The Medical Technology Blog

Welcome back to the Medical Technology Blog. Today’s article comes from the Cardiovascular Device Business Newsletter from Espicom Business Intelligence.

VentriPoint Diagnostics has met with the FDA to review its plans for the clinical trial and regulatory submission for the first application of the VMS heart analysis system for the congenital heart disease known as Tetralogy of Fallot. The FDA informed the company it had answered all its questions and addressed all of the earlier observations pertaining to the trial, paving the way for the start of the trial in the US.

The Tetralogy of Fallot study has begun in the US and is designed to show substantial equivalency between the gold-standard, MRI method and VentriPoint’s 2D-ultrasound, VMS technique. Based on advice from the FDA, the study has been designed to collect images at multiple sites and to analyse them in core labs. Nationwide Hospital in Columbus, OH is the lead centre for the study and the University of Nebraska has been named as a second site. A number of other clinical sites are expected to join the study. Nationwide Hospital has also been selected as the core lab for the analysis of MRI studies and the Hospital for Sick Children in Toronto, Canada has been selected to carry out all the analyses of the studies.

To date, 20 patients have been enrolled in the study and a total of 75 evaluable cases are required for study completion. VentriPoint anticipates enrolment will accelerate as the other centres become operational. The data collection should be completed this spring and a response from the FDA is anticipated this summer, depending on the rate or recruitment by existing and new centres.

VentriPoint estimates the market for product for Tetralogy of Fallot to be US$200 million and is already marketing the device in Europe and Canada, where it is approved for clinical use. The company has a target of placing 50 VMS devices in 2012 and anticipates that sales will increase rapidly during 2012 should FDA approval for Tetralogy of Fallow is achieved and approval for pulmonary hypertension is received in Europe and Canada.

The pulmonary arterial hypertension application is expected to over lap with the US congenital heart disease programme. A clinical evaluation of the pulmonary arterial hypertension application has already begun at the University of Chicago. This should be complete in a few weeks and, if successful, VentriPonit will use the data to file for CE mark and Canadian approval marketing applications. A number of medical centres have agreed to be part of this pivotal trial. Based on experience with the Tetralogy of Fallot trial, the company has already started the IRB and budget-approval processes with these major cardiovascular centres, as this is the most time-consuming part of the process. The sites will be selected shortly and will become operational as soon as possible.

Much of 2011 has been spent upgrading both hardware and software based on the feedback from the users and developing new applications such as pulmonary hypertension. The latest software, version 1.1, is completed and undergoing final testing. The major hardware feature expansion is the ability to interface with the newer digital ultrasound machines, which the company says is likely to  take over the market in the next five years. A key software enhancement is the ability to export VMS studies to the hospital PACS, enabling third party DICOM viewers to review the VMS results. Existing sites will be updated remotely with the new version as soon as it has been released for general use.

Looking ahead, VentriPoint is actively seeking partnerships with large manufacturers of ultrasound equipment for combination products and distribution. The company says there is considerable interest in developing a stand-alone system for pulmonary hypertension, as this would be a completely new application for ultrasound.

Article source: Lawrence Miller, editor Cardiovascular Device Business, and medical newsletters team leader at Espicom Business Intelligence



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Gilead submits sNDA for Truvada for reducing the risk of acquiring HIV

The Medical Technology Blog

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Gilead Sciences has submitted an sNDA application for the approval of once-daily Truvada (emtricitabine/tenofovir disoproxil fumarate) for pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection among uninfected adults. Truvada was approved by the FDA in 2004 for the treatment of HIV-1 infection and is currently the most-prescribed antiretroviral treatment in the US.

If the sNDA is approved, Truvada would be the first agent indicated for uninfected individuals to reduce the risk of acquiring HIV through sex, a prevention approach called PrEP. The application is based on the results of two large placebo-controlled trials of Truvada as PrEP, sponsored by the National Institutes of Health (NIH) and the University of Washington.

The first trial providing data to support the Truvada sNDA is a Phase III, randomised, double-blind, placebo-controlled trial known as the Pre-Exposure Prophylaxis Initiative (iPrEx), which was sponsored by the NIH and conducted among 2,499 high-risk HIV-negative adult homosexuals in the US and countries in Africa, Asia and South America. Results from the trial, published in the New England Journal of Medicine in November 2010, showed that once-daily use of Truvada for PrEP reduced the risk of acquiring HIV overall by 44 per cent compared with placebo and by up to 73 per cent among men who reported taking the drug consistently (defined as at least 90 per cent of days). Among men who took the drug consistently enough to have detectable drug in their body, the risk was reduced by more than 90 per cent.

The Truvada sNDA submission is also supported by data from Partners PrEP, a Phase III, randomised, double-blind, placebo-controlled trial conducted among 4,758 heterosexual couples in Kenya and Uganda, in which one partner was infected with HIV and the other was not. The trial, sponsored by the University of Washington, showed that once-daily use of oral Truvada by the HIV-negative participants reduced their risk of acquiring HIV by 73 per cent compared with placebo.

Additional supportive data come from two studies sponsored by the Centers for Disease Control (CDC). The first trial, known as TDF2, was a Phase III, randomised, double-blind, placebo-controlled trial conducted in Botswana among 1,200 HIV-negative heterosexual men and women. Participants taking once-daily oral Truvada for PrEP had 63 per cent fewer HIV infections compared with those receiving placebo. The second trial, known as CDC 4323, was a Phase II, randomised, placebo-controlled, double-blind study of homosexual men in the US primarily designed to assess the safety, adherence and acceptability of PrEP.

Although full details are not yet available, another separate Phase III study of Truvada for PrEP known as FEM-PrEP was stopped in April 2011 based on a recommendation by the study’s Independent Data Monitoring Committee that the trial would not be able to establish the efficacy of Truvada among HIV-negative women in sub-Saharan Africa. The reason for this outcome is not yet understood and a complete detailed analysis of the data is currently under way.

In all studies, side-effects included nausea, weight loss and serum creatinine elevations. The incidence of side effects was consistent with Truvada’s safety and tolerability profile when used as HIV treatment, which is supported by more than 1.8 million years of patient use. Overall, there have been more than 4.4 million patient years of experience with tenofovir-containing regimens. Three cases of resistance to emtricitabine were reported in the iPrEx trial among participants who tested negative for HIV infection by serology at enrollment, but were later found to have been infected with HIV prior to enrolment using a different assay. Two of these cases occurred in the active drug arm, and one case occurred in the placebo arm.

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FDA steps up bid to drive innovation in healthcare

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The FDA has handed over an award of US$2 million…

…to support two regional ‘Centres of Excellence in Regulatory Science and Innovation’ (CERSI) in the US. The centres, which will be located at the University of Maryland and Georgetown University, will focus on strengthening science and training needed to modernise and improve the ways drugs and medical devices are reviewed and evaluated.

In August 2011, the agency released the strategic plan for “Advancing Regulatory Science at FDA”, the main focus of which was to accelerate delivery of new medical treatments to patients, improve paediatric health, protect against emerging infectious diseases and terrorism, enhance safety and health through informatics, protect the food supply, modernise safety testing and meet the challenges of regulation. More recently, in October, the agency announced a related initiative, “Driving Biomedical Innovation: Initiatives for Improving Products for Patients”. This plan focuses on “continuing dialogue with companies, innovators, patients and other stakeholders to identify barriers to progress and better define what steps need to be taken to overcome any obstacles to innovation”.

Working with FDA scientists, CERSI researchers will assist the FDA in driving innovation in medical product development as well as in advancing laboratory, population, behavioural and manufacturing sciences. The agency chose to pilot the CERSIs in Washington, DC, to allow for the greatest possible face-to-face collaboration and training with FDA staff.

Thanks to Sophie Bracken for this article, Sophie is editor of Espicom’s business publication Drug Delivery Insight.


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US regulatory bodies respond to rapid rise of modern wireless technology and apps for medical devices

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The proliferation of broadband and wireless-enabled medical devices has prompted the FDA and US Federal Communications Commission (FCC) to issue a joint plan aimed at bringing clarity to the issue.

Although these devices represent the opportunity to enhance health and reduce the costs of healthcare, they aren’t without a few risks too. The devices, which include wireless sensors that remotely monitor heart rhythm and portable glucose monitoring systems, are increasingly playing a major role in treatments.

The US government agencies have come to the conclusion that clear guidelines are needed to make sure these devices are operated in a safe, reliable and secure manner. The FDA, in particular, is of the opinion that the industry, healthcare providers, patients, and other interested stakeholders in the medical environment should have clear regulatory pathways, processes and standards to bring the technology to market.

Although specific details are thin on the ground at the moment, the aim still pretty noble enough. “All Americans should be afforded the opportunity to benefit from medical technology advances with improved broadband and wireless technology” – the communiqué boldly claims.  At the end of the day though, by clarifying each agency’s scope of authority with respect to these devices, the hope is that interested parties will get a clearer picture of the regulatory process, streamline the application process, and make sure that innovation doesn’t get stifled through bureaucracy.
The move comes as the FDA grapples with even more complex issue of software applications (apps), the likes of which are increasingly been used in mobile medical technology, such as mobile phones, tablet computers and PDAs.

In general, the FDA’s position is that if a mobile app is intended for use in performing a medical device function it is a medical device, regardless of the platform on which it is run. This can range from mobile apps used on mobile phones to analyse glucose meter readings.

In consultation with the US public, the agency is looking to establish formal guidance that define a small subset of mobile medical apps that impact or may impact the performance or functionality of currently regulated medical devices. The offending apps could be used as an accessory to medical device already regulated by the FDA transform a mobile communications device into a regulated medical device by using attachments, sensors or other devices.

There’s an obvious need for some kind of monitoring in this area. Nowadays an app can be used by a healthcare professional to make a specific diagnosis by viewing a medical image on a mobile phone or tablet, whilst some apps can turn a smartphone into an ECG machine and be used to detect abnormal heart rhythms or determine if a patient is experiencing a heart attack. Understandably, the FDA is of the opinion that these particular mobile apps pose the same or similar potential risk to the public health as currently regulated devices if they fail to function as intended.

The FDA has set a deadline for 19th October 2011 for interest parties – including manufacturers and app developers, to submit comments relating to the agency’s draft policy document, with a view to formulating clear guidance on the matter once and for all.  One thing is for sure, it’s a good idea to revise the present guidelines – the FDA’s last significant attempt to address the topic was made in 1989!

Thanks to Lawrence Miller for yet another great article, Lawrence is the Espicom’s editor for Medical Industry Week, and medical newsletter teamleader. For more articles like this, or to start your subscription please click on the link to Medical Industry Week

 



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HQ relocation brings Nuvilex closer to the action

The Medical Technology Blog

Nuvilex, a company that dedicates itself to the development of natural and biotechnology products, has made the canny decision to up sticks and move its corporate headquarters from Scottsdale, AZ, to Silver Spring, MD – only four miles from the FDA’s doorstep. Nuvilex is hoping that the move – which is in its final stages – will give the company immediate access to the FDA’s resources as the company pursues clinical development of its pancreatic cancer treatment technology, as well as other biotechnology developments in the future.

Not only is the company’s HQ in the FDA’s backyard, it is also only about ten miles away from the National Institutes of Health, and the National Cancer Institute – both major sources of funding grants and research collaborations. To explain the move, Nuvilex’ President and CEO, Dr Robert F Ryan, said the new location “..will facilitate our interactions with the FDA, an important part of our overall strategic planning, especially given our recent entry into biotechnology and our plans for expansion in this area”.

Nuvilex’ pancreatic cancer treatment is currently being geared-up for more clinical trials, and apparently, significant advances are in progress with the company’s live-cell encapsulation technology. Natural products in development include Gluten-Free Cinnergen and others to enhance a healthy lifestyle. The company is also developing products designed for cosmetic use, flu treatment and the use of heavy-metal-free tattoo inks. Future developments are planned for Citroxin and Oraphyte, Nuvilex’ antimicrobial and antinematodal agents.

This article was kindly provided by Sophie Bracken, editor of Drug Delivery Insight for Espicom.



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ReGen Biologics has rejected the FDA’s offer of a hearing, before the agency formalises its plans to annul its 510(k) clearance of the company’s Menaflex meniscal implant.

Dr Gerald E Bisbee, Chair and CEO of Regen, thinks that any meeting would be a big waste of time and he might have a point judging by his company’s dealings with the FDA over the past six years. Bisbee says “enough is enough”, because safety and efficacy issues regarding the device were reportedly settled years ago at an FDA Advisory Panel meeting.  Bisbee said members of that panel were in favour of Menaflex, and any issues that need attention are the FDA’s own “arbitrary and unfair processes”.

Menaflex is a reabsorbable mesh that is used in meniscus surgeries to reinforce damaged or weakened meniscal soft tissues, providing a scaffold for replacement by the patient’s own soft tissue. The device was cleared in Europe in 2000 and 2006 for use in medical meniscus injuries and lateral meniscus injuries, respectively. After a three-year review under the 510(k) process (which included input from  the Advisory Panel of independent experts), December 2008 saw the FDA rule that the device is safe and effective, and cleared it for use. But after a change of management at the FDA two years later, the agency re-reviewed its own approval of the product. Dr Jeffrey Shuren, Director for the CDRH, rationalised the re-review by citing a September 2009 FDA report, of which he was co-author, called “Review of the ReGen Menaflex: Departures from Process, Procedures and Practices Leave the Basis for a Review Decision in Question”.

The report said that the original FDA review of the device was subject to a number of internal FDA departures from processes, procedures and practice that were compounded by external pressures. Bisbee believes that a careful reading of the report shows that within the reviewing there was “…widespread internal disagreement and confusion about the legal standard for 510(k) review”, and that the OCC (the FDA’s legal division), “advised that a review of a 510(k) involves a comparison of a device to a predicate rather than to a standard-of-care that there was no legal foundation for requiring a company to demonstrate clinical benefit in a 510(k)”. Bisbee says this interpretation supports ReGen’s argument that the CDRH was holding the device to the wrong review standard.

Almost exactly a year ago, ReGen wrote to the FDA Commissioner Hamburg about the report. The letter provided 0a detailed analysis of the report, suggesting that it contained “…inaccuracies, misrepresentations, speculation and bias, and omits material information… The extent and depth of these irregularities raise the question of whether the preliminary report was intended to discuss the results of the agency’s internal investigation or instead provide support for a foregone conclusion, ie, a re-examination of the Menaflex device 510(k) clearance”.  According to ReGen, Commissioner Hamburg is yet to respond to the letter.

The FDA’s re-review of Menaflex took almost a year and included a second Advisory Panel meeting, concluding with the decision that the device had a different intended use. According to this decision, Menaflex, despite being similar to other approved meshes, would not be regulated as a surgical mesh pursuant to 510(k), but would be treated as a novel Class III device. Shuren stated his intention to revoke the FDA’s original 510(k) clearance, a move that Bisbee finds “unbelievable”.

As it has declined the FDA’s offer of a hearing, ReGen has put the agency on notice that it will seek an “unbiased” review of Menaflex’ approval status under US law. ReGen says it knows the FDA has no legal authority to revoke Menaflex’ clearance, and believes the agency botched its review of the product at every stage. In a nut shell, will the FDA’s opinion that devices can be re-reviewed and revoked at any time, even long after they have been approved, chill US investors’ eagerness to invest in the development and distribution of new devices?

Thanks to Sophie Bracken for this article, Sophie is editor of Orthopaedic Business News Espicom’s monthly digest of news from the industry.

Thanks for reading, Paul.



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Vivelle-dot, an estrogen patch.

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Welcome back to the Medical Technology Blog once again Mylan are under fire from the authorities (see related articles below) please read on…

Mylan is being sued by Noven Pharmaceuticals and Novartis over alleged infringement of the latter’s Vivelle-Dot (oestradiol transdermal system) patch product. Noven filed the lawsuits in the US District Court for the Southern District of New York and the US District Court for the District of Vermont after Mylan submitted an ANDA application in the US for approval to market a generic version of Vivelle-Dot, before the expiration of the product’s patent protection in 2014.

As Noven and Novartis filed the suit within 45 days of hearing about Mylan’s ANDA submissions, the FDA is not allowed to approve the generic product until June 2013 at the latest, or until a district court decides the patent is invalid or the product infringing. However, Mylan believes it is the first to file an ANDA containing Paragraph IV certification for all strengths, and hopes to qualify for 180 days of marketing exclusivity, if approval is granted.

Mylan’s patch, a twice-weekly oestradiol transdermal system, has been submitted for approval for 0.025mg/day, 0.0375mg/day, 0.05mg/day, 0.075mg/day and 0.1mg/day strengths, for the treatment of the symptoms of menopause, the treatment of hypoestrogenism and the prevention of post-menopausal osteoporosis.

IMS Health says that Vivelle-Dot had sales in the US of around US$215 million for the 12 months ended 31st December 2010. Vivelle-Dot, which was launched in 2002, is marketed by Novogyne Pharmaceuticals, a joint venture specifically set up by Noven and Novartis to promote the product. With the prospect of generic competition taking a slice of its revenues, neither Noven nor Novartis are going to give up that easy and have served notice that they will “vigorously defend” their intellectual property rights from infringement.

Thanks to Sophie Bracken for this article, Sophie edits Espicom’s newsletter Drug Delivery Insight.



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Medical Technology Development Costs Cause Concern In US

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Biosensors highlights concerns over the time and costs of approving devices in the US

Jeffrey Jump, the recently appointed CEO of Biosensors is a frustrated man. His company – a Singapore-based stent manufacturer – has grown increasingly exasperated with the regulatory climate that exists in the US and he wants everybody to know just how difficult it is getting a device approved by the FDA.

Concerns over the lengthy and demanding regulatory process in the US are not new. For years, many of the groundbreaking devices to emerge in the healthcare market – not just in cardiovascular devices – have made their debut in markets outside of the US first. Indeed, many US companies have found themselves marketing their technology in Europe long before the clearance process in the US has been negotiated. Europe’s gain has been the US’s loss but there are fears the gap is widening. In its defence, the FDA’s supporters will argue that its processes are there to protect the American people and if that means a more strenuous approval process then so be it. However, as Mr Jump suggests, it seems as if this regulatory gap is getting worse and the issue has to be addressed.

Worldwide, the approval process continues to take less time and, more importantly, costs less to fund. It takes a device manufacturer three to five years to get a medical device approved in Japan and China, at cost of US$3 million or less in each market. In Europe, the time can range from six months to two years and cost just US$2 million. In contrast, getting approval in the US for a medical device can take between two and seven years and cost between US$50 to US$100 million.

This discrepancy in time and costs is raising a few questions that Mr Jump and other CEOs increasingly feel need to be answered as a business. Most importantly, is it really worth spending that much time, effort and money on securing FDA clearance? It’s an issue that doesn’t just trouble the smaller companies, even the bigger ones are weighing up the options. According to Mr Jump, major medical device companies could be facing bills in the region of US$200 million just to get approval for their next-generation stent technology in the US and, as a direct result, may seriously consider abandoning the US market for this important technology.

With the global economic downturn very much in the memory of CEOs, the stringent and lengthy requirements needed to accommodate the FDA have also seen innovative companies bite the dust as they get bogged down in the regulatory steps imposed by the FDA. For Biosensors this brings opportunities to acquire technology at much lower prices because these companies simply run out of cash and time.

Already, Mr Jump has snapped up CardioMind, a US company which has developed a drug-eluting stent (DES) for the treatment of small vessel lesions, and plans to complete the acquisition of another undisclosed device company shortly. Paying for such high quality assets at knockdown prices is possible for Biosensors because it looks to gain its market share from markets outside of the US, which ultimately place considerably less strain on its cashflow. How long will it be before other companies choose a similar path?

Whilst Abbott will probably find the prospect of not marketing its bioreabsorbable vascular scaffold (BVS) platform in its home country ultimately unpalatable, and you could say it’s big enough to handle the costs, the debate is unlikely to go away. China is set to become the largest market for medical device by 2016, so why go through the trials and tribulations of the US when there are richer pickings to be had elsewhere? Biosensors has already closed its R&D operations in the US and transferred its activities back to Singapore and its R&D centre in Morges, Switzerland – also a centre for R&D for Medtronic and Edwards Lifesciences – because the costs of manufacturing and marketing medical devices in the US do not justify the potential returns.

The FDA is unlikely to be too concerned at the comments made by Biosensors, even if they are shared by the CEOs of some of the largest US medical device companies.  But that could change in the future as there is a real possibility that advanced technology – and US-developed technology in particular – could find itself not available in the US, or at least be available several years behind the global market. This has potential ramifications not only for the US healthcare system but also for the skills base in the US. Will the US be able to keep hold of its expertise if companies are increasingly outsourcing such facilities internationally?

For Biosensors, the die has been cast. The company is committed to marketing its BioMatrix Flex abluminal biodegradable polymer DES in markets outside of the US, and it doesn’t market or manufacture any interventional cardiology products in the US. That’s not say the Biosensors is totally excluded from the US market – it also sells bare metal stents and balloon dilation catheters, as well as a sizeable business that includes critical care catheter systems, haemodynamic monitoring and related devices used during heart surgery procedures and intensive care treatment. It is also handily placed should Abbott market its BVS device in the US as it also incorporates royalty earning Biosensors technology. But, despite all of these points, you can’t help share Mr Jump’s disappointment that the US market is rapidly becoming out of bounds to innovation.

This post was brought to you by Lawrence Miller, Espicom Business Intelligence’s medical news team leader.



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FDA -More Research Into Heart Valve Replacement Procedures Needed!

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GIF-animation showing a moving echocardiogram;...
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Welcome back to The Medical Technology blog. My apologies for the lack of posts last week, but I  was extremely busy updating Espicom’s main website. Please read on….

Interesting news has come this week from a study funded by the FDA’s Agency for Healthcare Research and Quality (AHRQ) which gives qualified backing to the adoption of percutaneous heart valve replacement (PVR) procedures in preference to open heart surgery

The report, produced by the Duke Evidence-based Practice Center for AHRQ and published online in the Annals of Internal Medicine, found that PVR, a minimally-invasive procedure in which a replacement valve is implanted through a catheter rather than by open heart surgery, is a realistic option for some patients with heart valve disease, especially older or sicker patients.

The report concluded that this form of heart valve replacement may be a safe and effective alternative to open heart surgery, especially in the short term, for this patient group. However, the FDA body maintains that information is lacking on the potential long-term benefits and risks of this procedure, particularly compared with open heart valve replacement surgery.

In this study, approximately 92 per cent of patients who received a percutaneous valve survived the procedure, of which 86 per cent survived for at least 30 days. The authors looked at 62 published studies representing a total of 856 patients, as well as additional studies that have not yet been published. However, researchers were unable to make direct comparisons between percutaneous valves and traditional surgical replacement due to differences between patient groups receiving the treatments.

In total, seven percutaneous valves were featured in the study, namely the Sapien transcatheter heart valve (Edwards), CoreValve ReValving system, Melody heart valve (Medtronic), Paniagu heart valve (Endoluminal Technology Research), Lotus valve (Sadra Medical) and Ventor Embracer (Ventor Technologies). This particular study didn’t look at the comparative performance of the devices, leaving that to be revealed through other studies currently in progress in the US. The AHRQ argues that there are plenty of comparative “mine’s better than yours” studies but little in the way of  observational studies and decision modelling that could help inform clinical and health policy in the absence of randomised control trials.

It’s an important question since, as with most of the developed world, the US population  proportion of older adults continues to increase, bring with it higher incidences of degenerative heart valve disease. Calcific aortic stenosis (narrowing) and ischaemic and degenerative mitral regurgitation (leakage) are the most common valvular disorders in adults aged 70 years and older.

Mechanical and, more latterly, bioprosthetic heart valves, have radically transformed the way in which we treat patients with heart disease. The urgent need now is to make sure that includes policymakers, decision makers for third-party payers, clinicians, patients and investigators, get the right form of information.

Thanks for reading, and come back soon, Paul.



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