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Massachusetts Healthcare Industry Transparency Bill Becomes Law


Patrick

Despite vigorous objections from the medtech, pharmaceutical, and life sciences industries, on August 10 Massachusetts Governor Deval Patrick (D–MA) signed into law the Act to Promote Cost Containment, Transparency, and Efficiency in the Delivery of Quality Health Care. A major provision of the law requires the Massachusetts Department of Public Health (DPH) to establish a pharmaceutical and medical device marketing code of conduct, and develop and impose compliance and reporting requirements on pharmaceutical and medical device companies that have employees involved in marketing or selling prescription drugs or medical devices in the state.

Under the law's provisions, covered medtech, pharmaceutical, and life sciences firms must:

  • Adopt and comply with the DPH's most recent marketing code of conduct.
  • Establish a training program for compliance with the code.
  • Conduct annual audits and create reporting systems to monitor compliance.
  • Institute policies and procedures for investigating noncompliance.
  • Take corrective action in response to noncompliance.
  • Report any noncompliance to state authorities.
  • Specifically, the law requires affected companies to provide DPH with two annual reports that accomplish the following.

  • Describe the company's training program and investigation policies, provide information about the company's compliance officer, and certify that the company has conducted its annual audit and is in compliance with the DPH marketing code.
  • Report the "value, nature, purpose, and particular recipient" of any payment, fee, or economic benefit of at least $50 that the company provided to a physician, hospital, nursing home, pharmacist, or other specified healthcare practitioner. DPH will post this information on its public Web site.
  • Ubl
    AdvaMed's Ubl: Impeding interactions.

    While companies are concerned about the costs and administrative burdens involved in compliance, they take particular issue with the public disclosure aspects of the law. Industry representatives believe this requirement threatens the integrity and security of proprietary information belonging to companies pursuing research and product development initiatives with partner firms, doctors, hospitals, or other organizations. In contrast to FDA disclosure laws and the Physician Payments Sunshine Act pending in Congress, the Massachusetts law requires public disclosure of any collaborative relationship or industry partnering soon after such actions are first initiated—risking exposure of product development plans to competitive firms.

    Leahey
    MDMA's Leahey: Compromising innovation.

    Commenting on the bill prior to its becoming law, Stephen Ubl, president of industry association AdvaMed (Washington, DC) said, "We are committed to ethical arrangements and ensuring that interactions between industry and healthcare providers enhance the public health and foster public confidence. Unfortunately, this legislation would impede important interactions with providers and could drive this critical research and development out of state. Unlike other segments of the healthcare sector, medical technology is often developed and refined based on input from physicians who have direct and constant feedback from their patients."

    Prior to the bill passing, Mark Leahey, executive director of the Medical Device Manufacturers Association (MDMA; Washington, DC), said, "This legislation threatens to compromise the innovative medical technology industry in Massachusetts and would eventually limit patient access to innovative products." MDMA urged medtech manufacturers to voice their opposition to the legislation and provided contact information for Governor Patrick on its Web site.

    Johnson
    PhRMA's Johnson: Developing regulations.

    Ken Johnson, senior vice president at the pharmaceutical industry association Pharmaceutical Research and Manufacturers of America (PhRMA; Washington, DC), said, "In signing this legislation, Governor Patrick indicated his expectation that the state's Department of Health will develop regulations that 'enhance transparency' without requiring the disclosure of trade secrets and proprietary information, or impeding medical research or the education of healthcare providers. Although we remain extremely concerned with this strategy, we will work with state officials to ensure that the resulting regulations adhere to these sentiments."

    Kelly
    BIO's Kelly: Incongruities in MA.

    Patrick Kelly, vice president for state government relations with the Biotechnology Industry Organization (BIO; Washington, DC) said the bill was "incongruous" with Massachusetts' recently announced $1 billion life sciences initiative, which was intended to foster and expand industry investment in the state. "Governor Patrick's decision to sign this bill into law is deeply disappointing—and very likely damaging for medical partnerships, clinical research, and patients in Massachusetts."

    The law will go into effect on January 1, 2009, and will be enforced by the Massachusetts attorney general. It provides for fines of up to $5000 for each transaction, occurrence, or event that violates the law.

    In signing the bill into law, Governor Patrick said, it will "help ensure healthcare providers make choices about prescription drugs and medical devices for their patients based on therapeutic benefits and cost-effectiveness. I am confident the Department of Public Health, pursuant to its regulatory authority, will safeguard the confidentiality of companies' trade secrets and proprietary information and protect against roadblocks to medical research or the education of healthcare providers."

    Sommer
    MassMedic's Sommer: Stakeholder access.

    The Massachusetts Medical Device Industry Council (MassMedic; Boston) was an early critic of the legislation and aggressively pushed back on the bill as it was working its way through the state legislature. But like other industry leaders, MassMedic president Thomas J. Sommer is now taking Governor Patrick at his word that all stakeholders will have access to the Massachusetts Department of Public Health as it develops the final provisions of its code of conduct.

    The complete text of the Act to Promote Cost Containment, Transparency, and Efficiency in the Delivery of Quality Health Care (MA Senate, no. 2863), which Governor Patrick signed into law earlier this month, is available via www.mass.gov/legis/bills/senate/185/st02/st02863.htm.

    © 2008 Canon Communications LLC

    Return to MX: Issues Update.

    Spine Sector Shows Continued Growth


    In recent years, analysts have frequently referred to the market for spine treatment products as one of the hottest fields in the medtech industry. Although traditionally considered a subset of the orthopedics sector, the spine products market has become increasingly viewed by industry analysts and market research firms as a sector in its own right.

    Considering that worldwide spinal market revenues were less than a $100 million in 1990, grew to $3.5 billion by 2004, and reached more than $6 billion last year, growth of the segment has indeed been impressive. The pace of that growth may have cooled since the torrid 15–20% annual increases of a few years ago, but the spine segment continues to post year-over-year revenue gains as a steady stream of new companies enter the market.

    Going forward, most medtech analysts expect that the spine segment will post annual revenue growth rates of 8–10% over the next few years, particularly for large-cap companies. However, even greater growth for the segment has been projected by several market research firms that cover the field, including MedMarket Diligence LLC (Foothill Ranch, CA). In an extensive assessment of the spine industry published earlier this year, the firm projects a 14.4% compound annual growth rate for the segment over the next 10 years.1

    Driscoll
    Driscoll: A decade of growth.

    "The orthopedic arena in general, and spine surgery in particular, are major areas of continued opportunity in the medical technology industry," says Patrick Driscoll, president of MedMarket Diligence. "The global market for spine surgery will therefore continue to be characterized by changing caseload, introduction of new technologies and, most importantly, solid market growth—in double digit terms—for at least 10 years."

    The top four players in the global spine market are Medtronic Inc. (Minneapolis); DePuy Spine Inc. (Raynham, MA), a unit of Johnson & Johnson Inc.; Synthes Inc. (Solothurn, Switzerland); and Stryker Corp. (Kalamazoo, MI). These firms control an estimated 80% of the global spine market (see Table I). According to MedMarket Diligence, Medtronic dominates the market with a 35% share, followed by DePuy with 21%, Synthes with 20%, Stryker with 10%, Zimmer Holdings Inc. (Warsaw, IN) with 5%, and Biomet Inc. (Warsaw, IN) with 3%. Other players account for the remaining 6%.

    Company
    Market Share (%)
    Medtronic
    35
    DePuy
    21
    Synthes
    20
    Stryker
    10
    Zimmer Holdings
    5
    Biomet
    3
    Others
    6
    Table I. Market share of major companies competing in the market for spine surgery products.
    Source: MedMarket Diligence.

    Other major medtech companies with a presence in the spine sector include Abbott (Abbott Park, IL) and Smith & Nephew plc (London). Well over 100 more companies round out the market. In spite of the dominance of large, established firms, industry analysts generally see them ceding market share to smaller competitors—particularly those with innovative technologies.

    Much of the sales growth for the spine segment is taking place in North America. MedMarket Diligence cites a 76% share for the United States and Canada, 18% for Europe, 5% for Asia (Australia, Japan, and Korea), and around 1% for the rest of the world, primarily China, India and Latin America.

    Spine segment growth is essentially attributed to the same factors driving the medtech industry overall, and the orthopedics sector in particular: aging populations, product innovation, and the market demand of the baby-boom generation. So-called 'boomers' typically lead a more active lifestyle than their forebears, and have a lower tolerance for 'putting up with pain.' Additionally, the rising incidence of obesity, which places greater strain on the back and can create spinal problems, is also frequently cited as a contributing factor.

    The main impediments to segment growth generally revolve around reimbursement issues, particularly for newer, more innovative technologies that often struggle to demonstrate their cost-effectiveness in comparison with traditional approaches.

    Back pain is reported as the second-most-cited reason for seeking medical consultation with a doctor, resulting in more than 50 million physician office visits annually in the United States. According to a recent report in the Journal of the American Medical Association, $86 billion was spent on back pain in 2005, up from $52 billion in 1997.2

    Persistent or chronic back pain can be caused by a number of conditions, including congenital disorders, degenerative disk disease, injury or fracture, herniated disk, trauma, infections, spine tumors, and others.

    According to the National Library of Medicine (Bethesda, MD), spinal fusion has traditionally been considered the gold standard of care for back pain, representing 85% of procedures, and 78% of implant sales in 2006 (see sidebar). The most common spinal area treated is the lower (lumbar) spine. However, fusion can also be performed on the upper (cervical) spine.

    The MedMarket Diligence report on spinal surgery markets projects that spinal fusion will grow at an annual rate of only 3.3% between 2008 and 2017, while less-invasive and alternative technologies for greater motion preservation of the spine will post far larger gains. Procedures showing higher growth rates will include total disk replacement at 15.1%, nucleus replacement at 45.4%, vertebroplasty and kyphoplasty (combined) at 19.7%, bone graft substitutes at 14.7%, interspinous process spacers at 20.5%, and image-guided spinal surgery at 12.4%.

    Matson
    Matson: Chipping away.

    Taking advantage of the opportunities in the various subsegments, many new companies are continuing to enter the spine space (see Table II). Michael Matson, senior medical device analyst with Wachovia Capital Markets LLC (New York City), describes the segment as "very competitive, with a huge number of private companies." Matson notes that many analysts refer to these companies as 'ankle biters,' but nobody is dismissing the fact that they're taking share by chipping away at some of the established firms—either through product innovation or by using a more service-oriented business model. He cites NuVasive Inc. (San Diego) and Trans1 Inc. (Wilmington, NC) as prime examples.

    NuVasive has developed a minimally disruptive surgical platform called Maximum Access Surgery, resulting in less-invasive operative procedures, shorter hospitalization times, and faster recovery periods. The company has experienced significant growth since its launch in 1997. Company revenues for 2007 were $98.1 million, a 57% increase over 2006, which was itself a 59% gain over 2005.

    Describing NuVasive, Matson said, "They've been doing a great job at growing the business and taking share from some of the bigger spine companies out there, particularly Medtronic and Johnson & Johnson's DePuy."

    Trans1, founded in 2002, offers more novel, if not radical, approaches to both fusion and motion-preserving spine surgery. Trans1's 2007 revenues of $16.5 million represented a 183% increase over 2006. While Trans1 has seen some recent erosion of its stock price, primarily due to problems with sales, Matson still has an 'outperform' rating on the company.

    Denhoy
    Denhoy: Investor confidence.

    Raj Denhoy, research director for medical devices in the New York office of Thomas Weisel Partners LLC (San Francisco), notes that while Medtronic lamented its 8.1% revenue gain for the company's most recent reporting period, NuVasive posted a 61% boost in revenues. NuVasive has now revised its revenue forecast for 2008 to $240 million.

    But how many more companies are likely to replicate NuVasive's performance? Denhoy says that the spine segment boasts a steady stream of newcomers, but that many of their products are 'me-too' devices. "When you talk to spine surgeons, they're aware of the many new market entries, but are not particularly impressed with what's considered to be recent innovations," says Denhoy.

    Matson and Denhoy foresee overall spine segment market growth in the mid to high single digits, perhaps reaching 10% over the next few years. Both analysts remain bullish on the field. Denhoy notes that there are many opportunities unique to the spine segment, since there remains much about the physiological dynamics of the back and spine surgery that continues to unfold.

    Table II.: Representative sampling of 25 emerging and small-cap medtech companies in the spine market. Note: Some companies may also be involved in other medtech segments. Source: individual company documents and Web sites.
    (click to enlarge)

    In addition to the major medtech firms in spine, other public companies with products in the sector include: Alphatec Holdings Inc., ArthroCare Inc., BioMimetic Therapeutics Inc., Exactech Inc., Orthofix International NV, OrthoVita Inc., Osteotech Inc., and RTI Biologics Inc. (see Table II).

    Although experiencing some setbacks with insurance reimbursement, surgeon resistance, and patient lawsuits, artificial disks continue to offer great promise for dynamic spine stabilization—particularly as next-generation devices become available. According to Life Science Intelligence (Huntington Beach, CA), the U.S. market for artificial disk replacement will grow from $55 million in 2007 to $440 million by 2013.3

    Last year, Medtronic spent $3.9 billion to acquire Kyphon, which had itself earlier in 2006 acquired St. Francis Technologies for $525 million. This past February, Zimmer acquired privately held Endius Inc. (Plainville, MA), following up on its acquisition of OrthoSoft (Montreal) in October 2007. Earlier this month, Integra LifeSciences Holdings Corp. (Plainsboro, NJ) acquired Theken Spine LLC (Akron, OH) for $75 million plus the potential for additional performance payments of $125 million. Nevertheless, analysts don't anticipate that these earlier purchases will set off a round of major mergers or acquisitions—at least in the near term.

    Globus Medical Inc. (Audubon, PA), claims to be the world's largest privately held spine company, and the 10-largest overall. Other noteworthy private sector firms in spine include Atlas Spine Inc., Blackstone Medical Inc., Interventional Spine, K2M Inc., LDR Holding Corp., Nexgen Spine Inc., Scient'x, Sea Spine Inc., Small Bone Innovations LLC, and others.

    Industry analysts generally see continued growth in the spine sector for the foreseeable future. As medtech analyst Raj Denhoy says, "As new implants, surgical instruments and procedural technologies for improving and enhancing spinal motion preservation continue to demonstrate efficacy, safety, and cost-effectiveness, they will steadily be embraced by an increasing number of spine surgeons, who as a professional group, have demonstrated their openness and receptivity to new technology."


    References
    1. Spine Surgery: Products, Technologies, Markets, and Opportunities Worldwide, 2008–2017 (Foothill Ranch, CA: MedMarket Diligence, 2008).
    2. BI Martin et al., "Expenditures and Health Status among Adults with Back and Neck Problems," Journal of the American Medical Association 299, no. 6 (2008): 656–664.
    3. 2008 U.S. Markets for Spinal Disc Repair and Replacement Technologies (Huntington Beach, CA: Life Science Intelligence, 2008).

    © 2008 Canon Communications LLC

    Return to MX: Issues Update.

    Functional Imaging and Molecular Radiosensitizers

    COVER STORY: RADIATION THERAPY


    (click to expand)
    A lung cancer patient is imaged using Philips's Gemini TF with TruFlight time-of-flight technology. The results fuse anatomic and metabolic image data. (Image courtesy of PHILIPS HEALTH)

    The use of radiation for treating cancer emerged soon after the discovery of x-rays and radioactivity in the late 19th century. In recent years, major advances in tumor imaging and computing power have enabled increasingly accurate delivery of radiation to a targeted volume in the patient. Today, radiotherapy is widely used to treat several cancers and its efficacy compares favorably with other approaches, with demonstrated cost benefits. However, the current arc of development for radiotherapy fueled by improvements in physics and computing power is reaching its technological limits. The next technological step will likely be driven by an adjacent discipline: molecular biology.

    Molecular biology provides insights into the specific pathways that allow cancerous tissue to establish a presence, proliferate, fight immune system attacks, and repair damage. Future improvements in radiotherapy efficacy will arise by disrupting the biological repair mechanisms that some resistant cancer cells deploy in response to irradiation. This emerging field of molecular radiosensitizers, and its consolidation with functional imaging, enables insight into tumor biochemical activity beyond standard anatomical imaging and promises to dramatically change radiotherapy.

    The commercial potential of molecular radiosensitizers and functional imaging is well demonstrated by the emergence of multi-million-dollar alliances and several new companies. As results from current clinical trials are published and disseminated, innovation and clinical acceptance for this new field should increase dramatically.

    Radiotherapy for Cancer

    Residents of industrialized countries have a 30–50% chance of developing cancer over their lifetimes, and more than half of them will receive radiotherapy as part of their treatment.1,2 In the United States alone, radiotherapy was used to treat a million patients in 2004, and its increasing adoption has been accompanied by a significant growth in the number of treatment facilities.2 "General Principles of Software Validation; Final Guidance for Industry and FDA Staff," (Rockville MD: FDA) January 11, 2002. 1,3 In many countries with public healthcare insurance, the infrastructure for radiotherapy has been unable to satisfy demand. For example, in the UK, more than half the patients eligible for radiotherapy wait for longer than the recommended maximum period of four weeks due to a shortage of facilities.4

    Table I. (click to expand) Selected five-year disease-free survival rates of cancer patients in the United States by treatment modality. Compiled from various sources including Merck Manual Online and the National Cancer Institute.

    Currently radiotherapy is one of three major tools for treating cancers, along with surgery and chemotherapy. As a stand alone treatment, radiotherapy has demonstrated efficacy similar to other approaches for selected cancers. Its use in combination with other approaches is standard treatment for many advanced cancers (see Tables I and II).

    Table II. (click to expand) Overview of radiotherapy modalities.

    Current radiotherapy modalities use external beams, internal implants, or circulating tagged radionuclides to deliver ionizing radiation with the aim of preferentially killing tumor cells. More than 90% of radiotherapy patients are treated with external-beam radiotherapy (EBRT), the use of which has been spurred over the last two decades by techniques to deliver radiation doses to tumors with a high accuracy. Within EBRT, 3-D conformal radiotherapy (3DCRT) is the standard of care in most industrialized countries. This therapy uses 3-D tomographic images to design megavoltage x-ray beams that conform to the tumor volume, minimizing the dose to healthy organs and tissue. A recent innovation in EBRT is intensitymodulated radiotherapy (IMRT), introduced in 1999, which is supplanting 3DCRT primarily in the United States. IMRT deposits a large, specified radiation dose into a targeted volume by changing beam shapes and cross-sectional profiles at each angle of incidence. Medicare reimbursement championed IMRT by paying nearly $30,000 for a course of treatment, almost three times the payment for 3DCRT. Strong growth for IMRT is expected in Europe due to its recent positive clinical evaluations by national health systems.5

    Image-guided radiotherapy (IGRT), the successor to IMRT, uses imaging approaches incorporated into radiation delivery in real-time to dynamically track changes in tumor location and shape during treatment. The incremental clinical benefit of IGRT over IMRT is yet to be established and Medicare is reimbursing only 20% more for IGRT protocols. Similarly, arc/helical therapy, delivered by a beamlet of radiation rotating around the patient, has yet to demonstrate improved clinical outcomes that would spur displacement of existing systems.

    Stereotactic radiosurgery uses an external 3-D reference frame that is physically attached to the patient to precisely deliver radiotherapy with multiple beams. It primarily treats intracranial lesions, but is being extended to other areas of the body such as the lungs, liver, and pancreas.

    Brachytherapy and therapeutic radiopharmaceuticals both provide internal sources of radiation. Their future use (and that of cobalt 60 external beam sources) could be affected by rising security concerns over the transport of radioactive material. Brachytherapy uses sealed sources as localized implants. While patients with low-dose-rate implants are not constrained, radiotherapy with high-dose-rate seeds is done using special catheters for limited intervals as an outpatient procedure. The common patient preference for a painless, noninvasive procedure restrains the use of brachytherapy, and favors external-beam radiotherapy.

    The radiopharmaceutical iodine-131 has been used for thyroid treatment since 1946. For decades, radioimmunotherapy, involving tumor-targeting antibodies labeled with radioactive isotopes, has generated significant expectations. However, in contrast to the success of targeted immunotherapies, radioimmunotherapy products for lymphomas have not been commercially successful because their use requires an infrastructure involving nuclear pharmacies that is typically available only in large teaching hospitals.6

    The Radiotherapy Market

    The total market for radiotherapy is composed of two major elements: professional services and products. Services include charges for the professional medical staff such as radiation oncologists, medical physicists, dosimetrists, nurses, and facility administrators. Given the tremendous disparity in healthcare systems across the globe, professional service charges vary greatly and are difficult to compare. Charges for products, however, are more uniform and can be tracked easily. The total value for radiotherapy products in 2007 was $2.6 billion at manufacturer prices. The equipment is composed of linear accelerators (linacs) and specialized imaging equipment (simulators), specialized treatment planning software, internal radiation (brachytherapy) sources, and radiopharmaceuticals. Historical (2004–2007) and projected (2008–2011) growth rates for the radiotherapy market are 6.8% and 7.0%, respectively. Published market forecasts ascribe growth in the cancer market to immuno- and biotherapies, taking the view that radiotherapy products will continue to be expensive hardware such as linacs.

    The Multidisciplinary Approach to Curing Cancer

    Figure 1. (click to expand) Historical development of physics and biology approaches for cancer.

    The development of radiotherapy has been traditionally led by physics and engineering. As shown in the time line in Figure 1, the first attempts at curing cancer using ionizing radiation started almost immediately after the discovery of x-rays and radioactivity in the 1890s. The principles of radiation's effect on biological tissues began to take shape at the turn of the 20th century, with empirical observations on the effect of x-rays on cells that correlated their proliferative activity and radiosensitivity. A major technological leap in the 1950s was the switch from low-energy x-rays that severely damaged the skin to cobalt 60 sources and linacs providing megavoltage x-rays with deep penetrating power. Radiotherapy received a tremendous boost following the advent of computed tomography (CT) imaging in the 1970s. CT had tremendous computing power to generate 3-D images that could be used for effective treatment planning.

    In contrast, molecular biology is a more recent scientific discipline that blossomed after the structure of DNA was discovered. It now plays a fundamental role in elucidating both the basis of radiotherapy and molecular pathways underlying the various cancers.

    Future Trends in Radiotherapy

    The Physics Approach Gets More Expensive. The next-generation advance in radiotherapy involves the use of heavy particles for a greater precision in dose delivery at a targeted depth inside the patient. Biological damage from mega­voltage photons is spread over larger distances compared with damage caused by heavy particles such as protons or carbon ions. A more precise radiation dose delivery not only promises greater efficacy in eradicating the targeted tumor, but it also reduces side effects including the risk of secondary tumor formation in overirradiated normal tissue. Such increased precision comes at a price, however. Constructing a facility for delivering radiotherapy with heavy particles is estimated to cost more than $100 million.7 Despite some enthusiasm and deep pockets among academic medical centers in the United States, it is unlikely that more than a handful of these types of facilities will be built around the world.

    Imaging Highlights the Greater Role for Biology. While the delivery of radiation dose has become increasingly precise, accuracy in specifying the clinically significant tumor volume continues to drive developments in imaging. CT has been widely adopted in radiotherapy because it provides an accurate 3-D map of tissue density information that is an accurate basis for calculation of radiation dose. It also enables simulation of the radiotherapy process on the patient. Magnetic resonance (MR) provides more soft-tissue contrast, and in many instances does a better job of tracking spatial changes in the tumor during radiotherapy. Integrating different imaging techniques has required significant investment. It calls for upgrades to software that can seamlessly combine images from multiple modalities.

    Positron emission tomography (PET) has extended the role of imaging to include observation of tumor biochemical pathways in real-time.8 PET requires injecting imaging agents that contain a positron emitter. By localizing the origins of the two identical gamma rays traveling in opposite directions that result from each emitted positron's annihilation with an electron, users can map the PET radiotracer distribution.


    For more information on the regulatory aspects of imaging, click here.

    The most common PET tracer is the glucose analog 18F-fluorodeoxyglucose (FDG). While CT and MR provide anatomic images, FDG-PET provides a functional map that can be used for tumor staging and therapy monitoring. In particular, lung cancer, a disease for which the overall five-year survival rate is below 10%, has seen increased application of PET scanning for early tumor detection. Tumors consume abnormally high amounts of glucose (and FDG), which makes them visible with FDG-PET.

    Combined PET/CT scanners provide an accurate overlay of anatomic and functional images, with an imaging time of 5–10 minutes, which is significantly below the 45 minutes required by PET-only devices. PET/CT scanners now comprise 90% of PET equipment sales.9

    Figure 2. (click to expand) Classical (top) and current (bottom) strategies for radiosentization.

    A critical enabling technology for use of PET in identifying cancer is the development of injection targets combined with tracers. Monoclonal antibodies (mAbs) tagged with positron emitters that target individual biomarkers have been a promising innovation. Thus far, FDA has approved 21 mAbs for therapy and five for imaging, largely in oncology.10

    Different Radiation Doses for Different Tumors. The typical cellular response to radiation includes pathways in DNA repair, control of cell-division cycle checkpoints, programmed cell death (apoptosis), and signal transduction.11 In addition to these typical responses, cancer cells have unique adaptations such as the ability to promote growth of blood vessels (angiogenesis), and function in oxygen-starved environments (hypoxia).12,13 Each pathway provides targets for optimizing the radiation response by either blocking the pathway the cancer cell is using to repair the radiation damage or sensitizing the cancer cell to be more vulnerable to the radiation it is about to receive.

    The goal of developing radiosensitizers is to optimize the killing dose of radiation for the specific tumor being targeted and to inhibit the specific pathways the tumor uses to repair itself. This may vary by the life stage of the tumor as well. The need for intelligence on the specific pathways being exploited by a tumor underscores the forementioned close relationship of radiotherapy with functional imaging.14

    An overview of the current development strategies for molecular radiosensitizers is shown in Figure 2.15 Many of these approaches are currently being tested in clinical trials. Key examples of molecular radiosensitizers in development include the following:

    • Hypoxia confers resistance to radiation on cancer cells. A Phase III clinical trial for advanced head and neck cancer combines accelerated radiotherapy with carbogen (a hyperoxic gas) and nicotinamide (a vasodilator), which could enhance oxygen delivery to a tumor.16
    • GenVec (Gaithersburg, MD) is conducting a pivotal Phase II/III trial with TNFerade in patients with locally advanced pancreatic cancer. TNFerade is a modified virus that contains the gene for tumor necrosis factor-alpha, an immune system protein with well-documented anticancer effects, which is injected into tumors for use in combination with radiation, chemotherapy, or both.
    • Epidermal growth factor receptor (EGFR) is often over-expressed by tumor cells, and blocking it sensitizes the cells to radiation. Targeting EGFR using Erbitux (cetuximab) in patients with advanced head and neck squamous cell carcinoma significantly improved overall patient survival in a randomized pivotal trial.16
    • Avastin (bevacizumab) binds vascular endothelial growth factor (VEGF) molecules and inhibits angiogenesis, the mechanism by which tumors recruit new blood vessels. The effects of combining Avastin and other angiogenesis inhibitors with radiotherapy are being investigated. Inhibiting a tumor's blood supply can also make it hypoxic and less radiosensitive.17
    Figure 3. (click to expand) Ongoing clinical trials investigating radiosensitization grouped by tumor site.

    There are more than 200 clinical trials under way that investigate the use of radiosensitization (see Figure 3). Not surprisingly, the greatest number of trials is for cancers that have shown significant resistance to surgical, chemotherapy, and radiotherapy treatments. Nearly all are treated with existing chemotherapy drugs that may demonstrate radiosensitization properties. The development of new radiosensitizing agents is generally in the preclinical stage.

    Market Potential of Radiosensitizers

    (click to expand)
    A comparison of CT (left) and PET/CT for contouring a target volume for radiotherapy with the same lung cancer patient. Contouring using CT alone indicates a large tumor volume that is reduced when combining PET with CT.

    The market for radiosensitizers is potentially larger than the current total radiotherapy equipment market. The market estimate is built by analyzing those cancers for which radiotherapy is prescribed today and have less than 50% five-year survival rates. There are more than 500,000 patients in the United States alone that could qualify for radiosensitizers. At a price of $7200 per radiosensitizer (the weighted average cost of chemotherapy treatments), the total U.S. market potential is more than $3.7 billion. The potential for any one radiosensitizer would be a fraction of this opportunity. However, by comparison, the global market for all radiotherapy products in 2007 was $2.6 billion. This is clearly a high-growth potential market that has opportunities for multiple types of players including manufacturers of radiotherapy and diagnostic imaging equipment, small biotech firms, and big pharmaceutical companies.

    Conclusion

    Radiotherapy is in transition from being an empirical discipline driven primarily by physics to a clinical science founded in an understanding of molecular pathways. There is a strong interest in the oncology community to extend the successes of radiotherapy across various cancers by validating novel markers with functional imaging and exploiting molecular mechanisms underlying radiosensitivity. The current level of activity, with clinicians validating existing chemo- and targeted therapeutic agents for use with radiotherapy, suggests that radiotherapy will become a promising area for drug development within a few years. The market opportunity is expected to be very significant, given the essential role of radiotherapy in treating cancer.

    Usman Qazi is a principal at Scientia Advisors (Cambridge, MA), a consulting firm with a concentration in life sciences and healthcare. He can be reached at usman.qazi@gmail.com. Amit Agarwal is a partner at the firm, and he can be contacted at aagarwal@scientiaadv.com.

    References

    1. “Targeting Cancer Care, Annual Report 2006–2007,” [online] (Fairfax, VA: American Society for Therapeutic Radiology and Oncology [cited 14 July 2008]) available from Internet: www.astro.org/AboutUs/AnnualReports.

    2. NG Burnet et al. “Improving Cancer Outcomes Through Radiotherapy,” British Medical Journal 320 (January 2000): 198–199.

    3. Leslie K Ballas et al., “Radiation Therapy Facilities in the United States,” International Journal of Radiation Oncology, Biology, Physics 66, no. 4 (2006): 1204–1211.

    4. Ruth H Jack et al., “Radiotherapy Waiting Times for Women with Breast Cancer: A Population-Based Cohort Study,” BMC Cancer 7 (May 2007): 71.

    5. Haute Autorité de Santé (France), “Radiothérapie Conformationelle avec Modulation d'Intensité,” 2006.

    6. Ken Garber, “Users Fear That Lymphoma Drugs Will Disappear,” Journal of the National Cancer Institute 99 (April 2007): 498–501.

    7. B Jones, “The Case for Particle Therapy,” British Journal of Radiology 79 (2006): 24.

    8. Tom Blodgett et al., “PET/CT: Form and Function,” Radiology 242 (2007): 360–385.

    9. Van Dongen et al., “Immuno-PET: A Navigator in Monoclonal Antibody Development and Application,” Oncologist 12 (2007): 1379–1389.

    10. David S Boss et al., “Application of PET/CT in the Development of Novel Anticancer Drugs,” Oncologist 13 (2008): 25–38.

    11. Philip J Tofilon et al., “Molecular Targets for Radiation Therapy: Bringing Preclinical Data into Clinical Trials,” Clinical Cancer Research 9 (2003): 3518–3520.

    12. Henning Willers and Kathryn D Held, “Introduction to Clinical Radiation Biology,” Hematology/Oncology Clinics of North America 20 (2006): 1–24.

    13. Harrington et al., “Molecular Biology for the Radiation Oncologist: The 5 Rs of Radiobiology Meet the Hallmarks of Cancer,” Clinical Oncology (Royal College of Radiologists) 19 (2007): 561.

    14. CN Coleman, “Linking Radiation Biology and Imaging Through Molecular Biology,” Radiology 228 (2003): 29.

    15. Eric Deutsch et al., “New Concepts for Phase I Trials: Evaluating New Drugs Combined with Radiation Therapy,” Nature Clinical Practice Oncology 2 (2005): 456–465.

    16. Juliette Thariat et al., “Integrating Radiotherapy with Epidermal Growth Factor Receptor Antagonists and Other Molecular Therapeutics for the Treatment of Head and Neck Cancer,” International Journal of Radiation Oncology, Biology, Physics 69, no. 4 (2007): 974–984.

    17. Suresh Senan and Egbert Smit, “Design of Clinical Trials of Radiation Combined with Angiogenic Therapy,” Oncologist 12 (2007): 465–477.

    Copyright ©2008 Medical Device & Diagnostic Industry

    Bill Would Allow PMA Holders to Be Sued in State Courts

    NEWS TRENDS

    Rep. Frank Pallone says the Supreme Court's decision in Medtronic's case gave device makers blanket immunity for the life of a product.

    Democrats in Congress introduced a bill in late June that would change the law that allowed Medtronic to prevail in a product liability case decided by the Supreme Court. If it becomes law, it could make premarket approval (PMA) holders face more lawsuits.

    The Medical Device Safety Act of 2008 would overturn the federal preemption clause contained in the Medical Device Amendments of 1976. The high court cited language in that law in its 8–1 decision in favor of Medtronic. It interpreted the law to mean that makers of PMA products cannot be sued in state courts if the products did not violate federal regulations (that is, if they are not adulterated or misbranded). The wording established FDA as the sole arbiter of safety and effectiveness of PMA products.

    This preemption of lawsuits in state courts does not apply to 510(k) products, nor to PMA products that are found to be adulterated or misbranded. (The Medtronic product in question, a catheter, was neither, the court found.)

    The bill was introduced in the House by Representatives Frank Pallone (D–NJ) and Henry Waxman (D–CA), and in the Senate by Senators Ted Kennedy (D–MA) and Patrick Leahy (D–VT).

    “This bill reverses an unfortunate Supreme Court decision that denied victims any legal recourse and gave device makers blanket immunity for the life of a product,” said Pallone. “Congress should pass this legislation so that we can protect patients from dangerous and defective medical devices.”

    Waxman said that the 1976 law had never been interpreted as preemptive of state-court cases until the Bush administration was in place.


    From DeviceTalk:
    Click here for more of Ubl's take on The Medical Device Safety Act of 2008.

    As soon as the legislation was introduced, AdvaMed released a strongly worded statement against it. The organization charged that allowing such cases to proceed in state courts could allow states to set their own standards for safety and effectiveness of PMA products. This would be chaotic and could restrict patient access to innovative medical products, it said.

    “A patchwork approach to medical device approvals where state courts effectively review and regulate medical devices would result in a dizzying array of conflicting labeling and indications for use, and ultimately may result in technologies not being available for patients,” said AdvaMed president Stephen Ubl.

    Copyright ©2008 Medical Device & Diagnostic Industry

    Endicott Discovers Local Partners for Electronics

    OUTSOURCING NEWS


    A Binghamton University student examines a piece of flexible circuitry from Endicott Interconnect's CAMM facility.

    Remaining competitive in a world where companies are more frequently outsourcing beyond the United States can be a challenge. Endicott Interconnect Technologies Inc. (Endicott, NY) is collaborating with two universities to develop electronics products, an industry segment that continues to move offshore.

    With funding from the United States Display Consortium, Endicott Interconnect's Center for Advanced Microelectronics Manufacturing (CAMM) is working with Cornell University (Ithaca, NY) and Binghamton University (Binghamton, NY).

    James McNamara (right), president and CEO of Endicott Interconnect, met with Congressman Michael Arcuri and Binghamton University president Lois DeFleur at the CAMM facility in May.

    “R&D is our engine for the creation of new products and intellectual property as well as an important tool for solving today's manufacturing issues,” said James McNamara, president and CEO of Endicott Interconnect. McNamara spoke at a meeting with Lois DeFleur, president of Binghamton University, and Congressman Michael Arcuri (D–NY) in May.

    The partnership involves research and development related to microelectronics manufacturing in a roll-to-roll (R2R) format. The R2R process enables efficient production of components by integrating electronics on flexible plastic. It also presents opportunities for new application areas in flexible electronics.

    Endicott Interconnect expects the collaboration to lead to flexible, rugged, lightweight electronic components and products for next-generation applications. Academic and industry research groups will be able to conduct manufacturing applicability testing at CAMM as well.

    Copyright ©2008 Medical Device & Diagnostic Industry

    Hemodialysis Wand Holder Keeps Things Clean

    R&D DIGEST

    (click to enlarge)
    The hemodialysis wand holder provides a sanitary and easily accessible container for dialysis wands.

    Keeping hemodialysis wands clean can sometimes be an awkward task for clinicians. Once the wands are used and rinsed with deionized water, they're not always placed in a completely sanitary area. A nurse who saw this problem decided to develop a device that houses the wands and prevents their contamination between uses.

    “After asking hemodialysis technicians and registered nurses who work in the field about the storage of wands, the responders concurred,” says Virginia Graham, a registered nurse from Rosemead, CA. “There is no appropriate storage for the devices. They were hung on the machines exposed to the air or placed in a bucket, which caused them to sit in their own runoff water. That's a potential for cross-contamination.”

    Aptly named the hemodialysis wand holder, the product should help keep the wands clean and therefore prevent airborne contamination from bacteria and viruses. It should also give clinicians easier access to the wands for their next use. The plastic container provides a more hygienic alternative to current methods, according to Graham.

    The top of the rectangular device has a tightly fitted gasket. It holds up to eight wands, which are arranged in two rows with four circular openings each. The holes are smaller than the upper neck of the wands so that they hang just above the bottom of the container. This design provides room for water to drip off of the wands.

    The wands do not touch each other, and a handle on each end of the product aids the clinician in holding and moving the container while preventing contamination. A removable snap-on lid enables disinfection. Possible changes include varying the number of compartments to accommodate 10, 12, or 15 wands. In addition, a longer wand base would be useful to accommodate wands of different lengths.

    Graham specializes in hemo­dialysis, peritoneal dialysis, and continuous renal replacement therapies. She is confident in the need for the product and is hoping to find a company that will advertise, manufacture, and distribute it on a mass scale. “There are thousands of hospitals and chronic hemodialysis centers around the world [that would] purchase the HWH [hemo­dialysis wand holder].”

    Advent Product Development (Pawleys Island, SC) should be contacted for information about the licensing or sale of the device.

    Copyright ©2008 Medical Device & Diagnostic Industry

    Ashland Partners with Teknor Apex

    OUTSOURCING NEWS


    Ashland Distribution China will represent Teknor's PVC compounds in China.

    Ashland (Covington, KY) has agreed to sell Teknor Apex Co.'s (Pawtucket, RI) PVC compounds in China. Ashland will focus primarily on supplying the medical device market, notes Bertram Lederer, executive vice president of Teknor. The two companies have subsidiaries capable of making compounds identical to those developed by the parent company and are compliant with regulations widely required in major medical markets, according to a release from Teknor.






    Copyright ©2008 Medical Device & Diagnostic Industry

    Rotating Magnets Target Pathogens

    R&D DIGEST


    Web Exclusive!:

    Magnets could play a heightened role in diagnosing pathogens. Micron-sized magnetic particles are coated with antibodies that attract certain pathogens and are mixed with patients' blood samples. The sensitive technique, developed by researchers at Purdue and Duke universities, can selectively separate particles by size so that several diseases can be detected in a single sample.

    Gil Lee, a professor of chemical and biomedical engineering at Purdue, explains that the technology relies on a microchip containing an array of metal disks as wide as 5 µm. The magnetic particles are dispersed in a liquid and put in a container that also houses the chip. The container is surrounded by three electromagnets energized in sequence to produce a rotating magnetic field.

    As the magnetic field rotates, the particles move from one disk to another until they are separated from the rest of the sample. Rotating the magnetic field at specific speeds separates only particles of certain sizes, meaning pathogens attached to those particles would be separated from the sample by varying the rotation speed, said researchers.

    The technique, called nonlinear magnetophoretic separation, works using an array of disks made of cobalt and coated with chromium to prevent corrosion. The advantage of the technique is that it can be used to simultaneously separate and identify pathogens with sensitivity up to a million times higher than the immunoassays commonly used today for human diagnostics, explains Hao Shang, from Purdue's School of Chemical Engineering and Weldon School of Biomedical Engineering.

    Shang's company, MagSense Life Sciences Inc., is developing a method to produce the magnetic particles. The micron-sized particles are made from thousands of nano-sized particles. These particles are unique because they are superparamagnets, meaning that they are not magnetic unless they are in a magnetic field. The particles can be mixed in a solution without attracting each other or clumping together, which is critical for them to be distributed uniformly throughout the solution. When the rotating magnetic field is applied, the particles become magnetic.

    “When you walk into a doctor's office, the problem is that it could be one of five or six different pathogens giving you the symptoms,” Lee says. “The doctor[s] cannot determine which pathogen you have, so they simply give you a broad-spectrum antibiotic or tell you to go home and get some rest. There clearly is a need for technology that can recognize multiple pathogens simultaneously and at very low levels. It is likely they will be chip-based technologies that are easy to implement in medical environments.”

    Lee's work is based at the Birck Nanotechnology Center at Purdue's Discovery Park. The research has been supported by the Institute for Nanoelectronics and Computing, and funded by NASA.

    Copyright ©2008 Medical Device & Diagnostic Industry

    EMS Outsourcing: Make Sure You Know the Costs

    GUIDE TO OUTSOURCING: EDITOR'S PAGE

    Choosing global electronics manufacturing services (EMS) suppliers and then managing the programs for cost efficiency can be a complicated process. This is the conclusion of a detailed study of hundreds of cases across several industries, including medical. The study was conducted by Charlie Barnhart & Associates for the company's Leading Indicators monthly report. According to Barnhart & Associates (http://charliebarnhart.com), the study revealed the following three fallacies about electronics outsourcing:

    • Fallacy: Global outsourcing of electronics is a strategy that will save money. Fact: Not always. The study found that outsourcing is only a tool. “Only the most skilled practitioners are able to leverage this tool to competitive advantage on a total cost of ownership (TCO) basis,” it says. The research showed that some OEMs spend more on internal costs to manage the outsourcing relationship than the cost of the services themselves.


    • Fallacy: Centralizing spend in a low-labor-cost geography will reduce the total cost of outsourcing. Fact: Fully burdened labor rates and risk factors vary widely in the more than 20 geographies tracked by Barnhart's research. The research found that some OEMs in some industries are returning to a regional approach to save total costs.


    • Fallacy: It is necessary to build electronics in China to penetrate the market there. Fact: According to the study, a review of publicly traded electronics companies that have actively pursued the Chinese market reveals that this strategy has not come to fruition. The risks and costs of manufacturing in certain geographies outweigh the rewards.

    A key factor in assessing an EMS supplier, of course, is the cost of outsourcing versus the cost of keeping manufacturing in-house. According to Barnhart's report, the average cost of labor for EMS in most global geographies continues to rise at a rate equal to or slightly above the currency adjusted local inflationary index.

    The report says that the exceptions to this are the United States, Mexico, and India, where “the fully burdened cost of labor for both printed circuit board assembly and box build were down marginally on improved absorption.” The report noted that the largest increases in the cost of electronic value-added services occurred in Western Europe and China. It says that both of these trends are expected to continue in 2008.

    The report also notes that the overall situation in China in terms of risk and usable capacity continues to deteriorate. “Given the high concentration of outsourcing in this single geography, we have begun advising our clients to accelerate analysis and integration of alternative solutions,” says Barnhart.

    Sherrie Conroy for the Editors

    The Power of Persuasion

    FROM THE EDITORS

    When Congress voted to override President Bush's veto of a Medicare bill in July, it was a testament to the power of persuasion that the medical industry has, when it wants to use it. In the coming year, industry will have to use its political weight a lot more.

    Most of the coverage about the Medicare Improvement for Patients and Providers Act of 2008 focused on the repeal of proposed payment cuts to physicians. But it also affected two competitive-bidding programs in ways favorable to the medical device and clinical laboratory industries.

    First, the bill delayed a competitive-bidding program for durable medical equipment. Industry had complained that the bidding process was flawed, and that a price-based system would cause quality to suffer.

    Second, the bill repealed a clinical laboratory competitive-bidding project that had been halted by a federal judge in April. Industry had complained that its requirements were unworkable and that patients would suffer as a result.

    Now, you might think that arguing against a pair of programs touted to save significant costs to the healthcare system would be unpopular at best and a losing proposition at worst.

    But it's not that simple. It never is when the federal government is involved.

    In theory, competitive-bidding programs save the government money by having vendors bid against each other rather than having the government pay a set fee for each product.

    In practice, however, there have been serious problems with implementation—some of which had the potential for a negative influence on patient care. The agency implementing these programs is CMS (the same agency that was aware of but chose to do nothing about some vendors using dead physicians' names to collect $77 million worth of fraudulent payments over seven years).

    There were several problems with the competitive-bidding program for durable medical equipment. The most significant problem was that because winners were chosen almost exclusively on price, some winners had no history of serving the patient populations whose services they bid for. That meant there was no assurance that patients received consistent quality of care. The program was poorly constructed, failing to distinguish between inexpensive commodity items and expensive complex ones. In addition, CMS botched the vetting of potential vendors. It disqualified some for submitting insufficient financial information, without telling them of the shortcoming until it was too late. And small firms expressed concern that the program would force them out of business because they couldn't compete on price and volume alone.

    For similar reasons, a federal judge put a stop to the clinical laboratory competitive-bidding program, saying it could cause “irreparable injury” to laboratories and patients. Again, it was sloppily put together, making no distinctions among the various types of tests in use.


    To read more of Erik Swain's opinions, visit DeviceTalk - MD&DI's Blog on Medical Device Link.

    Industry advocacy groups, including AdvaMed and the American Clinical Laboratory Association, did an excellent job of making members of Congress see the flaws in the way the programs were set up without denigrating their positive aspects. Without such persuasion, Congress may have continued to buy the hype and not paid attention to the unintended consequences.

    This sort of dialogue will be even more important after the presidential election, as broad reform of the healthcare system will be on the table. Industry associations need your support in order to remind Congress that whatever form change takes, it shouldn't inflict undue punishment on device companies or the patients they serve.

    Erik Swain for The Editors