- Email: [email protected]
Clinical trials. A pending subject
+Model
ARTICLE IN PRESS
Rev Clin Esp. 2017;xxx(xx):xxx---xxx
Revista Clínica Española www.elsevier.es/rce
SPECIAL ARTICLE
Clinical trials. A pending subject夽 Blas Gil-Extremera ∗ , Pilar Jiménez-López, Juan Diego Mediavilla-García Departamento de Medicina, Universidad de Granada, Granada, Spain Received 30 March 2017; accepted 29 June 2017
KEYWORDS Clinical trial; Hypertension; Diabetes; Dyslipidaemia
PALABRAS CLAVE Ensayo clínico; Hipertensión; Diabetes; Dislipidemias
Abstract Clinical trials are essential tools for the progress of clinical medicine in its diagnostic and therapeutic aspects. Since the first trial in 1948, which related tobacco use with lung cancer, there have been more than 150,000 clinical trials to date in various areas (pediatrics, cardiology, oncology, endocrinology, etc.). This article highlights the importance for all physicians to participate, over the course of their professional career, in a clinical trial, due to the inherent benefits for patients, the progress of medicine and for curricular prestige. The authors have created a synthesis of their experience with clinical trials on hypertension, diabetes, dyslipidemia and ischemic heart disease over the course of almost 3 decades. Furthermore, a brief reference has been made to the characteristics of a phase I unit, as well as to a number of research studies currently underway. © 2017 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
Ensayos clínicos. Una asignatura pendiente Resumen Los ensayos clínicos son una herramienta fundamental para el avance de la medicina clínica en sus vertientes diagnóstica y terapéutica. Desde la aparición del primer ensayo en 1948, que relacionaba el tabaco con el cáncer de pulmón, se han realizado hasta la fecha más de 150.000 en diversas áreas (pediatría, cardiología, oncología, endocrinología, etc.). Este artículo resalta la importancia para todo facultativo de participar, a lo largo de su trayectoria profesional, en algún ensayo clínico por los beneficios inherentes al paciente, al progreso de la medicina, así como al prestigio curricular. Los autores hacen una síntesis de su experiencia
夽
Please cite this article as: Gil-Extremera B, Jiménez-López P, Mediavilla-García JD. Clinical trials. A pending subject. Rev Clin Esp. 2017. http://dx.doi.org/10.1016/j.rce.2017.06.006 ∗ Corresponding author. E-mail address: [email protected] (B. Gil-Extremera). 2254-8874/© 2017 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
RCENG-1414; No. of Pages 5
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B. Gil-Extremera et al. sobre ensayos clínicos en hipertensión, diabetes, dislipidemias y cardiopatía isquémica a lo largo de casi 3 décadas. Asimismo, se hace una breve referencia a las características de una unidad en fase i, así como a algunas investigaciones que actualmente se están realizando. © 2017 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). Todos los derechos reservados.
Background Cultural tradition dictates that all individuals should, over the course of their life, plant a tree, have a child and write a book. The latter of these is a most difficult task. As Miguel de Cervantes (1547---1616) wrote, ‘‘Does Your Grace think now that it’s not much work to make a book?’’ Transferring these statements to medicine, we could consider that all physicians over the course of their professional career should perform or participate in at least one clinical trial. James Lind (1716---1794), a Scottish surgeon in the British Navy, discovered the cure for scurvy (a slow condition of vitamin C deficiency and poor hygienic conditions) and was likely the first ‘‘author’’ of a clinical trial. However, it would not be until 1948 that British epidemiologist Sir Austin Bradford Hill (1897---1991) established the causal relationship between nicotine addiction and lung cancer. Since then, more than 150,000 clinical trials have been performed in developed countries in fields such as cardiology, oncology, pediatrics, endocrinology and cardiovascular risk factors such as hypertension and dyslipidemia. According to the General Health Law, clinical trials are necessary for authorizing drug products. Furthermore, the Law of Guarantees and Rational Use of Medicines and Healthcare Products dedicates the third title to clinical trials, according to Royal Decree 1090/2015. In the European Union, Regulation 536/2014 applies. The objectives of this article are (a) to state the decisive importance of clinical trials; (b) to make physicians aware of the clinical and educational value of participating in these studies; (c) to concisely show our group’s contribution; and (d) to highlight a number of clinical trials that are currently underway.
Concept and nomenclature Clinical trials are all prospective studies of humans conducted with an experimental assessment to determine a drug’s or diagnostic technique’s superiority (or lack thereof) --- propositum or testing --- in terms of safety and efficacy versus placebo or other known alternative procedure. Efficacy and tolerance are considered useful concepts for showing the superiority of a diagnostic or therapeutic modality. Clinical trials are the best scientific evidence available at this time. All clinical trials are known by a descriptive title on the objective(s) to be met. These titles are often long, which impedes communication and dissemination; for example, ‘‘A multicenter, randomized, double-blind comparison of the efficacy and safety of irbesartan and enalapril in adults
with mild to moderate essential hypertension, as assessed by ambulatory blood pressure monitoring’’, known by the Spanish abbreviation MAPAVEL (Monitorización Ambulatoria Presión Arterial APROVEL, Ambulatory Blood Pressure Monitoring APROVEL).1 Abbreviations are therefore employed to simplify and facilitate information among researchers and disseminate the results. A clinical trial’s abbreviation should be euphonious (‘‘a pleasant sound that results from the correct combination of the acoustical elements of the words’’) and have a positive and easy-to-remember message. In short, the search for a title and its corresponding abbreviation is not an easy task. There are specialists and commercial entities dedicated to offering appropriate proposals for each case. When an abbreviation is attractive and easy to evoke, it will enjoy greater acceptance; otherwise, the results will be inferior.
Drug development phases The implementation of any clinical trial involves a long and risky genesis, especially for long and complex experimental studies and laboratory studies that assess the pharmacokinetics and toxicology parameters of drugs. This process, which lasts no less than 20 years, is a sine qua non condition prior to research in humans (healthy volunteers and patients) and includes the study title and design, official approval, inclusion of participating centers, objectives, legal regulations by the appropriate organization, legal backing, financial insurance, periodic visits, findings, external audits, conclusions and publication of the results to the scientific community. Research to be conducted with patients must have their cooperation and must meet all requirements aimed at protecting patients as much as possible, avoiding any potential deleterious effect. For researchers, clinical trials constitute a constant challenge that requires careful patient care, frequent and protocolized medical visits and facilities of all types to achieve the planned objective. Clinical trials consist of a preclinical phase (laboratory) and 4 modalities or clinical stages (in humans): phase I (healthy patients; objectives: safety and pharmacokinetics); phase II (patients; objective: dose-finding); phase III (patients; objectives: efficacy, posology); and phase IV (patients; objectives: therapeutic efficacy, comparison versus a ‘‘historical’’ control). The importance of clinical trials includes (a) the scientific value; (b) therapeutic value, referred to as appropriate and effective dose-finding with the least adverse effects; (c) pharmaceutical safety; and (d) curricular importance, given that the results are usu-
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Clinical trials. A pending subject ally published in prestigious journals in the scientific setting. Obviously, approval of the clinical trial by the corresponding authorities is required before starting the long process required by the research study. A clinical trial covers unknown aspects of the use of drugs or techniques and employs various nonstandard methods of use. Roughly speaking, a clinical trial studies the clinical pharmacology, pharmacokinetics, absorption and distribution of the drug in the body, as well as its metabolism and excretion. The trial also studies safety aspects such as tolerance and adverse effects, interaction with food and other drugs and dose regimens (single dose or multiple). Clinical trials analyze cardiovascular and pulmonary responses, coagulation studies, biological markers, functional assessment of the central nervous system and psychometric methods. The development of the protocol includes its presentation to ethics committees, informed consent and previous examination of potential candidates to assess whether the patient meets the requirements for inclusion in the study, clinical phase (in the center or hospital), follow-up, check-ups and poststudy examination. In summary, according to current legislation, clinical trials are conducted only when 2 main requirements are met: (1) an independent ethics committee has positively evaluated the trial and (2) the trial has been submitted to the Ministry of Health along with the appropriate documentation.
First-hand experience of the group Our contribution to the world of clinical trials has developed over the course of almost 3 decades on diseases related to cardiovascular risk such as arterial hypertension, diabetes, dyslipidemia and ischemic heart disease. We started this task in 1990 with the international, multicenter, double-blind study ‘‘Systolic Hypertension in Europe,’’ known by the abbreviation SYST-EUR. The study was devised by the late clinician and researcher Antoon K.P.C. Amery (1933---1994).2 The objective of the study was to demonstrate that patients older than 60 years with isolated systolic hypertension should undergo drug treatment as do younger patients. To this end, 4695 patients were included in the study and treated over the course of 18 years (1989---2007). The study drugs, used interchangeably or in combination, belonged to 3 families: diuretics (hydrochlorothiazide), angiotensin-converting enzyme inhibitors (enalapril) and calcium antagonists (nitrendipine). Twenty-three European countries participated in the research study, including Spain and our Hypertension Unit at Clinic Hospital San Cecilio of Granada. Once the results were disseminated among the scientific community,3---6 professor Christopher Bulpitt of the Imperial College of London proposed a new research study as a continuation and supplement to the earlier ‘‘Hypertension in the Very Elderly Trial,’’ known as HYVET, in patients older than 80 years. The hypothesis seemed appropriate: If the drugs offered positive therapeutic possibilities to patients older than 60 years, it would be expected that these results were extrapolatable to older patients. HYVET was conducted in 2 stages. An open pilot study was conducted during the first stage, which included 1283 patients, with a large presence of our case series.7 After the
3 promising results, the proposal was to ratify them conclusively with the main, double-blind study to avoid all possible bias. This second stage started in 2004 and had a total of 2247 patients treated over the course of 5 years.8---10 As with SYST-EUR, the clinical findings were highly positive, such that the patients undergoing active treatment had a lower number of cardiovascular complications (myocardial infarction, stroke, peripheral artery disease) and lower mortality than the placebo group. The earlier nihilistic idea of not treating patients with drugs due to age was definitively ruled out because it was not ethical to use the fallacious argument of senescence for not prescribing the necessary drug in each case. The subsequent participation by our group in clinical trials exceeds 160 studies, whose results have been the subject of numerous publications. Reaching these goals has required ongoing effort, enthusiasm and dedication, while overcoming various obstacles: lack of sensitivity by the Center’s management, lack of staff, tiny physical space for conducting the study and delays, in many cases, in getting approval for the respective clinical trial, which frequently requires us to ‘‘race against the clock’’ to catch up with the investigators and centers that had started patient recruitment much earlier than us. Despite these adversities, however, we are satisfied with the part we have played in high-level clinical research studies, which has helped us understand, for example, the complex pathogenesis of hypertension and stroke11,12 and other aspects of cardiovascular risk factors.13---18 We have participated in other relevant clinical trials such as VALUE,19 CONVINCE,20 ONTARGET,21 STABILITY,22 DISTINCT,23 and TRANSCEND,24 which are discussed in the following section.
Clinical trials in progress In the field of diabetes, there are studies searching for new compounds that provide a better quality of life for numerous patients inexorably attached to parenteral insulin. A clinical trial is underway for patients with uncontrolled type 1 diabetes treated with insulin, aimed at studying the efficacy, safety and tolerance of sotagliflozin as a complement to the pancreatic hormone.25 Monoclonal antibodies represent a new therapeutic possibility. The currently underway clinical trial COMMANDER26 is analyzing the safety and efficacy of rivaroxaban in reducing mortality, myocardial infarction and stroke in patients with coronary artery disease after episodes of decompensated heart failure. THEMIS27 is a multinational, double-blind randomized, placebo-controlled clinical trial in progress to assess the effect of ticagrelor on the incidence of cardiovascular death and stroke in patients with type 2 diabetes. Studies with alirocumab (ODYSSEY OUTCOMES and ODYSSEY CHOICE II)28,29 are designed to assess cardiovascular complications (heart disease death, nonfatal myocardial infarction, unstable angina and fatal and nonfatal ischemic stroke) after an acute coronary syndrome. Finally, the clinical trial by Ridker et al.30 with similar characteristics to the previously mentioned study is aimed at assessing the efficacy, safety and tolerance of bococizumab in reducing cardiovascular complications in high-risk patients.
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Figure 1 Beds with complete monitoring. Phase I Unit, Bayer AG, Wuppertal, Germany.
B. Gil-Extremera et al.
Figure 2 Laboratory and instrumentation. Phase I Unit, Bayer AG, Wuppertal, Germany.
Characteristics of a phase I unit Not too long ago, the first signatory received an invitation from Bayer (created in 1863 by Friedrich Bayer [1825---1880]) to visit the facilities of their special phase I unit for healthy volunteers. The unit and the property that houses it are in the city of Wuppertal (North RhineWestphalia, Germany). The members of this center assess the following aspects in healthy volunteers: clinical pharmacology and pharmacokinetics consisting of elements of safety, tolerance/adverse effects, pharmacokinetic measurements and biological markers. The center has 36 beds distributed among the property’s 3 floors, with full monitoring on all floors (Fig. 1), a cardiovascular laboratory with echocardiography, spirometry, retinal vessel study, electrocardiography and transcranial ultrasound. The center comprises the following instrumentation and logistical support: central monitoring (a team for each floor), emergency team (one for each floor), 2 rooms for the general physical examination of participants, 4 laboratories, medical storage room, laboratory for preparing biological samples and storage for devices and instrumentation (Fig. 2). The institution also has 5 rest areas (Fig. 3) equipped with television, Internet access, cafeteria and game room, 3 kitchens with specialized staff, a participant recruitment area and another for nursing. The unit’s pharmacodynamic methods are appropriate for research and the necessary human resources: a physician, 12 full-time nurses, an assistant for recruiting participating volunteers, an administrative team and staff to care for the facilities. The recruitment office has ample physical space for dealing with study candidate interviews, press announcements, visit schedules, invitations, document preparation and catering (Bayer Gastronomie).
Conflicts of Interest The authors declare that they have no conflicts of interest.
Figure 3 many.
Rest area. Phase I Unit, Bayer AG, Wuppertal, Ger-
Acknowledgments We would like to thank Esperanza Velasco for her collaboration in creating the manuscript and Bayer Pharmaceuticals for the information regarding phase i studies.
References 1. Coca A, Calvo C, García-Puig J, Gil-Extremera B, Aguilera MT, de la Sierra A, et al. A multicenter, randomized, doubleblind comparison of the efficacy and safety of irbesartan and enalapril in adults with mild to moderate essential hypertension, as assessed by ambulatory blood pressure monitoring: The MAPAVEL study. Clin Ther. 2002;24:126---38. 2. Amery A, Birkenhäger WH, Bulpitt CJ, Clément D, de Leeuw P, Dollery CT, et al. Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: objectives, protocol, and organization. Aging. 1991;3:287---302. 3. Staessen JA, Thijs L, Birkenhäger WH, Bulpitt ChJ, Fagard R. Update on the systolic hypertension in Europe (Syst-Eur) trial. The Syst-Eur Investigators. Hypertension. 1999;33:7---1476. 4. Forette F, Seux ML, Staessen JA, Thijs L, Birkenhäger WH, Babarskiene MR, et al. Prevention of dementia in
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randomized double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur). Lancet. 1998;352:1347---51. Forette F, Seux ML, Staessen JA, Birkenhäger WH, Babarskiene MR, Babeanu S, et al. The prevention of dementia with antihypertensive treatment. New evidence from the Systolic Hypertension in Europe (Syst-Eur) Study. Arch Int Med. 2002;162:2046---52. Staessen JA, Thijs L, Fagard R, Celis H, Birkenhäger WH, Bulpitt CJ, et al. Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial. J Hypertens. 2004;22:847---57. Bulpitt CJ, Beckett NS, Cooke J, Dumitrascu DL, Gil-Extremera B, Nachev C, et al. Results of the pilot study for the Hypertension in the Very Elderly Trial. J Hypertens. 2003;21:2409---17. Beckett NS, Peters R, Fletcher A, Staessen JA, Liu L, Dumitrascu D, et al., HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887---98. García Puig J, Gil Extremera B. ¿Debemos tratar la hipertensión arterial en el muy anciano? Rev Clin Esp. 2008;208:481---2. Gil Extremera B. Estudio HYVET. Tratamiento del paciente hipertenso de 80 o más a˜ nos. Med Clin (Barc). 2008;131:538---9. Gil Extremera B, Gómez González JV. Hypertension as the major cause of stroke. J Clin Trial Cardiol. 2015;2:1---4. Gil Extremera B. Hypertension and stroke. Saarbrücken, Germany: Lambert Academic Publishing; 2017. Gil Extremera B, Tuomilehto J, Cía Gómez P. Hypertension in the elderly. Int J Hypertens. 2012:1---89 [special issue]. Farnier M, Roth E, Gil-Extremera B, Mendez GF, Macdonell G, Hamlin C, et al., for the Ezetimibe/Simvastatin+Fenofibrate Study Group. Efficacy and safety of the coadministration for ezetimibe/simvastatin with fenofibrate in patients with mixed hyperlipidemia. Am Heart J. 2007;153:335.e1---8. Gil Extremera B, Jimenez López P, Guarnido Ramirez AJ, Garcia Pe˜ nalver E, Abarca Martinez ML. Clinical trials on diabetes mellitus. In: Treatmentof type 2 diabetes. Vienna: Colleen Croniger; 2015. p. 117---43. Gil Extremera B. Aterosclerosis coronaria. Factores de riesgo vascular. In: Farreras/Rozman. Medicina Interna. XVIII ed., Volumen I Barcelona: Elsevier; 2016. p. 475---80. Shah S, Ceska R, Gil-Extremera B, Paolini JF, Giezek H, Vandormael K, et al. Efficacy and safety of extended-release niacin/laropiprant plus statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Int J Clin Pract. 2010;64:727---38. Gil Extremera B. Relevant aspects of hypertension. BAOJ Med Nurs. 2017;3:1---13. Zanchetti A, Julius S, Kjeldsen S, McInnes G, Hua T, Weber M, et al. Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan and amlodipine: an analysis of findings from the VALUE trial. J Hypertens. 2006;24:2163---8.
5 20. Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T, White WD, et al., for the CONVINCE Research Group. Principal Results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA. 2003;289: 2073---82. 21. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al., ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547---59. 22. White HD, Held C, Stewart R, Tarka E, Brown R, Davies RY, et al., STABILITY Investigators. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med. 2014;370:1702---11. 23. Mancia G, Cha G, Gil-Extremera B, Harvey P, Lewin AJ, Villa G, et al. Blood pressure lowering effects of nifedipine/candesartan combinations in high-risk individuals: subgroup analysis of the DISTINCT randomized trial. J Hum Hypertens. 2017;31: 178---88. 24. Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, copland I, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Telmisartan Randomised AssessmeNT Study in ACE intolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Lancet. 2008;372: 1174---83. 25. Clinical Trials.gov. A Service of the U.S. National Institutes of Health [accessed 30.03.17]. Available from: https://www.clinical trials.gov. ClinicalTrials.gov Identifier: NCT02421510. 26. Clinical Trials.gov. A Service of the U.S. National Institutes of Health [accessed 30.03.17]. Available from: https://www.clinical trials.gov. ClinicalTrials.gov Identifier: NCT01877915. 27. Clinical Trials.gov. A Service of the U.S. National Institutes of Health [accessed 30.03.17]. Available from: https://www.clinical trials.gov. ClinicalTrials.gov Identifier: NCT01991795. 28. Stroes E, Guyton JR, Lepor N, Civeira F, Gaudet D, Watts GF, et al., for the ODYSSEY CHOICE II Investigators. Efficacy and safety of alirocumab 150 mg every 4 weeks in patients with hypercholesterolemia not on statin therapy: The ODYSSEY CHOICE II Study. J Am Heart Assoc. 2016;5:1---11. 29. Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V, Diaz R, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J. 2014;168:682---9. 30. Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376:1527---39.
ARTICLE IN PRESS
Rev Clin Esp. 2017;xxx(xx):xxx---xxx
Revista Clínica Española www.elsevier.es/rce
SPECIAL ARTICLE
Clinical trials. A pending subject夽 Blas Gil-Extremera ∗ , Pilar Jiménez-López, Juan Diego Mediavilla-García Departamento de Medicina, Universidad de Granada, Granada, Spain Received 30 March 2017; accepted 29 June 2017
KEYWORDS Clinical trial; Hypertension; Diabetes; Dyslipidaemia
PALABRAS CLAVE Ensayo clínico; Hipertensión; Diabetes; Dislipidemias
Abstract Clinical trials are essential tools for the progress of clinical medicine in its diagnostic and therapeutic aspects. Since the first trial in 1948, which related tobacco use with lung cancer, there have been more than 150,000 clinical trials to date in various areas (pediatrics, cardiology, oncology, endocrinology, etc.). This article highlights the importance for all physicians to participate, over the course of their professional career, in a clinical trial, due to the inherent benefits for patients, the progress of medicine and for curricular prestige. The authors have created a synthesis of their experience with clinical trials on hypertension, diabetes, dyslipidemia and ischemic heart disease over the course of almost 3 decades. Furthermore, a brief reference has been made to the characteristics of a phase I unit, as well as to a number of research studies currently underway. © 2017 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
Ensayos clínicos. Una asignatura pendiente Resumen Los ensayos clínicos son una herramienta fundamental para el avance de la medicina clínica en sus vertientes diagnóstica y terapéutica. Desde la aparición del primer ensayo en 1948, que relacionaba el tabaco con el cáncer de pulmón, se han realizado hasta la fecha más de 150.000 en diversas áreas (pediatría, cardiología, oncología, endocrinología, etc.). Este artículo resalta la importancia para todo facultativo de participar, a lo largo de su trayectoria profesional, en algún ensayo clínico por los beneficios inherentes al paciente, al progreso de la medicina, así como al prestigio curricular. Los autores hacen una síntesis de su experiencia
夽
Please cite this article as: Gil-Extremera B, Jiménez-López P, Mediavilla-García JD. Clinical trials. A pending subject. Rev Clin Esp. 2017. http://dx.doi.org/10.1016/j.rce.2017.06.006 ∗ Corresponding author. E-mail address: [email protected] (B. Gil-Extremera). 2254-8874/© 2017 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
RCENG-1414; No. of Pages 5
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ARTICLE IN PRESS
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B. Gil-Extremera et al. sobre ensayos clínicos en hipertensión, diabetes, dislipidemias y cardiopatía isquémica a lo largo de casi 3 décadas. Asimismo, se hace una breve referencia a las características de una unidad en fase i, así como a algunas investigaciones que actualmente se están realizando. © 2017 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). Todos los derechos reservados.
Background Cultural tradition dictates that all individuals should, over the course of their life, plant a tree, have a child and write a book. The latter of these is a most difficult task. As Miguel de Cervantes (1547---1616) wrote, ‘‘Does Your Grace think now that it’s not much work to make a book?’’ Transferring these statements to medicine, we could consider that all physicians over the course of their professional career should perform or participate in at least one clinical trial. James Lind (1716---1794), a Scottish surgeon in the British Navy, discovered the cure for scurvy (a slow condition of vitamin C deficiency and poor hygienic conditions) and was likely the first ‘‘author’’ of a clinical trial. However, it would not be until 1948 that British epidemiologist Sir Austin Bradford Hill (1897---1991) established the causal relationship between nicotine addiction and lung cancer. Since then, more than 150,000 clinical trials have been performed in developed countries in fields such as cardiology, oncology, pediatrics, endocrinology and cardiovascular risk factors such as hypertension and dyslipidemia. According to the General Health Law, clinical trials are necessary for authorizing drug products. Furthermore, the Law of Guarantees and Rational Use of Medicines and Healthcare Products dedicates the third title to clinical trials, according to Royal Decree 1090/2015. In the European Union, Regulation 536/2014 applies. The objectives of this article are (a) to state the decisive importance of clinical trials; (b) to make physicians aware of the clinical and educational value of participating in these studies; (c) to concisely show our group’s contribution; and (d) to highlight a number of clinical trials that are currently underway.
Concept and nomenclature Clinical trials are all prospective studies of humans conducted with an experimental assessment to determine a drug’s or diagnostic technique’s superiority (or lack thereof) --- propositum or testing --- in terms of safety and efficacy versus placebo or other known alternative procedure. Efficacy and tolerance are considered useful concepts for showing the superiority of a diagnostic or therapeutic modality. Clinical trials are the best scientific evidence available at this time. All clinical trials are known by a descriptive title on the objective(s) to be met. These titles are often long, which impedes communication and dissemination; for example, ‘‘A multicenter, randomized, double-blind comparison of the efficacy and safety of irbesartan and enalapril in adults
with mild to moderate essential hypertension, as assessed by ambulatory blood pressure monitoring’’, known by the Spanish abbreviation MAPAVEL (Monitorización Ambulatoria Presión Arterial APROVEL, Ambulatory Blood Pressure Monitoring APROVEL).1 Abbreviations are therefore employed to simplify and facilitate information among researchers and disseminate the results. A clinical trial’s abbreviation should be euphonious (‘‘a pleasant sound that results from the correct combination of the acoustical elements of the words’’) and have a positive and easy-to-remember message. In short, the search for a title and its corresponding abbreviation is not an easy task. There are specialists and commercial entities dedicated to offering appropriate proposals for each case. When an abbreviation is attractive and easy to evoke, it will enjoy greater acceptance; otherwise, the results will be inferior.
Drug development phases The implementation of any clinical trial involves a long and risky genesis, especially for long and complex experimental studies and laboratory studies that assess the pharmacokinetics and toxicology parameters of drugs. This process, which lasts no less than 20 years, is a sine qua non condition prior to research in humans (healthy volunteers and patients) and includes the study title and design, official approval, inclusion of participating centers, objectives, legal regulations by the appropriate organization, legal backing, financial insurance, periodic visits, findings, external audits, conclusions and publication of the results to the scientific community. Research to be conducted with patients must have their cooperation and must meet all requirements aimed at protecting patients as much as possible, avoiding any potential deleterious effect. For researchers, clinical trials constitute a constant challenge that requires careful patient care, frequent and protocolized medical visits and facilities of all types to achieve the planned objective. Clinical trials consist of a preclinical phase (laboratory) and 4 modalities or clinical stages (in humans): phase I (healthy patients; objectives: safety and pharmacokinetics); phase II (patients; objective: dose-finding); phase III (patients; objectives: efficacy, posology); and phase IV (patients; objectives: therapeutic efficacy, comparison versus a ‘‘historical’’ control). The importance of clinical trials includes (a) the scientific value; (b) therapeutic value, referred to as appropriate and effective dose-finding with the least adverse effects; (c) pharmaceutical safety; and (d) curricular importance, given that the results are usu-
+Model
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Clinical trials. A pending subject ally published in prestigious journals in the scientific setting. Obviously, approval of the clinical trial by the corresponding authorities is required before starting the long process required by the research study. A clinical trial covers unknown aspects of the use of drugs or techniques and employs various nonstandard methods of use. Roughly speaking, a clinical trial studies the clinical pharmacology, pharmacokinetics, absorption and distribution of the drug in the body, as well as its metabolism and excretion. The trial also studies safety aspects such as tolerance and adverse effects, interaction with food and other drugs and dose regimens (single dose or multiple). Clinical trials analyze cardiovascular and pulmonary responses, coagulation studies, biological markers, functional assessment of the central nervous system and psychometric methods. The development of the protocol includes its presentation to ethics committees, informed consent and previous examination of potential candidates to assess whether the patient meets the requirements for inclusion in the study, clinical phase (in the center or hospital), follow-up, check-ups and poststudy examination. In summary, according to current legislation, clinical trials are conducted only when 2 main requirements are met: (1) an independent ethics committee has positively evaluated the trial and (2) the trial has been submitted to the Ministry of Health along with the appropriate documentation.
First-hand experience of the group Our contribution to the world of clinical trials has developed over the course of almost 3 decades on diseases related to cardiovascular risk such as arterial hypertension, diabetes, dyslipidemia and ischemic heart disease. We started this task in 1990 with the international, multicenter, double-blind study ‘‘Systolic Hypertension in Europe,’’ known by the abbreviation SYST-EUR. The study was devised by the late clinician and researcher Antoon K.P.C. Amery (1933---1994).2 The objective of the study was to demonstrate that patients older than 60 years with isolated systolic hypertension should undergo drug treatment as do younger patients. To this end, 4695 patients were included in the study and treated over the course of 18 years (1989---2007). The study drugs, used interchangeably or in combination, belonged to 3 families: diuretics (hydrochlorothiazide), angiotensin-converting enzyme inhibitors (enalapril) and calcium antagonists (nitrendipine). Twenty-three European countries participated in the research study, including Spain and our Hypertension Unit at Clinic Hospital San Cecilio of Granada. Once the results were disseminated among the scientific community,3---6 professor Christopher Bulpitt of the Imperial College of London proposed a new research study as a continuation and supplement to the earlier ‘‘Hypertension in the Very Elderly Trial,’’ known as HYVET, in patients older than 80 years. The hypothesis seemed appropriate: If the drugs offered positive therapeutic possibilities to patients older than 60 years, it would be expected that these results were extrapolatable to older patients. HYVET was conducted in 2 stages. An open pilot study was conducted during the first stage, which included 1283 patients, with a large presence of our case series.7 After the
3 promising results, the proposal was to ratify them conclusively with the main, double-blind study to avoid all possible bias. This second stage started in 2004 and had a total of 2247 patients treated over the course of 5 years.8---10 As with SYST-EUR, the clinical findings were highly positive, such that the patients undergoing active treatment had a lower number of cardiovascular complications (myocardial infarction, stroke, peripheral artery disease) and lower mortality than the placebo group. The earlier nihilistic idea of not treating patients with drugs due to age was definitively ruled out because it was not ethical to use the fallacious argument of senescence for not prescribing the necessary drug in each case. The subsequent participation by our group in clinical trials exceeds 160 studies, whose results have been the subject of numerous publications. Reaching these goals has required ongoing effort, enthusiasm and dedication, while overcoming various obstacles: lack of sensitivity by the Center’s management, lack of staff, tiny physical space for conducting the study and delays, in many cases, in getting approval for the respective clinical trial, which frequently requires us to ‘‘race against the clock’’ to catch up with the investigators and centers that had started patient recruitment much earlier than us. Despite these adversities, however, we are satisfied with the part we have played in high-level clinical research studies, which has helped us understand, for example, the complex pathogenesis of hypertension and stroke11,12 and other aspects of cardiovascular risk factors.13---18 We have participated in other relevant clinical trials such as VALUE,19 CONVINCE,20 ONTARGET,21 STABILITY,22 DISTINCT,23 and TRANSCEND,24 which are discussed in the following section.
Clinical trials in progress In the field of diabetes, there are studies searching for new compounds that provide a better quality of life for numerous patients inexorably attached to parenteral insulin. A clinical trial is underway for patients with uncontrolled type 1 diabetes treated with insulin, aimed at studying the efficacy, safety and tolerance of sotagliflozin as a complement to the pancreatic hormone.25 Monoclonal antibodies represent a new therapeutic possibility. The currently underway clinical trial COMMANDER26 is analyzing the safety and efficacy of rivaroxaban in reducing mortality, myocardial infarction and stroke in patients with coronary artery disease after episodes of decompensated heart failure. THEMIS27 is a multinational, double-blind randomized, placebo-controlled clinical trial in progress to assess the effect of ticagrelor on the incidence of cardiovascular death and stroke in patients with type 2 diabetes. Studies with alirocumab (ODYSSEY OUTCOMES and ODYSSEY CHOICE II)28,29 are designed to assess cardiovascular complications (heart disease death, nonfatal myocardial infarction, unstable angina and fatal and nonfatal ischemic stroke) after an acute coronary syndrome. Finally, the clinical trial by Ridker et al.30 with similar characteristics to the previously mentioned study is aimed at assessing the efficacy, safety and tolerance of bococizumab in reducing cardiovascular complications in high-risk patients.
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Figure 1 Beds with complete monitoring. Phase I Unit, Bayer AG, Wuppertal, Germany.
B. Gil-Extremera et al.
Figure 2 Laboratory and instrumentation. Phase I Unit, Bayer AG, Wuppertal, Germany.
Characteristics of a phase I unit Not too long ago, the first signatory received an invitation from Bayer (created in 1863 by Friedrich Bayer [1825---1880]) to visit the facilities of their special phase I unit for healthy volunteers. The unit and the property that houses it are in the city of Wuppertal (North RhineWestphalia, Germany). The members of this center assess the following aspects in healthy volunteers: clinical pharmacology and pharmacokinetics consisting of elements of safety, tolerance/adverse effects, pharmacokinetic measurements and biological markers. The center has 36 beds distributed among the property’s 3 floors, with full monitoring on all floors (Fig. 1), a cardiovascular laboratory with echocardiography, spirometry, retinal vessel study, electrocardiography and transcranial ultrasound. The center comprises the following instrumentation and logistical support: central monitoring (a team for each floor), emergency team (one for each floor), 2 rooms for the general physical examination of participants, 4 laboratories, medical storage room, laboratory for preparing biological samples and storage for devices and instrumentation (Fig. 2). The institution also has 5 rest areas (Fig. 3) equipped with television, Internet access, cafeteria and game room, 3 kitchens with specialized staff, a participant recruitment area and another for nursing. The unit’s pharmacodynamic methods are appropriate for research and the necessary human resources: a physician, 12 full-time nurses, an assistant for recruiting participating volunteers, an administrative team and staff to care for the facilities. The recruitment office has ample physical space for dealing with study candidate interviews, press announcements, visit schedules, invitations, document preparation and catering (Bayer Gastronomie).
Conflicts of Interest The authors declare that they have no conflicts of interest.
Figure 3 many.
Rest area. Phase I Unit, Bayer AG, Wuppertal, Ger-
Acknowledgments We would like to thank Esperanza Velasco for her collaboration in creating the manuscript and Bayer Pharmaceuticals for the information regarding phase i studies.
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5 20. Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T, White WD, et al., for the CONVINCE Research Group. Principal Results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA. 2003;289: 2073---82. 21. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al., ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547---59. 22. White HD, Held C, Stewart R, Tarka E, Brown R, Davies RY, et al., STABILITY Investigators. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med. 2014;370:1702---11. 23. Mancia G, Cha G, Gil-Extremera B, Harvey P, Lewin AJ, Villa G, et al. Blood pressure lowering effects of nifedipine/candesartan combinations in high-risk individuals: subgroup analysis of the DISTINCT randomized trial. J Hum Hypertens. 2017;31: 178---88. 24. Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, copland I, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Telmisartan Randomised AssessmeNT Study in ACE intolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Lancet. 2008;372: 1174---83. 25. Clinical Trials.gov. A Service of the U.S. National Institutes of Health [accessed 30.03.17]. Available from: https://www.clinical trials.gov. ClinicalTrials.gov Identifier: NCT02421510. 26. Clinical Trials.gov. A Service of the U.S. National Institutes of Health [accessed 30.03.17]. Available from: https://www.clinical trials.gov. ClinicalTrials.gov Identifier: NCT01877915. 27. Clinical Trials.gov. A Service of the U.S. National Institutes of Health [accessed 30.03.17]. Available from: https://www.clinical trials.gov. ClinicalTrials.gov Identifier: NCT01991795. 28. Stroes E, Guyton JR, Lepor N, Civeira F, Gaudet D, Watts GF, et al., for the ODYSSEY CHOICE II Investigators. Efficacy and safety of alirocumab 150 mg every 4 weeks in patients with hypercholesterolemia not on statin therapy: The ODYSSEY CHOICE II Study. J Am Heart Assoc. 2016;5:1---11. 29. Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V, Diaz R, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J. 2014;168:682---9. 30. Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376:1527---39.