PCORI Research Priorities, Will They Support Personalized Medicine?

The Board of Directors of the Patient-Centered Outcomes Research Institute (PCORI) met last week, outlined research priorities, and asked for public feedback. What I found most interesting, and a little disheartening, is that the priorities are drafted in vague language, making it difficult to determine how they may (or may not) support personalized medicine.

I hope that as PCORI moves forward, it will give assurance to the Personalized Medicine Coalition (PMC) and other stakeholders that its research supports personalized medicine, as was the intent of Congress at the time of the Institute’s formation.

Specifically, research conducted in the category, “Comparative Assessment of Options for Prevention, Diagnosis, and Treatment,” will compare treatments, but at what level?  Researchers now know more about individual response to some drugs based on biomarker information. For example, when comparing a red pill to a blue pill, it is imperative that biomarker information be included in those examinations, especially when biomarker information is in the label for the drug. A list of drugs with biomarker information in the label can be found on pages 20-25 of The Case for Personalized Medicine, 3^rd edition. But, without clearly defining the details of PCORI’s research, we really can’t know whether or how the Institute will consider biomarker information in its priorities and research agenda.

The research priority “Improving Healthcare System” can support patient-centered care through innovations, but how? PMC suggests that the research be predictive, preventative, personalized and participatory. By emphasizing the “4Ps,” health system evaluation can support personalized medicine. However, without getting more specific about research priorities, we don’t know whether PCORI will include research that addresses these aspects of care delivery.

To support personalized medicine, the “Communication and Dissemination Research” priority should require researchers to answer one question: “Why does this treatment work and for whom?” (or, more frequently, “How likely is this treatment to work for me, and what are the potential trade-offs?”).  It is not enough, in the PMC’s opinion, to say that one therapy works for most people. PMC suggests that the research should explain why a therapy works (or is more likely to work) and for whom. For example, in research comparing red and blue pills, the communication and dissemination of the research results should stress that although the red pill works for most, the blue pill is particularly effective for people with a specific biomarker.

We are at a pivotal stage in the design of an entity that is tasked with assisting patients, clinicians, purchasers and policymakers in making informed, evidenced-based health decisions. PCORI could foster research that answers the important questions about what interventions work, and for whom. Or, PCORI could be another investigator-driven research institute that allows funded researchers to pursue questions of great scientific import, regardless of their practicality. Such a mission would be redundant with many others, most notably the National Institutes of Health, would be less likely to result in a cohesive national research program, and less likely to ensure personalized medicine is appropriately integrated.

It is my hope that PCORI supports the science that will drive personalized medicine forward, and will engage stakeholders in driving personalized medicine forward, by proposing specific research priorities and research questions to get answers to the questions that science, medicine and, ultimately, patients demand.

Gene Patenting and Biological Methods in the Personalized Medicine Space

Richard S. Meyer contributed to this post.

Personalized medicine, including the application of genomic and molecular data to better target the delivery of health care and determine a person’s predisposition to a particular disease or condition, continues to expand and become the clinical standard of care for many medical conditions or diseases.  For the past several years, players in the personalized medicine space have seen the federal courts and the legislature debate the extent to which patent protection is available under U.S. law when it comes to biological molecules and methods of assessing biological molecules (e.g., diagnostic testing).

Recently, the debate has heated as a line of lawsuits have made their way through the legal system with sights set on the Supreme Court.  While the technology at issue in these cases is diverse, the questions before the courts always come back to where to draw the line between patent-eligible subject matter (an invention) and patent-ineligible subject matter (an abstract idea, scientific principle or natural phenomenon).  By excluding this type of subject matter from patent eligibility, naturally occurring phenomenon, scientific principles, and laws of nature remain available to all innovators and researchers.

These cases have drawn attention and input not only from biotechnology and diagnostics companies and industry organizations, but also from public interest, policy, legal, and medical organizations.  In particular, the Myriad case[i], focuses on the patent eligibility of isolated genetic sequences associated with breast cancer and diagnostic methods based on detecting those sequences.  How this case is decided will be partly guided by the Supreme Court’s decision in the Prometheus case[ii], for which oral arguments before the Supreme Court were held on December 7, 2011.  In the Prometheus case, the parties are arguing over the patent eligibility of biological methods involving measuring drug breakdown products (metabolites) after administering a drug to a patient to assist in determining appropriate drug dosage.

The courts have been presented with a number of policy arguments on the ramifications of either having or eliminating patent protection for these technologies.  Perhaps the largest policy debate focuses on whether the market exclusivity provided by patents on genetic sequences or diagnostic methods foster commercialization and thus availability of personalized medicine.  Supporters of patent protection for gene patents and diagnostic testing say that this protection enables better patient care by facilitating investment in and commercialization of diagnostic testing and dissemination of data to broaden medical understanding, which in turn leads to new research endeavors and the development of new technologies, and improves long-term public health.  Opponents argue that patent protection for these technologies impair patient health by limiting dissemination of medical knowledge and use thereof, limiting access to diagnostic testing by raising testing costs, and prevents access to second opinion testing to confirm diagnosis.

While important, these policy arguments may be outside the scope of the courts’ patent eligibility analysis of genetic sequences, diagnostic testing, and other biological methods under U.S. patent laws.  The recently implemented patent reform law (America Invents Act)[iii] made no changes to the patent eligibility standards, but did commission the US. Patent & Trademark Office to study access to second opinion testing for genetic testing, indicating that Congress feels further inquiry is needed before legislative action.

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[i]  Ass’n for Molecular Pathology v. U.S. Patent & Trademark Office, No. 10-1406 (Fed. Cir. July 29, 2011).

[ii]  Mayo Collaborative Services v. Prometheus Laboratories, Inc., 628 F.3d 1347 (Fed. Cir. 2010), cert. granted, 79 U.S.L.W. 3554 (U.S. June 20, 2011)(No. 10–1150).

[iii]Leahy-SmithAmerica Invents Act, Pub. L. No. 112-29, 125 Stat. 284, 325 (2011) (to be codified at 35 U.S.C. § 257)(enacted Sept. 16, 2011).

Adriana Jenkins and the Case for Personalized Medicine

Adriana Jenkins passed away on February 9, 2011 after battling breast cancer. Known for her tenacious advocacy on behalf of targeted therapies, Kelly Lindenboom, honored her passionate work within the personalized medicine community at the Boston Reception hosted by the Personalized Medicine Coalition on November 8, 2011.

Adriana Jenkins had an intoxicating personality and lived every day to the fullest — until, earlier this year, when she died from a rare form of breast cancer at age 41. Adriana was in the prime of her life — she had a thriving career in biotech public relations, was an incredible artist and had an extensive network of friends, that to Adriana, were her family. I’m part of her family.

At age 32, Adriana was engaged to be married, getting ready to start a new job with an up-and-coming biotechnology company and excited for what was to be the best time of her life. And then came the phone call from her doctor that changed everything. With a diagnosis of stage 3B inflammatory breast cancer — a rare, aggressive form of the disease — she had limited options to consider.

With less than a 50 percent chance of survival beyond five years, Adriana was desperate to explore any and all options that might give her better odds. Unlike the majority of people who are diagnosed with cancer every year, Adriana possessed a unique and intimate understanding of the pharmaceutical industry and was able to be her own best advocate after her diagnosis. When a colleague suggested she look into an investigational therapy — Herceptin — being tested locally at the Dana Farber Cancer Institute (DFCI) in Boston, she jumped at the chance. And as it turned out, she was a perfect fit for the trial and was enrolled in the study.

While the clinical trial was not always easy, Adriana responded wonderfully to the Herceptin, which was eventually approved by the Food and Drug Administration and is used today to treat many women with the same type of genetic marker, HER2, that was present in Adriana’s cancer.

Because of her success with Herceptin, one of the first so-called personalized medicines to be approved for use, Adriana was able to beat the odds. Really beat the odds. She credited personalized medicine treatment for giving her the nearly 10 years she was told she wouldn’t have. And she was thankful for every day that she had.

Unfortunately, despite encouraging results, personalized medicine is still a rarity in most cancer treatments. In her article “A Dying Wish,” published in Forbes magazine, written shortly before her death, Adriana made an eloquent appeal for the broad adoption of personalized medicines for cancer and other diseases based on her own incredible, nearly decade-long fight with breast cancer. In the article, she posed a question related to personalized medicine:

How do we convince drugmakers to focus their shrinking R&D budgets on this area of scientific discovery?

And then offered this potential challenge to our nation’s pharmaceutical companies and lawmakers:

“One idea is to create an incentive for drugmakers comparable to that in the Orphan Drug Act. Passed in 1983, it encourages companies to develop drugs for diseases that have a small market (fewer than 200,000 patients in the U.S.). Under the law, companies that develop such a drug may sell it without competition for seven years, in addition to often receiving quicker “fast track” regulatory review… A comparable law could push drugmakers to develop PM drugs for cancer and other deadly ailments.”

At the end of the article she offered this plea:

I urge patients, physicians and insurers to create a similar group to support the commercialization of personalized cancer drugs.

After her diagnosis with cancer, Adriana had the word “hope” tattooed onto the inside of her wrist as a constant reminder to herself for how she wanted to embrace life.

In the years that followed her remission, Adriana remained a strong advocate for the potential of personalized medicine, putting her public relations know-how to work by partnering with Herceptin’s developers to share her experience with the media and bring awareness to other women receiving a new cancer diagnosis.

The week that Adriana passed away, her article about the power and potential of personalized medicine was published in Forbes. And today, her friends are supporting her vision — keeping her “hope” alive — through the Adriana Jenkins Foundation for Personalized Medicine and a fundraising team with Stand Up To Cancer. Formed in Adriana’s name, the goal of the group is to raise awareness and be a proponent for development of personalized medicines, like the one that gave Adriana the nearly 10 years she never expected she would have.

Cancer is an extraordinarily complicated problem, and will only be solved through new approaches and ideas. Personalized medicine is one of them.

- These remarks were first made by Ms. Lindenboom at the Personalized Medicine Coalition Boston Reception on November 8, 2011. They were also posted on HuffingtonPost.com.

The Genomics and Personalized Medicine Act Needs a “Fresh Look”

“Now is the time for a national effort to move personalized medicine forward,” said Representative Anna Eshoo at the Center for the Study of the Presidency and Congress and Health Affairs’ Capitol Hill briefing held last week, on the same day that the Food and Drug Administration (FDA) released its plan Driving Biomedical Innovation:  Initiatives for Improving Products for Patients.

At the briefing, Congresswoman Eshoo affirmed the Personalized Medicine Coalition’s long-held contention that the 2010 version of the Genomics and Personalized Medicine Act needed an infusion of new ideas.  (See my blog post from August 23, 2011.)

Also speaking to the audience of congressional staff, reporters, patient advocates industry representatives, and others, were several government officials tasked with enforcing policies that affect personalized medicine innovation.  They presented their thoughts on the state of personalized medicine and their respective agencies’ roles, highlighting their progress. Both Janet Woodcock, M.D. and Elizabeth Mansfield, Ph.D. of FDA highlighted FDA’s efforts in bringing regulators and industry to the table to discuss the challenges of regulating personalized medicine products and services.  These discussions informed the agency’s new report—dubbed a blueprint for innovation—which includes major focus areas in building the infrastructure to drive and support personalized medicine and in creating a rapid drug development pathway for important targeted therapies.  They also acknowledged that changes are still needed at FDA to accommodate personalized medicine and that the agency will continue its leadership role by building a system to support the development of personalized medicines, including investments in regulatory science and by clarifying agency policies.

At the same time, Jeffrey Roche, M.D., M.P.H. from the Centers for Medicare and Medicaid services (CMS), underscored his agency’s time-consuming coverage decision-making process, which is based on published research used to determine what is “reasonable and necessary.”

Indeed more coordination is needed at the federal level.  Speakers representing academe, industry, and patients reinforced this sentiment, in addition to emphasizing the need for industry incentives to develop new products and services and a CMS reimbursement policy that can speed the adoption of personalized medicine by paying enough for personalized medicine diagnostic tests so that research and development costs are recouped.

Patient advocate and PMC-member Donna Cryer summed it up best, when sharing her thoughts on what can foster innovation and the adoption of personalized medicine: We need HHS level coordination, and a streamlined FDA process for personalized medicines and their diagnostic partners.  CMS needs to support the science of personalized medicine through a system of care that repays innovators for the research that goes into the development of these products.  And tax credits are necessary to help companies through what is still very difficult science. 

PMC is pleased by Rep. Eshoo’s leadership in advancing personalized medicine as evidenced by her participation in this event and her willingness to consider all of the policy proposals PMC and others have put forth.  We look forward to working with her to vet policy recommendations suggested by others and to see the Genomics and Personalized Medicine Act introduced in this Congress.

Our Health Policies Can’t Ignore Where Science Is Leading Us

Do we want continued progress in personalized medicine, or don’t we? Based on events last week, the answer might be ‘both.’ I attended a press conference here in Washington that celebrated the achievements made by the health sector in our efforts to turn cancer from a sure death sentence into a chronic disease. Simultaneous to this, the Medicare Payment Advisory Commission (MedPAC) proposed policies to offset the cost of a physician payment fix under Medicare. The disconnect between the two was striking. Unfortunately, the MedPAC proposals have the unintended effect of heavily impacting those on the leading edge of personalized medicine. Of the $233 billion in 10-year savings, $114 billion would come out of the biopharmaceutical and clinical laboratory sectors, thus possibly robbing seniors of access to the latest targeted therapies and the diagnostics used to guide them. The proposal includes savings from giving the Centers for Medicare and Medicaid Services (CMS) new authority to impose “least costly alternative” payment, which would result in locking us into our current one-size-fits-all medical paradigm and weakening physicians’ power to tailor care using diagnostics and targeted therapies.  Another troubling aspect of these suggestions is that they propose cuts by sector, ignoring the reality that personalized medicine brings efficiencies to the system of health care.

The proposal appears to reflect a lack of awareness of the impact that personalized medicine is making in health care and underscores the importance of the Personalized Medicine Coalition’s legislative work.  One of our policy suggestions, released over the summer, calls for inclusion of a personalized medicine representative on MedPAC and the creation of a new personalized medicine advisory committee to foster alignment of the policies across the entire Department of Health and Human Services with the science of personalized medicine. Personalized medicine challenges the status quo in medicine – the blockbuster business model, diagnostic coding and payment, or health care delivery systems. Maybe it’s time it challenged MedPAC, too.

Personalized Medicine: Celebrating Progress and Looking Ahead

The release of the American Association for Cancer Research (AACR) Cancer Progress Report last week, reminded me of the progress that has been made in cancer care since the passage of the National Cancer Act in 1971.  When President Nixon signed the law committing significant U.S. funds to cancer research, little was known about the disease and it was thought that a one-size-fits-all approach might eradicate cancer–what we know today is more than 200 different diseases; and that number will likely grow.  The personalized approach necessary to combat cancer was then not yet imagined, let alone understood.

But the progress in personalized cancer care, and in personalized medicine more broadly, has been recent.

For my September column in Personalized Medicine, I interviewed Harvard Medical School Professor of Genetics and Medicine Raju Kucherlapati, Ph.D., to discuss how personalized medicine has evolved since he launched Harvard’s annual personalized medicine meeting in 2005.  He explained that at first, business leaders and policymakers were skeptical that personalized medicine would have any impact in the near term, but that the many examples of personalized medicine products and new tools to speed innovation have changed minds and forever improved medicine.

No one better exemplifies progress in this field than President and Co-founder of the Institute for Systems Biology, Leroy Hood, M.D., Ph.D., who will be presented with PMC’s Award for Leadership in Personalized Medicine at this year’s Harvard conference. Dr. Hood envisioned the integration of scientific understanding into clinical practice by developing the first DNA and protein sequencer and synthesizer–laying the foundation for the development of personalized medicine.

I hope you will join me at this year’s Harvard conference, November 9-10, 2011, in Boston and at PMC’s cocktail reception to kick off the conference on November 8, 2011.  We will both celebrate the progress personalized medicine has made, thanks to the leadership of visionaries like Raju Kucherlapati and Leroy Hood; and discuss how we continue to move the paradigm of personalized medicine forward through scientific innovation, collaborative business partnerships, and supportive public policies.

New Personalized Medicine Products Signal Progress for Patients

The approvals of new treatments for two different types of cancer indicate that we are making significant progress in personalized medicine. Although the U.S. Food and Drug Administration (FDA) could further define a more transparent and predictable regulatory environment for personalized medicine products, the agency is clearly serious about personalized medicine. In August it cleared Xalkori® (crizotinib), which targets a rare form of lung cancer, ahead of its own priority six-month review goal and Zelboraf® (vemurafenib), which treats patients with melanoma also well ahead of schedule.

These combination products represent a harbinger of the future of medicine. By applying new genetic understanding of tumors to target treatments, drug and diagnostic companies working together are able to develop drugs that are safer and more effective, offering hope to cancer patients where none existed.

In the case of Xalkori®, Pfizer and Abbott Molecular co-developed the drug and a companion diagnostic test (Vysis ALK Break Apart FISH Probe Kit) to identify the subset of patients who are most likely to respond to the drug.  Around five percent of patients diagnosed with non-small cell lung cancer, the most common form of the disease, have tumors with an anaplastic lymphoma kinase (ALK) gene defect that responds to the drug – about 6,000 patients per year in the United States.  Xalkori® works by blocking proteins produced by the abnormal ALK gene.  It is the first lung cancer treatment developed and approved with a diagnostic test.

Stafford O’Kelly, Abbott Molecular Vice President and President Molecular Diagnostics, noted, “[This collaboration] marks a breakthrough in the advancement of personalized medicine…that will help a subset of lung cancer patients get treatment tailored to their unique genetic profile.”

Also recently approved is a targeted therapy to treat melanoma – the deadliest form of skin cancer.  Zelboraf® is indicated for treatment of patients with melanoma whose tumors express a gene mutation called BRAF V600E, which the drug blocks.  Approved with a diagnostic test (cobas® 4800 BRAF V600 Mutation Test) that determines which patients carry the mutation, the drug was clinically effective in 50 percent of these patients.

These new models for collaborative research and development of treatments are yielding positive results. They should keep us focused on the emerging field of personalized medicine and its promise to deliver the right treatment to the right patient with improved diagnosis, more efficient drugs, and better medical outcomes.

Looking Forward, Looking Back

At the Food and Drug Administration (FDA), I had a wonderful opportunity to spend nearly 20 years working in various capacities: in drug development science, regulatory oversight, and clinical pharmacology. Earlier this summer, I had the privilege to meet with the Personalized Medicine Coalition’s public policy committee to discuss the state of personalized medicine just after my departure from the FDA and before I began my new position leading the pharmacometrics and systems pharmacology initiative in the interdisciplinary Institute of Therapeutic Innovation at the University of Florida’s Research and Academic Center in Lake Nona (Orlando).  Personalized medicine will continue to be a passion for me in my new position.

The timing of my talk was serendipitous:  Dr. Steven Spielberg was just named as the new Deputy Commissioner for Medical Products and Tobacco at FDA. His perspective is strongly rooted in understanding disease at the molecular level, having served as director of the Center for Personalized Medicine and Therapeutic Innovation at Children’s Mercy Hospital in Kansas City, Missouri. And the FDA had just announced the draft guidance document for personalized medicine and companion diagnostics. This guidance should be seen as part of a mosaic of guidance documents from the FDA that will together guide the regulation of personalized medicine products. The Personalized Medicine Coalition has begun putting the mosaic together by listing the relevant guidance documents as a reference tool on its website.

I had a chance to reflect on the new direction FDA has taken over the past several years to embrace what we’re seeing in research and scientific discovery. Like the industrial revolution, the genomic revolution could take 60 years to fully unfold, but in the last ten years, the field and the FDA have made great progress. Many of these changes are leading researchers to re-evaluate how we focus research efforts, assess new therapeutics, and apply our shared learning through the R&D continuum.  As we’ve heard from the industry, researchers are stratifying medicines earlier in the R&D process and about 50% of new drugs have a biomarker that can potentially lead to a personalized approach. While many challenges remain, I am encouraged by the four-fold increase in Investigational New Drugs (INDs) and New Drug Applications (NDAs) that include genomic data since 2008.

To address this growth in genomic submissions, the FDA has new employees with expertise in genomics dedicated to review of these products and efforts to coordinate personalized medicine reviews will continue. I see a new era of personalized medicine not just in oncology but in cardiovascular disease, infectious disease, and neurodegenerative diseases, among others and the FDA is working to be ready.

I called on all members of the Personalized Medicine Coalition to find new ways to enable collaboration and to export the knowledge they are fostering at their companies and organizations to benefits for public health. By doing so, our combined efforts can lead to dramatic advances in improving therapeutics and healthcare. We are only just beginning to understand how new networks and powerful tools for sharing best practices can help us solve some of our most complex disease and drug response questions.

Legislative Specifications Would Create a Path Forward for Personalized Medicine

The Personalized Medicine Coalition has a long history of working with Congress on the Genomics and Personalized Medicine Act (GPMA); a bipartisan bill first introduced by Senators Obama and Burr in 2007.  The original bill was designed to take full advantage of our federal investment in the Human Genome Project by putting policies in place to enable personalized medicine.  Subsequent versions of the bill have not gone far enough to realign the health care system with personalized medicine.  In an effort to see a more effective version of GPMA introduced in this Congress – one that would move personalized medicine forward and would enjoy community support — PMC members developed a set of legislative specifications for Congressional consideration that are complementary to previous versions of GPMA.  We’ve asked Congresswoman Anna Eshoo to consider including them in her new version of the bill.

These recommendations include a range of important regulatory and policy concepts that can have a meaningful impact on advancing the discovery of and access to personalized medicine products.  They also echo important themes that emerged at the PMC’s Capitol Hill briefing in May.

Specifically, we propose codifying the Department of Health and Human Services’ Personalized Healthcare Initiative and providing the Secretary with an advisory committee populated by experts inside and outside of the government. We also reiterate the importance of ensuring adequate personalized medicine expertise and input on various federal advisory committees and within policy proposals.

Sponsors of personalized medicine products have had challenges taking drug-diagnostic combination products through the Food and Drug Administration (FDA). These experiences suggest that innovators need a predictable regulatory path at FDA so we propose an office for personalized medicine to coordinate therapeutic and diagnostic review, and enforce review timelines for both.

While the path from regulatory approval at FDA to adequate coverage and payment is clear (and usually predictable) for therapeutics, adequate coverage and payment for diagnostics can be long, complicated and frustrating.  To ensure that patients have access to the latest personalized medicines and diagnostics, we suggest policies at the Centers for Medicare and Medicaid Services that will ensure timely coverage and reimbursement for them.

Finally, to ease business model barriers, and incentivize the types of relationships that are the hallmark of personalized medicine, we suggest extending the qualifying therapeutic discovery tax credit from health care reform and expanding it to include personalized medicine companies.  We also suggest a new research and development tax credit to entities developing personalized medicine products.

We look forward to working with members of Congress in both chambers and in both parties to see that the Genomic and Personalized Medicine Act is introduced and signed into law.

The details of the legislative specifications can be found here.

FDA Issues Draft Guidance for Rx/Dx Co-Development – What’s Next?

FDA released long-awaited draft guidance on its regulation of co-developed drug diagnostic combination products.  PMC asked FDA to issue a draft guidance on this topic since innovators had many questions about how regulation of these two products together would work.  I can describe it in one word: short.

It outlines a collaborative process through FDA where the device and drug centers will coordinate review.  It reiterates the FDA practice of using ‘generic’ descriptors of diagnostic tests in drug labels and offers some flexibility and examples around products where a drug might be ready to go to market but the diagnostic is not yet.

While the community welcomes FDA’s current thinking on the topic, given the brevity of the document, I wonder if it left much unsaid.

For example: The focus (which will probably be welcomed by sponsors) is on collaboration between the drug and device centers but no details are given.  Also, while the personalized medicine community generally agrees that FDA regulation of companion diagnostics should be risk-based, there is a lot of debate in the community about what FDA means by risk in the case of a diagnostic.

In recent months, PMC has been working with over 100 members to develop legislative specifications for the next iteration of the Genomics and Personalized Medicine Act.  I will provide more detail on this in an upcoming blog entry, but one of the key concepts of these specifications is to “incentivize personalized medicine by creating a transparent and predictable regulatory environment for personalized medicine products.”  While the FDA’s draft guidance issued last week certainly leaves me wanting more, I do believe this represents an important step in that direction.

Nevertheless, our efforts toward this goal must continue. The FDA is seeking comment on the document for the next 60 days, and I encourage you to submit feedback.  We also welcome your participation in a discussion here at The Age of Personalized Medicine Blog by submitting a comment below.  We expect that FDA will continue to expand its guidance in the coming months, and receiving input from all stakeholders in the development, regulation, and use of co-developed drug diagnostic combination products is essential to their success.