an app and stay engaged throughout the trial, without the inconvenience of traditional site visits. They can interact with the investigator and study coordinator via the app, have blood draws and other lab tests done at any local lab, and non-specialized assessments can be done by a local physician.
Science 37 acts as a metasite to coordinate protocol approval through a central IRB, patient recruitment, and study implementation via a network of local physicians and nurses and via the use of mobile devices that keep the patient at the center of the study. This set-up allows them to reach a greater number of patients in all geographical areas and of all racial backgrounds, increasing the enrollment of minorities in the study.
Science 37 was founded by Noah Craft in 2014, and has already collaborated with sponsors and CROs on several trials in various therapeutic areas. So far, their focus has been on oncology, dermatology, and rare diseases, where traditional patient recruitment is particularly slow. Science 37 has helped to accelerate studies and cut costs, and has established collaborations with various organizations, including Genentech, Harvard Clinical Research Institute, and Los Angeles Biomedical Research Institute, among others.
mHealth – Where Has it Been and Where is It Going?
Kim Tyrrell-Knott, Epstein, Becker & Green
Clinical research, either done in a traditional way, or done using modern technologies like those implemented by Science 37, is highly regulated. Good clinical practice, patient rights, privacy laws, rules by the department of Health & Human Services (HHS) and other federal or state laws, all regulate clinical research. From a digital health perspective, many changes are happening, and the FDA is taking a more liberal and risk-based approach.
Overall, certain aspects of digital health are still highly regulated, while others are not regulated at all. A good example of an unregulated technology is the FitBit: lots of people have one, and each collects lots of data, but how to use this data for a highly regulated process like a clinical study, if the device itself is not regulated at all?
Cybersecurity is also an issue with telemedicine for the FDA and other entities. The Food and Drug Administration Safety and Innovation Act (FDASIA) has drafted guidance for industry for the use of mobile medical applications. For example, clinical decision-support (CDS) software is more or less regulated based on the significance of the healthcare decision (e.g. diagnose vs. treat disease) and on the severity of the condition.
Overall, data acquired via telemedicine and mobile devices need to be regulated in ways similar to data acquired in more traditional ways, avoiding the risk of subjecting new technologies to higher standards.
May 10, 2016
Optimizing Sponsor/CRO Relationships.
Report by Roberta Alexander, Ph.D.
On May 10, Rho offered a free online webinar on Optimizing Sponsor/CRO relationships, led by Jamie Arnott and Kristen Snipes from Rho. Here, Dr. Roberta Alexander of SDCRN summarizes the key points of this valuable webinar. You may also view the webinar, free, on-demand, here.
Key Factors for a Good Relationship
Pharmaceutical companies often rely on the help and expertise of Contract Research Organizations (CROs) in the execution of their clinical trials. It is important for the success of the trial that the Sponsor and CRO have a good working relationship. Key factors influencing a good relationship are communication, reports, financial management, and oversight of the project. The ideal relationship is based on trust, honesty, and mutual respect; mindfulness; understanding diversity; open communication; and having one point of contact. Business etiquette requires that all parties are on time at meetings and phone calls; are responsible, reliable, and follow through; use technology appropriately; follow proper business writing etiquette; and display appropriate body language in face-to-face meetings.
Best Use of Technology in Communication
When it comes to the use of technology in communication, keep in mind that your preferred method of communication may not be the preferred method of the other party, and that certain forms of communication may be more appropriate in some circumstances than others. For example, e-mail may not be appropriate for a brainstorming discussion. On the other hand, people who are not fluent in English may prefer an e-mail message to a phone call. In any case, mind the time zone when scheduling meetings, and always be professional and use proper grammar and spelling when writing e-mails. Communication needs to be concise and accurate, and of the appropriate frequency. It may be necessary to interact frequently at the beginning of the study, and less frequently when the trial is steadily enrolling. Avoid using your cell phone during a business meeting, as it is too easy to get distracted and lose focus. Texting can be appropriate to quickly alert somebody of something (e.g., I sent you an email) but text messages are not documented, so they should not be used to communicate something that needs to be documented.
Needs of Sponsor and CRO
Both Sponsor and CRO have their own particular set of needs in the relationship. The Sponsor needs a clear communication pathway and transparency; points of escalation if there are concerns; confirmation of key staffing; and adherence to timelines. For the CRO, important points include receiving clear directives as well as a unified message; having a point of contact; identification of the stakeholders, as the decision maker may be different from the point of contact; and deciding if the Sponsor’s or the CRO’s standard operating procedures (SOPs) are to be followed. Confirmation of key staffing may be particularly important if the relationship becomes tenuous, as it may be necessary to escalate the situation, externally or internally, to resolve conflict.
Part of the interaction between Sponsor and CRO involves negotiation. Prepare appropriately for the negotiation discussion; define what is important to you; understand the other party’s desired outcome vs. what they really want; do not make assumptions; and enter the discussion with an open mind. Most importantly, listen and ask open questions such as: Why? What? How? For example, why is this important to you? What is important to you about this? Why do you think this would be the best approach? What impact will this have on you or the project? In a negotiation, establish rapport and build trust (saying yes is not always the best thing to do); review the issue by stating your understanding of the issue and make sure everybody is on the same page; be clear about options, and be open to their ideas. Above all, listen, and be respectful and professional! As much as possible, come to an agreement. However, if agreement is not possible, it is fine to say no. Do not say yes just to please the other party, and then not be able to deliver what you said you or your team would do. At the end of the conversation, wrap up what was discussed. If some information was not available and the conversation seems stuck, a second round of discussion may be necessary at a later time. Likewise, if the conversation becomes heated, it is better to end it and continue it at another time.
Although the Sponsor transfers some responsibilities to the CRO, the responsibility of the study ultimately falls on the Sponsor. Thus, the Sponsor has to oversee the study; however, it should not micro-manage.
Reports assure proper communication between the Sponsor and the CRO. Determine the study reporting requirements and deliver the reports as the other party prefers: some may prefer the report be sent via e-mail, while others may want the report uploaded to a website. Adjust the frequency and content of the report as needed, as the information provided has to be relevant — there is no point in sending a report if it does not contain new information. In any case, always communicate clearly and be transparent.
Practical Case Studies
Having a good relationship is always important. Learn people’s names and make personal connections whenever possible. Be an active listener and understand the other party’s view. Stay informed by, for example, reading press releases. Consider the key factors of cost, quality, and time. These considerations may be important in various situations. For example, if the project manager of your study goes on parental leave, establish a relationship with the new project manager and bring him/her up to speed. If the CRO has been selected for a “rescue study”, try to understand what went wrong with the previous CRO. Bear in mind that the Sponsor is frustrated and lost time and money, and evaluate ways to solve the problem. But do not say yes to things you cannot do, as that will only increase their frustration.
Other situations may involve the sites. The Sponsor may want to use a certain site that the CRO does not consider appropriate: ask open-ended questions to understand why the Sponsor wants to use that site. Asking questions helps to build trust and shows that you are an active participant in the study. The Sponsor may want to do site initiation visits (SIVs) before the study is granted Institutional Review Board (IRB) approval. The CRO has to provide, in this case, a clear risk-benefit profile. Sites that are far from approval may go through a change in personnel or may forget the training by the time approval is granted, and there may also be protocol changes. Thus, in general, it’s not a wise strategy to conduct SIV ahead of IRB approval. Nonetheless, if the Sponsor really wants to do this, that’s fine, as long as the implications are clear.
To summarize, a good Sponsor/CRO relationship is similar to other relationships in that is based on trust, understanding, and mutual respect.
March 2, 2016
San Diego Clinical Research Network
The Big Picture in Clinical Research, What is Here, What is Coming, and How Will We Lead Through It?
Report by Teresa Gallagher, Ph.D., MPH
Here is link to the speaker’s slides
On March 2, San Diego Clinical Research Network (SDCRN) hosted Laurie Halloran, President and CEO of Halloran Consulting Group in Boston, who spoke at the Sanford Consortium for Regenerative Medicine on trends in clinical research- “The Big Picture, What is Here, What is Coming, and How Will We Lead Through It?” Halloran founded Halloran Consulting Group in 1998, and is recognized as an industry expert in improving the organizational effectiveness of clinical research programs. She reviewed recent trends in clinical research, trends coming in the next 5 years, and discussed how we might prepare for a successful organizational outcome in this environment.
In 2016, the “Big Picture” clinical research trends include impending changes to the Common Rule, patient centricity, and ongoing attempts to decrease inefficiencies in clinical trials. The Common Rule is a rule of ethics regarding research involving human subjects in the U.S. — some of the major changes being proposed are the rules relating to informed consent, which would be significantly tightened. Patient centricity involves designing protocols with patients in mind and incorporating modern technologies to ease the patient’s journey through the clinical trial.
The clinical research challenges today are not that different than they have been, but the alternatives for organizations are new, including – addressing the issue of increasing protocol complexity, adopting Cloud-based technology to increase efficiency, and leveraging study testing in patients’ homes to decrease costs.
Two major initiatives with high potential to transform the clinical research enterprise are technology and standardization. The digital or “site-less” clinical trial is “tantalizing, yet probably still off in the distance”, while improving protocol quality is “here and now.” Protocol quality can be improved by designing more patient-centric trials and using companion diagnostics to strengthen the patient population and endpoints.
We have new opportunities to enhance the participation of research sites and investigators, and novel initiatives are underway to address inefficiencies at the site level. Engaging with patients through direct-to-patient digital marketing and working with advocacy associations will help study recruitment. The Data Revolution, spurred by the massive drop in the cost of sequencing genomes in the last ten years and the increased speed of data processing, has led to the collection and availability of a variety and volume of data from diverse healthcare and life science sources. We will need to prepare for the data and apply standards to the data, including a single source of standard use across all systems.
How can we prepare for this future? Halloran recommends that having a crystal clear focus on your organization’s needs and goals; facilitating all the technology efficiency you can manage; and being prepared for intense pressure on development timelines in a highly competitive environment for talent are the key ingredients for favorable outcomes for life science organizations.