viewpoint: pharmaceutical innovation in...

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S ince he took up his role as chief executive at the newly formed Novartis in 1996, Dr Daniel Vasella has been credited with building the company into a market leader. His tactic has been to invest heavily in innovation, spending far more on research and development than other pharmaceutical companies. As a result, Novartis has had more drug approvals in the past 5 years than any other pharmaceutical company. In the past, much of the basic research needed for phar- maceutical innovation has been carried out in Europe, but Novartis, despite being based in Switzerland, moved its research headquarters to the United States in 2002. And, says Dr Vasella, “Unless changes are introduced to the way research is funded and regulated in Europe, investment in pharmaceutical innovation will continue to leave Europe, at a serious cost to the health and wealth of European nations.” According to Dr Vasella, the multiple layers of bureau- cracy in Europe mean that new products take longer to come to market than in other countries, such as the United States. “This increases the costs of launching new drugs for the pharmaceutical companies,” he explains. Dr Vasella says, “European regulators have started creat- ing ‘artificial delays’ in how quickly patients get access to new drugs, because of the implementation of cost-benefit studies and through delaying the reimbursement of a new drug by up to 3 years.” These delays, he believes, put obsta- cles in the way of evaluating efficacy and safety and slow down the final stages of drug development, making it less cost-effective for pharmaceutical companies to develop drugs in Europe than elsewhere. Another obstacle to pharmaceutical innovation in Europe is that the market here is less attractive than in the United States. Dr Vasella explains, “We don’t have a single European market, either from the point of view of pricing or from the point of view of regulation. In the short term, this probably doesn’t directly affect pharmaceutical innovation overall, because it is balanced out by opportunities in other countries such as the United States, where there is an attrac- tive market situation and rapid access. But European patients pay the price through delayed access to better treatments.” The European Union is, in theory, a single market, with a free flow of products between countries, but in reality there are differences in pricing between EU countries because prices are set by individual governments. This combination can mean that more money is made by intermediaries from a par- ticular drug than by the pharmaceutical firms themselves. According to Dr Vasella, this is a serious problem. “If you have a situation where a third party is profiting from parallel importing and is making more money than the company that invented, developed, and marketed the drug, then there is something wrong with the system.” Another area in which Dr Vasella feels Europe is losing out to the United States and other countries is in the amount of high-quality basic research that it supports. This is also related to how easy it is for researchers working in academia to bring the results of their work to the market. “Academic institutions are a great source of innovation,” says Dr Vasella. “In the United States, the professors and scientists are given more freedom than in Europe, and they have access to funds and venture capital that allow them to create their own start-up companies. This means that top scientists are more likely to be retained in academia.” “However,” Dr Vasella says, “this pattern is changing. Despite European researchers having access to fewer resources than their US colleagues, there are now as many biotech start-up companies in Europe as in the United States. There seems to be more courage, guts, and optimism in Europe than we saw in the past. If you are going into biotech, you have to be willing to fail, and in Europe this has traditionally been less well tolerated than in the United States.” But the most serious advantage that US researchers have over their European equivalents, from the point of view of pharmaceutical companies looking for innovation in biomedical research, is the amount of money that the US government puts into basic research through funding to the Daniel Vasella, MD, chairman and CEO of Novartis AG, warns that changes are needed if Europe is to remain a key site for pharmaceutical innovation. He explains his concerns to Emma Baines, MSc. European Perspectives in Cardiology European Perspectives in Cardiology History of Cardiology: Bloodletting From ancient times to the early 20th century, bloodletting has been seen as the answer to many cardiovascular conditions. Page f8 Spotlight on Gino Gerosa, MD Dr Gino Gerosa, University of Padova Medical School, Padova, Italy speaks about his career and special interests. Page f6 f5 Circulation: European Perspectives Circulation January 16, 2007 Viewpoint: Pharmaceutical Innovation in Europe by guest on June 20, 2018 http://circ.ahajournals.org/ Downloaded from

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Since he took up his role as chief executive at the newlyformed Novartis in 1996, Dr Daniel Vasella has been

credited with building the company into a market leader. Histactic has been to invest heavily in innovation, spending farmore on research and development than other pharmaceuticalcompanies. As a result, Novartis has had more drug approvalsin the past 5 years than any other pharmaceutical company.

In the past, much of the basic research needed for phar-maceutical innovation has been carried out in Europe, butNovartis, despite being based in Switzerland, moved itsresearch headquarters to the United States in 2002. And, saysDr Vasella, “Unless changes are introduced to the wayresearch is funded and regulated in Europe, investment inpharmaceutical innovation will continue to leave Europe, ata serious cost to the health and wealth of European nations.”

According to Dr Vasella, the multiple layers of bureau-cracy in Europe mean that new products take longer to cometo market than in other countries, such as the United States.“This increases the costs of launching new drugs for thepharmaceutical companies,” he explains.

Dr Vasella says, “European regulators have started creat-ing ‘artificial delays’ in how quickly patients get access tonew drugs, because of the implementation of cost-benefitstudies and through delaying the reimbursement of a newdrug by up to 3 years.” These delays, he believes, put obsta-cles in the way of evaluating efficacy and safety and slowdown the final stages of drug development, making it lesscost-effective for pharmaceutical companies to develop drugsin Europe than elsewhere.

Another obstacle to pharmaceutical innovation in Europe

is that the market here is less attractive than in the UnitedStates. Dr Vasella explains, “We don’t have a singleEuropean market, either from the point of view of pricing orfrom the point of view of regulation. In the short term, thisprobably doesn’t directly affect pharmaceutical innovationoverall, because it is balanced out by opportunities in othercountries such as the United States, where there is an attrac-tive market situation and rapid access. But European patientspay the price through delayed access to better treatments.”

The European Union is, in theory, a single market, with afree flow of products between countries, but in reality thereare differences in pricing between EU countries because pricesare set by individual governments. This combination canmean that more money is made by intermediaries from a par-ticular drug than by the pharmaceutical firms themselves.

According to Dr Vasella, this is a serious problem. “If youhave a situation where a third party is profiting from parallelimporting and is making more money than the company thatinvented, developed, and marketed the drug, then there issomething wrong with the system.”

Another area in which Dr Vasella feels Europe is losingout to the United States and other countries is in the amountof high-quality basic research that it supports. This is alsorelated to how easy it is for researchers working in academiato bring the results of their work to the market. “Academicinstitutions are a great source of innovation,” says DrVasella. “In the United States, the professors and scientistsare given more freedom than in Europe, and they haveaccess to funds and venture capital that allow them to createtheir own start-up companies. This means that top scientistsare more likely to be retained in academia.”

“However,” Dr Vasella says, “this pattern is changing. DespiteEuropean researchers having access to fewer resources thantheir US colleagues, there are now as many biotech start-upcompanies in Europe as in the United States. There seems tobe more courage, guts, and optimism in Europe than wesaw in the past. If you are going into biotech, you have to bewilling to fail, and in Europe this has traditionally been lesswell tolerated than in the United States.”

But the most serious advantage that US researchers haveover their European equivalents, from the point of viewof pharmaceutical companies looking for innovation inbiomedical research, is the amount of money that the USgovernment puts into basic research through funding to the

Daniel Vasella, MD, chairmanand CEO of Novartis AG, warnsthat changes are needed ifEurope is to remain a key sitefor pharmaceutical innovation.He explains his concerns toEmma Baines, MSc.

European Perspectives in CardiologyEuropean Perspectives in Cardiology

History of Cardiology: BloodlettingFrom ancient times to the early 20th century,bloodletting has been seen as the answer tomany cardiovascular conditions.Page f8

Spotlight on Gino Gerosa, MDDr Gino Gerosa, University of PadovaMedical School, Padova, Italy speaks abouthis career and special interests.Page f6

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National Institutes of Health. “The National Institutes ofHealth have a budget well in excess of $30 million a year,” DrVasella points out. “This generates research activities I considerextraordinary and with which Europe cannot compete.”

A similar Europe-wide funding mechanism could rein-state Europe at the heart of pharmaceutical innovation, DrVasella believes. “Creating a centralised funding mechanismwith an amount of funds comparable with the NationalInstitutes of Health would be an important step in makingEurope competitive,” he says. “But, instead of promotingegalitarianism, the decisions about European funding forresearch would need to start promoting elitism based onachievement. This would mean handing out grants solely onthe basis of the quality of research programmes, rather thanby nationality or region.” He goes on to say, “There are manygreat people working here in Europe. If we can ensure thatthe best are recognised and promoted and given opportu-nities, we will be more competitive.”

Dr Vasella adds that although at the moment the UnitedStates is Europe’s biggest competitor for pharmaceuticalinvestment, it will not be long before serious competition

emerges in the Far East. “The next wave of scientists andworld-class research will come from China,” he predicts.“The Chinese government is investing money in researchand pursuing policies that will make it an attractive place todo research. If you find a country where there is an attractivemarket, where there are a sufficient number of scientists oftop quality, where there are clear and transparent rules beingimplemented from the point of view of regulation and intel-lectual property, and where there is a good quality of life sothat people want to go and stay there, then you probablyhave a winning proposition.”

He concludes, “This is why research has been attractive inEurope in the past, and why, since World War II, it is increas-ingly carried out in the United States, and it is the reasonthat, in the future, we will be going to China.”

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The opinions expressed in Circulation: EuropeanPerspectives in Cardiology are not necessarily those of theeditors or of the American Heart Association.

Emma Baines is a freelance medical writer.

Dr Gino Gerosa is a member of the Italian Society forCardiac Surgery, the New Technology Committee of

the European Association for Cardio-Thoracic Surgery, andthe American Association for Thoracic Surgery. He nowoperates at the leading edge of cardiac surgery, with specificinterests in robotic surgery, transplantation, artificial hearts,minimally invasive surgery, tissue engineering, and regen-erative medicine.

But, he also recalls the days when he was learning hisskills. “I wondered whether I was physically and mentallyequipped to sustain the stresses of specialising in heartsurgery and able to perform those operations with accept-able results.”

It was time spent with Donald Ross, DSc, FRCS, at theNational Heart Hospital in London, United Kingdom inthe 1980s that helped Dr Gerosa focus on a career in car-diac surgery. He regards Dr Ross as an inspiration and a

“mentor for excellence.”Dr Gerosa says, “I always dreamed of becoming a heart

surgeon, and I became fascinated with the heart operationsI watched while in the 4th year of medical school at theUniversity of Verona, Italy. The year after, I went toLondon and spent some time as a visiting student withDonald Ross at the National Heart Hospital, and that wasthe final click.” Dr Gerosa explains, “He was not only amentor but a man with an incredible stamina, superbsurgical skill, an unexhausted scientific curiosity—and anelegant taste to fully enjoy the spirit of life.”

Dr Gerosa mentions Sir Magdi Yacoub, FRS, FRCS, asa man who inspired the idea of the scientist–surgeon.Another influence was Dr Gerosa’s Italian mentor, DinoCasarotto, MD, a professor at the Institute of CardiacSurgery at the University of Padova, “who taught me thefull dedication needed for this profession.”

Dr Gerosa was in residency at Verona University, Italy,from 1983 to 1988, and he worked as a registrar at theDepartment of Cardiac Surgery at Verona University Hospitalfrom 1989 to 1992. He then moved to the Department ofCardiac Surgery, Padova University Hospital, where heworked until 2000 before taking up his current position.

In recent years, he has developed his specialist interestsand was involved in performing the first Italian totallyendoscopic robot-enhanced coronary bypass on a beatingheart in 2001. He was the first Italian—and one of the firstin Europe—to perform totally endoscopic robot-enhancedpulmonary vein isolation for lone atrial fibrillation.“Robotic surgery is solo surgery,” he explains (see Figure).“You have to reinvent your surgical technique and skillbecause you don’t have an assistant helping you throughthe procedure. On the other side of the coin, the fine degreeof movement offered by the telemanipulated instrumentsallows you to surgically perform in a way that is impossible

Spotlight:Gino Gerosa, MDDr Gino Gerosa is associateprofessor of Cardiac Surgery,chief of the Cardiac SurgeryDepartment, and director ofthe School of Specialisation ofCardiac Surgery at theUniversity of Padova MedicalSchool, Padova, Italy. Hespeaks to Mark Nicholls abouthis career and special interests.

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for human hands.” He recalls one occasion inparticular. “I still remember the exact momentwhen I completed the totally endoscopic coro-nary artery bypass anastomosis. Such joy andsatisfaction, and all the team members wereclapping.”

But Dr Gerosa admits there have been disap-pointments. “Unfortunately, the great expecta-tion for cardiac surgeons to be competitive withinterventional cardiologists in terms of lessinvasiveness for myocardial revascularisationhas been substantially frustrated by the intro-duction of drug-eluting stents.” He has clearviews on where the future lies in response towhat he calls the “less than satisfactory” resultsof drug-eluting stents, and he advocates a returnto a hybrid procedure for treating patients withcoronary disease. This would be a left internalmammary artery anastomosis to the left anteriordescending coronary artery, combined withstents on the remaining affected vessels, thusgetting the best results from both techniques.

Dr Gerosa also expresses great satisfaction as he recallsperforming one of the first stem cell transplantations in apatient with ischaemic cardiomyopathy in 2002. “I havevivid memories of those days and of that patient who hadso much trust in the ability of such therapy to solve his ill-ness,” he says. “In Padova, we are still working in that field,and we are exploring the ability of stem cells to recreatehuman valves and to regenerate the failed myocardium.When I think of the success and failure in this field, I feelthat we can compare this experience to the first heart trans-plantation performed in 1967.”

He refers to the expectation, enthusiasm, and hype afterthe first human heart transplantation that was followedby “rather unsatisfactory” results. This meant that in the1970s, only centres in Cape Town, South Africa andStanford, United States continued to perform heart trans-plants for some years. “At the beginning of the 1980s, thediscovery of cyclosporine totally modified the results,improving organ and patient survival, and the scenariochanged completely,” he explains. “I believe that with stemcells we are mimicking that experience. We need to clarifysome things and find the missing pieces to complete thepuzzle. We can then properly use stem cells to solve theproblem of the failing heart. We are still in a phase of fullresearch, but there is light at the end of the tunnel.”

Dr Gerosa feels that cardiac surgery is about to entera new phase. “I believe that we are at the end of cardiacsurgery as we have interpreted it in the last two decades.Cardiac surgeons are retraining to perform and optimiseminimally invasive cardiac and intravascular procedures. Inaddition, cardiac surgeons should acquire the knowledge toemploy gene-enhanced cell therapy and tissue-engineeringtechniques.”

Dr Gerosa believes that a shortage of organ donors isdriving the need to find additional solutions. “Heart failure is

one of the most rapidly evolving fields,” he says, “where car-diac surgeons will be able to perform by combining newsurgical techniques, cell therapies, and mechanical devices.”

Yet, alongside all the innovation and technical advance-ment, Dr Gerosa also believes that cardiac surgeons inWestern countries should put more effort into providingcardiac surgery care for patients in developing countries,along the lines of Sir Magdi Yacoub’s Chain of Hopeorganisation.1

Talking about his personal life, Dr Gerosa says he wasborn in Rovereto, in the mountains in northern Italy. Awayfrom work, he enjoys skiing and golf. He is married to JanineGerosa, whom he met while training in London, UnitedKingdom, and he takes great pride in their 3 childrenEdoardo (age 15), Carlo Andrea (age 12), and Filippo Alberto(age 6). “Fatherhood is a lot more complicated and reward-ing than cardiac surgery,” he says with a smile.

He describes his children as his proudest achievement,but he also lists his 1991 article2 that reviewed the experi-ence of the Ross operation (a procedure where the patient’snormal pulmonary valve is removed and used to replace adiseased aortic valve, and the pulmonary valve is then replacedwith a pulmonary homograft) in children. He said it was thefirst article postulating the ability of the pulmonary autograftto grow after transplantation into the aortic position.

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Robotic surgery is solo surgery, says Dr Gerosa, as you have to reinvent yoursurgical technique and skill because you don’t have an assistant to help you.

Mark Nicholls is a freelance medical journalist.References

1. Nicholls M. Chain of hope. Circulation. 2006;114:f134–f136.2. Gerosa G, McKay R, Davies J, Ross DN. Comparison of the aortic

homograft and the pulmonary autograft for aortic valve or rootreplacement in children. J Thorac Cardiovasc Surg. 1991;102:51–60.

Editor: Thomas F. Lüscher, MD, FRCP, FACCManaging Editor: Keith Barnard, MB, BS, MRCS, LRCPWe welcome your comments. E-mail the managing editor [email protected]

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Since the early 20th century, the medical profession haslearned to revere, preserve, and sustain that amazing

carrier of oxygen and nutrients: the blood. Profligate extractionof this liquid is no longer considered therapeutic except incases of primary and secondary polycythaemia, but it has takenmany centuries to arrive at this conclusion.

Bloodletting is a medical practice that was employed bymany ancient peoples including the Egyptians, the Aztecs, theMesopotamians, and the Greeks. Hippocrates mentioned thepractice, but it was some centuries later that the popularity ofthe procedure increased with the advocacy of Claudius Galenin the second century AD. Not only was he the first physicianto take a patient’s pulse, but he discovered that veins andarteries were filled with blood rather than air as had previ-ously been thought. His belief in bloodletting was based on thenecessity of balancing the 4 “humours”— phlegm, black bile,yellow bile, and blood—to achieve health. To achieve thisbalance, physicians would either bleed the patient to removean excess of blood, or employ emetics or diuretics to inducevomiting or urination.

By the second millenium, and with the decline of thehumoural system, bloodletting was undertaken by barber–surgeons on the recommendation of physicians. The practice wasused both prophylactically and therapeutically into the 19thcentury (see Figure), although its efficacy was widely debated.The lancet was the primary instrument for bloodletting, butother methods included cupping, scarification, and leeching.

Cupping could be either “wet” or “dry.” Originally, animalhorns were used, but these were later replaced by sophisticatedcupping sets. Dry cupping necessitated the heating of the cupor glass, which was placed over the skin. As it cooled, it createda vacuum, bringing blood to the surface.

In the 1830s, Victor-Theodore Junod, MD, of Paris, France,believed in the therapeutic effect of “producing a fainting fitby drawing the blood from the brain to the foot without lettingblood.”1(p647) Scarification involved a device consisting of smallblades that were used to make several small incisions in wetcupping. This practice was often combined with warm sulphurbaths. On a visit to Hungary in 1815, Richard Bright, MD, ofEdinburgh, Scotland described seeing “a row of half-nakedfigures like those in the bath on whom a poor miserable surgeonwas practising the operations of cupping and scarification,studiously inflicting as many wounds as possible.”1(p409)

The application of leeches as a method of bloodletting wasparticularly popular with the French physician Francois-Joseph

Victor Broussais, MD, who believed gastroenteritis to be the“basis of all pathology.” He decided that gastroenteritis couldbe aborted by the application of as many as 50 leeches. Themethod became so popular that over 40 million leeches wereimported into France in the year 1833.

In their 1838 textbook, Dr Bright and Thomas Addison,MD, wrote that “when we have reason to think that the heart isexcited by a plethoric condition, very moderate general or localbleeding may occasionally be employed with advantage.”2

The exposure of the weaknesses of bloodletting came aboutmainly through the work of Pierre Charles Alexandre Louis,MD, of la Charité Hospital, Paris, France. He first criticised thetechnique in 1828, and he later produced statistical proof thatbloodletting was of little value for treating pneumonia and wasdubious for other ailments. In 1830, the British physiologistMarshall Hall, MD, FRS, also denounced bloodletting. He out-lined the severe symptoms such as syncope, convulsions,coma, and delerium that he believed might be directly traced tothat “minute instrument of mighty mischief,” the lancet.

Despite bloodletting’s gradual loss of credibility, it was stilladvocated as a treatment for cardiac problems as late as the1920s. In the revised ninth edition of the textbook written bythe world-renowned physician, Sir William Osler, MD, blood-letting was recommended for relief of the “embarrassed circu-lation” in cardiac insufficiency. The text states, “In those casesof dilation, from whatever cause, in mitral or aortic lesions ordistention of the right ventricle in emphysema, when signs ofvenous engorgement are marked and when there is orthopnoeawith cyanosis, the abstraction of 20–30 ounces of blood isindicated. This is the occasion in which timely venesectionmay save the patient’s life. It is particularly helpful in thedilated heart of arteriosclerosis.”3

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Circulation January 16, 2007

History of Cardiology:The Use of BloodlettingFrom ancient times to the early 20th century,bloodletting has been seen as the answer tomany conditons, including some manifestationsof cardiovascular disease. Diana Berry looksback at when it was in vogue and why.

In the early 19th century many physicians believed that disordersof the heart could be treated with bloodletting and the use of leeches.

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References1. Fielding H, Garrison AB. An Introduction to the History of Medicine.

4th ed. Philadelphia, Pa: WB Saunders Co; 1929:647.2. Bright R, Addison T. Elements of the Practice of Medicine. London.

Longman, Rees, Orme, Brown, Green & Longman; 1836:332.3. Osler W, McCrae T. The Principles and Practice of Medicine. 9th ed.

New York, NY: Appleton & Co.; 1920:788.

Diana Berry is a medical historian and freelance medical writer.

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European Perspectives

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2007 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation 2007;115:f5-f8Circulation. 

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