Financial Incentives to Encourage Development of Therapies That Address Unmet Medical Needs for Nervous System Disorders: Workshop Summary (2015)

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4 Patient Benefit and Engagement Highlights • Patients and caregivers can provide crucial information about what kind of risks they would be willing to accept in exchange for a possible new therapeutic agent in any given clinical situation (Boutin, Chiarello, and Maderis). • Value determinations for potential treatments might include con- sideration about impact on caregivers as well as patients; preven- tive medicines—including those that delay onset of serious nervous system disorders—can deliver tremendous benefits to pa- tients and caregivers alike (Comas-Herrera). • Public−private partnerships and advocacy groups could contribute significantly to activities that might bolster pharmaceutical company pursuit of CNS drugs (Boutin, Hyman, Kennedy, and Reddy). NOTE: These points were made by the individual speakers identified above; they are not intended to reflect a consensus among workshop participants. 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 51 

52 FINANCIAL INCENTIVES opportunities public−private partnerships and advocacy groups have in- sofar 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 de- velopment 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 availabil- ity 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, prog- nosis, personal choice, and numerous other issues. For example, the par- ticular 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 thera- pies 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 

PATIENT BENEFIT AND ENGAGEMENT 53 (PML), which is often fatal. There was an outcry because many MS pa- tients wanted access to this potent drug, one of the most effective com- pounds 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 free- dom from a wheelchair and the hope that another new treatment will ex- tend mobility down the road, said Gail Maderis. Patients want to be able to drive their risk decisions, Chiarello said, and have the relevant conver- sations with their health care providers. The drug has returned to the market and the manufacturers have instituted a risk minimization pro- gram 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 pro- spect of taking a new treatment with limited clinical data or the possibil- ity 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 involve- ment 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- 1 See http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInforma- tion for PatientsandProviders/-UCM107197.pdf (accessed April 22, 2015). 2 See http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM2005475. htm (accessed April 22, 2015). 

54 FINANCIAL INCENTIVES perience into the regulatory decision-making process. Patients might reg- ister 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 experi- ence 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, ex- ecutive 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 effec- tiveness data. Information about the effects of a given treatment contin- ues to amass after FDA approval, and the 21st Century Cures Act attempts to harness that knowledge. It includes mechanisms for compa- nies to communicate, so treatments whose known efficacy expands after initial approval can be used efficiently in new settings. Several partici- pants noted that the idea is to optimize patient care while retaining ap- propriate 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 exam- ple, in terms of the ability to keep a job or live life independently without the cost of caregiving services. Although value calculation from the pa- tient 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 complicat- ed, said Maderis, and does not necessarily align with the patient view- 

PATIENT BENEFIT AND ENGAGEMENT 55 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, in- creasing gross domestic product, and generating income taxes is signifi- cant. 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 measur- ing the value of drugs before considering whether they deserve preferen- tial 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 ex- ample of AD. DALYs do not properly measure the effects of AD for several rea- sons, 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 demen- tia is difficult. Research has demonstrated that people with severe de- mentia score higher on quality-of-life outcomes than do people in a moderately impaired state (Hounsome et al., 2011). Comas-Herrera sug- gested 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, conclu- sion 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 phar- maceutical companies. William Fisher suggested that the solution is to 

56 FINANC CIAL INCENTIV VES refine the metrics rather r than to o abandon thee DALYs appproach entirelly. The chhallenge, he said, is to better define asseessments of qquality of life. Allthough many y uncertaintiees limit econnomic forecassts, the care of peoplee with demen ntia will cost much more iin the future tthan it does tto- day without new th herapies, said Comas-Herrrera. Dementiia is not just an issue for f developed d countries; itt is a global pproblem (see Figure 4-1). Its prevalence is increaasing more quickly q in low w- and middlee-income couun- tries th han in high-iincome counttries. The Allzheimer’s Soociety has essti- mated that dementtia costs the United Kinggdom £26.3 bbillion per yeear ($40.44 billion), £11 1.6 billion ($1 17.8 billion) oof which is bborne by unpaaid familyy caregivers (Prince ( et al.., 2014). Thee situation iss similar in tthe Unitedd States (Hurd d et al., 2013)). Comas-Herrrera discusseed a project thhat models the hypotheetical impact on health annd social caree costs by 2040 of a neew treatment for AD (see Box B 4-1). FIGUR RE 4-1 Numb ber of people with dementi a in low- andd middle-incom me countriies compared too high-income countries. SOURC CE: Prince et al., 2013; pressented by Com mas-Herrera at the IOM Worrk- shop onn Financial Inccentives to Sup pport Unmet M Medical Needs ffor Nervous Syys- tem Disorders, Januarry 21, 2015. 

PATIENT BENEFIT AND ENGAGEMENT 57 BOX 4-1 Treating Alzheimer’s Disease: Modeling the Health and Social Costs As part of the Modelling Outcome and Cost Impacts of Interventions for Dementia (MODEM)a project in the United Kingdom, Comas- Herrera discussed a research project that modeled the hypothetical impact on health and social care costs by 2040 of a new treatment for AD. The research team had the following questions: • How many people with dementia will there be from now to 2040, and what will the costs be of their treatment, care, and support under present arrangements? • How do costs and outcomes vary with characteristics and cir- cumstances of people with dementia and caregivers? • How could future costs and outcomes change if evidence-based interventions were more widely implemented? The exercise assumed the following: • A new drug becomes available in 2020. • In 2020, the whole population ages 75 and older is screened (except those already diagnosed) for a biomarker that indicates high risk of developing AD. • The new drug is prescribed to all those who screen positive (plus those ages 65 to 74 already been diagnosed with the condi- tion). • Prescription is for the rest of the person’s life, and does not re- place existing symptomatic AD drugs. The model tested several scenarios, including some combinations of the following variables: the effects of a treatment that delays onset by 1, 3, or 5 years; slows progression by varying degrees, with and without an increase in life expectancy; and delays onset by 3 years and extends the mild and moderate state by 30 percent, with and without an increase in life expectancy. According to the analysis, the most expensive scenario arises if peo- ple remain in the mild and moderate stages of disease and live longer. Delaying onset of the symptomatic phase delivers the largest reduction to health and social program expenses as well as unpaid-caregiver costs. Drugs that delay the onset of the symptomatic phase therefore would save large amounts of money. If we measure effectiveness only by con- sidering the impact on the person who is ill, Comas-Herrera said, we 

58 FINANCIAL INCENTIVES miss a huge potential savings of disease-modifying interventions. Includ- ing the collateral costs allows one to build a stronger case for the value of early intervention. Many economists are arguing that clinical trials for such diseases should also assess the impact on unpaid caregivers, she said. Clinical trials measure physical and cognitive symptoms, but the impact of dementia is much more complex. Furthermore, people with ad- vanced cognitive deficits incur especially high costs due to co- morbidities and hospitalizations (higher risk for falls, urinary tract infec- tions, and respiratory infections compared to people without dementia) (Delavande et al., 2013; Zuliani et al., 2012). a http://www.modem-dementia.org.uk (accessed April 22, 2015). SOURCE: Presented by Adelina 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 de- veloping pull incentives for drug development in the neurosciences, ac- cording 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 communi- cating relevant information to government agencies. Similarly, public−private partnerships, advocacy groups, and non- profit health organizations have the opportunity to contribute to pro- posals 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 mat- ter, Steven Hyman said, and they differ from disease to disease. He pro- vided 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 develop- ment of a drug with a novel mechanism of action that delivers more bene- fit to individuals with depression. For AD and PD, in contrast, incentives 

PATIENT BENEFIT AND ENGAGEMENT 59 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 advo- cacy 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 lobby- ing 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 enter- prise whose mission is to foster and support exploration of the brain ra- ther 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). 

60 FINANCIAL INCENTIVES • 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 in- put, building political will, and contributing other crucial re- sources (Boutin, Chiarello, Kennedy, and others).