4

Patient Benefit and Engagement

Patients know more about their diseases than anyone else and, thus, they have much to offer any conversation about the value of any given drug, weighing risks versus benefits, and other key issues, emphasized several workshop participants. Many factors contribute to a drug’s worth, and the relative importance of each one will vary greatly from drug to drug and patient to patient. In addition, participants discussed the unique

opportunities public−private partnerships and advocacy groups have insofar as contributing to the endeavors discussed during this workshop.

PATIENT INVOLVEMENT: UNDERSTANDING RISKS AND BENEFITS

Throughout the workshop, many participants stressed the importance of including patient viewpoints on key discussion points in the drug development process, such as whether to get a drug on the market quickly or take longer to ensure safety, and how to weigh the advantages of increased market protections with the associated disadvantages of delaying availability of less expensive generic agents. Several participants discussed the unique and indispensable input patients can contribute into determining the value of a given treatment. “The notion of benefit–risk . . . has to reflect the end user,” said Marc Boutin, who emphasized that patients should be engaged from the very beginning of drug development. “Everyone in this room has a Smartphone,” said Boutin. “There is no company—Apple, Samsung, you name it—that would even change the color of that product without consulting the end user first. And yet in drugs and biologics, you do not consult with [patients] until post-market or at best Phase III. We can change that paradigm.”

Lauren Chiarello, senior director of federal government relations at the National Multiple Sclerosis Society, said that acceptable risk will differ depending on the illness, an individual’s disease trajectory, prognosis, personal choice, and numerous other issues. For example, the particular symptoms a person is encountering “can really dictate your risk/benefit tolerance,” she said. Furthermore, reaction to health status can change. A new diagnosis might shock a person, yet later, that same individual might learn how to accept and live with it.

MS currently has 12 disease-modifying therapies; however, none of them can stop or treat the illness (NMSS, 2015). Chiarello pointed out that a few months of approval time are significant for a person who is living in a wheelchair. “I know that a lot of those patients are looking for something similar to an accelerated approval pathway to help shorten this time, should there be a breakthrough for someone whose current therapies are not working,” she said. Chiarello gave a fairly recent example of individuals’ willingness to assume risk. A drug called Tysabri was put on the market, and 4 months later was removed because it put some people at risk for a condition called progressive multifocal leukoencephalopathy

(PML), which is often fatal. There was an outcry because many MS patients wanted access to this potent drug, one of the most effective compounds on the market, despite its potential drawbacks. For an MS patient, the small risk of a potentially fatal side effect, such as the possibility of developing PML, is balanced against the possibility of 2 years of freedom from a wheelchair and the hope that another new treatment will extend mobility down the road, said Gail Maderis. Patients want to be able to drive their risk decisions, Chiarello said, and have the relevant conversations with their health care providers. The drug has returned to the market and the manufacturers have instituted a risk minimization program for PML.¹

Legislation Encouraging Patient Involvement

Prescription Drug User Fee Act

Chiarello emphasized the importance of patient involvement for drug development, and noted that the most recent round of Prescription Drug User Fee Act² reauthorization called for increased patient participation in the drug review process. She suggested that expanding that enterprise to collect more information about the needs of patients would be beneficial as well. Maderis reinforced and extended this point. We often think of value in terms of the risk/benefit trade-off for patients, she said, and that varies from disease to disease and from patient to patient. For example, a newly diagnosed Alzheimer’s disease patient who is faced with the prospect of taking a new treatment with limited clinical data or the possibility that he or she might not recognize an unborn grandchild might opt to take the new treatment. Different people might make different choices in those situations, said Maderis.

21st Century Cures Act

In the latest version of the 21st Century Cures Act, patient involvement in drug development is discussed. Many participants observed that patients understand their illnesses better than anyone else, and the draft legislation proposes that FDA establish a way to incorporate patient ex-

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¹See http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/-UCM107197.pdf (accessed April 22, 2015).

²See http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM2005475.htm (accessed April 22, 2015).

perience into the regulatory decision-making process. Patients might register their opinions about, for instance, how heavily to weigh potential benefits versus risks associated with new treatments. Individuals (even those who have the same disease) vary in their willingness to accept any particular risk in exchange for any potential benefit. The legislation calls for FDA to deploy a process by which companies submit patient experience data that would be considered during the approval process.

Even with new incentives for developing drugs that address unmet medical needs, several participants stated that novel treatments will only move slowly toward patients unless clinical trial times are shortened. The 21st Century Cures Act attempts to strengthen the ability of companies to harness surrogate markers to assess efficacy in clinical trials. Formally qualifying such endpoints might encourage their use because companies would have more confidence that FDA would accept them during the evaluation process, said several participants, including Stevin Zorn, executive vice president at Lundbeck Research USA, Inc.

Furthermore, a few participants noted that FDA would be authorized under the legislation to approve drugs based on early safety and effectiveness data. Information about the effects of a given treatment continues to amass after FDA approval, and the 21st Century Cures Act attempts to harness that knowledge. It includes mechanisms for companies to communicate, so treatments whose known efficacy expands after initial approval can be used efficiently in new settings. Several participants noted that the idea is to optimize patient care while retaining appropriate safeguards. Then, the agency could hold companies responsible for assessing these features of drug use after it goes on the market. If companies fail to deliver on such post-marketing requirements, FDA could withdraw drugs from the market.

DETERMINING VALUE TO PATIENTS

Value can also be viewed in economic terms by patients—for example, in terms of the ability to keep a job or live life independently without the cost of caregiving services. Although value calculation from the patient perspective is complicated, drug development speed matters, said Maderis. The time to get to new treatments is absolutely crucial. Time equals life or quality of life for people with neurodegenerative diseases, she said. From the payers’ standpoint, the situation is equally complicated, said Maderis, and does not necessarily align with the patient view-

point. For many illnesses, prevention or early intervention leads to lower health care costs, so there is inherent value in treating disease early. Most neurodegenerative disorders, however, do not follow that trend, noted several participants. The costs associated with dementia often are not borne by third-party payers, but by family members who provide care (Thraves, 2014). The economic benefits of delaying progression may bestow mainly on the patient or the family. From a broader societal standpoint, the value equation is clearer. New treatments cost the health care system money, but the value in reducing disability payments, increasing gross domestic product, and generating income taxes is significant. The upshot is that time matters for patients and for society.

Delaying Disease Onset Could Save Billions of Dollars

Adelina Comas-Herrera, research fellow at the London School of Economics and Political Science, talked about the importance of measuring the value of drugs before considering whether they deserve preferential treatment in the patent system. Performing this assessment is not necessarily straightforward, and different appraisal schemes might lend themselves to different diseases. To illustrate this point, she used the example of AD.

DALYs do not properly measure the effects of AD for several reasons, noted Comas-Herrera. First, drug trials generally do not measure the impact of the treatment on caregivers (productivity, well-being, etc.), which can have economic implications (see Chapter 1). Furthermore, measuring the quality of life of someone with moderate to severe dementia is difficult. Research has demonstrated that people with severe dementia score higher on quality-of-life outcomes than do people in a moderately impaired state (Hounsome et al., 2011). Comas-Herrera suggested that those afflicted with severe dementia do not seem to care much that their cognition is worsening. They report stable quality of life that varies by degree of depression and anxiety, but not by degree of cognitive function (Hoe et al., 2009). A logical, but problematic, conclusion might be that someone with severe dementia is doing “better” than someone with moderate dementia, said Comas-Herrera. Furthermore, a drug that improves cognition might not improve quality of life, whereas such a drug could significantly reduce the amount of care a person needs. Economists who are trying to evaluate drug benefits have many of the same methodological problems with the information provided by pharmaceutical companies. William Fisher suggested that the solution is to

refine the metrics rather than to abandon the DALYs approach entirely. The challenge, he said, is to better define assessments of quality of life.

Although many uncertainties limit economic forecasts, the care of people with dementia will cost much more in the future than it does today without new therapies, said Comas-Herrera. Dementia is not just an issue for developed countries; it is a global problem (see Figure 4-1). Its prevalence is increasing more quickly in low- and middle-income countries than in high-income countries. The Alzheimer’s Society has estimated that dementia costs the United Kingdom £26.3 billion per year ($40.4 billion), £11.6 billion ($17.8 billion) of which is borne by unpaid family caregivers (Prince et al., 2014). The situation is similar in the United States (Hurd et al., 2013). Comas-Herrera discussed a project that models the hypothetical impact on health and social care costs by 2040 of a new treatment for AD (see Box 4-1).

FIGURE 4-1 Number of people with dementia in low- and middle-income countries compared to high-income countries.
SOURCE: Prince et al., 2013; presented by Comas-Herrera at the IOM Workshop on Financial Incentives to Support Unmet Medical Needs for Nervous System Disorders, January 21, 2015.

CREATIVELY ENGAGING PUBLIC−PRIVATE PARTNERSHIPS, ADVOCACY GROUPS, AND NONPROFIT HEALTH ORGANIZATIONS

Public−private partnerships, advocacy groups, and nonprofit health organizations can help foster, enrich, and inform activities aimed at developing pull incentives for drug development in the neurosciences, according to many participants. Such outlets provide a mechanism for facilitating conversations among patients about appropriate trade-offs between potential risks and benefits, and for collecting and communicating relevant information to government agencies.

Similarly, public−private partnerships, advocacy groups, and nonprofit health organizations have the opportunity to contribute to proposals for market protections and other measures. They could provide expertise on particular diseases that might inform relevant discussions, according to a few participants. In the end social benefits are what matter, Steven Hyman said, and they differ from disease to disease. He provided the example of depression and the search for a treatment more efficacious than imipramine (a tricyclic antidepressant), which was first produced in 1957. Ideally, incentives would be created for the development of a drug with a novel mechanism of action that delivers more benefit to individuals with depression. For AD and PD, in contrast, incentives

would be generated for prevention trials. To maximize social benefit, different contexts need to be considered, said Hyman.

Advocacy agencies and nonprofit health organizations might even function as venture groups in certain settings, said Kiran Reddy. If a company does not have the internal resources to pursue every promising drug candidate, it might choose to partner with an advocacy group (or another company). Biogen is already exploring such arrangements in its work on AD. Along the same lines, Boutin mentioned that members of the National Health Council, an umbrella organization for patient advocacy groups, work with NIH-funded researchers who had products that showed great promise for treating particular conditions, but insufficient patent protection to bring to market.

Advocacy groups can potentially have significant impact by lobbying for what they consider appropriate measures. The Honorable Patrick Kennedy proposed that people rally around a “race to inner space” that would “unlock the mysteries of the mind and pave the way for therapies and cures for the most disabling of all illnesses, CNS illnesses.” He strategized about how to assemble the equivalent of a NASA—an enterprise whose mission is to foster and support exploration of the brain rather than outer space—and emphasized the notion that such a venture must be a collective movement. It is time, Kennedy said, for groups that focus on individual nervous system disorders to join forces. “We have been so siloed by our diagnoses that we have failed to see that we have a more common cause,” he said.

Kennedy charged workshop participants and their organizations with developing a proposal and then getting politicians to “go to [Capitol] Hill and the American people and make this case in the kind of way that hits not only our minds, but hits our hearts as well.” He said that the issue is politically “bankable” because so many citizens are touched by brain disorders.

OPPORTUNITIES TO ENCOURAGE PATIENT INVOLVEMENT IN THE DRUG DEVELOPMENT PROCESS

• Encourage patient engagement with FDA to (1) address the risk/benefit trade-off between desired treatments and tolerable side effects, and (2) alleviate any other ethical concerns that arise (Boutin, Chiarello, Maderis, and others).

• Develop standardized definitions of value and allow patients to decide whether they want to pay more for a particular drug (Comas-Herrera, Longman).
• Work to creatively engage public−private partnerships that can advance and enhance “pull” incentives by providing patient input, building political will, and contributing other crucial resources (Boutin, Chiarello, Kennedy, and others).