Perspectives from the Medical Writing Team

“The End of Alzheimer’s disease”

Tahmeena Chowdhury, PhD, Medical Writer, PROMETRIKA, LLC

I recently attended the MIT Alumni Association webcast of an online faculty forum titled “The End of Alzheimer’s disease.”  This session presented an excellent opportunity to hear from panelists, Drs. Sarah Hopp (Massachusetts General Hospital), Matt Kaeberlein (University of Washington, Seattle), and Anant Paravastu (Georgia Tech), on new developments and potential therapies targeting this debilitating neurological disorder.  It was also very informative listening to audience questions and obtaining a better understanding of people’s concerns and thoughts on this disease.

The panel opened with an overview of the molecular pathology of Alzheimer’s disease (AD). Clinical symptoms of AD are attributed to the misfolding and oligomerization of proteins, such as amyloid-β (Aβ) peptide and tau, resulting in formation of amyloid plaques and neurofibrillary tangles.  The oligomers disrupt various, diverse molecular pathways, including dysregulation of ions in the calcineurin pathway and resulting loss of communication between neurons.  The loss of synaptic connections and neurons manifest in behavioral changes and deterioration of cognitive functions that are the hallmarks of AD.

The moderator, Barbara Moran, asked about the importance of inflammation in AD, a question that immediately grabbed my attention.  The disappointing study results of potential AD drugs over the last several years strongly suggest reassessing current therapeutic strategies, and I was keen to hear of recent developments that could support inflammation as a feasible treatment approach.  The panelists gave a brief overview of the lines of evidence linking inflammation to AD.  Inflammatory responses mediated by plaque-activated microglial cells in the brain have been implicated in AD.  Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has been demonstrated to have a beneficial effect on AD, albeit their use is associated with negative gastrointestinal and nephrologic effects.  Inflammation induced by senescent cells has also been proposed to play a role in AD.  With numbers increasing with age, these senescent cells secrete pro-inflammatory factors, leading to systemic inflammation.

Because of the complexity of how the inflammatory response affects AD pathology, targeting inflammation as a therapeutic approach poses a challenge.  Some inflammatory factors may have deleterious effects whereas others may actually be protective; the different stages of AD may also result in a differential response.  As more information on the mechanism of inflammation is uncovered, perhaps it will be possible to pharmacologically modulate levels and activities of specific players and, in combination with additional drugs, lead to an effective treatment strategy for AD.

For effective therapeutic intervention in general, both Drs. Hopp and Kaeberlein emphasized the importance of AD detection.  The possibility of an accurate detection of AD may increase the chances of treatment approaches being effective.  Diagnosis of AD is based mostly on clinical symptoms, e.g., loss of cognitive functions.  While levels of Aβ peptides can be detected in the blood and cerebrospinal fluid, no definitive imaging test is currently used in clinical settings to diagnose AD in patients prior to death; imaging can be performed on brain sections of deceased patients.  Positron emission tomography (PET) offers a powerful option as a diagnostic tool, allowing for detection of different stages of AD in living patients.  New PET techniques are already being used to image plaques and tangles in neurons under research settings and in clinical studies, but are not currently used for routine diagnosis in clinical settings.  It will be interesting to see if PET use in AD diagnosis becomes more common in medical practices, and what potential impact that has on clinical decisions made by physicians.

At this forum, the majority of the audience questions were regarding life styles and diets as risk factors for AD.  Most people agree that a healthy diet offers protection against onset of dementia.  Diabetes increases risk of AD about 2-fold, and people on vegan diets are generally at a lower risk for dementia and AD.  Glucose homeostasis has been linked to AD, with evidence suggesting involvement of insulin in amyloid plaque formation.  Despite these various links and correlations, a particular dietary guideline specific to AD prevention has not been established.

A question was posed regarding diet as a factor in the apparent lower incidence of AD in India, the answer to which was informative on both epidemiological and dietary points.  Curcumin, used in Indian cuisine, is a powerful antioxidant and share similarities with Congo Red, the original dye used to identify AD.  Studies in mice suggest that curcumin can cross the blood-brain barrier to bind amyloid plaques, with some evidence supporting an improvement in pathological traits of AD, e.g., decreases in cytokine levels and microglial activity.  Dr. Hopp pointed out, however, that the effectiveness of curcumin to treat AD in clinical settings has not been conclusively established.  In response to the same question, Dr. Paravastu appeared skeptical regarding epidemiological links to AD, due to the caveat of cases not being reported or not accurately diagnosed.  I think this is a valid point, especially when using data from countries where a substantial proportion of the population may not have access to quality healthcare.

In line with the forum’s topic, the panelists shared their thoughts on promising drugs to treat AD.  Current treatment options are disappointingly limited, and majority of recent studies on new drug candidates have failed at various stages of development.  Dr. Kaeberlein was an advocate of taking an aging-related approach to treating AD by delaying the molecular processes that lead to clinical decline in quality of life associated with aging.  United States Food and Drug Administration (FDA)-approved rapamycin, a potent inhibitor of the TOR pathway implicated in aging, has been demonstrated to decrease levels of Aβ peptides and tau, as well as improve cognitive functions in mouse models of AD.  Generic rapamycin is available, albeit no clinical trials to investigate its therapeutic role in AD are ongoing.  Several lines of evidence link mammalian TOR (mTOR) pathway with Aβ and tau pathologies; and having a well-studied, FDA-approved, and highly specific inhibitor of this pathway makes mTOR a promising target for therapy.  Dr. Kaeberlein also mentioned senolytics as potential therapeutic candidates to target inflammation associated with senescent cells, discussed above.  Dr. Paravastu emphasized the need for a multi-target tactic to treat AD, which I believe may be the most practical and efficient scheme.  Current approach has been focused on clearing plaques, but lack of effectiveness of the majority of candidate drugs strongly indicate the need to reassess this strategy.

One listener asked the question that perhaps all of us have been pondering:  how long until a cure for AD?  Dr. Kaeberlein’s response pertained to a “big picture” approach to combatting age-related disorders in general instead of focusing on cures for particular diseases, reiterating the importance of understanding the mechanism of aging and slowing it down to maximize health span at the population level.  Drs. Hopp and Paravastu, in contrast, gave a specific time range of 20 to 25 years until a curative treatment for AD.  Depending on how old we are, this prognostication may fill us with hope or dread on a personal level.  From a scientific perspective, however, the next few years promise to substantially expand our breadth of knowledge on AD and other age-related neurodegenerative diseases, as well as impact therapeutic strategies for complex diseases in general.

Observations from the MassBio 2017 Annual Meeting

Stephen Cropper, Senior Clinical Research Associate, Clinical Operations, PROMETRIKA, LLC

The Massachusetts Biotechnology Council (MassBio) is a not-for-profit organization focused on supporting and advancing the thriving life sciences “ecosystem” in Massachusetts. Founded in 1985, it represents nearly 1,000 biotechnology companies, academic institutions, disease foundations, and other organizations.

On March 30 – 31, 2017, MassBio held its Annual Meeting in Cambridge, MA. Along with Miganush Stepanians, Ph.D., the President and CEO of PROMETRIKA and LuAnn Sabounjian, PROMETRIKA’s Head of Clinical Operations & Drug Safety, I attended the event and would like to recap the highlights of the two days.

Washington, D.C. and the Outlook for Biotech

Like stakeholders in many other industries, people in biotech are watching eagerly (some might say anxiously) to see how actions by the new administration will affect us. MassBio President and CEO Robert K. Coughlin opened the event by speaking about the current global political climate.

He expressed concern about funding cuts that are impacting biotech and how those cuts will ultimately affect the people we are striving to help with new drugs and treatments. He stressed the importance of MassBio members aligning to take a stand against these kinds of actions and to ensure there open lines of communication across academia, pharma, and venture capital. Abbie Celniker, Partner at Third Rock Ventures and a member of the MassBio Board of Directors, agreed with Mr. Coughlin’s perspective and spoke about the need for diversity in the life sciences.

Sage Advice on Surviving Cancer from a “Chief Ice Cream Officer”

Dan Schorr is the Founder and Chief Ice Cream Officer of a company called Vice Cream. If the humorous title and company name catch your eye, you’ll understand why Dan chose them when you learn that he survived large B-cell lymphoma. He shared his personal cancer experience and his “humor with tumor” mantra. His story was funny and touching.

An athlete who had run marathons and competed in Ironman Triathlons, he decided to fight his cancer with the same grit and determination. In the course of that battle, he started a blog for others touched by cancer, created funny motivational cancer-themed t-shirts, and started an ice cream company. He shared the importance of face-to-face interactions between researchers and cancer patients and stressed the value in connecting people who are fighting cancer so they can share their stories.

Thoughts from Governor Baker

Massachusetts Governor Charlie Baker spoke about the importance of convergence in our industry and how it is needed if the state is to hold on to its leadership position in biotech. He also talked about the need to strengthen the Massachusetts Bay Transportation Authority and to ensure the availability of affordable housing as ways to support local biotech.

Looking to End Cancer

One of the sessions at the event focused on the Cancer Moonshot initiative and how Boston/Cambridge-area companies are having an impact. Some of the goals discussed included:

  • Efforts to understand tumor growth and evolution
  • The National Cancer Data System and ways to create a data ecosystem for sharing cancer information
  • The 3D Blood Cancer Atlas
  • Creating a network for direct patient involvement
  • Intensifying the focus on pediatric cancers
  • The importance of comprehensive digital health records

Biotech in the Era of Real World Evidence and Value

This talk centered on how organizations are trying to define the “value” of their efforts — whether that means improving survival rates, addressing affordability, assessing overall impact, etc. — and how to measure it. It also covered new financing and reimbursement models within biotech.

Wrapping it Up

From start to finish, the MassBio Annual Meeting was very informative and inspirational. It reaffirmed to all in attendance that the work we do is critically important and greatly valued by stakeholders, and that regardless of the political, social, and financial challenges we face, we will continue to make progress in our efforts to improve the human condition.

Rare Disease Clinical Development: The Crucial Need for Patient and Parent Involvement

LuAnn Sabounjian, Head of Clinical Operations & Drug Safety, PROMETRIKA, LLC

Rare Disease Clinical Trials

February 28th, 2017 was the tenth observance of Rare Disease Day worldwide.   Rare Disease Day awareness events took place in over 80 countries through the collaboration of countless foundations and patient advocacy organizations. This year’s theme was research that inspires and empowers the rare disease community, as captured in the slogan, “With research, possibilities are limitless.”

While there is no universal definition for the term “rare disease”, in the United States, a condition is considered “rare” if it affects fewer than 200,000 persons combined in a particular rare disease group. There are approximately 7,000 different types of rare diseases and disorders, with more being discovered each day. Over 30 million people in the United States are living with rare diseases – 50% of whom are children.

The people and families affected by rare diseases often feel isolated and helpless in the fight against their condition that is uncommon, complex, and often misunderstood by the people in their life, including healthcare providers in some cases. To cope with the lack of traditional resources, patients and their families become their own experts, tirelessly researching online and connecting with other rare families through social media communities and advocacy groups. This drive to learn and understand, coupled with their personal experiences living with a rare disease, makes their collaboration with researchers and industry experts especially productive. This partnership is essential to the success of rare disease clinical development programs.

Patient and Parent Participation in Clinical Trials

A family’s involvement in a clinical trial often calls for great sacrifice. In many cases, their home is not near a clinical site, which makes attending regular study visits a logistical challenge. Time away from work and travel costs can create financial strain. Then there is the discomfort and anxiety a patient experiences during regular visits and tests, and the burden of questionnaires and/or journals required throughout the trial. In order to be successful, a trial must be developed in a way that minimizes these hardships. Ultimately, the significant barriers families and caregivers may face should always be a key focus in tailoring study designs and expectations.

There are a number of steps that can be taken to help alleviate the significant physical, emotional, and financial impact on patients and families. They include utilizing best practices for recruiting and retaining participants, such as letting the prevalence of a rare disease in a geographic area drive patient recruitment and site activation, and increasing patient home support. There should also be a clearly-enunciated emphasis on identifying and collaborating on specific services or products to improve quality of life outside of the investigational environment. In addition, sponsors and CROs must collaborate with the patient community throughout a trial to learn from the feedback as the study progresses.

Incorporating the patient’s voice and needs from the start through a respectful and meaningful relationship must go beyond a research focus. A patient-centric approach of listening, understanding, adapting trial requirements, and giving back to the rare disease community can help ensure that there are adequate levels of participation to make the study as successful as possible. Collaboration and trust among families and disease-specific foundations, as well as support and advocacy groups is essential.

What can empower patients and families is the opportunity to provide input on sometimes marginal or unconventional outcomes or endpoints that directly affect quality of life. It is powerful for patients to be involved in the study design and meaningful outcome decision-making processes, reaffirming that the trial is designed for them. Adapting to more customized research methodologies not only can increase participation, but also maximize retention, adherence, and data quality.

PROMETRIKA Interview with Ovid Therapeutics

Ovid Therapeutics is a young company but one with significant experience working with people battling rare diseases. It is a key part of the company’s Vision and Mission to first and foremost consider the impact on patients and families in every phase of the design and execution of studies. It approaches rare disease development programs by first taking the time to understand and build relationships with the patient communities that it serves and using that information, along with strong relationships with patients and families, to develop transformative therapies.

Recently, PROMETRIKA’s Head of Clinical Operations & Drug Safety, LuAnn Sabounijan, connected with Vice President of Global Market Access for Ovid Therapeutics, Raquel Cabo, to discuss how that approach has helped them recruit and connect with patients and families for their Angelman syndrome program. Raquel’s answers provide tremendous insight on the challenges and rewards of patient involvement in rare disease research.

L. Sabounijan: As a seasoned veteran in rare disease clinical trials with a passion for working with patients at all stages of product development, can you share with us your history of collaboration with the Angelman syndrome patient/parent groups at Ovid?

R. Cabo: Ovid Therapeutics’ philosophy is that we are involved with the Angelman syndrome community for the long haul. While we are working to create innovative treatments, we strive to establish meaningful partnerships with patients and families that go beyond developing the medicine. Connecting with caregivers is critical in our studies as the patients we work with are non-verbal.

To ensure we develop the right medicine and that it is accessible, we are working closely not only with the patient and their family, but also with related foundations and organizations that represent the broader rare disease community. It takes many united voices to get regulatory and market access approval. When a medicine is on the market, ongoing feedback will be important as well.

Our goal is not just to produce a product. We strive to create a collaboration in which patients and families know they are leaving their mark on a study that will affect others battling their rare disease. We want them to feel engaged and empowered, and to know that the trial is “for them and by them” so to speak.

In an example of engaging and empowering the people we work with, we held an online competition to design the logo for the STARS clinical trial program in Angelman syndrome. Approximately 50 logo designs were submitted from which we narrowed the field down to three finalists, and then asked the community to vote. The winner by 300 votes was a logo designed by the mother of an individual with Angelman syndrome who was inspired by the strength and bravery of her child and shows a figure reaching for the stars. We now use it on all patient materials related to the study.

Another initiative we’ve sponsored is a “Make-a-thon” that encouraged industrial designers and engineers to collaborate on ideas to develop products for individuals with disabilities. In the Angelman Syndrome Make-a-thon the goal was to help a family save money on customized and expensive retrofitting. One of the results is a grid that can be placed over an iPad to frame icons so patients with poor fine motor skills can avoid touching two icons at once. The design of the accessory considered very specific details like the fact that a matte finish and sturdy materials would be much better for the patients with sensory and coordination challenges. Similar items sell online for $70 and are often made of more breakable materials, but the collaboration of the Make-a-thon allowed Ovid and its partners to manufacture their grids for a fraction of the price. This project really showcased the fact that there are creative and compassionate people outside the clinical space who are eager to help. Thanks to the teamwork and collaboration of all involved; it was a highly successful undertaking.

L. Sabounijan: In my experience working with patients and families at clinical research centers, I have seen the value of securing patient and family involvement in rare disease clinical trials. At a high level, can you share the key differences in outcomes with early patient/parent involvement in clinical development programs vs. non-involvement?

R. Cabo: Our development program in Angelman syndrome is our first sponsored program, and from the very beginning we have placed a huge importance on early patient and parent involvement. Parents are the experts when it comes to their children and what change would be most meaningful. Their input has helped us understand what aspects of the syndrome impact their child’s life, and their life, the most. Speaking with parents has helped us better understand the unmet needs given the current treatment pathway and the natural history of the syndrome. As is the case with many orphan conditions, there are limited established outcome assessments, working with parents and the foundations has helped us prioritize outcome assessments that are most relevant and feasible. Their input based on their experience, as well as what they’ve heard from other parents, has provided valuable insight.

When patients and parents are involved, it’s a much different story. You are able to co-create and navigate uncharted territory together.

L. Sabounijan: What are some best practices you have seen to involve parents/caregivers of children and young adults with rare developmental disabilities in clinical development planning?

R. Cabo: From our perspective, the key is transparency, communication, and collaboration.  You need to have an efficient mechanism for collecting feedback at all stages of the development program. It’s also critical to build trust and mutually beneficial relationships with the community and the foundations. It is also really helpful to share insights with other stakeholders, such as payers, clinicians, and regulators,

In one example, one insight that was truly eye opening was one mother’s explanation that any fine motor improvement which would enable her daughter, who communicates with hand signals, to go from two to three signals in her “vocabulary” would be truly life-changing for the family. This perspective helps to define what impactful “improvement” really looks like to a patient, especially in a rare indication without widely established or recognized efficacy endpoints.

We’ve been fortunate to have family input in many areas of our studies — from mapping out the patient journey to helping define inclusion/exclusion criteria and more. Their feedback on what makes it easier or more difficult for a family to participate is also key. We even ask for their assistance in reviewing brochures and other literature to ensure that it makes sense to them and uses the right wording and imagery. Patient and parent assistance can also be invaluable for clinicians working on natural history studies and registries.

L. Sabounijan: What do you see as some potential challenges of involving parents in decisions about clinical trial planning? What suggestions do you have for dealing with these challenges? 

R. Cabo: While each family is unique, most are very eager to give input and feedback. Providing them with education on what a clinical trial is and how it will progress is crucial as you get started. It is important to explain that while you do all you can to accommodate the patient’s unique needs, the protocol does have to be standardized to a degree. They should also understand how their time and effort will benefit the patient and the broader community, and that their feedback is necessary for the study to achieve its goal.

We hosted a series of webinars designed to answer family’s questions and found it to be an effective way to disseminate information about who can participate, how to enroll, and other aspects of the study. It’s also a good idea to talk with foundation leaders and ask if you can record those interactions and make them available to families on the internet.

Parting Thoughts

Ultimately, as Ovid Therapeutics and PROMETRIKA understand, rare disease development programs must be built on a foundation of deep respect and appreciation for all that patients and families are doing to help improve the quality of life of others with the disease. The best way to demonstrate that gratitude is to be as accommodating as possible in the study requirements, to provide exceptional support to patients and families, and to give back to the community whenever and wherever possible.

It has been said that too often “research is performed on patients, not with patients.”1 Especially in the case of rare diseases, an adaptable and collaborative approach to clinical trials is essential. As patient advocacy groups contend, patients and families should have a greater say in the decisions that affect them — an idea summed up in the phrase “nothing about me without me.”2

From initial planning and design through all phases of clinical trial management, there are several challenges unique to patient participation in rare disease trials. By involving patients and parents more extensively at all stages of a study and by learning more from their personal experiences and their hope for changes that matter, we can produce a broader, deeper, and more complete body of knowledge. Patient-centric rare disease clinical trials have greater potential to accelerate meaningful treatment and prevention breakthroughs that help patients and their families lead longer, healthier, and happier lives.

 

  1. Thornton S. Beyond rhetoric: we need a strategy for patient involvement in the health service. BMJ. 2014;348:g4072. [PubMed]
  2. Billingham V, Through the Patient’s Eyes, Salzburg Seminar Session 356, 1998


Ovid Therapeutics understands patient communities and weaves that knowledge with scientific insights to develop transformative therapies for patients and their families. The commitment to patient communities is about responsibility to seek innovation, to understand the challenges faced by patients and their families and to communicate with them clearly and openly, and ultimately to develop medicines that transform their lives.

PROMETRIKA works with many organizations that focus on developing treatments for rare diseases. With 14 years’ experience in more than 60 rare disease clinical trials, the company’s role ranges from full-service partner to preferred provider of specific functional services. Its expertise working under challenging research conditions helps facilitate exceptional outcomes. Whether that means consulting rare disease foundations or advocacy groups to develop creative patient-centric recruitment and retention methodologies, devising statistical strategies to accommodate low sample sizes in biometrics, or combining knowledge from natural history studies with data from clinical trials, the PROMETRIKA team knows from experience what it takes to make a rare disease development program a success.

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A Case Study: Complex Oncology Study and the Boutique CRO that Provides the Perfect Model

LuAnn Sabounjian, Head of Clinical Operations & Drug Safety, PROMETRIKA, LLC

Executive Summary

In assembling a team for a new trial studying a rare form of cancer, acute myeloid leukemia (AML), a prestigious cancer research center was looking for a CRO partner with unique qualities. Large or boutique, the partner had to first have highly-skilled staff with extensive experience in oncology studies. The partner selected would also have to provide hands-on involvement from its leaders throughout the complex trial, and an uncommon level of responsiveness. As the search unfolded, PROMETRIKA stood out amongst its competitors as the right choice for a partner for this sponsor.

A Transparent Approach to Finding a Partner

In embarking on the selection of a CRO partner for their AML program, this sponsor articulated a clear and transparent approach: Rather than focusing on the size of the CRO, they were more interested in finding a flexible and responsive organization that could best address the institutional challenges and anticipate their needs.

To that end, they asked a number of general questions, such as:

  • Who will give us undivided, high-touch attention?
  • Who has the expertise and experience to provide feedback on the study design to avoid later issues?
  • Are they willing and able to deep-dive into the study design complexities?
  • Are they willing and able to assign highly-qualified resources to provide the level of expertise needed during the study from start-up through writing of the Clinical Study Report?

In short… Who is the partner who will help us conquer cancer?

The team also had more specific questions, including:

  • Who will execute the Phase 1 trial efficiently and effectively?
  • Who will bring it to the next inflection point (positive or negative)?
  • Who will be able to present a suitable dataset for an external organization or partner to evaluate whether the compound is a suitable asset for future development?

In the end, the sponsor found the partner that could meet its specific needs.

Sponsor chooses PROMETRIKA as Partner

The sponsor selected PROMETRIKA because of its full support services, its industry experience and academic background of its staff, and its deep experience and expertise in oncology trials. Other attributes that factored into the decision included:

  • A clear focus on a shared goal: to make a difference for patients with cancer
  • A willingness for seamless integration and partnership with the sponsor team
  • A seasoned team throughout the full execution of the study who knows how to minimize the risks of the trial, including out of scope budgets and delayed timelines
  • A collaborative cross-functional approach, to ensure the timely delivery of high quality data.

With an experienced and cohesive team in place, PROMETRIKA is currently working collaboratively with the sponsor team to navigate through the inevitable challenges that occur during the conduct of most studies, let alone complex oncology studies. Utilizing industry-leading database technology of its partner, Medidata, PROMETRIKA is responsible for implementing customized solutions for the trial’s many complexities and leveraging its long history of working together to deliver quality data.

There’s Power in a Strong Partnership

What this sponsor and PROMETRIKA have affirmed is the impactful synergy that is produced when two organizations come together to undertake one mission. Powered by a shared appreciation of patients’ perspective and a focus on the end goal, this partnership is destined to deliver outstanding results.

The first steps in this trial were to identify the anticipated challenges and develop proactive solutions to minimize their impact. These fall into five key areas:

  • Study start-up
  • Study execution and conduct
  • Management
  • Safety monitoring
  • Budget

Study start-up

In launching this trial, the sponsor team faced a long list of challenges, not the least of which was the large group of stakeholders involved. Staff hours are limited, as researchers have time commitments for treating non-study patients. Drug accessibility was another issue, as the drug is not manufactured in the United States and importation created a high potential for delays.

The PROMETRIKA team was able to help them address their many challenges by first building a strong rapport with all stakeholders through face-to-face and online meetings and then developing an accurate and achievable timeline with a back-up mitigation plan to avoid delays. A seasoned clinical supply expert worked with the team to expedite the importing process and distribution of the study drug so that deadlines could be met.

Study execution and conduct

The complex nature of the protocol design with dose escalation also presents challenges. They include the frequency and the imperative for timeliness of Safety Review Committee meetings and the reliance on the local laboratory to provide on-time data. There are also recruitment challenges for relapsing or refractory patients with AML.

To manage these issues, PROMETRIKA conducted an in-depth protocol review, and identified critical influences that would affect the timeline. To become familiar with the patient community and ensure that enrollment will track toward success, the team conducted a thorough feasibility study. The team also reached out to members of the sponsor’s oncology practice to facilitate recruitment success.

Management

One of the management challenges of the study is that it is conducted by two organizations geographically distanced from each other. To address that challenge, regional monitors who had previously worked with the sponsor were recruited to bridge the distance gap. As the study progresses, investment of PROMETRIKA’s time and that of the sponsor is being continually assessed with an eye toward the scalability of the solutions for future collaborations. The PROMETRIKA team has also leveraged state of the art EDC and other technologies to provide integral real-time reports of the data to assist the stakeholders in monitoring operational performance and detecting data trends.

Throughout the study, involvement of PROMETRIKA’s upper management team ensures effective operations through a detailed communication plan, and efficient regular remote meetings with occasional face-to-face sessions as necessary.

Safety monitoring

The challenges of safety monitoring in this First-in-Man trial are met by frequent Safety Review Committee Meetings, ongoing reconciliation of clinical and safety data, and a vigilant approach to detecting and reporting unexpected events.

PROMETRIKA’s solutions incorporate consideration of both clinical research and clinical practice concerns and priorities to ensure that the diverse reviewers’ objectives are met using tools such as adaptable reports. Prospective plans for pharmacovigilance, clinical operations, data management, and statistical analysis ensure a harmonized and integrated approach to safety management, reporting, and analysis. The team has a keen focus on data triggers for early signal detection (dose limiting toxicities, discontinuations, missed doses and visits) and on applying early intervention to ensure best trial outcomes.

Budget

The funding mechanism for this trial requires a continual financial focus and avoidance of out of scope costs.

PROMETRIKA’s approach to handing these requirements involves advising on the collection of necessary data and avoidance of “nice to have” data collection, using data management tools to provide early feedback and minimize data query generation, and instituting monthly internal budget reviews to allow rapid response to operational challenges that may result in budgetary scope-creep.

Conclusion

The successful partnership between the sponsor’s program team and PROMETRIKA, all started with transparency and a clear understanding of the desired approach.  They knew that finding a flexible and responsive organization was paramount to addressing the needs they anticipated and they kept that their focus as they searched for the right CRO for this program.

Perspectives from the Medical Writing Team

“Gene Therapy 2.0”

 Tahmeena Chowdhury, PhD, Medical Writer, PROMETRIKA, LLC

MIT Technology Review (March/April 2017) lists “Gene Therapy 2.0” as one of the 10 Breakthrough Technologies of 2016.  I was intrigued to see this technology listed as “breakthrough” in 2016, since it had been studied for decades.  The results of this therapeutic approach were mostly negative, marked in particular by the death of 18-year-old Jesse Gelsinger in a clinical trial in 1999.  Recent developments, however, have brought gene therapy to the forefront of combating life-threatening disorders, including rare diseases.  Because of my specific interest in rare disorders and the special challenges they pose in drug development, this re-emergence of gene therapy as an effective tool is particularly exciting.

The theory behind gene therapy entails treating patients who have defective genes with copies of healthy genes, using viruses as a delivery tool.  The delivery system posed an obstacle in early studies by having serious deleterious effects on patients, including cancer, multiple organ failure, and brain death.  Many such challenges have been overcome in recent times, as exemplified by the approval of two gene therapies in Europe for treatment of inherited diseases:  Glybera for lipoprotein lipase deficiency, approved in 2012; and Stremvelis for a form of severe combined immune deficiency (SCID), approved in 2016.  Potential therapies in the US that could get approved in 2017/ 2018 include a therapy for a progressive form of blindness from Spark Therapeutics; gene therapies for treating hemophilia and epidermolysis bullosa are also under development.  According to a pediatrician and scientist at Stanford University, clinical trials of gene therapies to treat 40 to 50 different diseases are ongoing.

While considerable developments have been made in gene therapy research, challenges still remain, particularly in treating diseases with more complex molecular physiology, e.g., Alzheimer’s disease and diabetes.  For rare diseases and/or diseases with deficiencies in single genes, however, gene therapy already appears very promising.

Reflections on Rare Disease Day 2017

LuAnn Sabounjian, Head of Clinical Operations & Drug Safety, PROMETRIKA, LLC

On a cold, clear Tuesday morning, the State of Massachusetts commemorated the 10th anniversary of Rare Disease Day, which takes place annually all over the world on February 28th, with a celebration at the State House. I was lucky enough to be in the audience that day to hear compelling policy debate, heart-wrenching stories of struggle, and an inspiring call to action that all focused on one thing… research.

We kicked off the day with a discussion on the role of patient advocacy organizations in drug approvals. The discussion, which was organized by MassBio, was led by a panel of researchers, patient advocates, industry experts, and a former FDA director. What followed was a fascinating conversation about the difficult balance between science and empathy that faces rare disease researchers every day. This is the balance between the desire to bring life-saving medicines to market as quickly as possible, and the responsibility to make data-driven, scientifically-sound decisions that ensure only safe and effective medicines make it to patients.

Other key areas discussed were the increasingly significant role of patient advocacy groups in rare disease clinical trial design, particularly in coming up with meaningful study endpoints.  Also addressed was the challenge on the sponsor side of balancing the risks and benefits of rare disease drug trials in cross-cultural setting across various parts of the world where risks and benefits may be viewed differently.

Part of the discussion centered on the efficacy standard controversy that we’re all grappling with right now:  Should rigorous standards for evaluating a drug’s efficacy be relaxed? Everyone had a different perspective, but when it came to the real question at hand “Is this approach good for patients?” the consensus was overwhelmingly “No.”  People felt that regulators need a measure of a drug’s effectiveness in order to approve drugs that improve patients’ lives. Dr. John Jenkins, former director of the FDA’s Office of New Drugs, said this was akin to going backward at a time in history when we know more about medicine than ever before. He questioned the rationality of this idea, and also pointed out that payers would not pay for drugs without proof that they work.

Once the panel concluded, the Rare Disease Day Celebration program began and we heard firsthand how the regulatory challenges we had discussed earlier that morning truly impact those living with and working to fight rare diseases. We heard from neurologist and COO of the Epilepsy Foundation of New England, Dr. Elaine Kiriakopoulos, about how policies like fail-first medicine and step therapy practices – which require patients to take insurance-preferred medications before taking their doctor’s recommended medications – can have serious and even fatal consequences for epilepsy patients. Dr. Kiriakopoulus shared letters from patients and researchers in her organization pleading with legislators to help alter these policies which “severely limit patients’ access to care and cause immense financial and personal burdens,” and asking them to enact safeguards and a process for appeals. She finished with the declaration, “Fail first medicine and step therapy must end! Patients have a right to the best care available.”

We also heard from patients, caregivers, and advocates about what it’s really like to live with a rare disease. They spoke of the isolation and anxiety that patients and families experience when there is no one to talk to who understands what they’re going through. They described the financial, logistical, and emotional challenges families face when having to travel to meet with experts and attend regular doctor appointments. There wasn’t a dry eye in the house when Janice, who introduced herself as a “rare mom,” shared the story of her five-year-old son who has a first-of-its-kind, undiagnosed genetic disorder. She described the fear and uncertainty her family felt going through test after test looking for an explanation, and even the irrational guilt she feels knowing she passed along the genes that resulted in her son’s condition.

Janice and her fellow presenters talked at length about the enormous challenge rare disease patients and families face to learn everything they can about their condition and find ways to support the life-changing research that takes place every day. Janice asserted that she “learned more medicine in five years of being a rare mom than in 20 years of being a nurse.”

Another presenter, Patrick Lacey, shared his family’s incredible story of his infant son’s diagnosis that led him to establish Beat NB (neuroblastoma), which has gone on to fund 19 trials in the US to date. Beat NB has helped bring life-changing therapies to patients in need, including Patrick’s son, who surpassed all expectations when he turned twelve years old this year. Patrick spoke about his first, intimidating immersion in the world of medical research, saying, “Academic medicine is a confusing place to be.” He said that a parent’s role is to be in the room reminding researchers why we’re here and what we’re fighting for.

Finally, we heard patients, legislators, and researchers, alike, marvel at the incredible scientific advances that have been made in the treatment of rare diseases, and the hope they feel knowing how far we have come. Mr. Mark Borreliz, a lawyer and patient advocate who suffers from hemophilia A, described the impact of the many, life-changing advances that have been made in hemophilia treatment over his lifetime, saying, “I am the depiction of what research can do.”  Mr. Borreliz also spoke of the importance of awareness events and the recognition Rare Disease Day brings to the rare disease community. Speaking of the inspiration and support he’s received from fellow patients, he said, “Community gives you the ability to be more than one person.”

Mr. Borreliz assured us that, “There is great reason to hope,” and he is right. However, our fight against rare diseases won’t advance without the continued collaboration of countless individuals and organizations around the globe. Dr. Kirkakopoulos challenged everyone to do their part, saying, “Don’t just be inspired, move to action.” Mr. Lacey said he is “excited to see what happens if everyone makes the choice to work together and put the patient first.” No matter what your perspective, Rare Disease Day shows us the incredible impact that is made when patients, caregivers, legislators, physicians, and researchers all work together to bring about real change and improve the lives of patients worldwide. Perhaps moderator Katie Brandt said it best when she observed, “Alone we are rare. Together we are strong.”

Yes, there is hope. We’ve made great progress, and while there is still a long way to go, we are on a mission and we will find cures and treatments for many rare diseases – those known and those yet to be discovered. When cutting-edge science, insights from patients and families, and a caring approach to research come together, successful outcomes are just a matter of time and persistence.

Perspectives from the Medical Writing Team

“The Cancer Lottery”

Tahmeena Chowdhury, PhD, Medical Writer, PROMETRIKA, LLC

“The Cancer Lottery” in MIT Technology Review (January/February 2017) provides an excellent overview of precision medicine in treating cancer by following the journey of an artist living with cancer for over 30 years.  I find the linear approach, where we can hone in on a specific root cause of an event on an individual basis and then go “fix” it, very appealing; and hence, I was looking forward to learning more about precision medicine in a real world setting.

Developing drugs that target key specific mutations in diseases offers a simple and intuitive treatment approach.  The caveat, however, lies in taking a simplistic view of intricate disease mechanisms.  Despite demonstrating promising results in oncology, as evidenced by the blockbuster drugs Herceptin, Gleevec, and Zelboraf, precision medicine has mostly been ineffective due to the complexity of diseases.

Even in the absence of an existing drug targeting a mutation, the availability of tumor DNA data in an accessible database allows researchers to identify potential subjects for studies testing novel, experimental drugs.  Despite such promising results, precision medicine faces considerable challenges to its value as an effective and practical therapeutic approach.  Many patients do not respond to this therapy, with short-lived positive effects in the subset that do respond.  One researcher even refers to successes in precision medicine as winning the lottery.  Moreover, tumor DNA sequencing and treatment with targeted drugs remain expensive, and insurance companies do not always cover these costs.  Proponents argue, however, that even if a small percentage of patients benefit, that should be sufficient reason to pursue this approach.  As more and more data become available, they hope to increase the number of patients who respond to treatment.

The article is a fascinating read about the emerging therapeutic approach of precision medicine.  As clinical developments in the field progress, it will be interesting to see how the debate amongst researchers continues to develop and hear the thoughts of other stakeholders.  While it was fascinating to learn about developments in this emerging technology, the most thought-provoking part of the article, for me, was the discussion addressing the question:  “Is it worth it?”

Focus on Personalized Attention and Customized Reporting

Stacy Surensky, CPC, Director CDM, PROMETRIKA, LLC

Executive Summary

A small biopharmaceutical company with big aspirations and unlimited potential was not getting the personalized attention that they expected and deserved from their large CRO. Instead, their needs often took a backseat to the needs of larger organizations, which, in some cases, led to frustrating delays.

When the CRO did focus on their studies, it was unable or unwilling to accommodate requests for things like customized reports and specialized processes. In PROMETRIKA, they found a CRO that shared its views on collaboration, and served more as an engaged partner than a disinterested service provider.

A Company Shaped by Patient Needs

Like many biopharmaceutical companies, their business is shaped by the needs of the patients for whom its drugs are developed. Whether the team is creating new medicines or addressing the equally-critical task of getting those therapeutics to people around the world who need them, it’s the patients that inspire them.

The company’s complex work is guided by very simple core values: ownership, collaboration, innovation, excellence, and humanity. And the list is punctuated by the directive: Have fun! Unfortunately, their interactions with their large CRO were anything but.

The Quest for a Caring CRO

This company has an experienced internal data management team and understands what excellence looks like. Over time, they began to realize the service they were getting from their CRO did not meet that standard. While the largest CROs often serve the largest pharmaceutical companies in the world, they often overlook their other clients or assign junior team members to oversee their clinical data.

What’s more, while the CRO had powerful tools at its disposal, it couldn’t (or wouldn’t) create the custom reports that were needed.

When the team reached out to PROMETRIKA to discuss the possibility of collaborating on a study, it was clear that our companies have much in common. We are similar in size, have cultures that emphasize mutual respect and support among employees and toward partners, and we share many of the same goals and values.

“Our staff could immediately relate to their team,” says Dr. Miganush Stepanians, President and CEO of PROMETRIKA. “The company’s approach to the work they do, attention to detail, focus on quality, and highly-engaged management mirror the way we do business at PROMETRIKA. We see ourselves as their partner rather than their service provider.”

Taking the Lead on a New Trial

With PROMETRIKA chosen to data manage a new trial, the fact that our companies were well-aligned was immediately apparent in their approach — one that balanced the use of advanced technology with the understanding that there are some needs that technology can’t meet. Being in sync was critical on a trial of this size — a Phase III with over 1,000 screened patients, participating at almost 100 sites nationwide.

Our team designed and built the database, incorporating input from all stakeholders. We also developed specialized programming output for safety reports that provided weekly and bi-weekly metric updates for each site. This allowed the sponsor to be very involved and take action quickly for sites that needed attention. The complex nature of the study also required strong project and data managers and a great deal of flexibility to allow the sponsor teams to have a constant oversight of the data, both of which we were able to provide.

An STDM conversion was required to prepare the data for submission. Our biostatistics experts collaborated with the sponsor team early in the study and provided insight on what the data should look like. This proactive approach helped ensure that data capture and preparation was efficient and effective and ultimately made the trial a great success!

Are Digital Health Technologies Worth It? A Frank Assessment.

Kathy Zheng, MPH, Senior Project Manager, PROMETRIKA, LLC.

Without question digital health technologies are revolutionizing clinical development and execution. From electronic patient reported outcome (ePRO) systems to wearable devices, they can, when used properly, provide many benefits, including:

  • Accelerated trial timelines
  • Increased data accuracy
  • A patient-centric approach to data collection
  • Improved treatment adherence
  • Increased ability to study rare diseases

However, it is unwise to assume that a digital health solution is the right solution in every trial or for every aspect of a trial. There are many factors that must be considered before deciding how a study should be administered and what tools should be used.

Who is the patient population?

Rather than first asking “Can a digital solution work in this trial?” the initial question should instead be “Can a digital solution work for these patients?” Technology that makes the job of the sponsor or CRO easier while making participation more difficult for patients should, of course, not be used.

One of the more obvious delineations here is studies involving younger versus more mature populations. The former is likely comfortable with technology, having been born in an era when it is pervasive. The latter may find the use of digital tools challenging and even intimidating. Something as commonplace as a touch-screen interface, for example, may be unfamiliar to more mature populations.

And, of course, age is just one example of a factor that might affect the type of technology that can be effectively employed. There are many others. Patients with fine motor skill challenges or limited vision would find a small digital device difficult or impossible to use, for example. Ultimately, determining the appropriateness of digital solutions for a patient population is of paramount importance.

Can and should devices be integrated with the EDC?

In many cases, mobile health (mHealth) devices can be integrated with EDC systems. This can happen in one of two modalities. The first is full integration. Often used when immediate feedback is advantageous, it allows data captured by the device to be transmitted to the EDC in real time or when the device syncs. The second, appropriate when a large amount of data is captured and is not needed immediately, is batch uploading.

However, the fact that integration may be possible doesn’t necessarily mean it should be pursued. That decision should be based on protocol and technical considerations. Questions related to the protocol include:

  • Is the data needed for eligibility assessments?
  • Must the data collected from mHealth devices be checked against other clinical endpoints being captured in the EDC?
  • Is it important that data be available in real time?

Technical considerations include:

  • Does the EDC have an open application programming interface (API), which is required for integration?
  • Does a member of the study team have the technical skill available for creating this integration?
  • Can the EDC system accommodate the needed page type?
  • Is there enough time to complete the integration?

In short, integration is most appropriate when mHealth data 1) is needed to make real time decisions, 2) is key for primary endpoint evaluation, 3) is needed to provide context for the assessment of other data in the EDC, and 4) is discrete and manageable.

Integration is not ideal when data 1) is not required for decision making during the study, 2) is not necessary for primary endpoint evaluation, 3) is being cleaned by the mHealth vendor outside of the EDC, or 4) is continuous and therefore voluminous. And, of course, integration should also be evaluated in the context of the study timeline and cost.

Is more data better?

Digital solutions have the ability to collect literally millions of data points per subject per day. This presents obvious opportunities but also a number of challenges.

For example, how great is the potential for true data signals to be lost in the “noise” of a huge volume of data? And, can the EDC system manage the volume of data that the mHealth devices will be delivering? Some of the more robust systems are designed to handle extremely large datasets, but in an effort to control costs, many studies rely on a more basic version that will be unable to accommodate all the data produced.

In some situations, it may be that less truly is more.

Are there creative solutions to existing challenges?

While the use of digital health technologies comes with very real challenges, in many cases, there are solutions for them. For example, EDCs can be designed to capture data only at certain intervals, making huge volumes of data smaller and more manageable. Or, the handling of data can be entirely outsourced to the mHealth provider, who in some cases will have data management and or biostatistics expertise in-house.

Digital health technologies are here to stay. With proper forethought on when, where, and how they should be used, sponsors, CROs, and patients can maximize the benefits they deliver.

The Continuing Evolution of the Clinical Data Manager Role

Stacy Surensky, CPC, Director CDM, PROMETRIKA, LLC

Last year in our blog post titled “The New Clinical Data Manager,” we wrote about some key changes to the clinical data manager role that have taken place in recent years. What is fascinating to me is the pace at which the versatile position continues to evolve. Having worked on both the sponsor side and the CRO side in various Clinical Development roles, I have never seen this role change as rapidly as it is changing today.  To stay ahead of the curve there are five critical areas of growth that I believe all data managers need to be aware of:

  1. The acceleration of clinical trials due to new technology

Sponsors and CROs today are striving to accelerate the pace at which clinical trials are conducted, analyzed, and reported on in order to shorten the time to market for new treatments. And increasingly they are looking to technology for assistance in generating, collecting, cleaning, and analyzing data. EDC and use of Data Visualization tools are prime examples.

With EDC systems reducing the need for manual data cleaning, we CDMs find ourselves having to manage ever-larger volumes of increasingly complex information and needing to ensure that it is analyzable. Mobile health data will be adding to this flow, and we must be prepared for how to incorporate this sometimes less-than-perfect data into studies. Rather than solely focusing on the individual data points one at a time, we are being asked in our new role to look at the data as a whole. This is a major change, and it necessitates a greater level of collaboration with site monitors and biostatisticians than ever before, placing a new premium on our communication skills.

Continuous evolution and affordability of technology in clinical development puts a high demand on data managers to utilize the most recent technology advances for the benefit of clinical trials and subjects.  Patient-centric environment and a public demand for pharmacoeconomic data drive ever more frequent utilization of ePRO and wearable devices in a broad variety of indications. Today, CDMs are keen on integrating validated technology solutions for comprehensive data collection, leading the way to the future of Clinical Development.

  1. Cross-functional collaboration

There is a need to better collaborate across the many functions within a trial. This can be a tremendous challenge considering that, depending on the type of study and the way the CRO and sponsor are staffed, teams may be working for different types of organizations. Additionally, study teams can include anywhere from five to 10 or more different functional roles.

Both within a CRO and extending to the trial sponsor, the need to replace the silo mindset of the past with a more interactive, communicative approach has never been greater. Even very basic steps like conducting an online eCRF review session before the data collection and cleaning tools are finalized and having regular meetings as the study progresses help ensure that the aggregate knowledge of the group is leveraged most effectively. In particular, having the CDM, the CRAs, and the clinical project manager connect more frequently is imperative.

With the introduction of Risk-Based Monitoring and targeted SDV, a critical need to collaborate with the clinical teams in a new capacity spirals to new heights.  With the CRAs spending less time verifying source data, the Data Management teams take center stage leading the data quality assurance using smart tools and technology.  Collaboration with our clinical colleagues to co-create carefully calculated and executable Data Quality plans are a key step leading to data integrity and ability to accelerate data locks.

  1. Moving from a peripheral role to a pivotal one

In the past, the expectations of the CDM position limited the data management role to data review. Today we have taken on a more central position in clinical trials. While the majority of our time is still spent on the verification, clarification, and validation of data, with the advent of risk-based monitoring, we now play a pivotal role in focusing attention on problematic data sources (sites, countries, specific CRFs) early on in an effort to mitigate their impact on data integrity.

For example, the CDM can point out sites that are slow to provide data after a patient visit, that change data points frequently, fail to respond promptly to queries, or have many protocol deviations. In short, we are tasked with helping troubleshoot trials, but that requires having a much more comprehensive, “big picture” understanding of how the protocol was developed, how the data is being collected, a solid understanding of data quality standards, data trends, and the sponsor’s goals.

Also, more and more today our overall grasp of the data is resulting in other functional roles looking to us for our insights on other key advancements in Clinical Development, such as Real World Evidence (RWE), trial feasibility management, market access, pharmacovigilance, and genomics. As the experts in the unique position of being most familiar with the data while also understanding the trial’s parameters and goals, we are increasingly getting the opportunity to present the data and manifest our contribution to the study.

  1. Project management skills

As the role of the CDM continues to evolve, it is clear that we will benefit from having essential project management skills that were not as critical in the past. As each step of a trial is progressing, there is a trend to expect CDMs to be ready to provide immediate answers as to how accurate and complete the data is, and to lock the database as soon as the last subject has completed the study. This requires us to have an in-depth understanding of study endpoints, a good grasp of the project contingencies, advanced prioritization, and time management skills.

In fact, that expectation has begun to affect hiring decisions. Project management experience is now frequently included as a prerequisite on job postings for CDMs. Even when it is not specifically mentioned, savvy job seekers understand that a background in project management – everything from scope and timeline management to quality control – will increase their chances of landing an interview.

  1. Critical thinkers

People in other roles within the trial want to be reassured that we are looking critically and comprehensively at the data. They need us to help them interpret what the metrics mean, what trends are being revealed, and how the data trends can best be used for clinical decision making. That starts with fully understanding the study protocol.

This requires more than just reading it. We must intellectually dissect it, researching the clinical indications, leveraging our familiarity with similar protocols, consulting with our cross-functional colleagues, and calling on whatever other resources it takes for us to master the subject. Our teammates often look to us to understand the clinical meaning of the data points and coded terms, not in isolation, but in relation to one another. This depth of comprehension can’t be gained by simply searching the protocol for keywords and reviewing a schedule of assessments. There is a role for us to share our own insights and provide input to the best data collection practices based on our expertise.

A Bright Future for CDMs, CROs, and Study Sponsors

I find the expanded responsibilities of the new CDM role to be both challenging and exciting. With greater responsibility comes increased recognition and opportunities for career advancement. More importantly, there is a greater sense of contribution and accomplishment.