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2010 in Review: Genomic Medicine Experiences Growing Pains of Regulation, Economics, and Litigation

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By Turna Ray

"Another year gone, and the lessons from the Human Genome Project have yet to yield the medical breakthroughs promised."

That was the undertone of many personalized medicine discussions throughout 2010, a year that marked the tenth anniversary of the Human Genome Project. The verdict by many observers of the field can be summed up by a New York Times article that concluded that the project's primary goal to "ferret out the genetic roots of common diseases … remains largely elusive."

But while there are still undeniable knowledge gaps regarding the role of genomics in most diseases, the number of drug/diagnostic codevelopment deals inked over the past year, despite a less than robust economy, indicates that big pharma is adopting pharmacogenomics as part of its overall drug development strategy.

And one only needs to survey the abstracts presented at last year's American Society of Clinical Oncology meeting to realize that in the next few years, the use of molecular testing to gain insights into patients' tumor characteristics will be the norm, rather than the exception.

Furthermore, the amount of activity last year on the regulatory, reimbursement, legislative, educational, and intellectual property fronts is a sign that the wheels are slowly shifting toward creating a framework that will someday support and deliver genomically guided medicine, even though plenty of barriers and challenges need to be overcome on the path to that goal.

During 2010, the industry began having some serious discussions about the steps necessary to overcome those challenges. For example, the National Institutes of Health solicited public comments on the features of a web registry cataloguing all genetic tests; the US Food and Drug Administration held a meeting to hear stakeholders' concerns about the agency's intent to regulate all diagnostic tests; and stakeholders debated the impact of several court decisions that could impact the patentability of genes.

In short, 2010 was the year in which genomic medicine experienced some necessary growing pains.

Climate Changes

Early last year, the healthcare reform bill was passed by Congress and signed into law by President Barack Obama. This created a climate that was ripe for introducing personalized medicine concepts into policy discussions since the new law created an independent government entity, the Patient-Centered Outcomes Research Institute, tasked with conducting studies that inform the public and healthcare providers about the comparative risks and benefits of marketed drugs, devices, and medical products (PGx Reporter 03/24/10).

However, the bill wasn't a slam dunk for personalized medicine. Although the healthcare law instructs the institute to conduct CER into the utility of medical products in "various subpopulations" differentiated by race, ethnicity, sex, age, co-morbidities, as well as genetic and molecular subtypes, many believe that CER will be readily used to show the clinical and cost effectiveness of treatments for the general population. It is currently unknown how prominently genomic strategies will feature in the CER conducted by PCORI, but proponents of personalized medicine seemed bolstered by the fact that the institute's leadership includes genomics experts.

Although there are plenty of naysayers when it comes to healthcare reform, legislators from both sides of the aisle introduced bills last year seeking to advance genomic research, encourage the drug and diagnostic industry to work together to develop innovative products, and ensure the safety of personalized medicine products.

In the middle of the year, Congressman Patrick Kennedy (D-RI) and Congresswoman Anna Eshoo (D-CA) revived a personalized medicine bill introduced three years ago by then Illinois Senator Obama. The new version of the bill sought to create an Office of Personalized Healthcare within HHS, and included provisions for advancing translational research, reimbursing personalized medicine products by accounting for the "best available data," and clarifying regulation for genomically guided treatments (PGx Reporter 06/02/10).

Then, PGx Reporter learned of efforts by Senator Orrin Hatch (R-UT) to write legislation that would form a new FDA center for regulating so-called "advanced personalized diagnostics." According to a draft version of the bill that circulated around Capitol Hill last year, "advanced personalized diagnostics" are distinct from medical devices and therefore should be regulated separately. That bill, which was crafted with input from experts in the drug and diagnostics field, is still under development and has not yet been introduced in committee (PGx Reporter 06/23/10).

Another set of important meetings that took place last year was held by the American Medical Association in order to craft a new coding structure for molecular diagnostics. Ideally, the new codes would more accurately describe molecular diagnostics being performed at hospitals and doctors' offices, so payors know what they are paying for.

When one thinks of genomic medicine and all the sexy technological advances it promises to deliver in the future, improving the CPT coding structure to account for the increasingly complex procedures performed by sequencing and microarray-based diagnostics is not something that comes to mind. Still, its one of those needling growing pains that must be endured and dealt with by experts in the field before personalized medicine is adopted into the healthcare system.

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The AMA's CPT Editorial Panel made significant progress last year in agreeing to adopt a handful of codes for the most commonly used molecular diagnostics, but there are still plenty of details left to iron out when it comes to codes for tests based on more complex technologies, such as sequencing, and codes for so-called "boutique tests" that are developed by and performed at a single laboratory (PGx Reporter 10/20/10).

The AMA is planning to develop a website to address how less commonly used tests and diagnostics based on emerging technologies will receive CPT codes, and is also planning to form a new molecular pathology expert panel to help inform this process.

Letters and Investigations

"2010 was the year that the regulation started to catch up to the technology," observed Jim Prutow, head of the personalized medicine practice at the management consulting firm PRTM. After several years of keeping a close watch on the rapidly expanding consumer genomics industry, the FDA took regulatory action against several companies last year.

When DTC firm Pathway Genomics attempted to sell saliva collections kits for its online genomic analysis service at Walgreens and CVS stores, FDA drew the line. Before Pathway's spit kits could make it to retail store shelves, the FDA sent a letter asking Pathway officials to explain why its products have not been cleared through the appropriate regulatory channels (PGx Reporter 05/26/10).

The red flags raised by Pathway's actions had a domino effect on the rest of the DTC genomics industry. Soon after taking regulatory action against Pathway, the FDA also sent letters to Illumina, 23andMe, Decode Genetics, and Navigenics, asking them to meet with the agency about the regulatory status of their genome scans and services (PGx Reporter 06/16/10).

Simultaneously, while the FDA was keeping its silent vigil on the DTC genomics industry, it seems the Government Accountability Office was doing its own investigation of the nascent field. After a year-long investigation into the sector, the GAO testified last year before the House Committee on Energy and Commerce that genetic test results provided by the companies it probed were "misleading and of little or no practical use to consumers" (PGx Reporter 07/28/10).

Although the DTC genomics firms that testified before Congress — 23andMe, Navigenics, Decode Genetics, and Pathway — criticized the GAO's study methodologies, several of those companies have since backed away from the DTC model.

Prior to the agency's actions, DTC genomics firms operated without FDA oversight of their services, reasoning that they fell in the category of laboratory-developed tests, over which the agency has traditionally exercised "enforcement discretion." However, simultaneous to regulating the DTC genomics market, FDA also decided to extend its oversight over all diagnostic tests, regardless of where they were developed.

The agency changed its policy in recognition of the fact that LDTs are technically more complex than they were when its "enforcement discretion" policy went into effect three decades ago. Additionally, tests developed by labs are now being marketed to a broader population than before.

As these regulatory activities culminated over the summer, raising many questions among industry players as to the specific policy changes that FDA had in mind with regard to its oversight of diagnostic tests, the agency held a meeting to give stakeholders an opportunity to air their grievances and recommend changes to the system.

During these meetings, agency officials did more listening than speaking. Since the meeting, the agency has not released any official guidance, but has noted that the regulatory requirements for a particular diagnostic may increase or decrease based on the risk the test poses to public health (PGx Reporter 07/21/10).

The Right to Genomic Information

After the summer controversy over DTC genomics firms, the debate about whether individuals should have unfettered access to their genomic data migrated from Capitol Hill into college campuses.

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In May, University of California, Berkeley, had announced plans to launch a voluntary program in the fall semester that would provide genetic testing to students in the Class of 2014 for three genes involved in the metabolization of alcohol, lactose, and folates. But after the GAO report cast a negative spotlight on the DTC genomics industry, the California Department of Public Health restricted state-funded UC Berkeley from analyzing the saliva of students who had volunteered to take part in the educational exercise.

CDPH said it took this action since genomic analysis at Berkeley would not be performed at a CLIA-certified laboratory and since test results would be delivered to students without the involvement of a physician (PGx Reporter 08/18/10).

Although the CDPH directive restricted the university from providing students their DNA data, university professors involved with the program decided to hold lectures on consumer genomics to allow students to discuss and debate the ethical, legal, and societal issues associated with increased public access to genomic information. "Every single student who opened an envelope had to make the judgment for themselves: 'Do I want to subject myself to genetic testing of three variants that we think are quite innocuous or do I not?'" UC Berkeley genetics professor Jasper Rine said at the time. "That's a life lesson that I'm thrilled to have been able to teach."

Following Berkeley's experience, Stanford University, a privately funded California academic institution, also announced a class to educate students about issues related to consumer genomics. However, Stanford's program differed from UC Berkeley's by restricting genetic testing plans to an elective course for MD/PhD students, as opposed to incoming freshmen (PGx Reporter 06/09/10).

As commercial DTC genomics firms grow in popularity and genomic testing starts to become ubiquitous in clinical care, it will become more important for schools to provide a basic genomics education at the university and high school level. However, after UC Berkeley's experience with state health regulators, educators have become cautious when embarking on this type of innovative lesson plan.

For example, Duke University has said it is planning a hands-on genetic testing program, and will incorporate lessons learned from the "Berkeley experiment" in designing its course.

Future Uncertainties

Despite the heightened regulatory activity last year, there are still plenty of unknowns on the legal, reimbursement, and investment fronts that might impact the growth of personalized medicine in the coming years.

The future impact of the healthcare reform act is not yet known, but many in industry and in the investment world are of the opinion that it will become increasingly difficult to bring new and innovative medical products to market.

At a conference on CER and personalized medicine last year, representatives from the public and private payor community discussed some of the changes spurred by the new healthcare law to ensure that the most effective treatments are being reimbursed. However payors may feel about CER, when it comes to personalized medicine, it seems insurers are all too happy to use comparative effectiveness to continue to maintain a high evidence threshold for proving that genomically guided medicine improves outcomes and saves money over the standard of care.

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This, according to one life sciences investment tycoon, doesn't bode well for the types of innovations necessary for the personalization of healthcare. "The payor community … doesn't necessarily want to pay for the technology we bring to the marketplace," said Steven Burrill, CEO of the life sciences venture capital firm Burrill & Company, who spoke at the same conference on CER last year.

"We're naïve … because we live in a world where we invent things and throw it over the wall, assuming that someone on the other side will pay for that, and that's no longer a valid assumption," he said.

The economic downturn, combined with increased evidence requirements under CER, may discourage investors when it comes to funding emerging technologies. This may be particularly bad news for the rapidly evolving technologies enabling personalized medicine.

"CER has provided a barrier to entry and competitive advantage for the big [life sciences] companies," Burrill said, pointing out that the translation of innovations from the clinic to the marketplace is made possible through "hefty investments" from financial firms and venture capitalists.

"But people like me will not invest in something if we are uncertain about a [technology] because of what we have to prove because of comparative effectiveness," he stated.

Industry players and investors are also closely watching the outcome of Association for Molecular Pathology et al. vs. the United States Patent and Trademark Office et al., a case that is challenging the validity of Myriad's patents on BRCA1 and BRCA2 genes linked to the risk of hereditary breast and ovarian cancer. With 20 percent of the human genome already patented, the outcome of the case could impact the extent to which isolated gene sequences can be patented for the development of drugs and diagnostics.

Last year a federal district court surprised many by invalidating Myriad's patents. In issuing this decision, district court Judge Robert Sweet reasoned that isolated DNA sequences are not markedly different from sequences naturally occurring in the body, and that the process of isolating and purifying DNA is an abstract mental process. As such, Sweet deemed Myriad's patents invalid under 35 USC Section 101, the portion of the US patent code that describes what is eligible for patent protection (PGx Reporter 03/31/10).

However, Sweet's decision is not the last word. Myriad appealed the district court's determination last year in the Federal Circuit Court of Appeals. As such, the status of Myriad's patents, and gene patenting as a whole, remains in flux.

Further blurring future predictions with regard to gene patenting are the Supreme Court's decision in Bilski v. Kappos and the Appeals Courts' revisitation of Prometheus v. Mayo. When deciding AMP v. USPTO, the appeals court will likely look closely at how the so-called machine-or-transformation test — a way for determining patent eligibility based on whether something is tied to a particular apparatus or transforms an article into a different state — was applied in the above cases. Although Sweet deemed Myriad's method claims of "analyzing" and "comparing" gene sequences as abstract mental processes not meeting the transformation test, some legal experts believe that the recent decisions in Bilski and Prometheus may be applied to show that Myriad's patents do pass muster (PGx Reporter 12/22/10).

"We don't yet have an answer from the Federal Circuit on how it's going to handle gene patents, but we are seeing hints," Dan Vorhaus, an attorney at the law firm Robinson Bradshaw & Hinson and an ELSI advisor to the Personal Genome Project, told PGx Reporter. "From its two opinions in Prometheus, as well as other recent opinions like In re Kubin and Ariad, I think you can make the case the Federal Circuit sees the patentable subject matter test under Section 101 as fairly easy to satisfy and yet, at the same time, they are tightening up on other requirements to patentability: novelty, non-obviousness, and a full and specific description.

"That probably doesn't bode well for Sweet's opinion surviving at the Federal Circuit level, but it doesn't necessarily mean there's a rosy future ahead for gene and medical method patents either," Vorhaus added. This uncertainty is a cause for concern for some in the drug and diagnostics industry who fear that if the case goes to the Supreme Court and the federal district court's decision is upheld, it will drain funding for innovative personalized products that depend on gene patents to get a return on investment.

Currently there is no date set for a hearing in AMP by the federal appeals court. Some legal experts are guessing that a decision may come mid-year.

2011 Predictions

Uncertainties abound regarding the implementation and adoption of personalized medicine, so it's an open question as to what 2011 will bring. While sequencing vendors are continuing the race to lower the price tag of whole-genome sequencing, potential changes in the consumer genomics industry and legislative efforts could speed up or stall advances in the field.

On the legislation front, the Kennedy/Eshoo bill died in the previous Congress without gaining much traction. The Personalized Medicine Coalition, which keeps a close watch on legislation that might impact the field, found the Kennedy/Eshoo legislation "wanting" in its handling of the business, reimbursement, and regulatory barriers to personalized medicine.

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Amy Miller, PMC's public policy director, was more optimistic about the chances of the Hatch bill in the new Congress. Hatch's legislative team "is working with a number of stakeholders to remove one barrier to personalized medicine: the unclear regulatory path for personalized medicine diagnostics," Miller said. "When a discussion draft is circulated, it will give the community a common framework to respond to and is a great first step to overcoming one barrier. But, it’s a game-changer for a lot of stakeholders so there will likely be a lot of negotiations ahead."

Although there is some concern among supporters of healthcare reform that the new Republican-controlled House of Representatives will try to repeal the law, Miller does not believe that personalized medicine will be impacted. "Although there will be a lot of chatter about repealing healthcare reform in whole or part, no repeals will happen this Congress because such bills will not pass the Senate or earn the President’s signature," Miller said.

Still, 2011 stands to be a difficult legislative environment in general, since the House and Senate are controlled by different parties. "However, personalized medicine is not a partisan issue; members of all parties want higher quality healthcare," Miller pointed out. "FDA user fees must be reauthorized this Congress and that will give personalized medicine-related legislation a chance to become law."

Changes in the consumer genomics arena are also likely this year. 23andMe has already said that it will be experimenting throughout the year with different pricing structures to grow its customer base (PGx Reporter 01/05/11).

On the consumer genomics front, 2010's difficult regulatory environment could spur some M&A activity in that industry in 2011, observed PRTM's Prutow.

"The overall business model is going to change, so there's not going to be a direct-to-consumer genomics industry in this fashion any more. So, what 23andMe is doing now isn't going to continue long term," Prutow said.

Although several personal genomics companies have already given up marketing their services directly to consumers, 23andMe and Decode Genetics appear to be holding on to the model. Navigenics and Pathway market their services through doctors.

With FDA keeping a close watch on the types of claims DTC genomics firms are making, 2011 may see these types of companies separate into two groups: "fun" genomics and clinically relevant genomics, Prutow said. "What wouldn't surprise me is if [an] IVD firm acquired one of the DTC genomics companies."

In Prutow's view, companies such as Siemens, Abbott Molecular, and Roche wouldn't buy a consumer genomics firm to continue to market directly to consumers, but to gain access to a web-based platform for conducting research, as well as a large sample database for identifying biomarkers for drug and diagnostics development.

Other companies Prutow envisions being interested in acquiring a consumer genomics firm would be the likes of Quest and the Laboratory Corporation of America, "who might want to augment their test offerings with some of the offerings at DTC firms."

Being acquired by a more established company might help DTC genomics firms navigate the increasing regulatory pressures that they don't have experience handling.

"It's going to be extremely difficult for these DTC companies to put in place the quality systems … and controls that are going to be necessary," he noted. "The DTC business model will have to evolve in 2011."


Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.

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