Juliet Moritz

	Duchenne muscular dystrophy (DMD) patients almost universally lose the ability to walk as the disease progresses. Patients generally understand that loss of ambulation is to be expected, and as was learned from a patient preference study, they tend to put greater priority on maintaining use of their hands. Yet for many years, DMD drug trials included a specific endpoint requiring that they enroll only patients who were still able to walk-denying eligibility to a potentially large number of participants.

	That changed when a DMD-focused advocacy organization took the matter up with the Food and Drug Administration (FDA) and helped develop new trial guidelines that allow some non-ambulatory patients to participate in these trials.

	Engaging patients in clinical trial design is essential to ensuring that researchers devise relevant criteria, establish realistic expectations, and pursue goals that are meaningful to the study participants who are central to the success of these costly and risky endeavors. The expanding number and influence of patient advocacy groups in recent years-the National Organization for Rare Disorders lists nearly 1,900 such organizations

on its website-underscore the fact that patients are not passive subjects, but people who approach clinical trials with varying degrees of hope, fear, doubt, skepticism, anxiousness, and countless other emotions.

	Some may find symptom relief or even a disease modifying therapy, while others won’t have the same outcomes. Some recognize that the study drug won’t benefit them personally, but enroll so they might help others. What unites patients and families who participate in clinical trials is their willingness to sacrifice their time, energy, and so much more for an exercise whose outcome is uncertain at best.

	Major factors driving the need for thoughtful, effective, sensitive patient engagement include a sharp increase in the amount of drug research, changes in the regulatory environment that welcome and even mandate patient input into clinical development, and the growing complexity of trial protocols.

	The number of registered studies worldwide has surged in the past 15 years from 8,859 in 2004 to 319,841 in October 2019, according to ClinicalTrials.gov.

And these trials are more complex than ever. Data collected by the Tufts University Center for the Study of Drug Development

comparing Phase III pivotal trials from 2001-2005 and 2011-2015 shows:

		The number of investigative sites increasing by 63% and the number of countries by 100%

		Procedure costs per patient per visit up 34%

	Yet amid all that activity, the number of patients randomized 

18%, reflecting the growing challenge of recruiting and retaining patients for the exploding number of trials. It doesn’t help that trials are becoming more selective-during the same period, patient eligibility criteria increased by 61%.

	Changing U.S. government policy and a greater industry emphasis on pursuing orphan drugs translate to more studies being launched that require fewer participants to answer their main research question. A review of drugs approved in 2018

by the FDA’s Center for Drug Evaluation and Research shows that the 34 rare disease treatments authorized accounted for more than half of total novel drug approvals for the year-a historic high since the Orphan Drug Act was passed in 1984.

	There’s a lot of talk about “patient centricity” these days, and it’s easy to see why with stats like these. Sponsors and contract research organizations (CROs) are hiring patient engagement experts and even creating entire departments to sharpen their ability to design and execute trials that minimize the burden of participation to patients and their families as competition grows more intense and trials demand more from the volunteers they depend on.

	Clinical research can require significant commitments of time and energy on the part of trial participants. Blood draws, more frequent or intense monitoring of symptoms, diary entries, follow-up visits-and in some cases, long-distance travel-can take over a patient’s life and put major burdens on family members and caregivers. The difficulty is compounded in pediatric trials when there may be demands on time associated with school and, often, managing the needs of other children in the family. Most families have their hands full juggling children, careers, and life in general, and entering a clinical trial can stretch them beyond the breaking point.

	In this environment, anything sponsors and CROs can do to be accommodating and meet patients and families where they live can mean the difference between whether a patient enrolls or declines a potentially life-changing opportunity.

	Being patient-centric also means understanding what actually matters to patients, and thereby being equipped to design and execute better development plans and trials. As in the muscular dystrophy example, industry must look to patients and their families to make sure it’s pursuing the right goals-understanding the disease burden and what living with the condition is really like. Listening to patients might mean the difference between developing a therapy that changes a numerical value in a lab somewhere and one that produces improved medical or functional outcomes with real-world clinical benefit.

	Having a meaningful level of engagement also helps patients approach trials with realistic expectations. Even if a therapy shows significant benefit, people looking for a cure will often be disappointed. That’s especially true with precision treatments designed to treat rare diseases-for example, gene transfer therapy that may address some but not all symptoms of a condition, or an advanced therapeutic medicinal product that may have troubling side effects.

	Patient advocates play an increasingly central role in patient engagement. “Patient advocacy group” is a broad term that describes everything from organizations with large staffs and sophisticated fundraising capabilities-organizations that raise millions of dollars and heavily influence government policy-to distraught parents working to raise awareness of a condition that has thrown their lives into disarray. Regulators actively encourage the work of these groups: the FDA through the 21

Century Cures Act (and earlier via FDASIA, 2012 FDA Safety and Innovation Act) and the European Medicines Agency through its framework for interaction among the EMA, patients, and consumers.

Century Cures Act addresses greater use of patient experience data in the drug development and review process. Likewise, FDASIA was founded on the agency’s conviction that involving patients or their caregivers in drug development can produce better outcomes. 

	The EMA, through a 2014 revision of its framework on stakeholder interaction, aims to better understand the real-life experiences of patients and their use of medicines, more efficiently communicate with patients to support safe and rational use of treatments, and improve patient advocates’ understanding of the role of European Union drug regulators.

	For patients and families, there are many potential benefits associated with engaging with patient advocacy groups. Among them:

		Access to the available and constantly evolving research on a disease or condition

		Contributing to the understanding of the disease through natural history studies or registries

		Updates on medical and regulatory developments

		Identification of fundraising opportunities

		Support for patients and families as they confront the daily manifestations of a life-limiting condition

	In pediatric conditions, strategies for working with schools, some of which can be less than accommodating of students’ special needs

	Beyond information access, fundraising expertise, and other typical reasons people join patient groups, these organizations do important work to advance the availability of groundbreaking treatments. Through the FDASIA legislation, the FDA mandated a five-year Patient-Focused Drug Development program to learn from patients about the impact of diseases on their daily lives, and it convened numerous public meetings on specific disease areas. It also set up a public-private working group to advise the FDA on creating a risk-based regulatory framework on health information technology. Indeed, even though the authorization for FDA-led PPFD meetings expired in 2017, the agency encourages and participates in externally-led PPFD meetings which continue to the present.

	Another practical need for engaged patients and families is the process that yields insurance reimbursement decisions. If drug developers do not work with patients and families, they can’t fully appreciate a potential therapy’s value to the community for which it is being developed. And if they don’t understand what the value is, they can’t make their best case to a reimbursement body or insurance company to make the therapy available to patients who need it. That might lead to reimbursement being denied, delayed, or granted conditionally pending further patient input.

	Involvement with advocacy groups can take many forms, from helping with fundraising to petitioning government leaders in support of policy initiatives. Some people take their advocacy to heroic levels-people like Sharon King, who founded Taylor’s Tale after her daughter was diagnosed in 2006 with a sub-type of Batten disease called CLN1, one of a group of rare and always fatal nervous system disorders.Taylor died in 2018, but her mother continues to run the organization in support of the overall rare disease community.

	While advocacy groups can open important doors, patients and families can be wary about aligning with these organizations. It’s a highly personal decision, and patients have cited a number of reasons to hesitate, the foremost being privacy concerns. Some people are just not comfortable sharing intimate details with strangers, in part because they may fear being stigmatized socially, while others worry about data privacy in an era of frequent online hacks and data breaches. 

	In truth, there are few well-founded privacy worries. The membership rolls of advocacy groups are kept confidential, and most of these organizations do not share information externally, and certainly not without first getting permission from the patient or the patient’s legal representative. 

	Industry is adapting as it takes cues from patients, families and advocates on where and how to best connect with them in the rare disease conversation. Film festival sponsorship is one such example. Disorder: The Rare Disease Film Festival

, held in San Francisco in November, featured more than 50 films from the rare disease community worldwide. It was the second edition of this event, founded in 2017 by two fathers of children with rare diseases. The first was held in Boston and featured about 30 films, mostly documentaries, addressing two dozen diseases. The films, ranging in length from two minutes to longer than an hour, told stories of sacrifice, financial challenges, pain, joy, and hope.

	“We created this festival after asking, ‘Who is the best audience for those awareness efforts?’” said Daniel DeFabio

, a festival co-founder whose daughter suffers from the USP7 gene mutation. “We wanted to get the right people in the same room sharing these stories: the patients, the advocates, the researchers, and industry.”

	Researchers writing in the National Institutes of Health’s Annals of Translational Medicine

described the need for patient engagement and advocacy succinctly, “We need to avoid having patients and advocates being viewed as token requirements, and lead by including them as an active part of the research team that provides unique perspectives and fulfills roles that most scientists and researchers cannot.” And the earlier engagement with patients begins, the better. By talking with patients, their caregivers, and their advocates early, industry can design and execute studies that close the gap between marketing authorization and the reimbursement decision while reducing the burden on patients and their families.

Vice President, Patient and Stakeholder Engagement, Rare Disease & Pediatrics at 

https://rarediseases.org/for-patients-and-families/connect-others/find-patient-organization/

https://clinicaltrials.gov/ct2/resources/trends

https://www.bioworld.com/content/tufts-clinical-trials-face-tough-going-data-densities-grow-0

https://www.mdmag.com/conference-coverage/nord-2019/approvals-rare-diseases-reached-historic-high-2018

https://www.rarediseasefilmfestival.com/about2

https://premier-research.com/blog/disorder-premier-research-sponsors-rare-disease-film-festival/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985270/

Articles

For years, Duchenne muscular dystrophy drug trials included a specific endpoint requiring that they enroll only patients who were still able to walk. That changed when a DMD-focused advocacy organization took the matter up with the FDA and helped develop new trial guidelines.


Patient Engagement and Advocacy: Advancing the Cause of Clinical Drug Research

, an organization run by the National Institute of Health’s Office of Rare Disease Research, and you’ll find a listing of 22 research consortia that together comprise more than 130 patient advocacy groups. There’s also a Data Management and Coordinating Center for collection, storage, and analysis of data from researchers who work across the rare disease spectrum. The group is currently researching more than 200 diseases and has worked with nearly 44,000 patients to date.
	
	One of those 130-plus consortia, the Lysosomal Disease Network alone consists of 35 organizations that specialize in various aspects of lysosomal storage disease - disorders that render the body’s cells unable to produce an enzyme that breaks down large molecules. Those 35 groups today are studying 42 specific disorders with strong support from the patients and family members who endure the devastating consequences common to these afflictions.
	
	Thirty years ago, it was a much different world. Patient advocacy groups were far fewer in number and impact, their work relegated largely to promoting awareness, raising money, and helping drug companies promote clinical trials. It wasn’t until a not-so-rare disease - the HIV and AIDS epidemic of the 1980s - that advocates took on a more substantial role. In particular, 1988 stands out as the year that the FDA began working with AIDS activists and awakened to the power of patient engagement.
	
	

	It did not happen quietly. In 1988, AIDS activists staged a Columbus Day rally at the Department of Health and Human Services in Washington, D.C., and the next day seized control of the FDA headquarters in suburban Maryland. The highly publicized unrest focused the nation’s attention on the AIDS crisis and gave rise to productive dialogue between the agency and the patient community.
	
	Three years later, the agency began recruiting patient advocates into its Patient Representative Program, which coordinates recruitment, training and retention of patient representatives who have direct experience with diseases. Today, the program claims members who are knowledgeable and experienced in more than 300 diseases and conditions, sit on 47 FDA advisory committees and panels, and serve as voting members - and it’s actively recruiting people who have been diagnosed with, or who have advocacy experience with, 16 conditions.
	
	But probably the greatest impetus for expanding the advocate role is FDASIA, the FDA Safety and Innovation Act of 2012. The law specifically requires the agency to develop and implement strategies to solicit patient viewpoints during the development of medical products and to consider patient perspectives during regulatory deliberations. It also authorizes the FDA to collect industry user fees to fund reviews of drugs, medical devices, and biosimilar biological products; promotes innovation to speed access to safe and effective products; and enhances the safety of the drug supply chain.
	
	FDASIA mandated the institution a five-year Patient-Focused Drug Development program to learn from patients about the impact of disease on their daily lives and convened numerous public meetings focused on specific disease areas. It also set up a public-private working group to gather input from a variety of stakeholders and experts to advise the FDA on creating a risk-based regulatory framework pertaining to health information technology.
	
	A couple of other FDA firsts:

		In 2001, the agency began seeking patient input on early development of medicinal products, and 2012 saw the debut of the FDA Patient Network. With more than 200 patients, caregivers, patient advocates, and disease-specific advocacy organizations, the network facilitates patient engagement with agency decision-makers and educates people about how new medications and medical devices move from concept to market.

		Agency guidance issued in 2015 on treatment of Duchenne muscular dystrophy marked the first time the FDA published recommendations initially composed by a disease community. Advocacy group Parent Project Muscular Dystrophy led the preparation of the document, drawing on input from patients, parents, caregivers, clinicians, academic experts, and representatives from the pharma industry to draft what frames the agency’s current thinking on the subject. Never before had an external organization made such a profound impact on U.S. government drug policy.

	Parent Project Muscular Dystrophy is one of a relatively new breed of advocacy organizations - large and sophisticated, with big budgets and lobbyists and run by boards of directors. At the other extreme are shoestring organizations, in some cases no more than a couple of parents just trying to raise money to fund research and hope. Wherever they fall in this continuum, all these organizations share a commitment to being involved - by supplying us with data and by taking on the role of research partner.
	
	I frequently encounter people from these organizations as I travel, and a clear common denominator is a deep commitment to their causes. They view their relationship with pharma companies and CROs as very much a two-way street and want to know how the data they’re supplying is being used. They want seats on advisory boards and committees and seek input into trial design and execution. In short, they want -and I believe they deserve - insight into the end game. Recognizing the potential benefits from this emerging partnership, organizations that provide trial funding have begun to insist on participation from advocacy groups.
	
	Industry has moved far beyond treating an advocacy strategy as a “nice-to-do” and is doing more to engage with these groups up front and make clear exactly what we want from them - and what we’re willing to give back. These very positive trends are leading to highly productive dialogue that is advancing the cause of scientific discourse. 

, representing biotech companies in New Jersey, observes that many biopharmaceutical companies have established patient advocacy functions within their corporate structures - recognizing that sound relationships with advocates “foster relationships with patients, their caregivers, and the disease-specific nonprofit advocacy groups that support them.”
	
	About a year after FDASIA was formed in 2012, the FDA created a working group to address its goals of expanded patient participation in medical product development. The group sought public input on the subject in late 2014, gathering 185 comments from patients, advocacy groups, and industry trade organizations. In January 2016, the agency 

 summarizing the comments in five major categories:

, including creation of a central office to advise the FDA commissioner on patient engagement activities. The agency wants drug companies and researchers to more actively listen to patients, and for good reason. Researchers sometimes focus on measures of progress that may not really be meaningful to the people we’re trying to help. For example, establishing an endpoint of alleviating symptoms when all the patients really want is for their symptoms to stop getting worse.

 to promote early interaction between the FDA and sponsors, and clearer guidance on interactions between patients and manufacturers to facilitate collaboration in the early stages of R&D.

, including a regular report that summarizes participation in the Patient Representative Program and increased transparency in how patient input is evaluated and incorporated into agency decision-making. Also recommended: a patient data collection tool that organizes issues by disease area and facilitates communication among organizations.

, such as expanded use of patient-centered and patient-reported outcomes on such measures as physical function and quality of life - much like what the EMA has done in its Patient-Reported Outcome qualification process.

 to promote cooperation among patients, industry, clinicians, the scientific community, and the FDA.

	Patient advocates are “witnessing a shift in the culture of drug development,” with sponsors and regulatory agencies showing more interest in incorporating the perspectives of patients, the nonprofit EveryLife Foundation for Rare Diseases declared in a 

 that proposed a framework for patient engagement. The authors correctly assert that, in the face of limited quantitative information, greater patient involvement and input are necessary to achieving higher drug development success rates, new therapeutic options, and improved health outcomes.
	
	

 is Executive Director of the Strategic Development Department of Rare Diseases, Premier Research

Patient advocates are witnessing a shift in the culture of drug development as sponsors and regulatory agencies show more interest in incorporating patient perspectives.

Juliet Moritz

Articles

Patient Engagement and Advocacy: Advancing the Cause of Clinical Drug Research

Drug Developers Embrace the Rising Prominence - and Influence - of Patient Advocacy