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Sep 07, 2015
 |  BioCentury  |  Strategy

Back to School: Changing the subject

23rd BioCentury Back to School Issue: Let patients show the way in drug development

No longer content with a walk-on role as research subjects, and empowered by access to more information and the necessity of shouldering a bigger share of the healthcare bill, patients are demanding a speaking role on the global healthcare stage. At the same time, regulators and drug industry bodies have concluded that patient input is key to improving clinical trials, defining meaningful treatment outcomes and assessing the amount of risk that is acceptable for a given amount of benefit.

The goal is more than laudable; the patient voice is essential when worldwide healthcare systems are resource constrained, demand for medical treatments and services is expanding in all major markets and "value" is the watchword on the lips of payers, legislators, physicians and patient groups.

The goal is also real. Patient engagement is BIO and PhRMA's top priority for PDUFA reauthorization and was given an entire section of the 21st Century Cures Act (H.R. 6) passed by the U.S. House of Representatives on July 10 (see "Patient Focus 2.0," page 6).

But a large swath of companies, as well as regulators and health technology assessment agencies, are doing little more than paying lip service to "putting the patient at the center of drug development" in websites, presentations, conference agendas and white papers.

In fact, the rhetoric of "putting patients at the center" itself fails to recognize that patients themselves can show the way when it comes time to translate great science into medicines that they really want and society will pay for.

BioCentury's 23rd Back to School essay argues that patients, patient representatives and caregivers should be helping to set translational research agendas. They should be working alongside drug developers and clinical investigators to develop clinical trial protocols. They should be creating clinical trial networks and establishing, running and managing the data from biobanks and registries. And they should be collaborating with regulators to establish approval parameters and with HTA authorities and payers on coverage and reimbursement policies.

Drug companies should be clearing the path for them to do so by advancing the science of preference research and by helping to build the capacity of patient groups to participate in the drug development process.

Companies also should commit to meeting patient needs beyond clinical trials and the delivery of approved drugs by finding ways to grant access to data and experimental therapies.

There are many pitfalls to comprehensive patient engagement -- both real and imagined -- including difficulty turning anecdotes into data, fear of recriminations for activities perceived to be off-label marketing, and the complexities inherent in providing support without exerting undue influence that undermines the credibility of patient advocates.

Certainly, making patient needs the basis for decision making throughout the product life cycle will be difficult and uncomfortable. It may lead to dropping programs that companies find exciting -- and have already invested in -- but that don't meet patient needs. It will require changing deeply ingrained behaviors, processes and beliefs.

But drug sponsors cannot afford to cling to established ways of thinking and focus on risk avoidance to the detriment of product opportunity and patient need. They must recognize that patients taking a seat at the table is both inevitable and essential to improving product offerings, shortening development times and achieving product approval and reimbursement.

All of that means ceding some control in order to make room for new points of view that will reshape the drug development enterprise.

The situation

Drug sponsors traditionally have reached out to patients only late in the product life cycle, usually to recruit participants for a clinical trial or to increase awareness and education about a new drug. When patient views were desired, drug sponsors and regulators historically consulted physicians as proxies.

As a result, prescription drugs remain the only high-value products created with little or no input from the individuals who use them.

It's tempting to shrug off the comparison because communication between manufacturers and consumers in other industries is not regulated to the extent imposed on drug companies. But that would be a mistake. There is no phase of drug development that couldn't be improved by a more active, thoughtful approach to patient engagement.

Drug companies have spent billions of dollars creating products that patients don't want and won't use. Pfizer Inc.'s Exubera inhaled insulin is the apocalyptic example, but a multitude of smaller scale mismatches between patient needs and product characteristics play out in wasted investment of money and other resources.

Vertex Pharmaceuticals Inc.'s Incivek telaprevir is but one example. The HCV drug flew off the shelves following its May 2011 launch, posting $74.5 million in 2Q11 sales. But sales in the U.S. and Canada peaked at $456.8 million in 4Q11 and then steadily declined, which Vertex attributed to a glut of HCV clinical trials in the U.S., and to patients deciding to wait for an interferon-free regimen that was still a year away from the market.

Doctors contacted by BioCentury agreed those were contributing factors, but they added another reason: a difficult time managing some of the drug's side effects, which was time-consuming for physicians and hard on patients.

By March 2014, doctors reported to BioCentury that less than 10% of HCV patients had chosen to take either Incivek or Victrelis boceprevir from Merck & Co. Inc. because of side effects such as anemia, and complicated regimens requiring several doses a day.

Side effects and dosing regimens made compliance difficult -- a negative consequence of failing to account for patient needs.

Vertex discontinued Incivek in the U.S. in August 2014.

The scale of the adherence problem has been well documented. According to a 2005 paper published in the New England Journal of Medicine, about half of patients with chronic conditions such as high cholesterol or depression stop taking their medications not long after starting therapy. Side effects and complicated dosing are among the reasons, along with poor communication with patients about the benefits and side effects that should be expected, not to mention the high costs of drugs.

Non-adherence hits drug companies right on the top line, as illustrated by Juxtapid lomitapide from Aegerion Pharmaceuticals Inc. Because the discontinuation rate of 14% seen in clinical trials grew to over 30% in long-term real-world use, last October the biotech reduced its FY14 sales guidance to $150-$160 million from prior guidance at the lower end of $180-$200 million.

Aegerion also told investors it was working with nurses and dietitians to help patients understand the drug's GI side effects and keep them on treatment longer.

Industrywide, the costs of non-adherence are staggering, according to a 2012 study by Capgemini Consulting.

"The US pharmaceutical industry alone loses an estimated $188 billion annually due to medication non-adherence. This represents 59% of the $320 billion in total US pharmaceutical revenue in 2011," the consultants wrote.

Moreover, according to Capgemini, the lost revenue amounted to 37% of $508 billion potential total revenue that would have accrued had patients stayed on therapy.

"Extrapolated to the global pharmaceutical market, revenue loss is estimated to be $564 billion, or 59% of the $956 billion in total global pharmaceutical revenue in 2011 and 37% of the $1,520 billion annual potential total revenue," the authors wrote.

In addition, because the needs and aspirations of patients are not understood and prioritized, clinical trials -- the most expensive part of drug development -- take too long to enroll, suffer from high dropout rates and often have endpoints that do not reflect the burden of disease that patients and caregivers experience.

A 2014 study from the Icahn School of Medicine at Mount Sinai found that 25% of 7,776 cancer trials registered on ClinicalTrials.gov between September 2005 and November 2011 were stopped prematurely. One in 10 were terminated because they failed to accrue enough patients, and industry-funded studies were more likely to be stopped prematurely.

Narrow inclusion criteria, limited sites or onerous follow-up requirements can lead to failed trials simply because companies can't accrue patients.

For example, it has become difficult to enroll patients with acute myelogenous leukemia into trials comparing new agents with chemotherapy, because up to 80% of AML patients either are unfit for chemotherapy or refuse it. AML patients with a short life expectancy are reluctant to enter a trial that could make them feel worse or that would require travel to an infusion center or otherwise interfere with the quality of their remaining time.

In addition, standard approaches to study blinding can compromise the ability of participants to seek follow-up care if their disease does not respond or recurs during a trial.

Failing to engage patients when target product profiles are crafted also causes drug developers to miss opportunities to differentiate products based on their impact on quality of life, and to create new products that improve QOL.

Several of these opportunities have surfaced at FDA's patient-focused drug development meetings, where patients have testified that marketed products and most clinical programs aren't addressing the symptoms and side effects that are their most pressing concerns (see "Unmet Need, Indeed").

Even when a company does develop a product that meets patient criteria, the lack of robust engagement from patients, their advocates and caregivers has made the regulation and reimbursement of drugs more difficult, contentious and conservative than necessary.

This is in large part because regulators, physicians and patients assess risk very differently. Side effect profiles that physicians, regulators and payers consider trivial or minor, such as nausea, edema or cosmetic rash, can be very important to patients who have to live with a treatment for years.

Conversely, in exchange for relief of their suffering, some patient populations have shown themselves willing to tolerate risks that have been unacceptable to regulators or physicians.

For example, by conducting a patient preference survey, Johnson & Johnson found that migraine patients would tolerate a much larger risk of heart attack than regulators would condone.

"We studied 200 adult migraine patients and asked them a variety of questions showing them alternative treatments with various benefits and harms, and they would say which one they prefer. They would do this over and over again, and it went into a model," said Bennett Levitan, senior director for benefit-risk assessment in J&J's Janssen Research & Development LLC unit.

"It turns out, in exchange for completely removing their functional limitations -- in exchange for taking a patient from being stuck in bed and allowing them to run around and take care of their family or go to school -- they would be willing to accept on the order of a two out of 1,000 chance of a heart attack per year," he told BioCentury. "Regulators would almost never approve something like that for such high-functioning patients, but these migrainers are saying they regard that risk as worth the benefit."

Similarly, FDA's patient-focused drug development meetings, which patient advocates negotiated as part of the agency's PDUFA V commitments, have demonstrated that regulator assumptions about what patients want are frequently incorrect.

"Regulators, reviewers, academics and providers thought they understood the patient perspective, and in each one of the meetings they've walked away saying that what they thought was most important to patients was wrong," Marc Boutin, CEO of the National Health Council, told BioCentury.

The NHC is a non-profit advocate for patients with chronic diseases. Its members include more than 100 healthcare organizations and companies.

Perhaps the biggest gap -- and the biggest opportunity -- is embedding patient perspectives into determination of the value of medical products and subsequently into coverage and reimbursement decisions.

According to a survey conducted between the end of 2010 and the fall of 2011 by the European Patients' Forum, "Very few HTA agencies currently involve and integrate patients' perspectives in their reports and conduct formal evaluation of the impact of patient involvement in HTA. Apart from financial resource constraints the main challenges are perceived to be the lack of capacity, time and good methodologies to involve patients."

Survey data showed less than half of HTA agencies involved patients in assessments, and less than half of patient organizations had ever participated in an HTA.

Moreover, a quarter of the reimbursement authorities said they had no intention of involving patients (see "Lack of Participation").

In 2014, Back to School proposed that price should be based on the patient- and payer-defined value of the outcomes a drug is expected to deliver, requiring industry to work with patients and payers to develop a consensus on value for money.

That argument still holds in 2015. And while industry and payers are beginning to experiment with new pricing models aimed at tying price to value, the patient voice remains underrepresented.

On the private payer side, interactions with patient groups are sporadic.

Anthem Inc. has started to reach out to patients, but only after developing its new policy for coverage of cancer drugs without any patient input at all.

The insurer launched a reimbursement model that provides a financial incentive for oncologists who follow a specific treatment pathway. It was selected based on feedback from external clinical experts, Anthem's own P&T committee and treatment guidelines from the National Comprehensive Cancer Network (NCCN).

The model does not directly reimburse for physician services that are important to patients, such as counseling to help patients understand their treatment options, and time physicians must take to address treatment side effects.

Anthem began to seek patient feedback after the pathways were developed, but before they were launched in June 2014 and is using the feedback to update them. For example, in response to patient concerns, Anthem updated its breast and colorectal pathways so that patients whose genomic testing results indicate they would not benefit from the preferred treatment pathway can be given other treatment.

The path forward

Patients, industry, regulators and, at least outside the U.S., some payers have taken steps to increase the role of patients and caregivers in developing new medical products -- sometimes to stunning effect.

The benchmark for patient-driven drug development is the breakthrough therapy pathway, which was conceived by Friends of Cancer Research and included in the FDA Safety and Innovation Act in 2012.

Another case is the patient advocacy group Parent Project Muscular Dystrophy (PPMD). It enlisted the support of patients, caregivers, academia and industry to author a document that FDA then issued as a draft guidance, with fairly minor revisions, on Duchenne muscular dystrophy (see "Patient Power in Duchenne," page 5).

There also have been a few remarkable examples of patient groups funding and guiding R&D. The Cystic Fibrosis Foundation (CFF) drove the molecule that became Vertex's Kalydeco ivacaftor from a scientific hypothesis into a life-enhancing product, financing the high throughput screening that led to the discovery of the compound and funding its early development.

The foundation also prepared the way for Kalydeco and other therapies by collecting data for decades in patient registries to elucidate the natural history of CF, and creating a clinical trial network to efficiently test investigational agents.

These are exceptions, however; very little has been done to comprehensively focus medical product development on the needs and preferences of the individuals who are supposed to benefit.

In the value-based world, patients and caregivers are demanding an end to paternalistic doctor-knows-best medicine -- and are voting with their voices and their wallets as they shoulder an increasing proportion of the costs of healthcare through insurance premiums, deductibles and co-pays.

The reality, as Back to School has been pointing out since 2013, is that meeting today's reimbursement test will require retooling pipelines and R&D programs to focus on patient- and payer-defined needs, and that understanding those needs requires an intensely collaborative effort.

Back to School sees at least four areas where industry should take bold action to accelerate comprehensive partnering with patients.

First, managements should reorient medical product development so that patients are partners in defining what products are needed and in determining both how to develop them, and how to ensure access.

Back to School does not argue that patient priorities should replace or trump scientific inquiry. Industry's ability to bring scientific inventiveness to bear on problems of biology and translation will remain the foundation for medical product innovation.

That said, translational and clinical research should go forward only when there is a clear and compelling need for the results, and a pathway for parlaying them into patient benefit.

Inviting patients to help set translational research agendas will uncover hidden opportunities to create medicines that better meet patient needs.

Further downstream, incorporating patient advice into clinical trial design will enhance recruitment, shorten timelines and improve the information that trials generate, which in turn will support regulatory and reimbursement decisions that facilitate access.

Patient partners can also help define the value of medical interventions for payers, and for other patients, in ways that are far more convincing than anything drug developers can say.

To engage with patients as partners, industry will need to advocate for the regulatory clarity that is necessary to enable the free-flowing discussion enjoyed by other stakeholders in the healthcare system -- government, payers, regulators and healthcare providers.

Nevertheless, waiting for regulatory safe harbors should not stop drug developers from engaging with patient advocacy groups on topics related to diseases rather than the design of new products. And there are ways to engage in information-gathering about desirable product characteristics without discussing existing or pipeline products in a way that could be construed as promotional -- or indeed without discussing them at all.

Second, the drug industry should invest in validating patient-preference research methods via public-private partnerships and third-party research.

Patients are demanding that their judgments about the trade-offs of benefits and risks be given precedence over those of doctors and regulators. But applying patient judgments in development and regulatory decisions requires moving beyond current approaches, which rely too much on anecdotes and personal testimony. What's needed are validated research methods that produce reliable, scientifically rigorous data.

The tools exist, but they need to be validated for use in drug development and medicine. The pharma industry has both the resources and the scientific acumen to move patient preference research toward quantifiable metrics and peer-reviewed social science methods.

In many cases, industry should not be conducting this research itself lest it be perceived as tainting the outcome. Here, patient groups themselves, public-private consortia and third-party researchers are better placed to produce compelling data that regulators, payers and patients will find trustworthy.

Third, to accomplish the first two objectives, industry must help build the capacity of patient groups to engage with companies and regulators -- without compromising the advocates' independence and credibility.

An increasing number of patient advocacy organizations understand the process of drug development and the regulatory system. But they are still the minority, and it has taken the best of these organizations many years to develop their expertise.

Industry should participate with regulators, healthcare providers and other stakeholders to build the skills patients, advocates and caregivers need to fully participate in product development, regulation and reimbursement decisions.

These engagements must include leaders among healthcare providers, researchers, regulators, HTAs and payers, and be based on a consensus on rules of the road, especially when it comes to financing these efforts.

As with preference studies, this may require the creation of precompetitive collaborations dedicated to specific diseases or conditions, funding of third-party organizations, and/or creating and funding an independent body that can award educational grants to patient organizations.

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