Assumptions in Clinical Trial Designs and Therapies
2018; Elsevier BV; Volume: 40; Issue: 11 Linguagem: Inglês
10.1016/j.clinthera.2018.10.006
ISSN1879-114X
Autores Tópico(s)Neurogenetic and Muscular Disorders Research
ResumoIn life and in science when needed facts, data, information, or knowledge are missing or incomplete, people often make assumptions. In the United States, this is sometimes called filling in the blanks or connecting the dots. Wiktionary defines the latter term as making connections in one's mind, thereby arriving at a more holistic understanding of a situation.1Wiktionary Connect the dots. https://en.wiktionary.org/wiki/connect_the_dots. Accessed Sep 25, 2018.Google Scholar This definition puts a positive spin on the value of making assumptions. My goal in the following sections is to raise questions about using assumptions when it comes to health care decision making, in clinical trial design and analysis, in one's own assessment of study results, and in the application of research data to clinical practice. In clinical trials of treatments for orphan or rare diseases, the use of historical controls assumes that the basic information about the disease has not changed. A key premise is that no epigenetic factors or mutations have changed the course, severity, or outcomes of the disease. However, making this assumption can be problematic. For example, sporadic amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) is generally thought to be caused by some combination of as yet unknown genetic and environmental factors. Historical data suggest that 50% of patients with ALS will live for about two to three years once the diagnosis is recognized. One-fifth to one-quarter will live closer to five years, and 10% will live for 10 years or longer. The majority of ALS sufferers die from respiratory failure.2National Institute of Neurological Disorders and Stroke. Amyotrophic lateral sclerosis (ALS) fact sheet. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet. Accessed Sep 25, 2018.Google Scholar, 3ALS News Today. Prognosis of ALS. https://alsnewstoday.com/prognosis-of-als. Accessed Sep 25, 2018.Google Scholar, 4Chio A. Logroscino G. Hardiman O. et al.Prognostic factors in ALS: a critical review.Amyotroph Lateral Scler. 2009; 10: 310-323Crossref PubMed Scopus (663) Google Scholar Jean-Martin Charcot, the famous French neurologist, was the first person to recognize ALS in 1869.5Kumar D.R. Aslinia F. Yale S.H. et al.Jean-Martin Charcot: the father of neurology.Clin Med Res. 2011; 9: 46-49Crossref PubMed Scopus (61) Google Scholar Possibly because of its rarity, ALS did not become better known until Henry Louis (Lou) Gehrig was diagnosed with it at the Mayo Clinic in 1939. Born in 1903, Gehrig was an outstanding professional baseball player. In 1939, he realized that he had been slowly losing his muscle strength. His ALS was rapidly progressive; he died on June 3, 1941, several weeks before his 38th birthday.6Biography.com Editors. Lou Gehrig biography. https://www.biography.com/people/lou-gehrig-9308266. Accessed Sep 25, 2018.Google Scholar His unfortunate downhill course is typical. By contrast, Stephen Hawking was a striking ALS outlier.7Wikipedia. Stephen Hawking. https://en.wikipedia.org/wiki/Stephen_Hawking. Accessed Sep 25, 2018.Google Scholar Living until age 76 with his slowly progressing form of ALS, he was a gifted cosmologist and theoretical physicist. His first symptoms began at age 21. He received devoted care but soon lost his ability to speak. He was then able to communicate by using unique computer-based speech-synthesizing software developed by Walter Woltosz.8Internet Movie Database. Walter Woltosz. https://www.imdb.com/name/nm5621878/bio. Accessed Sep 25, 2018.Google Scholar Woltosz had invented this software for his mother-in-law who also had ALS. Although confined to a wheelchair and needing 24-h care, Hawking and others developed additional specialized aids that enabled him to continue to teach and be productive until the time of his death in the spring of 2018. Another long-living ALS sufferer was Sam Shepard (Samuel Shepard Rogers III), the Pulitzer Prize winning American playwright and actor.9Wikipedia. Sam Shepard. https://en.wikipedia.org/wiki/Sam_Shepard. Accessed Sep 25, 2018.Google Scholar Shepard died in the summer of 2017 at the age of 73. I have a vivid memory of his portrayal of Charles E. (Chuck) Yaeger in the movie adaptation of Tom Wolff's book, The Right Stuff. In preparation for this role, Shepard flew in a jet with Yaeger even though he had a strong fear of flying. Yaeger was the first pilot to break the sound barrier. Yaeger is still alive at the age of 95.10Wikipedia Chuck Yaeger. https://en.wikipedia.org/wiki/Chuck_Yeager. Accessed Oct 7, 2018.Google Scholar Because of his many active and productive years, I assume Shepard's ALS was of late onset. I was unable to locate any details of the course of his illness. Studies comparing past cohorts with more recent ones suggest that quality of life for patients with ALS has improved after the introduction of riluzole, a drug thought to work by blocking tetrodotoxin-sensitive sodium channels on damaged neurons, as well as by inhibiting kainate and N-methyl-d-aspartate (NMDA) receptors.11Drugscom Rilutek (Riluzole).July 2, 2018https://www.drugs.com/pro/rilutek.htmlDate accessed: September 25, 2018Google Scholar Previously available only in pill form, riluzole was recently approved in a thickened, easily swallowed, liquid form.12ITFPharma. Tiglutic (riluzole). https://www.tiglutik.com/?gclid=EAIaIQobChMI6snxouPO3QIVhksNCh2J0w1VEAAYAiAAEgL8M_D_BwE. Accessed Sep 25, 2018.Google Scholar Edaravone, whose mechanism of action remains unknown, was developed in Japan and marketed in the United States in 2017.13Mitsubishi Tanabe Pharma Corporation. Radicava (edaravone injection). https://www.radicava.com/patient. Accessed Sep 25, 2018.Google Scholar When rated on a global scale of overall daily functioning, edaravone appears to reduce the rate of decline in patients with ALS. Additional help comes from the use of noninvasive pressure ventilation and nutritional support by gastrostomy. These treatments provide needed calories and reduce pseudobulbar emotional lability, excessive salivation, and breathing and swallowing difficulties. Because ALS is always fatal, some have questioned the cost/benefit of riluzole.14Messori A. Trippoli S. Becagli P. et al.Cost effectiveness of riluzole in amyotrophic lateral sclerosis Italian cooperative group for the study of meta-analysis and osservatorio SIFO sui farmaci.Pharmacoeconomics. 1999; 16: 153-163Crossref PubMed Scopus (28) Google Scholar Cost/benefit studies often make assumptions that many can challenge. Given these facts, in a survival analysis that used death as the outcome variable, no single time end point would seem obvious. Nevertheless, any treatment that could delay death well beyond five years for 75% of patients would surely be approved. In non-inferiority clinical trials, the constancy assumption plays an essential role. In these trials, an active comparator treatment is chosen that is expected to provide a consistent magnitude of improvement compared with placebo.15Koopmeiners J.S. Hobbs B.P. Detecting and accounting for violations of the constancy assumption in non-inferiority clinical trials.Stat Methods Med Res. 2018; 27: 1547-1558Google Scholar In other words, the effect size from prior trials is assumed to be stable enough to be used in the non-inferiority comparison. Put even more simply, what was true about the comparator in the past is assumed to be true in the present study (ie, a variation of an historical control). When it is not, non-inferiority may be incorrectly concluded, resulting in false-positive findings.16Streiner D.L. Noninferiority trials.J Clin Psychopharmacol. 2014; 34: 184-186Crossref PubMed Scopus (4) Google Scholar Experience has taught me that it is not unusual for trial populations to differ across trials because of varying levels of severity, age and sex distributions, and adherence, in which case assuming constancy can be problematic. Another approach that involves assumptions is Bayesian statistics.17Ortega A. Wagenmakers E.J. Lee M.D. et al.A Bayesian latent group analysis for detecting poor effort in the assessment of malingering.Arch Clin Neuropsychol. 2012; 27: 453-465Crossref PubMed Scopus (15) Google Scholar, 18Lunn D.J. Thomas A. Best N. et al.WinBUGS a Bayesian modelling framework: concepts, structure, and extensibility.Stat Comput. 2000; 10: 325-337Crossref Scopus (4335) Google Scholar, 19Berry S.M. Carlin B.P. Lee J.J. et al.Basics of bayesian inference.in: Bayesian Adaptive Methods for Clinical Trials. CRC Press, Boca Raton, FL2010https://www.taylorfrancis.com/books/9781439825518/chapters/10.1201%2FEBK1439825488-5Google Scholar Bayesian methods use prior information, beliefs, or assumptions and combine them with new data to generate conditional probabilities for an event or finding. An advantage of this approach is the ability to update conditional probabilities whenever new information becomes known. Unfortunately, as Professor David Streiner points out, the “Bayesian approach can result in rejecting strong evidence or accepting weak evidence, based on one's subjective prior probabilities.“20Norman G.R. Streiner D.L. Biostatistics: The Bare Essentials.4th ed. PMPH US, Shelton, CT2014: 66Google Scholar The Bayesian approach is becoming more popular when adaptive designs are used. New data can be added after interim analyses and input from data safety monitoring boards can be incorporated. As such, the Bayesian approach to analysis in clinical trials is best suited for Phase I and IIa trials, although it may have its place in Phase III trials when some new safety issue turns up. In my view, Bayesian statistical models are so complicated that they should be used only by experienced statisticians. I selected the topic of assumptions for this month's Note because of a recent article I read. Sacks et al21Sacks C.A. Lee C.W.C. Kesselheim A.S. et al.Medicare spending on brand-name combination medications vs their generic constituents.JAMA. 2018; 320: 650-656Crossref PubMed Scopus (36) Google Scholar published their paper, Medicare Spending on Brand-name Combination Medications vs Their Generic Constituents, in a July issue of the JAMA. Using 2016 data, they concluded that medication costs could be reduced through better prescriber education and by using appropriate generic and therapeutic substitutions. I wholeheartedly endorse this conclusion. However, one of the examples they used caused me to question their assumption about therapeutic equivalence and substitution. Are therapeutically equivalent drugs necessarily clinically equivalent? A short answer is no. The following sections elucidate my answer. For the treatment of hypertension, Sacks et al21Sacks C.A. Lee C.W.C. Kesselheim A.S. et al.Medicare spending on brand-name combination medications vs their generic constituents.JAMA. 2018; 320: 650-656Crossref PubMed Scopus (36) Google Scholar propose substituting generic losartan, an angiotensin receptor competitive antagonist, for the more expensive, brand-named azilsartan (Edarbi), also an angiotensin receptor competitive antagonist, with either of these drugs given in combination with chlorthalidone, a generically available, long-acting thiazide diuretic. Readers who remember mechanisms of action may recall that angiotensin receptor competitive antagonists inhibit the binding of angiotensin II to its receptor, which, in turn, inhibits the reabsorption of sodium chloride (salt) from the proximal tubule of the kidney. Thiazides inhibit the reabsorption of sodium chloride from the distal convoluted tubule of the kidney. By influencing two different pathways to lower the sodium chloride burden, these combinations can be effective therapeutic interventions. The brand-named combination is called Edarbyclor. The paper's authors propose a potential savings of US$11 million from using the two generic drugs instead of Edarbyclor. The angiotensin receptor competitive antagonists, losartan and azilsartan, are considered to be therapeutically substitutable. I question the assumption that they are clinically comparable. Hypertension that is severe enough to require more than one antihypertensive agent is likely to be comorbid with other cardiovascular problems. Such patients will generally be taking other medications. Azilsartan is actually marketed as azilsartan medoxomil22Wikipedia. Azilsartan. https://en.wikipedia.org/wiki/Azilsartan. Accessed Sep 25, 2018.Google Scholar. This product is a prodrug for azilsartan. Conversion takes place through hydrolysis in the gastrointestinal tract. Azilsartan is primarily metabolized by cytochrome P450 2C9 (CYP2C9), and its elimination half-life is 11 h. Its two primary metabolites are not active at the angiotensin II receptor, and its bioavailability is ∼60%. Losartan is primarily metabolized by CYP2C9 and CYP3A423Wikipedia. Losartan. https://en.wikipedia.org/wiki/Losartan. Accessed Sep 25, 2018.Google Scholar. Its principle metabolite is EXP3174. EXP3174 is significantly more potent at the angiotensin II receptor at which it is a noncompetitive antagonist. The elimination half-lives of losartan and EXP3174 range from 1.5 to 2.5 h and from 3 to 9 h, respectively. Losartan's bioavailability is ∼32%. Curiously, and perhaps of meaningful clinical significance, EXP3174 compared with losartan is a more potent antagonist for angiotensin II-induced responses in vascular smooth muscle cells24Sachinidis A. Ko Y. Weisser P. et al.EXP3174, a metabolite of losartan (MK 954, DuP 753) is more potent than losartan in blocking the angiotensin II-induced responses in vascular smooth muscle cells.J Hypertens. 1993; 11: 155-162Crossref PubMed Scopus (56) Google Scholar. EXP3174 also appears to reduce the incidence of ischemic ventricular arrhythmias in a canine model of myocardial infarction25Lynch Jr., J.J. Stump G.L. Wallace A.A. et al.EXP3174, the AII antagonist human metabolite of losartan, but not losartan nor the angiotensin-converting enzyme inhibitor captopril, prevents the development of lethal ischemic ventricular arrhythmias in a canine model of recent myocardial infarction.J Am Coll Cardiol. 1999; 34: 876-884Crossref PubMed Scopus (16) Google Scholar. Neither losartan nor captopril, an angiotensin converting enzyme inhibitor, had this reducing effect. These properties and observations raise two questions: (1) is azilsartan the safer drug in the presence of other drugs that inhibit CYP3A4? and (2) is the combination of losartan with chlorthalidone not only cheaper but also possibly more clinically useful in patients with comorbid heart disease because of the potential actions of its metabolite EXP3174? In my view, we need head-to-head clinical trials before we assume that therapeutically equivalent drugs are clinically comparable. Perhaps then we should more appropriately subdivide seemingly comparable drugs into two categories: (1) those that are truly therapeutically equivalent across populations, and (2) those that are more aptly described as therapeutically similar—this latter term was provided to me by my long-term colleague, Professor David J. Greenblatt. Sacks et al21Sacks C.A. Lee C.W.C. Kesselheim A.S. et al.Medicare spending on brand-name combination medications vs their generic constituents.JAMA. 2018; 320: 650-656Crossref PubMed Scopus (36) Google Scholar did not suggest substituting valsartan, even though some evidence suggests it may be more efficacious than losartan25Lynch Jr., J.J. Stump G.L. Wallace A.A. et al.EXP3174, the AII antagonist human metabolite of losartan, but not losartan nor the angiotensin-converting enzyme inhibitor captopril, prevents the development of lethal ischemic ventricular arrhythmias in a canine model of recent myocardial infarction.J Am Coll Cardiol. 1999; 34: 876-884Crossref PubMed Scopus (16) Google Scholar, 26Nixon R.M. Muller E. Lowy A. et al.Valsartan vs. other angiotensin II receptor blockers in the treatment of hypertension: a meta-analytical approach.Int J Clin Pract. 2009; 63: 766-775Crossref PubMed Scopus (59) Google Scholar. Valsartan has been marketed in the United States since 1996, but standalone generic versions did not become available until 2014. Unfortunately, many versions of valsartan, alone and in combination products, are now under a voluntary recall announced by the Food and Drug Administration as of July 13, 201827Food and Drug Administration FDA Announces Voluntary Recall of Several Medicines Containing Valsartan Following Detection of an Impurity.July 13, 2018https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm613532.htmDate accessed: September 25, 2018Google Scholar, 28Food and Drug Administration FDA Updates on Valsartan Recalls.August 22, 2018https://www.fda.gov/Drugs/DrugSafety/ucm613916.htmDate accessed: September 25, 2018Google Scholar. Higher than acceptable levels of N-nitrosodimethylamine (NDMA) were found in various lots of formulations that incorporated valsartan sourced from China. NDMA is an animal carcinogen that may have the potential to cause cancer in humans. Readers should note that NDMA is not the same as N-methyl-d-aspartate (NMDA), a compound that binds to glutamate receptors. For heuristic purposes, I offer the following simplified definitions (Table).TableDefinition of terms.TermDefinitionPharmaceutical equivalenceTwo or more drugs have the same active ingredient or ingredients present in the same strengths and are administered by the same route; excipients and particle size may differGeneric equivalenceTwo or more drugs are pharmaceutically equivalent and, in addition, after a single dose must have comparable dissolution and absorption characteristics, Cmax, and AUCs, and, for certain drugs having single-dose clinical effects Tmax should be similarTherapeutic equivalenceTwo or more drugs have the same mechanism of action, clinical benefits, safety profile, and off-target effects; they are interchangeable in clinical practiceTherapeutic similarityTwo or more drugs have the same primary mechanism of action, clinical benefits, and comparable on-target effects but have different off-target effects Open table in a new tab For orphan or rare diseases, preapproval exposure in patients is typically limited. As such, less frequently occurring untoward effects may not be revealed until after a drug is already marketed. When an event does occur, causality may be difficult to establish. Deciding what is a safety signal is an assumption that can only be clarified by further investigation. Past Updates in Clinical Therapeutics initiated our efforts to bring more information on pharmacovigilance to our readership. For more discussion on pharmacovigilance of orphan drugs, readers are referred to Dr. John Price's commentary in our December 2016 Update, Pharmacovigilance in the New Millennium29Price J. What can big data offer the pharmacovigilance of orphan drugs?.Clin Ther. 2016; 38: 2533-2545Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar. In our December 2018 issue, several additional papers will describe the current challenges facing the global drug safety industry, including signal detection, case reporting, causality assessment, and harmonization. I am pleased to announce that we are introducing a new coverage area in Clinical Therapeutics. Two distinguished pharmacoepidemiologists have joined us as Consulting Editors, Cynthia Willey, PhD, and Greg Calip, PharmD, MPH, PhD. Pharmacoepidemiology is especially relevant for orphan and rare diseases and for post-marketing surveillance. We look forward to publishing more papers on this important topic. In our July 2018 Update, Topic Editor Kenneth Kaitin, PhD, and Guest Editor Christopher Milne, DVM, JD, MPH, initiated our coverage of regenerative medicine30Milne C.P. Kaitin K.I. Regenerative medicine at the forefront of innovation: update from Japan.Clin Ther. 2018; 40: 1798-1800Abstract Full Text Full Text PDF Scopus (1) Google Scholar, 31Shigeto J. Ichiki T. Nii T. Konno K. Nakanishi Y. Sugiyama D. Preclinical toxicity studies for regenerative medicines in Japan.Clin Ther. 2018; 40: 1813-1822Abstract Full Text Full Text PDF Scopus (6) Google Scholar, 32Sawada M. Sugiyama D. Nii T. Konno K. Kagimoto H.T.S. A Japanese Bioventure Company's Application of tem Cell Technology in Regenerative Medicine.Clin Ther. 2018; 40: 1801-1806Abstract Full Text Full Text PDF Scopus (5) Google Scholar, 33Tsuruya N. Kawashima T. Shiozuka M. Yoichi N. Sugiyama D. Academia-industry cooperation in the medical field, matching opportunities in Japan.Clin Ther. 2018; 40: 1807-1812Abstract Full Text Full Text PDF Scopus (8) Google Scholar, 34Asano S. Nakanishi Y. Sugiyama D. Intellectual property in the field of regenerative medicine in Japan.Clin Ther. 2018; 40: 1823-1827Abstract Full Text Full Text PDF Scopus (3) Google Scholar. Milne and Kaitin continue in this vein in the present issue by bringing us a series of papers covering various aspects of Japan's progress in this exciting and innovative area. To achieve a goal of preeminence in regenerative medicine research and care, the Japanese Ministry of Health, Labor and Welfare developed a Strategy of SAKIGAKE35Ministry of Health, Labour and Welfare. Strategy of Sakigake. https://www.mhlw.go.jp/english/policy/health-medical/pharmaceuticals/140729-01.html. Accessed Oct 1, 2018.Google Scholar. A project team was appointed in 2015 and given the task of coordinating the efforts and contributions of many disparate elements within the Ministry. Emphasis is placed on innovative approaches in both basic and clinical research. When I read about this, I wondered what SAKIGAKE means. I tried to find out by looking up the meaning of the words saki and gake. I hope no one will assume that I really meant sake. Saki means “pioneer” or “ahead” and gake means “cliff.” From this, I assumed the following meaning: a plan to tackle new and difficult challenges like climbing up the face of a steep cliff. I was filling in for my lack of knowledge of the Japanese language. Next, I decided to contact a learned Japanese colleague, Dr. Hiroyuki Uchida, to find out the real meaning. He and colleagues recently published an article, Psychopharmacology in Japan: An Overview and Recent Topics36Yoshida K. Suzuki T. Uchida H. Psychopharmacology in Japan: an overview and recent topics.J Clin Psychopharmacol. 2018; 38: 415-419Google Scholar. Dr. Uchida informed me that sakigake is a Samurai-derived term used to describe brave Samurai rushing ahead of others to be the spearhead in a battle. He went on to indicate that its current meanings are “pioneer” or the “act of tackling a new challenge.” It seems that my assumption was pretty close. From the years when I was teaching translational pharmacology, I recall that approximately one-fifth (18%–23%) of the Japanese population are poor metabolizers of drugs whose metabolism is mediated by CYP2C19. This subgroup has the polymorphism CYP2C19*237Yamaori S. Yamazaki H. Iwano S. et al.Ethnic differences between Japanese and Caucasians in the expression levels of mRNAs for CYP3A4, CYP3A5 and CYP3A7: lack of co-regulation of the expression of CYP3A in Japanese livers.Xenobiotica. 2005; 35: 69-83Crossref PubMed Scopus (58) Google Scholar, 38ScienceDirect. CYP2C19. https://www.sciencedirect.com/topics/medicine-and-dentistry/cyp2c19. Accessed Oct 1, 2018.Google Scholar. This frequency is less than what is found in India (∼33%) but more than is typical in the United States (∼13%). Examples of drugs metabolized in whole or in part by this enzyme include proguanil, S-mephenytoin, diazepam, clopidogrel, and omeprazole. I wondered if any polymorphisms have been identified that militate against the successful use of stem cells. Graft versus host reactions (GvHR) can lower the success rates of allogenic stem cell transplantation. Beyond matching for human leukocyte antigens, almost nothing is known about other genetic polymorphisms that influence immune responses to allogenic stem cells. In Caucasian Belarusians (n = 483) undergoing hematopoietic stem cell transplantation, polymorphisms of the NOD2/CARD15 gene were associated with an increased risk of extensive chronic and steroid-resistant GvHRs39Lavrinenko V. Takun K. Minakovskaya N. et al.NOD2/CARD15 gene polymorphisms are associated with increased risk of extensive chronic and steroid resistant graft versus host disease after hematopoietic stem cell transplantation.J Transpl Technol Res. 2016; 6https://www.omicsonline.org/proceedings/nod2card15-gene-polymorphisms-are-associated-with-increased-risk-of-extensive-chronic-and-steroidresistant-graft-versus--55471.htmlGoogle Scholar. I found no studies of these polymorphisms (C2104T in exon 4, G2722C in exon 8, and 3020insC in exon 11) in Japanese patients with GvHRs. However, in two studies of Japanese patients with Crohn's disease (n = 272 with polymorphism of C2104T in exon 4, n = 483 with polymorphism of G2722C in exon 8) and controls (n = 292 with polymorphism of 3020insC in exon 11), no mutations in the NOD2/CARD15 gene were found, suggesting that such polymorphisms are rare or absent in Japanese40Yamazaki K. Takazoe M. Tanaka T. et al.Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn's disease.J Hum Genet. 2002; 47: 469-472Crossref PubMed Scopus (259) Google Scholar, 41Inoue N. Tamura K. Yoshitaka K. et al.Lack of common NOD2 variants in Japanese patients with Crohn's disease.Gastroenterology. 2002; 123: 86-91Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar. These apparent differences between Japanese, Caucasian, and other ethnic groups should remind us of the need to consider pharmacogenomic variations before generalizations are made about treatments or diseases. How any months have 30 days? Many people when asked this respond “Four.” They are assuming a connection to the mnemonic: “Thirty days has September, April, June, and November, all the rest have 31, except for February which has 28 and leap year which has 29.” The correct answer is 11. All months have a 30th day, except February. I am reminded of an episode of the television version of The Odd Couple during which the always amusing Tony Randall (Felix Unger) says to a woman something like: “Ah, you assumed. My dear, you should never assume. You see, when you assume, you make an ass out of you and me“42Internet Movie Database. The Odd Couple (1970-1975) Quotes. https://www.imdb.com/title/tt0065329/quotes. Accessed Oct 1, 2018.Google Scholar. This episode of The Odd Couple was written by the late Jerry Belson who, in turn, attributed this idea to one of his past teachers43Wikipedia. Jerry Belson. https://en.wikipedia.org/wiki/Jerry_Belson. Accessed Oct 1, 2018.Google Scholar. In closing, I want to take this opportunity to say that we are aware of our growing Asian presence, and, as a result, we are adding additional Asian editors and reviewers to our editorial team.This month's Drugs and Biologics Update is a special feature which is available as FREE ACCESS content on the journal's website. One of the previous Drugs and Biologics Updates, entitled “Global Regenerative Medicine,” was published in Volume 40, Issue 7 of Clinical Therapeutics. To view the previous Update, see the articles below:Milne CP, Kaitin KI. Challenge and Change at the Forefront of Regenerative Medicine.Glicksman MA. Induced Pluripotent Stem Cells: The Most Versatile Source for Stem Cell Therapy.Hossain I, Milne C. Can Regenerative Medicine Help Close the Gap Between the Medicine Pipeline and Public Health Burden of Cardiovascular and Musculoskeletal Diseases?Okada K, Sato Y, Sugiyama D, Sawa Y. Establishment of the National Consortium for Regenerative Medicine and National Regenerative Medicine Database in Japan.Banda G, Tait J, Mittra J. Evolution of Business Models in Regenerative Medicine: Effects of a Disruptive Innovation on the Innovation Ecosystem. This month's Drugs and Biologics Update is a special feature which is available as FREE ACCESS content on the journal's website. One of the previous Drugs and Biologics Updates, entitled “Global Regenerative Medicine,” was published in Volume 40, Issue 7 of Clinical Therapeutics. To view the previous Update, see the articles below: Milne CP, Kaitin KI. Challenge and Change at the Forefront of Regenerative Medicine. Glicksman MA. Induced Pluripotent Stem Cells: The Most Versatile Source for Stem Cell Therapy. Hossain I, Milne C. Can Regenerative Medicine Help Close the Gap Between the Medicine Pipeline and Public Health Burden of Cardiovascular and Musculoskeletal Diseases? Okada K, Sato Y, Sugiyama D, Sawa Y. Establishment of the National Consortium for Regenerative Medicine and National Regenerative Medicine Database in Japan. Banda G, Tait J, Mittra J. Evolution of Business Models in Regenerative Medicine: Effects of a Disruptive Innovation on the Innovation Ecosystem.
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