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  • The MedTech industry is undergoing an era of unprecedented change
  • Pressure on revenues and margins have forced leaders to cling tightly to business as usual
  • In the next decade business as usual will come with significant commercial risks
  • For commercial success future MedTech leaders will need to be different to past leaders
 
Who should lead MedTech?
 
Questions about who should lead medical device (MedTech) companies in the future and what strategies and business models they should pursue are critical. Over the next decade MedTech faces an era of unprecedented change, when it will be necessary to develop new strategies, new business models, new markets, new capabilities and new technologies, while keeping the legacy business running. Future MedTech leaders will be tasked with bridging the gap between traditional manufacturing and sophisticated, digitally driven services while managing unprecedented change and significant competition. For the past 20 years MedTech leaders have been drawn from a relatively narrow set of people with a relatively narrow set of skills. Although this has served the industry well, it might not be the most appropriate policy to ensure commercial success over the next decade.
 
In this Commentary

In this Commentary we: (i) describe the traditional MedTech market, indicate the structure parameters of the industry and note that there is a rapidly evolving parallel digital healthcare technology market: one that is growing more than twice as fast and soon will be comparable in size to the traditional manufacturing-based market, (ii) suggest that MedTech leaders tend to be men in their 50s with limited understanding of this parallel digital healthcare universe, which is positioned to play a significant role in  shaping MedTech companies of the future, (iii) suggest that because MedTech leaders have performed relatively well over the past two decades, they have tended to become prisoners of their own traditions and felt little or no need to evolve their strategies and business models, (iv) contend that MedTech leaders’ principal response to market changes to-date has been increased M&A activity, which has made companies bigger but not better, (v) suggest that the industry is undergoing a significant market shift from manufacturing to solutions and services driven by the 4th industrial revolution, which is characterized by a fusion of technologies, and (vi) conclude that future MedTech leaders will require a deep knowledge and understanding of the 4th industrial revolution if they are to successfully transform traditional strategies and business models in order to deliver superior healthcare solutions at lower prices.
 
MedTech market and the structure of the industry

MedTech is a conservative manufacturing industry, which produces and markets a diverse group of product offerings predominantly in a few developed wealthy markets. Over the next decade the MedTech market is expected to change significantly. For the past two decades the industry has fallen into three broad segments: (i) diagnostic products, which include imaging devices, with a global market of some US$100bn, (ii) medical aids including consumer durables, such as hearing aids and bandages with a worldwide market of about US$150bn, and (iii) surgical products that include equipment and instruments used in the operating room, which has a global market of some US$140bn.
 
A 2017
EvaluateMedTech report suggests the global MedTech market is projected to eclipse US$500bn in sales by 2021, over 33% of which is expected to be derived from the US. The worldwide market is projected to continue growing at a compound annual growth rate (CAGR) of 5%. Ranked by 2017 revenues, seven of the world’s largest MedTech companies are American and a significant proportion of the world’s MedTech companies trade on Nasdaq. This includes 13 large companies with a market cap in excess of US$10bn, some of which are divisions of even larger corporations such as Johnson & Johnson Medical Devices and Diagnostics, with estimated global sales of US$38bn for 2018; this equates to approximately 7.6% of the worldwide MedTech market. Medtronic, which is the world's largest stand-alone MedTech company, has a market cap of US$117bn and in 2017 recorded revenues of US$29.7bn; 26% of which was generated in the US. Nasdaq has about 24 mid-cap MedTech companies ranging in value from US$2bn to US$10bn. The majority of these are American and tend to be regionally based with relatively small markets outside the US, Europe and Japan. There are some 27 small-cap companies with market caps between US$300m and US$2bn, 46 micro-cap companies ranging from US$50m to US$300m and finally some 28 nano-cap MedTech companies with market caps less than US$50m.
 
In recent years, a digital healthcare technology industry, where medical devices meet innovative software, has grown substantially, but mostly in parallel to the traditional manufacturing-based MedTech industry. According to
Transparency Market Research, in 2016 this industry, which is based on healthcare information systems and wearable devices, had annual sales of US$180bn, and is projected to grow at a CAGR of 13.4% between 2017 and 2025, reaching US$537bn in annual sales by the end of 2025.

 
MedTech executive leadership
 
There is a relative dearth of data specifically on MedTech leaders and the demographics of MedTech C-suites (senior executives which tend to start with the letter C). Notwithstanding, there are data on Fortune 500 and S&P 500 company leaders from regular surveys undertaken by executive search firms Korn Ferry, and Spencer Stuart. Some of the larger MedTech companies, such as Abbot Laboratories, Baxter International, Stryker and Boston Scientific, are listed in the Fortune 500 and S&P 500. If we assume a significant similarity between the demographics of Fortune 500, S&P 500 and MedTech company executives, then MedTech leaders will tend to be white males in their 50s, predominantly drawn from similar sector company C-suites and will have an average tenure of about eight years.
  
Middle-aged men
 
Over the past 20 years MedTech leaders have benefitted from the industry’s commercial success, albeit in recent years at a slower pace than before 2007. Most leaders are constrained by quarterly earnings targets, shareholder expectations, regulations and the high risk and cost associated with changing manufacturing systems. MedTech CEOs received their formative education before the widescale uptake of the Internet and email. Many had just started their careers in large corporations when giant technology companies such as Amazon (launched 1994) and Google (1998) in the US and their Chinese equivalents - Alibaba (1999) and Baidu (2000) - were start-ups, and the Chinese and Indian economies were still somewhat underdeveloped and inchoate. Consequently, most MedTech leaders were entering middle-age when US social media giants such as Facebook (2004), YouTube (2005), WhatsApp (2009) and Instagram (2010) and their Chinese counterparts such as WeChat (2011), RenRen (2005), Weibo (2009) and Youku (2005), were just taking off.
 
This might partly explain why some MedTech leaders appear to be challenged by the rapidly evolving new digital technologies and the industry’s shift from manufacturing to solutions and services. Such is the pace of change, it will require a shift of mindset among incumbent MedTech leaders if they are to fully grasp this new and significant opportunity set.
 
Similarly, with emerging markets. Most CEOs have knowledge of the wealthy MedTech markets, in particular the US and Europe. Few, however, have in-depth knowledge or first-hand experience of the large and fast-growing emerging economies such as Brazil, Russia, India and China (BRIC). The BRIC countries are at a similar stage of their economic development, and have a combined population of more than 3bn, which equates to about 40% of the global population. BRIC countries are differentiated from other promising emerging markets by their demographic and economic potential to rank among the world’s largest and most influential economies in the 21st century, and by having a reasonable chance of realizing this potential.
 
A future HealthPad Commentary will examine the opportunities for Western MedTech companies seeking or expanding their franchise in China and will suggest that they might not find it as easy as it would have been 5 years ago. Opportunities in China for global MedTech players are becoming tougher as the Chinese economy slows and restructures; Beijing’s healthcare reforms kick-in and local MedTech producers, buoyed by legislation, revenue growth and increased capacity, become commercially stronger, more technically sophisticated and take a bigger share of both the Chinese domestic and international emerging MedTech markets.
 
Underrepresentation of women
 
Not a single woman serves as CEO of a large MedTech company. Only 22% of their board members are women, which is about the same proportion as the Fortune 500 overall (20%), and about 22% of MedTech C-suites are women. In 2017, nearly 50% of the US labour force were women and 40% of these worked in management, professional and related occupations.  Although women are underrepresented in MedTech leadership positions they are key stakeholders in healthcare. About 35% of active US physicians are women. According to the Association of American Medical Colleges, (AAMC), 46% of all physicians in training and almost 50% of all medical students in the US are women.  60% of pharmacists in America are women.

It should not be forgotten that women have played significant roles in medicine and healthcare. For example, Marie Curie, the only person to win a Nobel Prize in two different sciences, pioneered research on radioactivity. Curie made a significant contribution to the fight against cancer and is credited with having created mobile radiography units to provide X-ray services to field-hospitals during World War I. Sussman Yalow, was awarded the Nobel prize in Physiology or Medicine in 1977 for the development of the radioimmunoassay technique, and Gertrude Elion won a Nobel Prize in Physiology or Medicine in 1988 for her work in helping to develop drugs to treat leukaemia and AIDS. More recently, Jennifer Doudna, and Emmanuelle Charpentier, were credited with the discovery of the ground-breaking CRISPR-Cas9 gene-editing technology, which effectively changes genes within organisms and is positioned to radically change healthcare and MedTech in the 21st century.

In addition to under-representation, which suggests that the pipeline of women candidates for top jobs in MedTech is weak, there is some evidence to suggest that the MedTech industry does not have a positive attitude towards women. Findings of a 2015 survey conducted by AvaMed, the industry’s principal trade association, suggest that women in the industry feel discriminated against. Some 42% of women respondents of the survey said they, “felt held back from senior leadership positions” and 37% felt “overtly discriminated against”. "The world cannot afford the loss of the talents of half its people if we are to solve the many problems which beset us,” said Yalow in her 1977 Nobel Prize acceptance speech.
 
MedTech’s business model
 
Over the past two decades MedTech leaders have drawn comfort from the fact that the global MedTech market is highly centralized. The US, Western Europe and Japan, which represent only about 13% of the world’s population, account for more than 86% of the global MedTech market share (US: 42%, Europe: 33%, Japan: 11%). Conversely, the BRIC countries, which represent about 40% of the world’s population, currently only account for about 5% of the global MedTech market. This has enabled MedTech leaders to market their product offerings to healthcare providers principally in a few wealthy developed regions of the world via well-compensated sales representatives with deep product knowledge and expertise. The industry’s predominant business model has been to raise prices on existing products and market new offerings at higher prices than the products they are meant to replace. This worked very well before 2007 during a period of sustained global economic growth, predominantly fees-for-service healthcare systems and relatively benign reimbursement policies; all of which contributed to high margins and significant sales growth.
 
Market changes not perceived as acute enough to trigger transformation
 
Since the 2008 recession the MedTech market has changed. The global economy has weakened, debt (sovereign, corporate and personal) has escalated, populations have continued to grow, and the prevalence of chronic lifetime diseases and multi-morbidities have increased. Over that period, healthcare systems have become fiscally squeezed, costs have become pivotal and impacted all stakeholders. This has led to: (i) a shift in healthcare systems from fees-for-service to fees-for-value (ii) increased consolidation, convergence, and connectivity of stakeholders and a consequent change in purchasing decisions from individual (fragmented) hospitals and clinicians to centralized procurement bodies, which can leverage economies of scale and negotiate for larger purchases at volume discounts, (iii) the decline of MedTech R&D productivity, and (iv) increased competition from new market entrants, often from different industries. MedTech’s gross margins have been squeezed and annual growth rates have slowed to a CAGR of between 4 and 5%. Notwithstanding, MedTech leaders, buoyed by continued but slower revenue growth, and doubtless comforted by a prolonged surge in US equity markets, have not perceived these market changes as being with sufficient acuity to transform their strategies or business models.  Their principal response has been to increase M&A. 
 
M&A main strategic response to market changes
 
Over the past decade M&A has provided MedTech leaders with a means to: (i) increase scale and leverage, (ii) drive stronger financial performance, (iii) obtain a broader portfolio of product offerings, (iv) enhance therapeutic solutions and (v) increase international expansion; without changing their companies’ fundamental manufacturing structures and strategies. According to a January 2018 McKinsey report, between 2011 and 2016, 60% of the growth of the 30 largest MedTech companies was due to M&A. The report also suggests that between 2006 and 2016, only 20% of 54 pure-play publicly traded MedTech companies, “mostly relied on organic growth”.  M&A activity has resulted in bigger MedTech companies but not necessarily better ones. This is because M&A and collaborative relationships have not encouraged healthcare providers to change their strategies and business models and develop powerful data-sharing networks, which help drive integration across the continuum of healthcare.
 
Need for portfolio transformation
 
Encouragingly, the 2018 McKinsey report also suggests that some MedTech companies are beginning to use M&A to acquire “non-traditional” assets, such as software and service companies, to assist them in transforming their portfolios. Notwithstanding, portfolio change in a rapidly evolving and increasingly competitive healthcare ecosystem requires a sound strategic understanding of the potential role that the 4th industrial revolution can provide for MedTech. Given our discussion so far, it seems reasonable to assume that many current MedTech leaders and C-suite executives might not have fully grasped the commercial implications of this revolution for their industry. Portfolio change in the MedTech industry is arguably more likely to be led by executives from, or with an intimate knowledge of, adjacent, service-based companies; those who have successfully employed sophisticated digital technologies and big data strategies to transform their business models and who are now looking to do something similar in MedTech and healthcare markets.
 
The relative slowness of the MedTech industry to transform its strategies and business models is perceived as an opportunity by giant technology corporations. They sense the disruptive potential, just as they do in financial markets due to Wall Street’s inertia to digital change.  For example, in early 2018, Amazon, Apple, Google, and Uber announced their intentions to enter and disrupt the healthcare market by leveraging digital technologies to provide quality healthcare solutions and services at lower costs.
 
Rather than marketing products, MedTech companies are now increasingly being tasked with marketing solutions that can deliver better care at lower prices. The 4th Industrial Revolution is a primary enabler for achieving this. However, given the demographics and the conservatism of the MedTech industry, it seems reasonable to suggest that companies in the sector, which do not adapt, run the risk of becoming simple commodity producers stuck in the middle of a new and rapidly evolving value chain.

 
The 4th Industrial Revolution

The 1st industrial revolution used water and steam to mechanize production, the 2nd used electric energy to create mass production, the 3rd used electronics and information technology to automate production. The 4th industrial revolution, also known as ‘industry 4.0’, is characterized by a fusion of technologies, which is blurring the boundaries between medical devices, drugs, software and patient data and redefining relationships between the physical, biological and digital worlds. These exogenous shifts are likely to demand different strategies, different business models and different leaders for the MedTech industry.
 
Industry 4.0 provides MedTech with an opportunity for portfolio transformation by developing sophisticated data and digitization strategies to enhance company operational and financial performance. Industry 4.0 is driven by greater connectivity via the Internet and computing devices embedded in physical objects and advanced digital technologies, which enable them to send and receive data to help integrate producers, suppliers, business partners and customers; at the same time providing opportunities for MedTech companies to become smarter, more efficient and fully-networked organizations.
 
Key for superior shareholder returns
 
To date, MedTech leaders have been relatively slow to integrate new and evolving digital technologies into their core business operations, although there are encouraging signs that some companies are beginning to do so. Findings of a 2017 report by the Boston Consulting Group, (BCG) suggest MedTech companies are, “masking unsustainably high costs and underdeveloped commercial skills” and relying, “on an outdated commercial model”.  The BCG findings are based on a survey of some 6,000 MedTech employees in commercial functions, more than 100 interviews with MedTech leaders and benchmarking financial and organizational data across 100 MedTech businesses (including nine of the 10 largest companies) worldwide. According to BCG, although the industry overall has made little progress to change its business model and upgrade its skill levels, the companies, which have done so, are winning in the market and generating superior shareholder returns.

MedTech leaders should not mistakenly think that because their companies hold plenty of enterprise data they are implementing industry 4.0 strategies. Often, enterprise data do not provide any competitive advantage whatsoever but are simply a legacy cost of doing business. New sources of data, and the ability to use data’s power, are essential to enhance a company’s competitive advantage. A next-generation enterprise resource planning (ERP) platform, launched by SAP in 2017, is already being used by service companies to provide them with a digital core, which helps to create real-time matrixed data produced by social media, third party information, genetics, the Internet of Things, points of sale, etc.

 
Shift from selling products to selling solutions

To remain competitive in the next decade MedTech leaders will need to employ artificial intelligence (Al), augmented reality, robotics, advanced sensors, the Internet of Things (IoT), blockchain, nanotechnology, 3D printing, petabytes of data, enhanced processing power and storage capacity to help them transform their strategies and business models and enable their companies to evolve from being product-centric to customer-centric, with an emphasis on digitization and the capture and communication of data. Industry 4.0 and the convergence of the physical, biological and digital worlds will fundamentally change MedTech strategies and business models, as decision-making powers continue to shift from manufacturers to other healthcare stakeholders. Critical to this transformation will be those MedTech leaders who are well positioned to ensure that companies remain competitive in their core markets while establishing new markets underpinned by 4.0 technologies.
 
"Out-of-touch leaders" the main cause of company failure

A book published in 2016 entitled Lead and Disrupt suggests that company transformations fail because of out-of-touch leaders rather than competition. According to Michael Tushman, co-author of Lead and Disrupt, “The things that help organizations execute their current strategy - the cultures they build, the structures they forge, the processes that work so well to get today’s strategy executed - actually collude to hold the organization hostage to that soon-to-be-obsolete strategy. The more firms engage in getting today’s work done, it actually reduces the probability of making shifts in innovation and strategy. That is what is so strikingly paradoxical to leaders: The very recipes that work so well for today often get in the way of the future. It’s a challenge to incrementally improve what you’re doing as you’re trying to complement it with something different. The dual strategies are inconsistent.”
 
Takeaways

Over the past two decades MedTech companies have helped to shape healthcare systems in wealthy advanced industrial societies and have been rewarded with commercial success. But just as the fund investment axiom tells us, past performance is no guarantee of future success.

Crucial to the future success of MedTech companies will be their leaders. We have suggested that employing recruiting criteria, which have worked in the past might not guarantee future success. The next 10 years will be an era of unprecedented technological change for MedTech companies when the boundaries between medical devices, drugs, software and patient data become blurred.

Business as usual, which has served the industry well in the past, is unlikely to bring continued commercial success in this new healthcare ecosystem. In recent years, investment in digital healthcare has soared and the momentum towards a digital future has gathered pace. Future successful MedTech leaders will be those who combine a deep understanding of the 4th industrial revolution to leverage sophisticated digital technologies and data to assist them in creating and delivering enhanced healthcare solutions at lower costs, with an ability to keep the legacy manufacturing business running.  

MedTech companies face a stark choice: either appoint leaders similar to those of the past and become challenged or appoint leaders able to integrate new and evolving technologies into the core of the business to create and market cost effective quality healthcare solutions and remain profitable. MedTech leaders might consider adopting the motto: tempora mutantur et nos mutamur in illis.
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  • A novel drug called niraparib which freezes tumours and can prevent ovarian cancer recurring is now available to NHS patients
  • Ovarian cancer is a silent killer: each year in the UK it affects 7,400 women and kills 4,100
  • Oncologists have called niraparib, which is taken as a daily pill, a “game changer
  • Approval of niraparib is predicated upon a clinical study that enrolled 553 patients with recurrent ovarian cancer
  • The endpoint of the study was progression free survival
  • The study reignited discussion about the relative merits of different metrices used to assess the efficacy of cancer therapies
  • Patient groups and some oncologists suggest health-related quality of life should be given more significance in the measurement of drugs
 
Niraparib made available on the NHS to halt the spread of ovarian cancer

There is some good news for women in Britain living with ovarian cancer. In June 2018 niraparib, a life extending drug, was recommended by the UK’s National Institute for Health and Care Excellence (NICE) for inclusion in the Cancer Drugs Fund, (CDF) which will make niraparib available on the NHS to women living with ovarian cancer, who already have had two or more courses of chemotherapy.  The drug, which was first marketed in the USA in April 2017, is the first PARP inhibitor (described below) taken as a daily pill to be approved in Europe that does not require BRCA mutation or another biomarker testing. (Women with harmful mutations in the BRCA1 or BRCA2 genes have a 10 to 30 times higher risk than normal of ovarian cancer). Niraparib is expected to benefit around 850 UK patients each year at an annual cost of about £58,661 for the 200mg daily dose or £86,786 for the 300mg dose; but is available to the NHS at an undisclosed discount. Some oncologists have heralded niraparib as a “game-changer” because it freezes tumours and can prevent ovarian cancer recurring for 12 to 16 months.
 
In this Commentary

This Commentary: (i) describes niraparib and how it halts the spread of ovarian cancer, (ii) summaries the findings of the clinical study, which is the basis on which niraparib has been approved, (iii) describes questions raised about the endpoints of clinical studies and the growing debate about a trade-off between progression free survival and health-related quality of life, (iv) briefly describes the epidemiology of ovarian cancer, (v) uses video of a leading oncologists to describe the standard of care for the disease, (vi) explains the reasons why ovarian cancer is frequently diagnosed late with more video contributions from leading clinicians, and (vii) emphasises and repeats the signs and symptoms of ovarian cancer in an attempt to help educate women and encourage them, whatever their age, to seek immediate attention from their primary care doctor if they have any tell-tale signs of the disease.
 
How niraparib works

Niraparib is one of a class of drugs known as poly(ADP-ribose) polymerase (PARP) inhibitors and is indicated for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Because of the high recurrence rates associated with ovarian cancer maintenance therapy, measured by progression free survival (PFS) rather than overall survival (OS), has become the appropriate treatment for this disease.  Niraparib is a targeted therapy, which uses agents to identify and attack cancer cells while causing minimal damage to normal cells. Such therapies attack cancer cells' nuclei that contain the programs, which differentiates them from normal healthy cells. Each type of targeted therapy works differently, but they all change the way a cancer cell grows, divides, repairs itself, or interacts with other cells.
 
NOVA clinical study

The approval of niraparib is predicated upon findings of an international Phase 3 clinical study called NOVA, which were published in the December 2016 edition of the New England Journal of Medicine. The study sought to evaluate the efficacy of niraparib versus placebo as a maintenance therapy for patients with platinum-sensitive, recurrent ovarian cancer. The double-blind study enrolled 553 patients with recurrent ovarian cancer, who had achieved either a partial or complete response to their most recent platinum-based chemotherapy. The primary endpoint of the study was progression free survival.

Researchers were keen to discover whether having a BRCA mutation affected how well the therapy worked. Approximately 66% of participants did not have BRCA mutations. Findings demonstrated that women with an inherited BRCA gene mutation saw the time to relapse increase from 5.5 months to 21 months compared with chemotherapy alone. Niraparib was also shown to help women without a BRCA mutation, doubling the length of time before recurrence from 3.9 months to 9.3 months. So, niraparib significantly increased progression free survival in patients with or without BRCA mutations as compared to the control group. The results of the study position niraparib as the first PARP-inhibitor to reduce the risk of ovarian cancer progression or death by 73% in patients with BRCA mutations and by 55% in patients without BRCA mutations. Research is ongoing.
 

More data needed
While the NOVA study represents a significant step forward more data is needed before all asymptomatic patients with recurrent platinum-sensitive ovarian cancer can be treated effectively with niraparib and other maintenance PARP inhibitors. The challenge for clinicians is to select the right drug for the right patient at the right time. To decide which patient receives PARP inhibition and at what point in her therapy is challenging and stands to benefit from further research. Until further research is undertaken on niraparib and other PARP inhibitors, patients with advanced ovarian cancer will continue to incur treatment related toxicity without definitive benefits. 
 
Quality of life versus progression free survival

The side effects from approved cancer therapies raise questions about the metrices clinical studies use to measure their endpoints. All drugs have safety risks. The sole reason why a patient would want to take a drug is because it: (i) improves survival, (ii) results in a detectable benefit, (iii) decreases the chances of developing complications or undesirable side effects. Primary endpoints in clinical studies should be something that are important to a patient and can be objectively measured. When clinical studies use surrogate endpoints, similar tests apply. Thus, clinically meaningful endpoints directly measure how a patient feels, functions, or survives and include overall survival (OS), progression-free survival (PFS) and health-related quality of life (QOL).
The NOVA study used progression free survival (PFS) as its primary endpoint. This is an accepted metric for maintenance therapy for advanced ovarian cancer and other metastasized cancers.  Employing PFS instead of overall survival as the primary outcome has the advantage that study completion can be quicker with fewer patients required and it is cheaper. While the NOVA study successfully demonstrated that niraparib helps to stop ovarian cancer returning, it failed to show that the drug reduces health-related quality of life for patients.
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After 20 years of the cancer drug Herceptin is less more?
There is some evidence to suggest that women with ovarian cancer might be willing to accept lower progression free survival for enhanced health-related quality of life. A study published the December 2014 edition of Cancer suggested that women with recurrent ovarian cancer were prepared to trade several months of PFS for reduced debilitating side effects of chemotherapy, which include nausea and vomiting. The most common adverse reactions to niraparib, which affect about 10% of patients, include thrombocytopenia, anaemia, neutropenia, leukopenia, palpitations, nausea, constipation, vomiting, abdominal pain, mucositis/stomatitis, diarrhoea, dyspepsia, dry mouth, fatigue, decreased appetite, urinary tract infection, AST/ALT elevation, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnoea, cough, rash, and hypertension.
 
Ovarian Cancer

Epithelial ovarian cancer accounts for 90% of all ovarian tumours. It typically presents in post-menopausal women and is a significant challenge for gynaecological oncologists since most patients are diagnosed when the disease is already advanced and therefore have a poor chance of survival. The natural history of the disease is characterized by a high response rate to primary treatment of debulking surgery followed by platinum-taxane chemotherapy, which is quickly followed by early recurrence and a second-line treatment with platinum; then most patients experience further platinum-resistance and die from the disease. Although ovarian cancer is relatively rare - based on 2013-2015 data 1.3% of women are expected to contract the disease sometime in their lifetime -  it is the 7th most common cancer in women worldwide. In 2012 there were 239,000 new cases of the disease diagnosed globally. In the UK ovarian cancer is the 5th most common cancer in females, the 2nd most common malignant gynaecological disease and the 1st cause of death from gynaecological malignancy. The UK has one of the highest incidence rates of the disease in Europe, affecting some 7,500 women every year, and its survival rates are among the lowest. Every year 4,100 women in Britain lose their lives to the disease, which equates to about 11 women every day. Over the past 2 decades there has been a slowing of the rate of diagnosis of ovarian cancer in the UK, which is partly due to the large number of women having taken the oral contraceptive pill after it was made available on the NHS in December 1961 and is known to have a protective effect. According to the World Ovarian Cancer Coalition, over the next 2 decades the incidence rates of ovarian cancer worldwide is expected to rise by 55% and by 15% in the UK. This is mainly because: (i) post-menopausal women are living longer, (ii) populations are increasing, and (iii) there is a significant increase in the rate of urbanization.
 
The standard of care for ovarian cancer
 
Although advances in research and technology have contributed additional and sometimes more effective therapy options for women with ovarian cancer such as niraparib and other PARP inhibitors, both the American and European guidelines recommend surgery as the initial approach to ovarian malignancies. After surgery, adjuvant chemotherapy is mandatory in cases of suboptimal debulking, advanced stages, or early stages with a high risk of recurrence. Mike Birrer, Professor of Medicine at Harvard University Medical School, Director of Medical Gynecologic Oncology and also Director of the Gynecologic Oncology Research Program at the Massachusetts General Hospital Cancer Center describes the standard treatment for ovarian cancer. “Ovarian cancer is diagnosed surgically. It’s important that the patient undergoes proper diagnostic and staging procedures. This would include an exploratory laparotomy (a surgical procedure, which involves an incision through the abdominal wall to gain access into the abdominal cavity), which would then evolve onto a staging laparotomy, (to determine the extent and stage of a cancer), which would include a TAH (total abdominal hysterectomy), BSO (bilateral salpingo-oophorectomy, which is when either the uterus plus one ovary and fallopian tube are removed, or the uterus plus both ovaries and fallopian tubes are removed), removal of the ovaries and the uterus. The removal of the omentum (a layer of fatty tissue that covers the abdominal contents like an apron; the procedure to remove it is called an omentectomy, which involves removing the uterus, cervix, fallopian tubes and ovaries), and lymph nodes in the regiterial cavity, scraping of the upper abdomen and then a peritoneal lavage (a procedure to determine if there is free floating fluid, most often blood, in the abdominal cavity). This would give accurate staging for the patient and anything less would be considered less than the standard of care. Once the stage is established and the patient has an advanced stage of the disease, which has spread throughout the abdomen or outside the abdomen, the patient would then undergo further therapy. This would inevitably involve a combination of chemotherapy. The specific regimen would depend, in part, upon the surgical results.”  See video below.
 
 
Current options for ovarian cancer maintenance therapy

In addition to niraparib, current options for ovarian cancer maintenance therapy include bevacizumab and olaparib. The former is a monoclonal antibody designed to block a protein called vascular endothelial growth factor (VEGF). Some cancer cells make this protein and blocking it may prevent the growth of blood vessels that feed tumours, which can stop the tumour from growing. Notwithstanding, bevacizumab can only be given once and improves progression-free survival by just a few months. Olaparib is a PARP inhibitor, which blocks how PARP proteins work in cancer cells that have a BRCA gene mutation. Without PARP proteins, these cancer cells become too damaged to survive and die. In the first instance, olaparib was only approved in patients with a germline BRCA mutation, which accounts for about 10–15% of ovarian cancer patients. In 2014, when olaparib was approved in Europe and the USA, it was the first cancer treatment targeted against an inherited genetic fault to be licensed. Subsequently, evidence suggested that the drug could also benefit patients whose tumours have defects that are not inherited.
 
Non-specific signs and symptoms

The unresolved challenge for ovarian cancer is that in its early stage it rarely presents with any symptoms. Compounding this is the further problem that later stages of the disease may present few and nonspecific symptoms, which are commonly associated with benign conditions. Were ovarian cancer detected in its early stage when the disease is confined to the ovary it is more likely to be treated successfully. Ovarian cancer suffers from another challenge because screening for the disease in not an option, as we explain below. Further, often women do not know what symptoms to look out for and primary care doctors misdiagnose the disease especially in younger women. This results in about 80% of ovarian cancer cases being diagnosed late when 60% have already metastasised, which reduces the 5-year survival rate from 90% in the earliest stage to 30%. Signs and symptoms of ovarian cancer include abdominal bloating or swelling, quickly feeling full when eating, weight loss, discomfort in the pelvis area, changes in bowel habits such as constipation, and a frequent need to urinate.
 

A patient’s view
The 3 primary symptoms of ovarian cancer are bloating, feeling full and pelvic pain. Secondary symptoms include fatigue, bowel and urinary issues. In reality women don’t have all the primary symptoms and they may not have any of the secondary symptoms but may have a combination of the 2. The most prevalent symptom is bloating, especially if it persists. If this occurs women should immediately go to their doctors and ask for a CA-125 blood test. And whatever the outcome of the test they should also insist on a TVUS scan. There is no one easy method of diagnosing ovarian cancer and doctors sometime mistake the symptoms for something less serious like irritable bowel syndrome,” says an ovarian cancer patient. In addition to a pelvic examination, the 2 most frequent diagnostic tests for ovarian cancer are transvaginal ultrasound (TVUS), which puts an ultrasound wand into the vagina to examine the uterus, fallopian tubes and ovaries and the CA-125 blood test, which measures the amount of the protein CA-125 (cancer antigen 125) in your blood.
 
Late diagnosis

According to Christina Fotopoulou, Professor of Surgery at Imperial College London and Consultant Gynaecological Oncologist at Queen Charlotte’s Hospital NHS Trust , “Ovarian cancer is a very silent disease. It has a tumour dissemination pattern of very small nodules spread throughout the whole skin of the abdomen. In the beginning these nodules are so small that they go undetected. The nodules are only detected when they get larger and produce water. So, women with ovarian cancer get abdominal distention and water in their tummies, which prompts them to seek advice from their doctors. But then it’s too late because it’s already at a late stage of the disease.” See video below.
 
 
The ‘bar’ is too high to screen for ovarian cancer
 
Hani Gabra, Professor of Medical Oncology at Imperial College London and Chief Physician Scientist and Head of the Oncology Discovery Unit at AstraZenecaUK supports Fotopoulou and says, “Ovarian cancer is often diagnosed late because in many cases the disease disseminates into the peritoneal cavity almost simultaneously with the primary declaring itself. Unlike other cancers the notion that ovarian cancer goes from stages 1 to 3 is possibly a myth. In reality these cancer cells often commence in the fallopian tube with a very small primary tumour and disseminate directly into the peritoneal cavity. In other words, they go from the earliest stage 1 directly to stage 3, which renders screening a significant challenge. This is compounded by the fact that ovarian cancer is relatively rare in the population. So, to be effective a screening test would have to be extremely sensitive and extremely specific, which it does not have to be for commoner cancers. The combination of these makes screening for ovarian cancer extremely difficult to achieve.”
 
 
Takeaways

Ovarian cancer is a devastating disease, which is diagnosed more infrequently and often at a later stage. Patients are typically older, symptoms are non-specific and easily confused with a number of benign conditions. In its earliest and most curable stage, there may not be any physical symptoms, pain or discomfort. Standard treatment is radical and a harrowing experience for women diagnosed with the disease. About 85% of patients experience a recurrence of the disease after their first treatment cycle, which means that they often face repeated bouts of chemotherapy to keep the disease under control. In a significant proportion of cases even after a second round of chemotherapy the cancer can recur. Previously, at this point patients have had limited pharmacological help, but as research advances, this is beginning to change, and some novel and efficacious drugs are entering the market. Niraparib is one of the latest PARP inhibitors, which has demonstrated efficacy in the treatment of advanced ovarian cancer.
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  • 15 to 20% of breast cancer patients suffer a type of the disease that could benefit from the drug Herceptin
  • Herceptin is very effective and normally administered for 12-months but it is expensive and can cause heart damage
  • New research has found that the treatment period for Herceptin could be reduced from 12-months to 6 without compromising outcomes
  • A 6-month course would reduce the cost of the drug, increase access and potentially reduce the number of patients suffering debilitating side effects
  • The research findings reignited broader concerns about the sustainability of cancer care and the competing interests of patients, producers and providers
  • Herceptin’s patents are expiring and biosimilars are entering the market which is expected to lower costs and increase access
 
After 20 years of the cancer drug Herceptin is less more?

Findings of a phase III clinical study funded by UK government grants and presented at the June 2018 meeting of the American Society of Clinical Oncology (ASCO) suggest that the time a patient needs to spend on Herceptin, (chemical name trastuzumab), a drug widely used to treat an aggressive form of breast cancer, could be halved from 12 to 6 months. This would save insurers, governments, healthcare providers and patients significant sums of money and possibly reduce the incidence of side effects, which can include heart problems.
 
In this Commentary
 
This Commentary: (i) summarizes the findings of the clinical study and some expert reactions to it and (ii) describes the different subtypes of breast cancer and the drug trastuzumab.  The Commentary also broaches a broader concern about the escalating costs of life-saving or life-extending cancer therapies, which show no sign of either slowing or reversing. According to ASCO, in the US, newly approved cancer drugs cost on average US$10,000 per month, with some costing as much as US$30,000 per month. This causes financial hardship for many American patients and their families. In the UK, which has a large devolved public healthcare system, cancer therapies are a postcode lottery because medicines that patients receive depend on whether their local healthcare provider can afford them. In emerging economies, where the prevalence of breast cancer is rising, only a privileged few breast cancer patients have access to trastuzumab. Notwithstanding, patients should gain some comfort from Herceptin’s patents expiring and biosimilar versions of trastuzumab entering the market, which is expected to make the drug cheaper and more accessible.  
 

Breast cancer and HER2

Breast cancer is a heterogenic disease and biomolecular changes in breast cancer involve the expression of genes. The disease is classified according to the 4 subtypes of genes expressed: (i) luminal A, which accounts for 51 to 61% of all breast cancer patients, (ii) luminal B, which accounts for 14 to 16%, (iii) basal-like, which accounts for 11-20% and (iv) the HER2 subtype, which accounts for 15 to 20% of all breast cancer patients and is the focus of this Commentary. Each subtype has different clinical features, different prognoses and different responses to therapies. HER2 protein overexpression is the result of amplification of the HER2 gene and is associated with aggressive tumour growth and consequent high rates of recurrence and mortality in patients. HER2-positive breast cancer is not inherited but is a somatic genetic mutation, which occurs after conception and therefore the new DNA does not enter the eggs or sperm.
 
Trastuzumab the first gene targeted drug
 
Trastuzumab was first approved by the US Food and Drug Administration (FDA) in 1998 and became the first FDA-approved therapeutic antibody targeted to a specific cancer-related molecular marker. The FDA recommended that the drug should be administered for 12 months. Robert Leonard, formerly Professor of Cancer Studies at Imperial College London, UK, and a consultant medical oncologist specialising in breast cancer at the BUPA Cromwell Hospital, the London Clinic and the London Oncology Clinic describes HER2 positive breast cancer and trastuzumab: see video below.  “We like to talk about targeted therapies since we’ve learnt more about the basic biology of cancer, which uses subtle techniques of investigation including biological and immunological profiling of cancers. We now have the ability for new molecules to target specific abnormalities in cancer cells and these can be effective in sublimating standard breast cancer treatments. A good example are Herceptin and Lapatinib, both of which target the HER2 pathway, which is a very important pathway in breast cancer,” says Leonard.
 
Trastuzumab and advanced breast cancer
Trastuzumab’s approval followed 4 randomized clinical studies involving more than 8,000 patients with stages II or III HER2-positive breast cancers. These showed that when trastuzumab was administered for a period of 12 months in combination with or after chemotherapy agents, it potentiated the efficacy of chemo- and immunotherapy; reduced the risk of breast cancer recurrence by approximately 50% and significantly improved survival. In 2000, trastuzumab's use for advanced breast cancer was approved in Europe and has since been approved in a number of countries outside Europe. In 2002 the UK government’s watchdog, the National Institute for Health and Clinical Excellence (NICE), endorsed the use of trastuzumab for advanced HER2 breast cancer.



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Cancer drugs that neither improve nor extend lives


Trastuzumab and early stage breast cancer
Shortly afterwards, trastuzumab expanded its use to early stage HER2 breast cancer. Findings of 2 papers in the October 2005 edition of the New England Journal of Medicine (NEJM), suggested that following initial interventions, a 12-month course of trastuzumab in combination with other agents, could also be a lifesaver for those still in the early stages of breast cancer because it reduced the risk of recurrence and death of patients by 46% compared with chemotherapy alone. In this respect trastuzumab has been viewed as a possible “cure” for early stage breast cancer. Based on these findings, trastuzumab’s approval was extended for the treatment of early stage HER2 cancers. Commenting on the 2 studies in the same edition of the NEJM Gabriel Hortoboagyi, a breast cancer specialist from MD Anderson Cancer Center in Huston, USA, said, “the results reported in this issue of the Journal are not evolutionary but revolutionary. . . . . . trastuzumab and the two reports in this issue will completely alter our approach to the treatment of breast cancer.” In September 2013, a time-saving subcutaneous formulation of trastuzumab was approved in Europe, which can be administered in just 2 to 5 minutes, rather than the standard 30 to 90 minutes intravenously.
 
Was the 12 months treatment time a “guess”?
After regulatory approval in 1998 and following some subsequent clinical studies, a 12-month regimen for trastuzumab became the standard of care. Notwithstanding, some oncologists view the 12-month treatment period as a “guess”, and some smaller trials have questioned the duration of treatment.
 
Clinical study and the 2018 ASCO Meeting
 
The study presented at the 2018 ASCO meeting is the largest and most significant study to-date, which suggests that the treatment time for trastuzumab could be halved. The randomized clinical study followed 4,088 women with early-stage breast cancer across 152 sites in the UK for a median of more than 5 years: 2043 received trastuzumab for 6 months and 2045 received the drug for 12 months. The disease-free survival rate at 4 years was 89.4% with 6 months of therapy and 89.8% with 12 months of therapy. In addition, 4% of patients on the shorter treatment dropped out due to cardiac toxicity versus 8% of those treated for a year. Across both groups, cardiac function recovered within a few months following treatment with trastuzumab but patients in the 6-month group recovered more rapidly.

Helena Earl, Professor of Clinical Cancer Medicine at the University of Cambridge, UK and the study’s lead investigator is confident that the study will, “mark the first steps towards reduction of treatment duration for many women with HER2-positive breast cancer." According to Richard Schilsky, ASCO’s Chief Medical Officer, “There’s no reason to not immediately change practice. The findings are persuasive”.

 
Expert reaction to the study

Although oncologists view the study’s findings as “persuasive”, changing the length of treatment time for trastuzumab might not occur quickly. Generally, clinicians appear hesitant to immediately support a shorter duration of trastuzumab as a new standard of care. Some believe that since so few women have died or relapsed after being treated with trastuzumab, longer follow-up may be required to make sure the findings hold up before guidelines are changed. 

My guess is that people will continue to aim for a year of treatment' because of lingering concerns that longer use is better, as a smaller previous study suggested,” says Harold Burstein, a breast cancer expert at the Dana-Farber Cancer Institute in Boston, USA. However, Burstein is mindful that a shorter treatment regimen might increase access to trastuzumab for patients in emerging economies where the prevalence of breast cancer is increasing but where many women cannot afford a 12-month treatment course of the drug.  Other experts suggest that the study’s findings are significant for women who suffer the toxic effects of trastuzumab.

Jennifer Litton, a breast cancer specialist at MD Anderson Cancer Center points to another issue the ASCO study raises. She suggests the study’s findings show just how important it can be to study drugs that are already on the market. “It's really important that we continue to have public funding for clinical trials, so we can continue to ask all of these questions for our patients. Scaling back treatment whenever possible is important to patients,” says Litton.

Industry response
A spokesperson for Roche Genentech, Herceptin's developers, suggested that the ASCO study should be viewed along with several smaller studies, which conclude that the optimum duration for trastuzumab is 12 months. The goal of the treatment, “is to provide people with the best chance for a cure.” Courtney Aberbach, a spokesperson for Genentech, which was acquired by Roche, in March 2009 for US$$46.8bn, suggested that previous studies had not found that a shorter duration worked as well as the longer one. She said the 12-month course was still the only regimen approved for early-stage disease by the FDA and recommended by several international organizations that issue treatment guidelines.

The HERA Trial
Industry views are influenced by a clinical study sponsored by Roche in the expectation that the 12-month trastuzumab treatment period could be doubled. Referred to as the HERA trial, the study was conducted by France's Institut National du Cancer and reported at the 2012 meeting of the European Society for Medical Oncology (ESMO). HERA was an international multi-centre, phase III randomized study involving 5,102 women with early HER2-positive breast cancer. After finishing primary therapy with surgery, chemotherapy and radiotherapy, they were randomly assigned to trastuzumab therapy every 3 weeks for 1 year, 2 years or observation.
 
In April 2012, when the study’s findings were presented at the ESMO meeting, the overall survival rate of the 24-month treatment cohort versus the 12-month cohort was comparable. The principal conclusion of the study was that 12-month treatment remains the standard of care for HER2 positive early breast cancer patients. Results also suggested that shortening treatment of trastuzumab to 6 months may offer a worse result than a 12-month course of treatment. While the study’s findings meant that Roche missed an opportunity to expand sales of trastuzumab on the back of a longer recommended treatment period, they were also a relief to the company, which had faced the risk of losing significant sales revenues from trastuzumab had a shorter treatment period turned out to be as effective as the current standard of 12-months.
 
Unsustainable of cancer care

Cancer treatment has always been expensive, but the costs of newer molecular targeted therapies, such as trastuzumab, have escalated, which significantly reduces access for a lot of breast cancer patients to efficacious drugs. According to a 2015 study by the US National Bureau of Economic Research, each year between 1995 and 2013 the prices of cancer drugs increased 10%. This finding led some health professionals to suggest that cancer therapies are becoming “unsustainable”. In England, NICE has come under intense criticism from patient groups for rejecting numerous cancer drugs for use on the NHS because they were not judged to be cost effective. The UK’s Cancer Drugs Fund, which was set up in 2011 to plug gaps in NHS funding for cancer drugs, overspent its allocated budget by 35% between 2013 and 2015. The debate of the rising cost of cancer therapies is exacerbated by the revenues generated by cancer drugs for big pharmaceutical companies. For example, in 2017 Roche-Genentech recorded annual sales of US$6.8bn for Herceptin alone, which some analysts suggested was driven partly by the duration of the treatment and partly by strong sales growth of the drug in Brazil and China.

When vast revenues from the sale of drugs are mentioned there is negative reaction directed at giant pharmaceutical companies. In their defence drug producers stress the vast costs of developing new drugs and the tenure of patents, which limit the time drug companies have to recoup R&D costs before copycats are introduced into the market. According to the most recent report from the Tufts Center for the Study of Drug Development, and published in the May 2016 edition of the Journal of Health Economics; the cost of developing a medicine from invention to pharmacy shelves is estimated to be some US$2.7bn. Patents protect drugs for 20 years after the initial invention. This exclusivity is designed to promote a balance between new drug innovation and greater public access to drugs, which result from copycat versions.  Notwithstanding, big pharmaceutical companies stress that it can take 8 to 12 years after invention to accumulate enough data to get a drug past the FDA.
 
Biosimilars

For 20 years now Roche-Genentech has benefited from its 90% market share of the HER2-positive global breast cancer market. Notwithstanding, the main EU patent for Herceptin expired in 2014 and is due to expire in the US in 2019. Already, the market has experienced the entry of biosimilar versions of trastuzumab, which are expected to be cheaper and therefore extend patient access to the drug. Biosimilars are not to be confused with generic drugs. Regulators require biosimilars to be “highly similar” to the “reference product” but not exact copies of the biologic medicine. Biologic medicines are comprised of large complex molecules, which may be composed of living material. Here we provide some examples of the biosimilar versions of trastuzumab, which are coming onto the market.
 
Trastuzumab biosimilars
 
In December 2017, a biosimilar version of trastuzumab was approved by the FDA and is marketed in the US as Ogivri. Approval of Ogivri was based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data and other clinical safety and effectiveness data, which demonstrated that Ogivri is biosimilar to trastuzumab. In 2018, Merck Sharp and Dohme (MSD) launched Ontruzan, in the UK, which is Europe’s first biosimilar to Herceptin. Clinical studies have shown Ontruzan to be similar to trastuzumab in terms of its structure, biological activity and efficacy, safety and immunogenicity profile. Studies also showed that in early breast cancer, breast pathologic complete response rates were 51.7% with Ontruzant and 42% with Herceptin, while overall response rates were 96.3% and 91.2% respectively. Mylan and Biocon have launched a biosimilar version of trastuzumab called Canmab in India, and Celltrion, has launched Herzuma, another biosimilar version of trastuzumab in South Korea. According to Mark Verrill, head of the Department of Medical Oncology at the Newcastle upon Tyne Hospitals NHS Foundation TrustUK, “The launch of biosimilar trastuzumab provides a high-quality treatment alternative for patients, while offering significant potential savings for health providers and patients.”
 
Takeaways
 
The clinical study presented at the June 2018 meeting of ASCO suggested that the treatment time for trastuzumab could be reduced from 12 months to 6 without compromising outcomes. This would significantly reduce the cost of trastuzumab and thereby make the drug available to more breast cancer patients. Although the study’s findings are “persuasive” there is a reticence among clinicians to reduce the treatment time of trastuzumab. The ASCO study throws light on the challenges to reconcile the competing interests of patients, healthcare providers and drug companies. While pharmaceutical companies spend billions on R&D they are challenged to reconcile the demands of shareholders and society. Public funds for medical research, while important, are limited especially at a time of relatively slow economic growth and fiscal constraint. Given that there does not appear to be any credible suggestion to curtail the vast and escalating cost of cancer care more generally, the current situation, which incentivises giant pharmaceutical companies to invest in R&D with 20-year patents, appears to be a formula that will prevail for some time to come, and patients will have to wait significant lengths of time before they get access to biosimilars.  
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  • A Lancet study suggests moderate alcohol use over time can “significantly shorten your life
  • Experts call for the study’s findings to be widely disseminated and discussed
  • A 2010 Lancet study suggested alcohol is more harmful than heroin or crack cocaine
  • Alcohol related harm is a global epidemic caused by a commercial product
  • There are 3.3m deaths each year caused by alcohol use
  • Policies to reduce the harmful effects of alcohol are palliative rather than preventative
  • A few giant alcohol beverages corporations dominate the global market
  • But 50% of the market is in the hands of informal small-scale producers
  • There is a dearth of reliable information on the alcohol beverages industry
  • Public health research has not kept up with the industry’s ability for innovative marketing
  • British drinkers contribute more in alcohol-related taxes than the direct costs of alcohol-related health and crime issues
  
Moderate alcohol use can kill
 
Just when you thought you knew everything there is to know about the harmful effects of alcohol, a study published in the April 2018 edition of The Lancet, brings new evidence to suggest that even modest alcohol use over time is as dangerous as smoking and can “significantly shorten your life”.  The study reinforces the fact that alcohol-related harm is a ‘global epidemic’ caused by a commercial product, which is aggressively marketed throughout the world. Policies aimed at reducing the harmful effects of alcohol have a limited effect and alcohol use continues to be a significant challenge to medicine and society.  
 
In this Commentary

This Commentary discusses some of the reasons why public policies to limit alcohol use fail to dent the vast and escalating burden caused by alcohol use. We begin by describing the findings of The Lancet 2018 study, which highlights the association between regular modest drinking and early death. The study’s findings motivated healthcare professionals to renew calls for lower limits on alcohol use. A study published in The Lancet in 2010 suggested alcohol is more harmful than heroin or crack cocaine. Public policies to reduce the harmful effects of alcohol use are compromised by the competing interests of the principal industry stakeholders. Such policies tend to be orientated towards the demand side of the market and focus on individual consumers and are less engaged with the supply side and large producers. This results in: (i) public policies that are more palliative than preventative, (ii) alcohol use continuing to be a major healthcare and social challenge, (iii) giant alcohol beverages producers receiving a “free pass”, and (iv) governments enhancing their “political capital” by pointing to the millions spent to correct the drinking habits of vulnerable individuals. This ecosystem is further influenced by: (i) the duty and tax revenues governments collect from alcohol use, (ii) public research failing to keep pace with the sophisticated marketing strategies of large drinks companies, and (iii) well resourced, and smart producers’ marketing strategies out-maneuverering government bureaucracies in endeavours to influence the tastes and preferences of individuals.
 
The Lancet study

The contribution of alcohol use to premature death is less well recognised than the connection between smoking, lung cancer and early death. The Lancet 2018 study helps to redress this by improving on previous meta-analyses to define low-risk drinking thresholds, and to suggest that people who consume more than 7 drinks a week can expect to die sooner than those who drink less. According to a February 2018 World Health Organization (WHO) report, an estimated 3.3m people a year worldwide die as a result of alcohol misuse. The harmful effects of alcohol ranks among the top 5 risk factors for disease, disability and death globally, and alcohol misuse is the 5th leading risk factor for premature death and disability worldwide. Most people who die because of their drinking patterns are not alcoholics, but are people who drink regularly over a number of years.
 
The Lancet 2018 study is significant because of its size and methodological robustness.  There is a high degree of comparability in the datasets used by the authors, which combined data from 83 previous studies undertaken in 19 countries, which yielded a cohort of 600,000 current drinkers for analysis. The previous studies used by the researchers to attain their cohort employed similar methods to quantify alcohol use, cardiovascular risk factors, and cardiovascular disease outcomes and cause-specific deaths. All participants in the cohort were from developed industrial economies, displayed similar patterns of alcohol use and none had a known history of cardiovascular disease.
 
The study’s findings imply that drinking alcohol is as harmful as smoking and suggest that there is a significant increase in all causes of death when more than 100g of alcohol (equivalent to about 4 large glasses of wine) is consumed weekly over a period of time. Every glass of wine or pint of beer over the daily recommended limit - the upper “safe” limit in the UK is 5 standard 175ml glasses of wine or 5 pints of beer a week - will cut 30 minutes from the expected lifespan of a 40-year-old and increase the risk of stroke, fatal aneurysm (a ruptured artery in the chest), heart failure and death. A 40-year-old who drinks up to twice that amount (200g or 8 large glasses of wine per week) will shorten their life expectancy by 6 months. Drinking between 200g and 350g (8 to 20 large glasses of wine) a week will reduce their life expectancy by 1 to 2 years, and 40-year-olds who drink more than 350g (>20 large glasses of wine) a week over a period, shorten their lives by 4 to 5 years.
 
Lowering the recommended limits of alcohol consumption
 
According to Angela Wood, from the University of Cambridge in the UK and lead author of the 2018 study, “The key message of this research for public health is that, if you already drink alcohol, drinking less may help you live longer and lower your risk of several cardiovascular conditions.” Although moderate drinking is commonly associated with reducing your chance of a non-fatal heart attack, “This must be balanced against the higher risk associated with other serious, and potentially fatal cardiovascular diseases,” says Wood. According to the researchers the study’s findings support, “limits for alcohol consumption that are lower than those recommended in most current guidelines [and add] long-term reduction of alcohol consumption from 196g per week (the upper limit recommended in US guidelines) to 100g per week or below was associated with about 1–2 years of longer life expectancy at age 40 years”. Co-author Naveed Sattar, Professor of Metabolic Medicine at the University of Glasgow’s Institute of Cardiovascular and Medical Science in Scotland said: "This study provides clear evidence to support lowering the recommended limits of alcohol consumption in many countries around the world."

 
Experts call for lower limits on alcohol use

Commenting on the study’s findings, Tim Chico, Professor of Cardiovascular Medicine at the University of Sheffield,UK, said, smokers lose on average 10 years of their life. “However, we think from previous evidence that it is likely that people drinking a lot more than 43 units (about 14 large glasses of wine a week) are likely to lose even more life expectancy, and I would not be surprised if the heaviest drinkers lost as many years of life as a smoker. . . The study makes clear that on balance there are no health benefits from drinking alcohol, which is usually the case when things sound too good to be true.”

In a commentary in the same edition of The LancetJason Connor and Wayne Hall both professors from the University of Queensland Centre for Youth Substance Abuse Research in Australia, anticipated that the suggestion to lower recommended drinking limits would be opposed by giant alcohol beverages corporations. “The drinking levels recommended in this study will no doubt be described as implausible and impracticable by the alcohol industry and other opponents of public health warnings on alcohol. Nonetheless, the findings ought to be widely disseminated and they should provoke informed public and professional debate,” say Connor and Hall.

 
A 2010 study published in The Lancet claims alcohol is more harmful that heroin

In the November 2010 edition of The Lancet David Nutt, Professor of Neuropharmacology at Imperial College London and co-author of the study suggested that alcohol is more harmful than heroin or crack cocaine when the overall dangers to the individual and society are considered. Nutt was the clinical scientific lead on the 2004-5 UK Government Foresight initiative “Brain science, addiction and drugs”. The Lancet 2010 study suggested that if drugs were classified on the basis of the harm they do, alcohol would be a class ‘A’ drug, alongside heroin and crack cocaine. In 2006 Nutt was dismissed for challenging the UK Government’s refusal to take the advice of the official Advisory Council on the Misuse of Drugs,  which he then chaired.

In answer to The Lancet 2010 study a UK government Department of Health spokesperson said: "In England, most people drink once a week or less. If you're a woman and stick to 2 to 3 units a day, or a man and drink up to 3 or 4 units, you are unlikely to damage your health".
No agreed international limits for alcohol use
 
The reality is that there are no internationally agreed limits on alcohol use and current recommended limits vary significantly between nations. In a study published in the June 2012 edition of the Drug and Alcohol Review  researchers from the University of SussexUK, examined government issued guidelines on alcohol limits in 57 countries and found, “a remarkable lack of agreement about what constitutes harmful or excessive alcohol consumption on a daily basis, a weekly basis and when driving”.

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Alcohol use and dementia

In 2016 the UK Government updated its 1995 guidelines  for limits on alcohol use and recommended that neither men nor women should drink more that 14 units of alcohol per week. A unit in the UK is equivalent to 8g of pure alcohol. This means British men are now being told they should drink less than those in Ireland (21.2 British units), Denmark (21), New Zealand (19) and considerably less than the recommended upper limit for men in Spain (35).
 
 
The supply side of the alcohol industry

Current public policies and industry pledges
Although public policies to reduce the harmful effects of alcohol use are aimed at both the individual and population levels, they tend to orientate towards individual problem drinkers. Among the most effective policy options are alcohol taxes, restrictions on alcohol availability and drink-driving countermeasures. The giant alcohol beverages corporations advocate responsible drinking and pledge their commitment to, “supporting balanced initiatives that are linked to their core business functions and those that address wider social and public health issues, relying on initiatives that are evidence based, culturally sensitive, and collaborative.” The drinks producers support the WHO’s Global Strategy to reduce the harmful Effects of Alcohol, and are committed to: (i) reducing under-age drinking, (ii) strengthening and expanding marketing codes of practice, (iii) providing consumer information and responsible product innovation, (iv) reducing drinking and driving, and (v) enlisting the support of retailers to reduce harmful drinking.  

Growth of service economies and the importance of individual preferences
Despite public policies and industry pledges to limit alcohol use, the large and escalating burden of alcohol problems continue to present significant challenges to medicine and public health. In part, this is because population-based public health policies tend to be overlooked in favour of policies oriented towards individual drinkers. This orientation can be explained by globalization.
 
Over the past 40 years globalization has shifted the economic base of developed nations from manufacturing to services, which places greater emphasis on consumer markets and individual preferences. In such a context, efforts to reduce the harmful effects of alcohol use are mainly focused on the demand side of the market, emphasising individual behaviours and preferences; and less focused on the supply side, which is dominated by producers. As a consequence, public policies to limit alcohol use tend to focus on the choices of vulnerable individual drinkers and call for responsible drinking. In effect this provides producers with a “free pass” to pursue and develop their strategies to sustain consumption.
 
50% of alcohol production is in the hands of “informal” small producers
Shifting the policy emphasis to focus equally on the demand and supply side of the alcohol beverages market is not straightforward. Although nearly half of the of the world's alcohol supply is dominated by giant producers, more than 50% is in the hands of ‘informal’ home and local producers. At the national level the industry comprises large and small beer, wine or spirit producers or importers, as well as bars, restaurants and a variety of retail outlets, which markets alcohol to the public. These players have diverging interests as well as interests in common in regard to policy frameworks. There is a dearth of reliable information on the industry and the principal sources of information come from market research firms and business journalism.  
 
Large global fast-growing market
The alcohol beverages market is large, global and fast growing. According to an April 2018 report by Transparency Market Research, in 2017 the market was worth US$1,205bn and is expected to expand at a CAGR of 6.4% and reach US$2,000bn by the end of 2025. Recent consolidation in the industry puts a significant and increasing proportion of alcohol production, distribution and marketing in the hands of a few giant corporations, which dominate national, regional and global markets and wield considerable political influence. Mergers and acquisitions are expected to continue, so the consolidation of the industry is expected to continue.

The market is driven by increasing urbanization, the global young-adult demographic, high and growing disposable incomes and increasing consumer demand for premium and super premium beverages. The latest figures suggest that the average alcohol use in the UK is about 9.7 litres per adult, which compares with 8.8 litres for adults in 34-member countries of the Organisation for Economic Co-operation and Development  (OEDC), and ranks the UK 16th out of the OEDC countries. Since 1970, alcohol consumption has decreased by an average of 15% across OEDC countries, while in the UK it has risen 14% over the same period. Alcohol use has declined 69% in Italy, 48% in France, 36% in Spain and 30% in Germany, but has increased 51% in Ireland. Consumption of alcohol per head in the UK has fallen by about 17% since its recent peak in 2004. But that followed a steep rise.

A study reported in 2015 in the International Journal of Advertising suggests that advertising has little impact on how much we drink, but it is effective at influencing what we drink. ‘Premiumization’ is a term used in the industry to describe how spirit brands have had success convincing consumers that they should drink “higher quality” and more expensive beverages. An example of this is the recent boom in the sale of gin, which corresponded with the industries premiumization strategies that linked gin with “fashionable” early 20th century style.
 
UK alcohol taxes far exceed the costs to public services
 
The “free-pass” enjoyed by alcohol beverages corporations is strengthened by the relative lack of public scrutiny they receive. This might be partly explained by the fact that governments benefit significantly from alcohol related taxes and duty. Consider Britain. In 2016 the UK government made nearly £3.4bn in tax revenue from spirits; beer sales made the UK government £3.3bn in 2017. Some 60% of the price of a pint of beer is taken in VAT and alcohol duty, while VAT on the price of a bottle of gin is 76%. Wine is the biggest earner for the UK exchequer yielding over £4bn in taxes from sales in 2016. These sums accord with a September 2015 Institute of Economic Affairs (IEA) study on alcohol taxes, which suggests that the annual revenue generated from alcohol taxes in the UK is  “illogical and excessive.”  Rather than tax alcohol the UK government taxes drinks. For instance, a unit of alcohol is taxed at 28p if it happens to be in a glass of whisky but only 8p if it is in a pint of cider. Further, if the cider is strong, the tax is 7p but if it is fizzy the tax is 34p. The tax on a unit of alcohol in a glass of wine is 20p, but if wine is sparkling, the tax is 25p. Confused? The structure of alcohol excise taxes is partly restricted by an EU Directive, which sets out different tax rates for different alcoholic beverages.

Revenues from UK alcohol taxes and duty far exceed the actual direct costs of alcohol-related health and crime issues. According to the IEA study, the UK exchequer collects about £10bn a year in alcohol taxes while the direct costs of alcohol related problems to the health, police, prison services, welfare system and judiciary, amount to some £4.6bn per year. Although studies that report cost-of-alcohol data are notoriously unreliable, the IEA suggests that British drinkers contribute about £6.5bn each year to the UK exchequer and believes that, even within the current constraints, the UK tax system could more effectively target problem drinking. In a February 2017 paper the IEA describes a suggested reform of the UK’s alcohol tax policy.

 
Takeaways
 
Findings of the 2018 study published in The Lancet suggest that risks from alcohol start from any level of regular drinking and rise with the amount being consumed and any amount of regular alcohol use can significantly shorten your life. This echoes a 2010 study also published in The Lancet, which suggested that because alcohol is so widely available it is more harmful than heroin and crack cocaine.

This commentary reaffirms the global epidemic of disease, injury, social problems and death caused by alcohol and suggests an explanation why for decades governments have failed to effectively limit alcohol use.
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