Ius Gentium

University of Baltimore School of Law's Center for International and Comparative Law Fellows discuss international and comparative legal issues


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International Clinical Trials: Shaky Grounds for Bioethics

Jasen Lau

Isai in the Moldavian region of Romania, Megrine in northern Tunisia, Tartu in Estonia, and Shenyang in Northern China all have something in common. Unfortunately, they are not the world’s best vacation spots. No, large pharmaceutical companies have targeted these locations as places to run clinical trials.[1] These towns are among many similar towns – poor, distant, and isolated from major cities – that are often favored by many pharmaceutical companies. This recent globalization of clinical trials has raised many questions about both the ethics and efficacy. As international clinical trials grow in popularity, serious consideration needs to be given to the bioethics of conducting such trials in developing countries.

Clinical trials are the backbone of pharmaceutical development. The Food and Drug Administration (FDA) requires them before a drug can be marketed to the public.[2] Clinical trials are often broken into four segments – Phase I, II, III, and IV – and are used to assess the safety and efficacy of the developing drug.[3] Phase I begins with a smaller sample – usually around 20 to 30 people – and is the most dangerous part of the trials.[4] Phase I is where the level of safety and efficacy of the medication is mostly unknown. As the trials progress to Phases II and III, so, too, do the number of participants. Phase IV is post-market observation.[5] This phase monitors the drug after it has been released and is meant to document what effects arise from large-scale use. Clinical trials are meant to uncover the dangers and risks of medication, but this procedure can often take a lot of time and money.

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Most clinical trials can take around a decade.[6] During such time, costs can be around $2.6 billion – not including post-market procedures.[7] These costs come from advertising, subject compensation, and general research procedures, like conducting international clinical trials. With such high costs, many pharmaceutical companies seek to lower costs. International clinical trials have been very popular since 2008.[8] Currently, roughly 60% of the clinical trials being conducted are recruiting research subjects outside of the U.S.[9] By conducting trials overseas, pharmaceutical companies are saving vast amounts of money. For example, in India, a case report from a “first-rate” research center costs $2,000, which is less than one tenth the cost of recreating that same report in a “second-tier” research center in the U.S.[10] This is where the research subjects from developing countries come into play.

In nations where income is low[11], the chance of receiving state of the art medicine is a welcomed opportunity. However, in these remote locations where the US holds no jurisdiction, what assurances do these subjects have that they will be treated fairly? The Nuremberg Code requires basic ideas such as voluntary consent, maximizing benefits while minimizing costs, and taking patient care as first priority.[12] In addition, the Declaration of Helsinki expands upon this and includes the idea of protecting vulnerable populations (the elderly, incarcerated, pregnant, and children), a duty to protect the integrity of the patient, ensuring that those who are harmed are compensated.[13] These codes are meant not just for the U.S. but the global practice of medicine. It is important to note, however, that these ethical guidelines are precatory – not mandatory. Further, prior to the start of the trial, research groups must submit their proposal or application to an Institutional Review Board (IRB). These IRBs are comprised of both medical and non-medical staff that determine the safety of the trial and ensure the welfare of the test subjects.[14] While these protections are in place, the question becomes to what extent and how thoroughly do these guidelines and procedures protect the subject?

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Informed consent is one of the many things required when conducting research. Without going too deeply into the nuances, what true choice do these subjects from developing countries have? Even in a developed country, such as the U.S., many scholars have speculated the true need for informed consent in the practice of medicine.[15] In the end, in part due to the extreme disparity in medical knowledge expertise between subject and researcher or patient and doctor, the subject is more or less consenting to the trustworthiness of the doctor – not the actual procedure. Likewise, the subjects of these nations may not truly be consenting to the research procedure. Rather, their need for medical care at no cost to them greatly incentivizes assent. If that is the case, what point is there, then, in informed consent for these kinds of subjects?

IRBs play a key role in approving clinical trials. However, they are American citizens. Their job is to determine if the trials are ethical and take patient welfare into consideration, but they are not present to routinely monitor the clinical trials.[16] Even the FDA, those who ultimately approve a drug based on these trial results, do not inspect all – nor even a significant number of – these international clinical trials. In fact, the FDA inspects only around 0.7% of such trials.[17] If an IRB is not physically present to protect patient welfare, and the FDA seldom inspects these trials, who is actually protecting these test subjects?

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With the benefits of a relatively large population, all of whom are nearly always willing to partake in studies, and being outside the jurisdiction of the FDA, pharmaceutical companies are greatly incentivized to conduct their research outside of the U.S. There is concern that this will eventually lead to more harm than benefit. There is no assurance that researchers will abide by ethical guidelines, and even if the researchers practiced according to those guidelines, harm can still come to the subjects. When a test subject is harmed, where are they to turn for treatment? Or does this globalization turn a cold shoulder to international research subjects? Further, if the medication is mostly tested on international citizens, whose diets, lifestyle choices, and environmental factors greatly differ from American citizens, how safe is the medication for the average American?

 

The unfortunate conclusion to these rhetorical questions is that clinical trials are growing ever more appealing. While there is not yet currently any solid argument for harm, the obvious threat looms over subjects from developing countries. Such subjects, in need of modern western medication, may not be able to give informed consent to research. Yet, without these treatments, some of these subjects will be no better off than before. Globalization of clinical trials leads to a plethora of bioethics issues, and as it often is with bioethics, there is rarely a concrete answer now nor will there be one in the near future. Adding on the increased complexity of international jurisdiction, the question is whether these American pharmaceutical companies should be made more responsible, and if so, who should – or can – enforce that kind of duty or even impose it? The best thing that can be done at the moment is consistent, thorough analysis of all clinical trials. At the very least, the FDA should increase investigation of these international trials. The future merely holds a balance of powers and desires: cost-saving options for pharmaceutical companies and the bioethics thereof versus the length of reach of FDA’s regulatory authority.

Jasen Lau is a third year law student at the University of Baltimore School of Law. He graduated from the University of Maryland in 2013 with a Bachelor of Arts in English. Jasen took it upon himself to become a certified pharmacy technician and studied several continuing education credits that focus on Medicare Fraud and Abuse prevention, HIPAA privacy and security laws, and ethics in the pharmacy workplace. Jasen has long been in the health care field either working directly with patients or as an assistant to providers. During that time, his obsession with working in health care has grown into policy analysis and counseling. Along with being a CICL fellow, he is also a law clerk for Johns Hopkins Hospital.

[1] Donald Barlett & James Steele, Deadly Medicine, Vanity Fair, Jan. 2011, http://www.vanityfair.com/news/2011/01/deadly-medicine-201101.

[2] Step 3: Clinical Research, U.S. Food and Drug Admin., Nov. 23, 2015, http://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm.

[3] Id.

[4] Id.

[5] Id.

[6] Cost to Develop and Win Marketing Approval for a New Drug is $2.6 Billion, Tufts Ctr. for the Study of Drug Dev., Nov. 18, 2014, http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd_2014_cost_study.

[7] Id.

[8] Daniel Levinson, Challenges to FDA’s Ability to Monitor and Inspect Foreign Clinical Trials, Dept. of Health & Human Serv., June 2010, http://oig.hhs.gov/oei/reports/oei-01-08-00510.pdf.

[9] Trends, Charts, and Maps, ClinicalTrials.gov, February 2016, https://clinicaltrials.gov/ct2/resources/trends (54% of the studies are recruiting exclusively outside the U.S. while an additional 6% is recruiting both in and out of the U.S.).

[10] Seth Glickman et al., Ethical and Scientific Implications of the Globalization of Clinical Research, 360 New Eng. J. Med. 816 (2009).

[11] Romania Average Salaries & Expenditures, World Salaries, (Feb. 26, 2016), http://www.worldsalaries.org/romania.shtml (Prices have been converted to U.S. currency for ease of understanding. A dentists average salary is less that $500 a month, engineers make about $700 a month, and physical therapists makes just over $400); see also China Average Salaries & Expenditures, World Salaries, (Feb. 26, 2016), http://www.worldsalaries.org/china.shtml; Occupational Employment and Wages, May 2014, Bureau of Labor Statistics, Mar. 25, 2015, http://www.bls.gov/oes/current/oes291021.htm; see also Occupational Employment and Wages, May 2014, Bureau of Labor Statistics, Mar. 25, 2015, http://www.bls.gov/oes/current/oes291021.htm (The average salary of dentists and physical therapists is about $14,000 monthly and $6,800 monthly, respectively).

[12] The Nuremberg Code, U.S. Dept. Health & Human Serv., Nov. 7, 2005, http://www.hhs.gov/ohrp/archive/nurcode.html.

[13] WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects, World Med. Ass’n, (Feb. 26, 2016), http://www.wma.net/en/30publications/10policies/b3/.

[14] Clinical Trials, MedlinePlus, January 28, 2016, https://www.nlm.nih.gov/medlineplus/clinicaltrials.html.

[15] Peter Schuck, Rethinking Informed Consent, 103 Yale L.J. 899, 1994.

[16] Glickman, supra.

[17] Levinson, supra at 15.

 

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Research and Public Welfare: Working with the French, We Can Have Our Cake and Eat It Too!

Jasen Lau

The US healthcare system is a system that ultimately prioritizes research. However, that is not to say we cannot have public universal healthcare. No system can offer absolute public welfare without taking away funding from research, but there can be a system that doesn’t take away as much. Keeping the research oriented priorities in mind, the US can still adopt a sort of inverted French healthcare system to provide public universal healthcare without significantly hindering medical and pharmaceutical research.

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The World Health Organization praised France for having the best healthcare system in the world[1]. Indeed, they are often touted as having the closest to perfect system in terms of patient satisfaction[2], and their system works because it is regulated but not socialized. The French healthcare system is delivered through their Social Security(SS), and financing their SS works much like ours; much of the money for SS comes from income and payroll taxes. This money is then used to insure patients through general funds, and this general fund covers around 70% of all expenses[3]. The rest of the amount owed is either paid out of pocket or through the more popular choice of voluntary insurance. This voluntary insurance works much like the private payer of the US and is often offered through employment. So, on paper, it seems that the French have most or even all of their healthcare costs covered, which is true[4]. However, the French government plays a big role in these prices.

Unlike the US, the French regulate and control the costs of medical services, products, and pharmaceutics. For example, doctors are often paid much less in France than the US[5]. So, these lowered costs are more easily covered by both the public insurance and the voluntary insurance. Therefore, to follow any model of the French healthcare system, some regulation of costs would be necessary. For the US, and to preserve the goal of research rather public welfare, absolute regulation is not necessary – just some to limit the financial burden on the government.

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Rather than having SS pay for the majority, the US could complement private insurance. Of course, this would require that the person have insurance in the first place, now mostly possible due to the Affordable Care Act (ACA) and its individual mandate, requiring everyone to have insurance or suffer penalties. Therefore, the US need only cover the gaps not paid by the private insurer. Further, the US government would also have to regulate either insurance payment or cost. To avoid significantly hindering research in the US, regulating insurance payments would not interfere with funding research. To regulate costs means to ask physicians, medical technology manufacturers, and pharmaceutical companies to relinquish money from funding in order to serve the public welfare. Thus, the US can adopt an inverted French healthcare system and regulate insurance companies to achieve a public universal healthcare.

With the ACA requiring everyone to have insurance, the first step of this proposal is met: almost everyone will have some level of insurance. The person will have their choice of what insurance to get, but to get people to choose the right insurance, the patient will have to pay premiums and some amount of copayment for services. After all, if there is absolutely no cost to the patient, everyone in the nation will, undoubtedly, choose the best – and often most expensive – coverage policy. However, if that is the scenario, that the patient should able to afford such prime insurance that all needs and wants are fully covered, then there is no need for that patient to be a part of the supplemental SS insurance. Perhaps, in those situations, a tax break could be offered. Otherwise, SS can then pay for coverage gaps in a person’s private insurance, and such funding will come from where it always has: mainly payroll and income taxes and, if need be, subsidy by other government bodies. Now, the SS payment need not cover all copayments or costs. In France, patients still have copayments, though they may simply be an extraordinary low[6]. The US can and should follow suit. The key costs to keep would be insurance premiums. To avoid excessive costs to both the healthcare system as a whole and to the supplemental SS system, patients should be made aware to buy only what is necessary to their needs. This, again, is to emphasize the concern patients must establish in choosing healthcare. Putting in baseline copayments – even if nominal – will tell the patient what can be considered a costly or non-preferred treatment.

There will need to be some insurance regulation. For if there is no insurance regulation, insurance companies court contract with providers to let the federal government bear the financial burden instead of the private insurance. So, there has to be some regulation that deters or otherwise prohibits insurance companies from diverting costs from themselves. There can be no solid solution without great deliberation, but a good starting point would be a percentage coverage regulation. Such a regulation would require that the insurance cover some reasonable amount that does not greatly deviate from what they would cover had the patient not have a federal gap coverage plan. As for physicians, reimbursement rates would be on par with Medicaid or medicare reimbursement rates, relatively low[7]. On that note, this plan would take the place of Medicare but not in the place of Medicaid. Like the US Medicaid, French Social Security offers healthcare to those who are poor[8]. The poor would not have the option to purchase private insurance to later be supplemented by SS coverage. Medicare however, is not inherently for the poor, merely the elderly, the permanently disabled, and those with end-stage renal disease.[9] So, Medicare should be replaced with this proposed private-SS coverage plan.

The general French system offers coverage for those who have worked. Those who are poor or have not worked at all are given a special fund for their coverage, often subsidized by the wealthy and working. Implementing this in the US, states could keep their Medicaid, of which the federal government subsidizes. However, Medicare will be eliminated and replaced with this proposed inverse French Healthcare system. Though, no significant harm shall come of this. Private insurance companies can and will step in to cover seniors with specific plans designed to cater to the medical needs of the elderly. In fact, much of that already occurs now. Medicare Part C is a plan handled almost exclusively by a private insurer instead of Medicare. When an elderly patient needs a plan that caters to their personal needs – of which Medicare cannot meet – patients are able to seek out Medicare Part C plans through private insurers[10]. Therefore, this inverted French plan is no different than putting every elderly person on Medicare Part C. There are, however, some elderly patients who are unable to afford private insurance. In the US, about 10% to 11.5% of those above 65 live below or at the poverty line[11]. For those patients, Medicaid would apply. This way, the vast majority of the population will be covered without extensive inhibitions to research funding.

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An inverted French healthcare system can benefit the general welfare of the US. Granted, this does come at a slight cost to funding research. The coverage gap, of which would have been normally paid in full out of the patient’s pocket, is now paid at a lesser rate due to this proposed federal coverage gap insurance. However, this is a small cost to pay for the public welfare of the US citizens.

Jasen Lau is a third year law student at the University of Baltimore School of Law. He graduated from the University of Maryland in 2013 with a Bachelor of Arts in English. Jasen took it upon himself to become a certified pharmacy technician and studied several continuing education credits that focus on Medicare Fraud and Abuse prevention, HIPAA privacy and security laws, and ethics in the pharmacy workplace. Jasen has long been in the health care field either working directly with patients or as an assistant to providers. During that time, his obsession with working in health care has grown into policy analysis and counseling. Along with being a CICL fellow, he is also a law clerk for Johns Hopkins Hospital.

[1]http://www.who.int/whr/2000/media_centre/press_release/en/

[2]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1447687/#r5

[3]http://www.npr.org/templates/story/story.php?storyId=92419273

[4] Id.

[5]http://prescriptions.blogs.nytimes.com/2009/09/11/health-care-abroad-france/?_php=true&_type=blogs&_r=0

[6]http://www.slate.com/articles/business/dispatches_from_the_welfare_state/2014/01/french_socialized_medicine_vs_u_s_health_care_having_a_baby_in_paris_is.2.html

[7]http://www.forbes.com/sites/merrillmatthews/2015/01/05/doctors-face-a-huge-medicare-and-Medicaid-pay-cut-in-2015/

[8]http://www.npr.org/programs/day/features/2008/jul/france/dutton.pdf

[9]https://www.cms.gov/medicare/eligibility-and-enrollment/origmedicarepartabeligenrol/index.html

[10]https://www.medicare.gov/sign-up-change-plans/medicare-health-plans/medicare-advantage-plans/how-medicare-advantage-plans-work.html

[11]https://www.americanprogress.org/wp-content/uploads/issues/2008/07/pdf/elderly_poverty.pdf; see also http://kff.org/other/state-indicator/poverty-rate-by-age/


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Universal Health Care vs. Research – Why the United States Must Prioritize the Latter

Jasen Lau

Universal health care is a hot topic in America. Many other countries have already implemented universal health care, and to many, America seems backwards, late, and uncaring of its citizens. The truth is that America is not uncaring, but rather, America has its focus elsewhere. America, unlike many other countries, focuses on research, development, and advancement of medical technology and pharmaceutics instead of public welfare. Now, that isn’t to say that America is uncaring. America still has state medical assistance for those below the poverty line, Medicare for the elderly, and child health insurance programs for children whose families are above the poverty line yet are too poor to purchase private insurance, but the American healthcare system is designed to ultimately pay manufacturers and research institutes, not go back into the public. America currently leads the world in medical technology and pharmaceutics, producing more than half the world’s medications[1]. The American healthcare system rewards and incentivizes research instead of the public welfare of one nation because the goal of the US is to advance medicine as a whole, not just improve one nation.

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With the advent of the Affordable Care Act (ACA), many people in the US now have healthcare. However, the ACA only required the purchase of insurance[2]. The ACA is not universal healthcare. Quite to the contrary, the ACA pushes more money goes into a system of healthcare professionals that ultimately fuel research. Patients pay premiums to pay for insurance companies; the insurance companies pay providers; those providers then have money to purchase medical equipment, pharmaceuticals, or other healthcare assets; those purchases further fund the institutes that directly advance the research for better medical technology; and they get their money from selling those technologies and advancements to providers. This unending cycle does not exist within many other countries.

Other nations, like England, Germany, Japan, Korea, Australia, and many, many others, have a ministry of health which directly provides healthcare to its citizens. For example, England follows a health constitution, the National Health Service Constitution for England (NHSC), to regulate how health care is covered. The system promises that no one will be denied care and that all health care is free[3]. On the surface, this sounds like what many people in the US want. However, the NHSC limits when the care may be provided. Directly on their main page, the NHSC suggests that vaccinations for the Shingles disease be given to people age 70 and up[4]. However, the Center for Disease Control (CDC) in the US recommend the vaccination as early as 60 years of age. Even the European Medicines Agency recognizes that the Shingles vaccine is meant for people as early as 50[5]. Therefore, how significant is a difference of 10 years? According to both England and the US, Shingles can often lead to pain – ranging from mild to moderate and described as sharp and stabbing pain[6]. In fact, the pain from Shingles is so debilitating that it is cited as the number two reason for suicide in elderly adults[7]. Further, 15 of 100 elderly people who suffer from shingles may become blind[8]. Most universal healthcare nations, however, cannot afford the vaccine on a nationwide scale that early. The point of determining when healthcare is allowed is to stagger the payments. It’s better to have 10 separate payments made instead of one massive lump sum. However, in the US, providers and hospitals are not state employees that must rely on taxpayer money to buy vaccines from drug manufacturers or machines from medical technology companies.

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In many countries where there is public universal healthcare, the vast majority of providers are state employees. Taking everything into account, nations like England have one insurance, one large organ of healthcare providers, and therefore one major purchaser of healthcare technologies and pharmaceuticals. With one entity fueling the money in a system, the layman would believe that money would be better controlled, and to a certain extent, that is correct.

Insurance companies negotiate reimbursement rates for providers[9]. So, the standard $100 rate for cash paying patients may be less for certain insurances where the doctor only gets $70, as an example. With a promise of lowered rates, though, insurance companies boasts their number of subscribers. So, the tradeoff is a lowered rate for the prospect of an increased number of patients and payment security. In America, where there are many insurance companies, providers are often given a wide selection with whom to contract and power to negotiate rates. However, in nations such as England, providers are employees of the State. The government need only compensate the provider at an agreed salary rate, and all the money for providers and research comes from taxes. These same taxes, therefore, are also used to purchase MRI machines, purchasing pharmaceutics, and developing whatever research is possible with the miniscule amount of money remaining. So, the entire financial burden of setting up hospitals, paying for providers, and buying medical equipment fall upon one single entity that controls nearly the entire healthcare system, and this can have grave consequences.

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No other country in the world rivals the US in availability of medical testing. MRI machines, for example, are more readily available in the US than any other country. For example, the US has more than 11,000 MRI machines, around 35 machines per 1,000,000 inhabitants. The second highest country is Korea, having only around 1,200 MRI machines or roughly 24 machines per 1,000,000 inhabitants[10]. Having a lesser number of machines available for use means an expected wait time in many other countries. Therefore, wait times in many other countries can exceed two weeks just for a simple scan[11]. In America, though, hospitals need not wait for taxpayer money from the government. As their own business, hospitals may purchase newer, more efficient medical technology in whatever quantities they deem necessary. This is what runs the US healthcare system: the flow of money back into research, not into the people.

Jasen Lau is a third year law student at the University of Baltimore School of Law. He graduated from the University of Maryland in 2013 with a Bachelor of Arts in English. Jasen took it upon himself to become a certified pharmacy technician and studied several continuing education credits that focus on Medicare Fraud and Abuse prevention, HIPAA privacy and security laws, and ethics in the pharmacy workplace. Jasen has long been in the health care field either working directly with patients or as an assistant to providers. During that time, his obsession with working in health care has grown into policy analysis and counseling. Along with being a CICL fellow, he is also a law clerk for Johns Hopkins Hospital.

[1]http://www.forbes.com/sites/gracemarieturner/2012/05/23/though-the-u-s-is-healthcares-world-leader-its-innovative-culture-is-threatened/

[2]42 U.S.C.A. § 18091 (West)

[3]The National Health System for England, The NHS Constitution, https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/448466/NHS_Constitution_WEB.pdf (last visited Sept. 1, 2015).

[4]The National Health System for England, Shingles, http://www.nhs.uk/conditions/shingles/pages/introduction.aspx (last visited Sept. 1, 2015).

[5]http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000674/human_med_001185.jsp&mid=WC0b01ac058001d124

[6]The National Health System for England, Shingles, http://www.nhs.uk/conditions/shingles/pages/introduction.aspx (last visited Sept. 1, 2015). The Center of Disease Control and Prevention, Shingles (Herpes Zoster), http://www.cdc.gov/shingles/about/prevention-treatment.html (last visited Sept. 1, 2015).

[7]Ricardo J. Gonzalez-Rothi, One shingles shot can prevent future pain (2012), available at http://med.fsu.edu/uploads/files/newsPubs/print/Shingles%20shot,%20Gonzalez-Rothi,%20democrat.pdf

[8]The Children’s Hospital of Philadelphia, A Look at Each Vaccine: Shingles Vaccine, http://www.chop.edu/centers-programs/vaccine-education-center/vaccine-details/shingles-vaccine#.VeYv6vlVikp (last visited Sept. 1, 2015).

[9]http://www.hcplive.com/physicians-money-digest/practice-management/negotiating-contracts-with-insurance-companies-fontes

[10]Magnetic Resonance, 21-01 What is the Organ Distribution of MRI Studies?, http://www.magnetic-resonance.org/ch/21-01.html (last visited Sept. 1, 2015).

[11]Martin Beckford, Britain has fewer high-tech medical machines than Estonia and Turkey, The Telegraph (Mar. 30, 2011), http://www.telegraph.co.uk/news/health/news/8413647/Britain-has-fewer-high-tech-medical-machines-than-Estonia-and-Turkey.html.