Sequenom data debacle will have systemic effects: Dealing with Federal agencies just got harder

The ongoing data integrity scandal at Sequenom is very bad news for anyone seeking FDA clearance or insurer coverage for an innovative medical technology or pharmaceutical. For all the safeguards, system controls and audits that are part of a well-controlled and maintained clinical data system, the entire edifice still relies upon faith – the faith of government agencies, insurers, service providers, physicians and patients – in the essential integrity of the clinical data reported by companies and clinical trial sponsors.

Here is the unfolding story. Sequenom is a publicly-traded San Diego based genetic diagnostics company that had been a stock market darling on account of its late first trimester maternal blood test for Trisomy (Downs Syndrome). The appeal of the test rests in its ability to provide a definitive diagnosis of Downs Syndrome earlier in the pregnancy than is otherwise possible and without the need for amniocentesis (with its attendant risks). Sequenom’s shares were being watched closely by the analyst community, and it share price peaked at @ $25 on a January 28, 2009 Press Release and Investors’ Teleconference that trumpeted new clinical data demonstrating a 100% positive predictive value and a 99.9% negative predictive value for the Downs Syndrome test.

An April 29, 2009 Sequenom press release announced a delay in the expected June launch of the test, on account of “discovery by company officials of employee mishandling of R&D test data and results.” The share price plummeted to < $3.00. On September 28, the company released the results of an investigation by independent members of the Board, which concluded that none of the previously released data on the test could be relied upon, and announced the firing of the CEO/President, the Senior VP for Research and Development, the CFO, one other officer, and three other employees. An October 5 regulatory filing disclosed that Sequenom’s management had met with representatives of the U.S. Attorney's Office, the Securities and Exchange Commission, and the Federal Bureau of Investigations. Shares are trading at @ $3.37 as I write.

We don’t as yet know exactly what happened inside Sequenom, whether there was intent to deceive or simply a breakdown in controls, and if there was intent whether it originated from the top, or how and by whom the data errors were discovered. We do know that corrupt data were disseminated to the public and to regulatory agencies, that a lot of money was lost by investors, and that the test was close to launch. Had the company not stepped forward (and there is as yet no information as to how the problem was discovered and by whom) when it did, the test would have been covered by most insurers and widely and rapidly adopted – all on the basis of flawed or falsified data.

The medical device industry has for years urged CMS to consider “external data” – data from sources other than the agency’s own data files, in calculating payment rates and/or in making coverage determinations for various services. After all, some new technologies are used earlier in non-Medicare patients, and there can be substantial and relevant data from external sources that can illuminate service costs and impacts before there is a large body of Medicare data. Openness to all data sources would, the argument goes, yield better and faster decisions than reliance solely on Medicare data. CMS has generally responded that it is not sure it can rely upon data that are externally generated and controlled – it simply doesn’t trust such data. In recent years there has been a bit more openness – but the Sequenom debacle can only heighten distrust and set back recent progress.

Medicare's Inpatient New Technology Add-on: The Trials of InfraReDx, the Triumph of Spiration

The problem of adequate payment for innovative new technologies has from the beginning been a difficult one for the Medicare Inpatient Prospective Payment System (IPPS) for acute care hospitals. Since cases are assigned to DRGs on the basis of diagnosis and/or surgical procedure, and payment for each DRG is based primarily upon historical cost data, the system from the outset had no mechanism to properly recognize the cost of newly introduced technologies that improved outcomes but entailed incremental spending.

Effective FY 2002, Medicare implemented a mechanism - the Inpatient New Technology Add-on - designed to address this issue (see 66 CFR 46917). Under the new program, if a qualifying new technology added substantial cost, Medicare payment to the hospital would be the applicable DRG payment plus 50% of the cost attributable to the new technology. The Program held, over hospital and medtech industry protest, that 50% payment struck a good balance between a financial impediment to technology adoption and a blank check. Besides, the add-on was simply a temporary mechanism, allowing reasonable adoption until the cost of the technology could be reflected in the standard calculation of payment for the DRG. The most notable observations from 9 years of experience with the add-on (including decisions just announced for FY 2010) are the surprisingly small number of technologies that have applied for the extra payment, how few of the applications have been successful, and how minor an impediment the 50% limit on incremental payment has been. We'll use two applicants for FY 2010 - InfraReDx's Lipiscan vulnerable plaque diagnostic and Spiration's IBV intrabronchial valve system - to document the process and the problem.

CMS has clearly articulated 3 standards that must be met for new tech add-on qualification:

1. Newness - the first commercial distribution of the technology must be sufficiently recent so that cost of the technology is not reflected in the data used to calculate DRG relative weights; effectively, this means first commercial introduction less than 2 years prior to application; commercial introduction is the FDA clearance date, unless there is some reason distribution was delayed;
   
2. Cost - the incremental cost attributable to the new technology must bring the charge per case above the lesser of a) 1.75 times the mean standardized charge (MSC) for the DRG or b) the MSC for the DRG + 75% of one standard deviation above the MSC; CMS annually publishes the threshold amount for each DRG; if a technology would be used for patients in multiple DRGs a volume-weighted MSC is calculated; and
3. Substantial clinical improvement - there must be evidence that the new technology provides real clinical benefits as compared to existing technologies or services.
   

Only one technology qualified for the new technology add-on for FY 2009 - the Syncardia CardioWest temporary total artificial heart. On its face, the CardioWest device is anything but new: a direct descendant of the Jarvik 7 heart, CardioWest has been used as a bridge to transplant with FDA approval since October 2004 (after use in clinical trials for many years). But because artificial hearts were denied Medicare coverage until a coverage policy revision in May 2008, data on the cost of the CardioWest has never found its way into calculation of DRG payment rates. Consequently, Syncardia's application for an add-on was accepted for FY 2009, and has now been extended to FY 2010. It will likely qualify for a third and final year of add-on payments in 2011. The case for meeting the cost threshold was ironclad, and the CardioWest does inarguably succssfully bridge some patients to transplant who have no other therapeutic option.

Only two new add-on applications were pursued to the end of the process for FY 2010 (four applications referenced in the NPRM for FY 2010 were withdrawn for various reasons - different forms of "inevitable rejection" - before the Final Rule was completed). In the case of the InfraReDx Lipiscan, CMS had in the NPRM questioned whether the device met any of the three qualifying criteria, and requested public comment on all three. The challenge re: the "newness" criterion was most interesting. The Lipiscan was cleared for marketing in 2008 under the 510k route, referencing as predicate an earlier InfraReDx technology first cleared, for a different indication, in 2006. How, CMS asked, could a device be claimed to be "substantially equivalent" to existing technology in an application to one agency but new and innovative in an application to another. Further, CMS quoted FDA's 510k approval letter to make its point:

“The LipiScan Coronary Imaging System utilizes the same basic catheter design as the predicate, the InfraReDx NIR Imaging System (June 23, 2006). These devices have a similar intended use, use the same operating principal, incorporate the same basic catheter design, have the same shelf life, and are packaged using the same materials and processes. The modifications from the lnfraReDx NIR Imaging System to the LipiScan Coronary Imaging System are the improved
catheter design, improved user interface (including PBR and console), and the additional
testing required to support an expanded indication for use.”

Was the new indication for use sufficient to establish Lipiscan as "new" for add-on payment purposes? The answer seemed to be "no", but the question was left open for public comment. And InfraReDx ultimately had a compelling comment to make - the predicate device had never been distributed because it had commercially unacceptable operating problems - i.e. it didn't work. No one had ever bought one, so no cost for it had ever been reflected in DRG weights. An interesting inversion: if the predicate device had been clinically and operationally acceptable, the Lipiscan would have failed the newness criterion.

This one victory was not sufficient to carry the day. Nor was CMS' eventual agreement, after much parsing of numbers, that LipiScan met the cost criterion. The sticking point became substantial clinical improvement. InfraReDx relied on the fact that it had demonstrated a diagnostic capability - the identification of vlulnerable plaque - that was wholly original, and that the use of that diagnostic capability would allow better identification of risks and targeting of therapeutic interventions. It even submitted an opinion from counsel arguing (in essence) that under the applicable statute "better diagnosis" constituted "clinical benefit". This may have been a tactical error. CMS acknowledged the unique diagnostic capability of Lipiscan, but concluded that there was no documented clinical evidence to demonstrate, or any consensus among clinicians, that the diagnostic - whatever its virtues - produced improved outcomes. That, the agency insisted, was their standard: application denied.

On the newness criterion, the Spiration IBV valve system confronted a problem opposite to that of both the Lipiscan and the CardioWest heart. The IBV was approved by FDA under the Humanitarian Device Exemption (HDE) mechanism in 2008. There was now comparable prior product on the market. But use under an HDE requires approval by each user hosital's IRB, and at publication of the NPRM no IRB approvals had yet been received. As a device cannot be new until it receives final regulatory approval, qualification for the add-on depended upon receipt of IRB approval before publication of the Final Rule for FY 2010. Happily, Spiration was able to document initial IRB approval on March 12, 2009, and that was recognized by CMS as the initial commercial distribution date for the IBV System.

Spiration's challenge with regard to substantial clinical benefit was closely related to the IBV's HDE approval route. An HDE requires demonstration of "safety and potential benefit", far less than the demonstration of safety and effectiveness required by the PMA process. HDEs are typically granted based on very limited clinical trials - in Spiration's case, fewer than 10 patients. There was no randomized clinical trial required for HDE approval, and no data from a randomized trial available for review. The NPRM questioned whether there was evidence of cliical benefit and requested public comment.

The comment received was universally positive. Every commenter made essentially the same case from personl experience: postoperative air leaks from pulmonary surgery are extremely dificult to treat, clinically problemmatic, and expensive; the experience with the IBV was positive; the system appeared to close air leaks effectively. CMS, impressed by the consistency of comments from the clinical community, accepted the propositio being argued. The final rule makes it clear that the agency isn't fully and finally convinced, but that the argument is strong enough to carry the day: application approved.

Both the Lipiscan and the IBV System ultimately were judged to qualify under the cost criterion, but in bolth cases the process was laborious. One reason was that both technologies could be used on patient swho fell into a large number of different DRGs, and the method for calculating a weighted standardized cost across mltiple DRGs is convoluted. Furthermore, there is a lot of moving back and forth between costs and charges required in the calculation; every time charge data must be converted to costs, or cost data must be converted to charges, there are statistical manipulations that are clear to CMS but not to many outside the agency. Professional help is essential here. But a further interesting problem was that both InfraReDx and Spiration refused to provide information on the selling price of their devices - even though that information would have simplified the calculations enormously and (in both of these cases) guaranteed meeting the criterion. Spiration went even further to protect proprietary data: it would not give CMS data on the number of valves used in each procedure (the number can vary depending on patient-specific needs), necessitating an enormously convoluted and potentially misleading process of inference.

CardioNet: Reimbursement at the heart of the matter

It has not been a good year for investors in CardioNet (NASDAQ: BEAT), the once high-flying Pennsylvania-based cardiac monitoring company touted by many as the best pure play in wireless patient monitoring and diagnostics. CardioNet stock closed on July 14 at $6.20, down 83% from it 52 week high of $35.89. For the second half of 2009, the company’s share price mirrored the broader market. In Q1 of 2009 it outperformed the market, returning by late April to the level it had enjoyed in mid-July 2008. But the trend turned in May; CardioNet shares have plummeted in the last 2 ½ months. For those seeking an explanation, the answer seems simple and comes in one word - reimbursement. The company would express it more vigorously – arbitrary and unwarranted reimbursement reductions. But, as is often the case, the story is somewhat more complicated. CardioNet made specific corporate strategy decisions that increased its exposure to reimbursement risk.

Let’s look at the background and review some pertinent history. CardioNet provides Mobile Cardiac Outpatient Telemetry (MCOT) using an internally developed proprietary technology platform. MCOT allows continuous cardiac monitoring for up to 30 days, with the capability for real-time review and querying from a monitoring center. The technology allows for the identification of heart rhythm irregularities that elude the commonly used shorter-term monitoring technologies (e.g. holter monitoring), and many insurers, including Medicare, cover MCOT for defined subsets of patients who experience serious but unpredictable arrhythmias that have not been adequately evaluated by those other techniques.

Diagnostic tests like MCOT are represented by two CPT codes. One code identifies the Professional Component (PC) of the test – the physician’s interpretation of the test result as it relates to the individual patient; the second code identifies the Technical Component (TC) of the test – in this case the resources required to provide and conduct the test and generate a test report (the MCOT equipment, the monitoring center with its technology and staff, the computerized analysis of data, the generation of a report to the physician, etc.) CardioNet operates as a physiological testing laboratory – monitoring patients nationwide from its base in Pennsylvania and billing insurers for the TC of the test; the referring physician bills for the PC, which is small compared to the TC.

MCOT was approved for commercial use in 2002, and CardioNet set up its testing center that same year. As a Pennsylvania-based facility, the center did all of its Medicare billing to a single regional Medicare Part B carrier, Highmark Medicare Services. The test was provided under a temporary Category III CPT code through the end of 2008. In October of that year, however, CardioNet announced approval of permanent codes for MCOT – CPT 93228 for the PC and CPT 93229 for the TC – effective January, 2009, and a carrier-determined reimbursement rate for the TC of $1,123.07.

CardioNet had gone public earlier in 2008, and the analyst community is extremely sensitive to reimbursement issues, particularly for single product companies where one reimbursement decision can be make-or-break. That sensitivity can sometimes take the form of rumor-fed speculation, often resulting in share price instability. CardioNet was not immune to this phenomenon, and on April 28, 2009 the company issued a press release to refute analyst speculation about an imminent Highmark payment reduction for the MCOT TC. On May 18, a further press release solidified the situation, announcing formal Highmark posting of the $1,123.07 rate originally announced in October of the previous year. Things were looking good on the reimbursement front.

But there has been nothing but bad news since. On June 30, a press release announced a downward revision of guidance for 2009 based on lower than expected commercial reimbursement rates. Analyst concern over Medicare reimbursement was heightened by this news, and confirmed in a July 12 CardioNet announcement of a revised Highmark TC payment rate effective September 1 – a more than 30% reduction to $754. On the following day, the company announced termination of its agreement to make what had been positioned as a key strategic acquisition to strengthen its position in the wireless telemetry ; a failure by the target to comply with conditions of the agreement were cited as the reason. The jilted acquisition target, BioTel, Inc., disagreed vehemently and is weighing its legal options. It is difficult to dismiss the reimbursement catastrophe as an underlying cause.
We cannot yet know whether CardioNet did the best possible job of reimbursement advocacy, why it didn’t prevail, or why it was apparently blindsided by Highmark’s action. So we can’t, from outside the company, determine which of the following three possible scenarios best describes this case:

1. Weak or ineffective advocacy for a case that ought to have prevailed on its objective merits;
2. An objectively weak case that could not prevail on its merits; or
3. A payer decision that was in fact arbitrary, or based on factors other than objective analysis of costs.

What we can know is that CardioNet made a number of conscious business strategy decisions that, whether or not they were dictated by compelling business reasons, increased its reimbursement jeopardy.

First, by maintaining all of its operations in a single location, CardioNet put its entire Medicare business into the hands of a single local Medicare contractor. Had operations been regionalized, there would have been a different contractor for each region. A single contractor would then have impacted only a portion of the Medicare business, not all of it. There is a trade-off at work: a single carrier increases jeopardy by putting all of the eggs in a single basket; multiple carriers spread the risk, but require commensurately broadened advocacy communications and reimbursement support. CardioNet opted for operational consolidation (which may also have carried substantial operating cost advantages), valuing business simplification over reimbursement risk mitigation.

If multiple carriers were handling CardioNet’s claims, Medicare would have had an incentive to set reimbursement at a single nationally-determined level, especially if there were regional disparities that could not be supported by differential costs. But a single explicitly national rate established centrally is greatly preferable to an effectively national rate set by a single regional carrier. At the national level, there are procedural rules, formal opportunities for comment on proposals, and public notification of the basis upon which a decision is made. Local carriers are not bound by any of these requirements. Furthermore, local carriers do not have substantial payment policy staffs wide broad experience in understanding cost profiles and operating requirements across many different types of provider organization; the sophistication of their decision processes varies widely and cannot be relied on.

Second, CardioNet chose to operate as a physiological testing laboratory rather than selling its technology to independent laboratories. Had it done the latter, the company would have been free to sell the technology at a price of its own choosing. This would transfer primary reimbursement risk to CardioNet’s customers, but it would also provide those customers with unequivocal documentation of an important cost element required for the test – the technology cost. Under the scenario CardioNet chose, there is no such documentation, as there is no arms-length transaction between technology supplier and testing facility. Under these circumstances, Medicare invokes special accounting rules applicable to “related party transactions”; the relevant aspect of those rules is that transfers between related parties occur at the cost of manufacture or acquisition – no margin (markup) is recognized. Thus, to the extent CardioNet wants to provide real cost data, Medicare will calculate the cost of providing the TC without allowing a markup on cost of manufacture.

I suspect that CardioNet made the choice it did in order to capture a larger share of the total TC revenue stream – not an unreasonable goal. But again, there was a tradeoff: control of the total revenue stream increased direct exposure to reimbursement risk. And there was a more conservative choice available: sell the technology to testing facilities until reimbursement was clearly established, and then expand into the testing business once reimbursement risk was minimized.

That conservative strategy may not have been aggressive enough for the investment community. And therein lies the third risk-increasing strategic decision CardioNet made: the decision to go public before solidifying its business position and before removing reimbursement risk from the equation. Perhaps an IPO was the only way to raise enough money to build the business. An IPO was certainly the way for early investors to cash out and take profits, and for management to realize substantial capital gains. But IPOs increase all sorts of exposure, create enormous pressure to accept risk in order to grow quickly, and expose companies to extraordinary volatility when best-case scenarios are not realized. When things were going well, it seemed as if CardioNet management was on top of the key issues; when they went sour, management appeared to be caught unaware and unprepared, having oversold financial growth and understated risk.

The reimbursement challenge for advanced prosthetics

We are aging, and inevitably that means that we - or at least some of our parts - are wearing out. Increasingly, there are demands for wider availability of "replacement parts" to restore physical functionality and quality of life. And while tissue engineering and stem cell research may hold the promise of biological replacement parts, grown to order from the patient's own cells, clinical realization of that promise remains in the fairly distant future. For years to come, advances in prosthetic devices will be the dominant mode for replacing the function of non-functional body parts or organs. Our imagination tends to be grabbed by the technology projects that aim at vital organ replacement - Abiomed's AbioCor Total Replacement Heart (apparently, excuse the expression, moribund), the various artificial pancreas projects that receive publicity from time to time (such as this one), liver replacement technologies, wearable artificial kidneys, etc. - but the real current action seems to be in the orthopedic arena, where basic technology is in place, but there are exciting innovations in the pipeline.

It seems reasonable to ask: "Who will pay for these prosthetic devices, and for which patients?"
The "who" is fairly clear. The population in need is primarily elderly and the dominant payer will be Medicare. The Medicare program has a long-standing and well-understood prosthetic device benefit (see Section 1834(h) of the Social Security Act), which provides payment for devices that replace the functionality of permanently non-functional body parts or organs. The benefit covers the obvious orthopedic prostheses for amputees, but also extends to implanted replacement knees, hips and other joints, external and implanted mechanical circulatory support devices, total parenteral nutrition (i.e. replacement of non-functional gut), ostomy and colostomy procedures and supplies, and a host of other technologies. For covered prosthetic devices, Medicare pays for any medical procedures required to initiate device use, the device itself, and any supplies and equipment required for ongoing functionality. To meet the "permanence" standard, the program requires clinical evidence that the impairment in function be "of long and indefinite duration" - the potential for recovery of function at some indeterminable future time is not disqualifying. For clinical procedures, implanted devices and professional services provided under the prosthetic device benefit, Medicare pays under the various payment schemes for hospitals and physicians. External prostheses and prosthetic device benefit supplies and equipment are paid under the rules and procedures for durable medical equipment, with a 20% patient copay obligation.

Coverage for prosthetic devices - determination of whether Medicare will pay for a particular device class, and if so under what circumstances - is subject to the conventional coverage standard of "reasonable and necessary". As usual, it is in the application of this standard that the potential for controversy resides. Even for vital organs, where complete failure means death, Medicare has struggled with three difficult questions:

1. What is the threshold - the degree of organ failure - for coverage under the prosthetic device benefit;
2. When is a device good enough - i.e. a sufficiently effective replacement - to warrant coverage; and
3. Is there a performance level for a prosthetic device beyond which incremental improvement is defined as unnecessary and therefore non-covered? How good a replacement are we willing to provide?

The most common implanted prosthetic devices are replacement hips and knees. We all know someone with one or more of these (I myself have two replacement knees). Qualification for coverage is straightforward - without the replacement the patient cannot walk; with it he/she can; every insurer finds it reasonable and necessary to cover replacement of these joints to restore mobility. And while the devices have been incrementally improved over the years to wear better, last longer, get placed easier and more precisely, etc. - all unequivically good things for patients, surgeons and insurers, there have been no substantial changes in the degree of functional capability they provide, and therefore no significant coverage issues raised. Insurers might resist a hypothetical new model knee that provides 10% increased functional longevity at a 50% increase in cost, but that value calculation is itself pretty straightforward.

A recent newsletter report about replacement ankles raised a significant coverage policy question. There are several FDA approved ankle arthroplasty (replacement) devices, a fair number of orthopedic surgeons want to do favor them and want to use them, but insurance coverage is rare. Dr. Michael Pinzur, writing in Foot & Ankle International, the official journal of the American Orthopaedic Foot and Ankle Society, wants to know why:

• "It seems curious that the FDA agrees with the [foot and ankle society] that total ankle replacement is a reasonable treatment option . . . while several insurance providers do not find ankle replacement as a reasonable treatment option for ankle arthritis," and
• "Should insurance companies make decisions on what treatments are appropriate and what treatments are deemed experimental?"

It turns out, of course, that FDA has never opined that total ankle replacement is a reasonable treatment option. Ankle replacement systems are class II devices. FDA has cleared at least three through the 510k process, but that signifies nothing about "reasonable" (a word and a consideration wholly absent from FDA marketing approval processes) and very little about anything else beyond the fact that the systems were deemed "substantially equivalent" to systms already on the market.

Medicare has no formal coverage statements on ankle arthroplasty, indicating that coverage may be granted on a case by case basis by the medical directors of the various fiscal intermediaries. But several major private insurers ( e.g. Anthem, Cigna,) provide detailed reviews of ankle replacement and why they don't cover the procedure: lack of reliable supportive clinical data (in part because FDA did not require clinical results for market clearance), uncertainty of superiority over surgical options, high percentage of re-ops required, lack of data based guidance concerning circumstances/sandards for use, etc. In short, advocates for ankle replacement haven't yet done what insurers reasonably expect them to do - make a strong clinical case for why and when the technology provides benefits beyond the available treatment alternatives. Contrary to Dr. Pinzur's view, this kind of decision is precisely what insurers always do, and what we need them to do.

The third question - when is a prosthesis too advanced to be necessary - is raised by recent developments in artificial lower limb prostheses, with the advent of computer- assisted joints which allow prostheses to perform in increasingly natural ways. New knee and ankle prostheses (like this one) under development will allow recipients almost perfectly normal looking gaits, much improved balance on uneven surfaces, and greatly decreased workload for given amounts of movement (translating into dramatic improvement in stamina). These prostheses will raise the ceiling on amputees' athletic performance and will provide them with capabilities increasingly approaching full normality, but functional and aesthetic. Wow! - but will insurers pay?

The answer, I think, is "Maybe someday, but not very soon." Insurers pay for prostheses that are reasonable and necessary to restore function, and the restoration target is predicated on the functional level deemed "normal" for the individual. We can see this in current coverage policies for non-computerized limbs, where Medicare and private insurers all provide prostheses capable of supporting the functional level deemed obtainable by the individual patient absent the amputation. A patient bedbound or wheelchair-bound for reasons unrelated to an amputation would not be covered for a prosthetic limb; one capable assisted ambulation becvause of cardiac conditions will be covered for the most basic prosthesis; one capable of ambulation on an uneven surface for extended periods of time will qualify for a more advanced prosthesis. Aesthetics do not enter the equation; neither does enhanced mobility for athletic or avocational purposes. Insurers will pay what is necessary for technology to help an amputee maximize his/her independance, maximize mobility in normal day to day activities, and get back to work ... but they will not pay more for appearances, or to facilitate running a marathon or climbing a mountain.

Normal function is socially defined. As these advanced technologies become available and their potential is more widely understood, it is likely that it will become increasingly difficult for insurers to maintain the "necessity" line where it is today. Technology invariably carries rising expectations with it. What is readily available and desirable becomes required. I think that will happen with advanced prostheses, aided by (relatively) decreasing unit costs as volumes grow. But not for a while, perhaps for a long while.

Medicare and Health Technology Innovation: Facilitator or Obstacle?

If we listen to the leadership of the Obama healthcare reform effort, we cannot help but be impressed by the consistent focus on the development and utilization of innovative health technologies as a significant element in efforts to improve quality and control costs. The theme was reiterated on May 11 by Margaret Hamburg, FDA commissioner-designate, in a confirmation hearing (Video here) before the Senate Health, Education Labor and Pensions Committee. And the Congress - at least the majority - is on board as well; witness full HELP Committe hearings on innovative healthcare delivery systems scheduled for May 13 and 14 .

At the same time, recent Medicare program regulatory publications and coverage policy determinations can only cause us to question whether the commitment to innovation has as yet penetrated to the operational level. Last week, advocates of personalized medicine and genetic tesing were handed a setback as Medicare issued a Proposed Decision Memo for Pharmacogentic Testing for Warfarin Response. Warfarin is a commonly prescribed anticoagulant used to prevent blod clot formation in at risk patients; at any given time, millions of Americans are on Warfarin therapy. The potential vlue of pharmacogentic testing for Warfarin sensitivity is outlined in the NCA:

Warfarin has a narrow therapeutic window, meaning that there is a small difference in dosage (at times, less than one milligram of warfarin per day) between dosing that is too little, just right, or too much. Standard clinical practice for warfarin titration requires periodic testing of its anticoagulant effect. This is assessed with the prothrombin time (PT) and the International Normalized Ratio (INR). In the PT/INR test, the ratio of the patient's PT to the mean PT for a group of normal individuals is calculated, and that ratio is then raised to a power which adjusts for differences among different types of reagents used in the test procedure. Commonly, the PT/INR is assessed frequently during the first few weeks or months while warfarin therapy is begun, and after that, less frequently when the patient demonstrates a stable response. More frequent testing may be required if the patient exhibits signs of over- or under-treatment or if the patient begins (or stops) taking another drug that is recognized to affect warfarin action or metabolism.

The putative use of pharmacogenomic testing is to predict a patient’s response to warfarin before the initiation of the drug. This would be an once-in-a-lifetime test, absent any reason to believe that the patient’s personal genetic characteristics would change over time.

The Warfarin test had been seen as a major step forward for genetic testing bcause of the size of the potential affected population and the therapeutic utility of the test - more accurate prediction of patient-specific Warfarin response wold, it was argued, hlp to reduce adverse events associated with over-dosing and/or under-dosing during early stages of the dose titration process. But Medicare's NCA concluded that "CMS believes that the available evidence does not demonstrate that pharmacogenomic testing to predict warfarin responsiveness improves health outcomes in Medicare beneficiaries", and proposed that "."Pharmacogenomic testing to predict warfarin responsiveness is covered only when provided to Medicare beneficiaries who are candidates for anticoagulation therapy with warfarin and only then in the context of a prospective, randomized, controlled clinical study when that study meets [specific detailed] standards." Coverage with Evidence Development (CED) - viewed by some as an entry wedge for promising but as yet unproven technologies, by others as one more way for Medicare to temporize in accepting innovations.

This week, the imaging community received a similar jolt, as CMS published its Decision Memo for Screening Computed Tomography Colonography (CTC) for Colorectal Cancer affirming a proposed non-coverage determination originally released in February. CTC advocates point to the sensitivity of the test, its lower cost, and its greater acceptability to the patient population as compared to colonoscopy. Research indicates that many individuals who ought to be screened are unwilling to undergo the colonoscopy procedure; CTC would increase the proportion of at-risk individuals screened, thereby identifying and allowing early treatment of more colorectal cancers; while CTC requires a confirmatory colonoscopy for "positives", advocates claim the total cost impact of using the new technology for initial screenings would also be beneficial.

During the formal 30 day comment period following that release, CMS had met (on March 3) with representatives of the American Cancer Society, the American College of Radiology, and the American Gastroenterological Association, as well as (on March 10) with representatives of the Medical Imaging and Technology Alliance; the Agency also received 357 written comments on the proposed non-coverage decision. Industry representatives and the supportive medical societies had been hopeful that their meetings and comments, along with new clinical data provided during the comment period, would change CMS' proposed policy.

A review of the formal comments is instructive. First. they were overwhelmingly in favor of coverage for CTC - "Of the total 357 comments, 16 expressed agreement with the proposed decision not to expand the colorectal cancer screening benefit to include coverage of the CT colonography screening test, and 337 commenters were opposed to it. Of the 357 total commenters, 101 were one of a couple of variations of form letters. Four commenters did not offer a specific opinion on whether on not the test should be covered for average risk individuals". CMS tends to discount the form letters, as they are generated by highly-interested third parties (usually the affected technology companies), but they do in fact provide a sense of the depth of spport from the general user communty.

Among organizations submitting comment, 6 favored coverage for CTC and 4 supported CMS' proposed noncoverage policy. CTC supporters were the American Cancer Society, medical societies the American College of Radiology (combined comments with the Society of Gastrointestinal Radiology and the Society of Computed Tomography and Magnetic Resonance) and the American Gastroenterological Association, device industry trade associations the Advanced Medical Technology Association (AdvaMED) and the Medical Imaging and Technology Alliance, and private insurer United Health Care. Those opposed were the American College of Gastroenterology (ACG), the American College of Preventive Medicine (ACPM), the American Society for Gastrointestinal Endoscopy, and insurance industry trade association American’s Health Insurance Plans (AHIP). A pattern is discernible: organizations that "win" if CTC is covered are favorable to the technology (CT companies, imaging organizations, radiologists); "losers" (gastroenterologists, many insurers) are opposed to coverage. There is also room for simpler disagreement (e.g. American Cancer Society, American College of Preventive Medicine).

It is tempting to view these coverage policy developments as institutional efforts by CMS to avoid incurring the costs asociated with new technologies. But a careful reading of the documents - which in both cases are lengthy, highly detailed, and heavily documented - leads to a more complex and less emotionally satisfying understanding. For warfarin testing, CMS essentially concludes that, whatever the accuracy of pharmacogenetic testing for dosage titration, the practical protocols for use of the test are not yet established and/or documented in a manner that provides clearevidence of superiority in clinical practice; more needs to be known about how to use the test before it can be seen as superior to current titration protocols; ergo CED:

A clinical study seeking Medicare payment for pharmacogenomic testing to predict warfarin responsiveness provided to the beneficiary pursuant to Coverage with Evidence Development (CED) must address one or more aspects of the following question.

Prospectively, in Medicare aged subjects whose warfarin therapy management includes pharmacogenomic testing to predict warfarin response, what is the frequency and severity of the following outcomes, compared to subjects whose warfarin therapy management does not include pharmacogenomic testing?

• Major hemorrhage
• Minor hemorrhage
• Thromboembolism related to the primary indication for anticoagulation
• Other thromboembolic event
• Mortality

Answer those questions in clinical practice for the Medicare population, the challenge is made, and then come back for broad coverage outside the research setting.

For CTC, CMS concludes that none of the published research on CTC effectiveness allows conclusions to be drawn about the utility of the test in the Medicare (> age 65) population, and that population differs in meanigful ways from the populations repoted in published research:

Overall, when considering potential benefits and potential harms, there is insufficient evidence to conclude that the use of CT colonography improves health outcomes in Medicare beneficiaries. Data on the health outcomes, potential benefits and harms from small lesions, extracolonic findings and radiation are needed from well designed clinical studies. In addition, with the higher prevalence of polyps in the older Medicare population, the rate of referral to optical colonoscopy is extremely important and also unknown at this point. If there is a relatively high referral rate, the utility of an intermediate test such as CT colonography is limited.

Medicare is consistent. Innovative technologies must be shown to be relevent to the Medicare population, and they must be shown to bepractically useful in the clinical setting. The lesson is clear: bringing innovative technologies into standard use is a more complex challenge than is sometimes assumed by developrs.