Originally published June 9.
By Turna Ray
In a speech before personalized medicine advocates this week, John Castellani, CEO of the Pharmaceutical Research and Manufacturers of America, was careful not to make any boosterish remarks about the field's future or overpromise the advances that may come out of the drug industry.
Instead, in a realistic and sober talk before the Personalized Medicine Coalition, Castellani said that while the drug industry's commitment to using genomic strategies to advance targeted therapies is growing, the road ahead is fraught with scientific, regulatory, and reimbursement challenges.
Though excited by the "power and potential of personalized medicine," Castellani said he was also "humbled" in the recognition that there are no easy paths to bring genomically targeted medicines to market. "It seems the more we learn about the influence of genetics on disease and treatment response, the more we realize we don’t know. And the technology is disruptive, posing challenges to business models, regulation, and policy," he observed. "So, the real challenge we face today and into the future is: can we overcome the barriers to personalized medicine and fulfill its potential?"
In his speech, Castellani reflected on the experience of Adriana Jenkins, a biotech public relations representative who died in February from cancer. Jenkins had originally benefited from Genentech's HER2-positive breast cancer drug Herceptin, which extended her life for nine years. However, the cancer recurred in her brain and spinal fluid. Before her death, she published an essay in Forbes, titled "A Dying Wish," in which she urged for more incentives to drug developers to encourage investments in personalized medicine products, such as Herceptin.
"Despite Herceptin's success, the pharmaceutical industry seems loath to focus on developing other PM drugs, which often means reducing potential profits. After spending $1 billion over 15 years to develop a drug, companies are eager to recoup their money fast," she wrote. "The business side of the equation wants as many people to take the drug as possible, whether it's effective or not."
Jenkins wrote that she worked at a biotech company whose CEO "championed personalized drugs in public statements. But its first product was not a PM drug" because the firm, which she did not name, was under "too much pressure to become profitable for it to further reduce an already small patient population with a diagnostic test."
Discussing the challenge before the drug industry, Castellani described a scenario in which biopharmaceutical companies recognize that personalized medicine is the future, but they also face tremendous economic and scientific struggles. Although the obstacles are tough to tackle, Castellani doesn't believe they are insurmountable. "While we are humbled at the complexity of the science and the challenges of translating it into better tests and treatments, this should not be reason for us to reduce our effort, but rather to redouble it," he said. "Patients like Adrianna demand that we do."
In his speech, the text of which PhRMA provided to PGx Reporter, Castellani assured that biopharmaceutical companies are "strongly committed" to personalized medicine. He cited personalized medicine success stories such as Herceptin and Gleevec, and noted that drug developers are "heavily invested" in bringing to market similar genomically targeted products.
In a survey conducted last year, the Tufts Center for the Study of Drug Development found that around 80 percent of pharmaceutical firms are working with academic medical centers, research institutions, and healthcare practitioners on personalized medicine projects. Within the 21 pharma and biotech companies interviewed in the survey, Tufts found that between 12 percent and 50 percent of their current clinical development pipelines involve personalized medicines (PGx Reporter 11/21/2010).
It's no secret that drug developers have been reluctant to embrace pharmacogenomically guided drug development, since doing so would cut into a drug's market size and revenues. After several costly late-stage drug failures and reputation-bashing incidents where drugs had to be removed from the market due to adverse reactions, pharma companies appeared more open to supporting personalized medicine strategies, at least in their public statements. However, even then, industry observers questioned whether pharma's verbal support was really reflective of internal changes in their R&D pipelines.
After last week's American Society of Clinical Oncology's annual meeting, where researchers presented thousands of abstracts on molecularly targeted treatment strategies, there is little doubt that at least in oncology drug developers are investing in personalized medicine.
In addition, there are signs that drug developers are also exploring ways in which pharmacogenomics can bolster drug profits, instead of shrink them.
For example, Roche and Genentech presented data at ASCO showing that non-small cell lung cancer patients with EGFR mutations who received Tarceva lived twice as long without disease progression compared to patients who received platinum-based chemotherapy, currently the standard of care for first-line NSCLC therapy (PGx Reporter 06/08/2011). Tarceva is currently indicated for the second- and third-line NSCLC settings.
Based on the finding, Roche has applied to the European Medicines Agency to extend the current label for Tarceva in European markets to include first-line use in people with advanced EGFR-activating mutation-positive NSCLC. The company is also discussing a submission with the US Food and Drug Administration to add a similar indication to Tarceva's label. The drug would be marketed with a companion diagnostic test to help identify patients with activating EGFR mutations who would receive first-line treatment with the drug.
Tarceva sales in 2010 were 1.3 billion Swiss Francs ($1.6 billion), including the drug's indications in lung and pancreatic cancer. It is estimated that between 10 percent and 30 percent of people with advanced NSCLC are EGFR-activating mutation-positive.
Castellani's comments suggest that while the industry's commitment to personalized medicine is critical to advancing the field, there are several hurdles to making genomically targeted medicines broadly available to the public that are beyond pharma's control.
First, there are scientific challenges. Ten years after the completion of the Human Genome Project, researchers involved with that effort are facing criticism that it hasn't yet yielded any cures for complex diseases such as cancer.
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"[M]any are asking, 'Where are the miracle cures?' Some have criticized the scientific community for over-promising and under-delivering," Castellani noted. "But those critics miss two important points: First, there has been incredible progress and, second, translating the basic information from the genome into treatments has been much more difficult than expected. Sequencing of the human genome, while important, was just the beginning."
Furthermore, Castellani noted that regulation has been slow to address rapidly advancing technologies in drug and diagnostics development. The FDA is in the process of updating its regulatory policies to address emerging drug/diagnostic combination products, thought of as the lynchpin of personalized medicine. The agency has also acknowledged that the diagnostics field is becoming more complex and is expanding with unprecedented speed. As such, the FDA is working on new criteria by which advanced diagnostics should be developed and reviewed.
These proposed regulatory changes have brought an onslaught of criticism from industry players who believe that the agency's policies will stifle innovation in personalized medicine, rather than spur it. The agency has yet to issue any guidelines on Rx/Dx codevelopment or on the regulation of laboratory-developed tests, which comprise a large sector of the diagnostics field.
"Federal regulation of diagnostic and laboratory testing remains unclear, creating uncertainty for innovators and providers," Castellani said. "And efficient pathways for premarket review of drug/diagnostic combinations need to be more clearly defined by FDA. We … look forward to the planned release of draft guidance on this topic."
Reimbursement, another oft-cited barrier to personalized medicine, was also on Castellani's mind. Molecular diagnostics developers have asserted that current reimbursement policies don’t capture the value of tests in the personalized medicine era, where tests can save the healthcare system money by picking out which patients will respond to a drug and those who are likely to experience a life-threatening adverse reaction.
"Personalized medicine means the development of high-value treatments targeted to a small patient group using advanced diagnostics," Castellani said. "If reimbursement policy only looks narrowly at per-unit costs in a budget silo, it will fail to reflect and incentivize the full value of personalized medicines."
Republican Utah Senator Orrin Hatch has been working with personalized medicine stakeholders to craft a bill that would address many of the regulatory and reimbursement challenges facing the industry (PGx Reporter 01/19/2011).
However, the post-healthcare-reform environment in Washington, DC, has made it very difficult to get any healthcare-related bills through Congress, and it is unknown when Hatch's bill will be introduced on the Senate floor. The PMC has said that personalized medicine is a non-partisan issue, with supporters on both sides of the aisle.
However, advancing personalized medicine requires broad infrastructural changes in reimbursement and regulation, significant government resources to update outdated healthcare delivery systems, and shifts in industry's thinking about the entire healthcare enterprise. While biopharmaceutical companies may be united in their overarching support for personalized medicine, disparate industry players haven't always agreed when it comes to specific policies impacting the personalized medicine field, and this could carry over into legislative circles.
For example, healthcare industry stakeholders hold different views about where personalized medicine fits into comparative effectiveness research being funded by the government, which aims to weigh the efficacy, safety, and cost data of different interventions to inform development and coverage decisions.
Before CER became mandated under the healthcare reform law, some drug industry leaders had lobbied heavily against federal measures to use cost-effectiveness data to make coverage decisions. Former PhRMA CEO Billy Tauzin, who as a cancer survivor was an enthusiastic supporter of personalized medicine, did not back the use of CER for coverage determinations.
The healthcare reform bill, signed into law last year by President Barack Obama, provided for the creation of the Patient-Centered Outcomes Research Institute, an independent entity that would conduct research on the comparative risks and benefits of marketed drugs, devices, and medical products (PGx Reporter 03/24/10). CER coming out of this institute can be used in coverage decisions, as long as other data backs up the payment policies for a specific intervention.
With regard to personalized medicine, PCORI has been directed to examine the utility and effectiveness of medical products and services in "various subpopulations" differentiated by race, ethnicity, sex, age, co-morbidities, as well as genetic and molecular subtypes. It is currently unclear, however, to what extent PCORI will conduct CER investigating personalized treatments against one-size-fits-all drugs in genomically targeted subpopulations of patients.
Castellani extended PhRMA's support in aligning CER initiatives with personalized medicine paradigms. "lt is important for [CER] to align with and support the emergence of personalized medicine," he said. "Done well, CER can close evidence gaps involving personalized medicine, and can help illuminate the role of genetics and other factors that cause patients to respond differently to treatments. Done badly, CER will rely on broad population averages that do not incorporate genetic information and obscure patient differences."
Ultimately, in Castellani's view, the most compelling reason for drug developers to invest in personalized medicine is an economic one. "Personalized medicine is good for patients, it’s good for health care, and it’s also good for the economy," he said in his speech to the PMC, adding that the biopharmaceutical sector directly facilitates 650,000 jobs and contributes to more than 2.4 million jobs in other sectors.
"This is the kind of leading-edge innovation we need to be supporting right now to spur creation of jobs here in the US."
According to Amy Miller, PMC's public policy director, the non-profit is developing an "incentives package" to improve the ecosystem for personalized medicine. The proposal will address the business model and policy barriers facing industry players investing in personalized medicine and will aim to create a stable and predictable regulatory and reimbursement environment for drugs and diagnostics.
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