Case 1:20-cv-01644-RGA Document 1-16 Filed 12/03/20 Page 1 of 4 PageID #: 864
`Case 1:20-cv-01644-RGA Document 1-16 Filed 12/03/20 Page 1 of 4 PageID #: 864
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`Comment
`
`and this paradox has also been detected in other
`COX-2 studies.5 Laine speculates that this fi nding is due
`to a divergent role of COX-1 inhibition, with moderate
`COX-1 inhibition causing the mucosal defect while
`profound COX-1 inhibition would lead to bleeding.
`However, peptic ulcer complications are relatively
`rare, and the MEDAL programme might have been
`underpowered to detect an actual treatment eff ect.
`Indeed, if there is a true protective eff ect, can we
`estimate how large this would be? To this end it
`is benefi cial to express the benefi t in the number
`of patients that need to be treated to avoid harm
`rather than to mention hazard ratios. If we calculate
`this benefi t on the basis of the results in Laine and
`colleagues’ table 3, we would need to treat 259 patients
`with etoricoxib to prevent one uncomplicated gastro-
`intestinal event in one patient. So, although the
`eff ect might well be statistically signifi cant, the eff ect
`is certainly not large and might not be clinically
`relevant. Furthermore, the clinical signifi cance of an
`uncomplicated (small) peptic ulcer, if (as shown in
`the MEDAL programme) complications do not occur,
`remains to be seen.
`The MEDAL programme represents industry-driven
`research. The statistical analysis, key to the results,
`was by employees from Merck Research Laboratories
`and the company had infl uence over all aspects, in-
`cluding data analysis, safety monitoring, and re porting
`of the MEDAL programme. This control might not
`necessarily aff ect the credibility of the results, but the
`demise of rofecoxib6 indicates that independent data-
`analysis—done here by Frontier Science Foundation—is
`desirable.
`The real question is whether a COX-2 inhibitor, such
`as etoricoxib, is safer than a PPI added to a standard
`non-steroidal anti-infl ammatory drug. The advantage
`of the PPI option is that it is less expensive, potentially
`
`in terms of
`less cardiotoxic, and advantageous
`reducing dyspepsia, but confi rmation of this needs
`a new randomised trial. A Cochrane review supports
`the safety of add-on PPI,7 and an observational study
`suggests that this strategy has a similar safety profi le
`to COX-2 inhibition alone.8 The nature of the MEDAL
`programme, however, does not allow a defi nitive
`answer to that question. As such, Laine and colleagues’
`article merely generates the hypothesis rather than
`answering it.
`
`2
`
`4
`
`*Joost P H Drenth, Freek W A Verheugt
`Department of Gastroenterology and Hepatology (JPHD) and
`Department of Cardiology (FWAV), Heart Lung Centre,
`Radboud University Nijmegen, Medical Centre,
`6500 HB Nijmegen, Netherlands
`joostphdrenth@cs.com
`JPHD declares he has no confl ict of interest. FV has served on a clinical event
`committee of a coxib trial sponsored by Novartis.
`1
`Laine L, Curtis SP, Cryer B, Kaur A, Cannon CP, for the MEDAL Steering
`Committee. Assessment of upper gastrointestinal safety of etoricoxib and
`diclofenac in patients with osteoarthritis and rheumatoid arthritis in the
`Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL)
`programme: a randomised comparison. Lancet 2007; 369: 465–73.
`Hawkey CJ, Langman MJ. Non-steroidal anti-infl ammatory drugs: overall
`risks and management: complementary roles for COX-2 inhibitors and
`proton pump inhibitors. Gut 2003; 52: 600–08.
`3 Moore RA, Derry S, Phillips CJ, McQuay HJ. Nonsteroidal anti-infl ammatory
`drugs (NSAIDs), cyxlooxygenase-2 selective inhibitors (coxibs) and
`gastrointestinal harm: review of clinical trials and clinical practice.
`BMC Musculoskelet Disord 2006; 7: 79.
`Cannon CP, Curtis SP, FitzGerald GA, for the MEDAL Steering Committee.
`Cardiovascular outcomes with etoricoxib and diclofenac in patients with
`osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and
`Diclofenac Arthritis Long-term (MEDAL) programme: a randomised
`comparison. Lancet 2006; 368: 1771–81.
`Hooper L, Brown TJ, Elliott R, Payne K, Roberts C, Symmons D. The
`eff ectiveness of fi ve strategies for the prevention of gastrointestinal
`toxicity induced by non-steroidal anti-infl ammatory drugs: systematic
`review. BMJ 2004; 329: 948.
`Krumholz HM, Ross JS, Presler AH, Egilman DS. What have we learnt from
`Vioxx? BMJ 2007; 334: 120–23.
`Rostom A, Dube C, Wells G, et al. Prevention of NSAID-induced
`gastroduodenal ulcers. Cochrane Database Syst Rev 2002; 4: CD002296.
`Rahme E, Barkun Y, Toubouti Y, Rochon J, Lelorier J. Do proton pump
`inhibitors (PPI) infer additional gastrointestinal protection in patients
`given celecoxib? A retrospective cohort study. Gastroenterology 2005; 128:
`A24 (abstr).
`
`5
`
`6
`
`7
`
`8
`
`Non-invasive prenatal diagnosis of fetal aneuploidies
`
`Published Online
`February 2, 2007
`DOI:10.1016/S0140-
`6736(07)60116-0
`See Articles page 474
`See Viewpoint page 526
`
`In today’s Lancet, Ravinder Dhallan and colleagues
`report a new concept for non-invasive prenatal
`diagnosis of aneuploidies (eg, trisomy 21, the cause
`of Down’s syndrome) by analysis of free fetal DNA
`circulating in maternal plasma.1 Since its discovery by
`Lo and colleagues in 1997,2 free fetal DNA has been
`
`successfully used for determination of fetal sex and
`rhesus D status on a routine basis by some specialised
`laboratories.3,4 Although some other applications have
`been published, they remained anecdotal because
`of technical diffi cul ties, and a large-scale application
`(eg, for Down’s syndrome) remains to be attained. One
`
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`www.thelancet.com Vol 369 February 10, 2007
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`Case 1:20-cv-01644-RGA Document 1-16 Filed 12/03/20 Page 3 of 4 PageID #: 866
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`Comment
`
`The printed journal
`includes an image merely
`for illustration
`
`Science Photo Library
`
`Recently the American College of Obstetricians and
`Gynecologists recommended, as did several European
`countries, that all women be off ered the option of
`genetic screening, irrespective of maternal age.11 The
`false-positive rate of Down’s syndrome screening tests
`is around 5% with a detection rate of abnormal fetuses
`of 64–96%.12 The techniques developed by Dhallan and
`Lo and their respective colleagues cannot be compared
`with currently available screening tests. Although the
`sensitivity and specifi city of the SNPs tests can compare
`favourably with those of the serum screening double
`or triple tests, these studies are preliminary and have
`been done on very few patients. The sensitivity and
`specifi city of the serum screening tests have been
`assessed on thousands of patients and are technically
`easy and reproducible by multiple centres. Dhallan’s test
`is promising and opens a new era in prenatal diagnosis
`but to be optimally used as a routine prenatal screening
`or diagnostic test, their fi ndings need to be replicated in
`a large-scale multicentre setting.
`Although we can be reasonably optimistic that a
`non-invasive diagnosis for fetal aneuploidies will become
`a reality in the near future, it is only the beginning of a
`new chapter. The substantial resources invested in this
`research should help to reach this goal.
`
`drawback was that fetal chromosomal abnormalities
`could not be identifi ed because of the inability to
`distinguish (at a minimum) or to isolate (ideally) fetal
`DNA from the maternal DNA background in maternal
`plasma. This idea has been recently challenged by
`two studies. The fi rst focused on detection of fetal
`trisomy 18 by analysis of epigenetic allelic ratios in
`maternal plasma,5 the other on genotyping of fetal
`paternally inherited single-nucleotide polymorphisms
`(SNPs) by fractionation at diff erent sizes of fetal and
`maternal DNA.6
`A further step has now been made toward non-
`invasive diagnosis of fetal aneuploidies. Dhallan and
`colleagues postulated that SNPs could be used to
`determine the number of fetal chromosomes
`in
`maternal blood. This approach is not novel.7 However,
`the method that Dhallan reports—quantifi cation and
`comparison of allele ratios for multiple SNPs sites on
`chromosomes 13 and 21 after fetal DNA enrichment in
`maternal plasma—is original. Their study is a prelimin-
`ary clinical study in 60 patients, but only three carried
`a fetus aff ected by trisomy 21. Some technical issues
`still need to be overcome. First, the amount of free fetal
`DNA in maternal blood is low (3–6%),8 and although
`the use of formaldehyde allows an increased amount
`to be isolated from maternal blood, yields are irregular,
`ranging from 17% to 94%.9 Second, Dhallan assessed
`only eight women in the fi rst trimester; further testing
`in this stage of pregnancy will be essential. Further-
`more, a large number of SNPs are needed for the
`technique to work.
`Meanwhile, Lo and colleagues have targeted nucleic
`acid molecules that are specifi c to the fetus to diagnose
`fetal chromosomal aneuploidy from maternal plasma.10
`They used a circulating placental mRNA transcribed
`from a chromosome of interest. They showed that
`the RNA-SNP allelic ratio of PLAC4 mRNA released
`into the maternal plasma refl ects the allelic ratio of
`chromosome 21 in the placenta itself, and therefore in
`the fetus. Both the sensitivity and specifi city of the test
`are high (90% and 96·5%, respectively), and it seems
`possible to use this test, which relies on a single SNP
`marker, in all three trimesters of pregnancy. However,
`the technique is only applicable to informative cases
`that are heterozygous for the studied SNP. Nonetheless,
`it could be extended to a broader population by use of a
`panel of SNPs in other candidate genes.
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`www.thelancet.com Vol 369 February 10, 2007
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`Case 1:20-cv-01644-RGA Document 1-16 Filed 12/03/20 Page 4 of 4 PageID #: 867
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`Comment
`
`*Alexandra Benachi, Jean-Marc Costa
`Université Paris-Descartes, Faculté de Médecine; AP-HP,
`Maternité, Hôpital Necker-Enfants Malades, 75015 Paris, France
`(AB); and Laboratoire de Biologie Moléculaire, Hôpital Américain
`de Paris, Neuilly sur Seine, France (J-MC)
`alexandra.benachi@nck.aphp.fr
`We declare that we have no confl icts of interest.
`1
`Dhallan R, Guo X, Emche S, et al. A non-invasive test for prenatal diagnosis
`based on fetal DNA present in maternal blood: a preliminary study.
`Lancet 2007; published online Feb 2. DOI:10.1016/S0140-6736(07)60115-9.
`Lo YM, Corbetta N, Chamberlain PF, et al. Presence of fetal DNA in maternal
`plasma and serum. Lancet 1997; 350: 485–87.
`Costa JM, Benachi A, Gautier E. New strategy for prenatal diagnosis of
`X-linked disorders. N Engl J Med 2002; 346: 1502.
`Bianchi DW, Avent N, Costa JM, van der Schoot CE. Non invasive prenatal
`diagnosis of fetal rhesus D: ready for prime(r) time. Obstet Gynecol 2005;
`106: 841–44.
`Tong YK, Ding C, Chiu RW, et al. Noninvasive prenatal detection of fetal
`trisomy 18 by epigenetic allelic ratio analysis in maternal plasma:
`theoretical and empirical considerations. Clin Chem 2006; 52: 2194–202.
`
`2
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`3
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`4
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`5
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`10
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`6
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`7
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`8
`
`9
`
`Li Y, Wenzel F, Holzgreve W, Hahn S. Genotyping fetal paternally
`inherited SNPs by MALTI-TOF MS using cell-free fetal DNA in maternal
`plasma: infl uence of size fractionation. Electrophoresis 2006; 27:
`3889–96.
`Tsui NB, Chiu RW, Ding C, et al. Detection of trisomy 21 by quantitative
`mass spectrometric analysis of single-nucleotide polymorphisms. Clin Chem
`2005; 51: 2358–62.
`Lo YM, Tein MSC, Lau TK, et al. Quantitative analysis of fetal DNA in
`maternal plasma and serum: implications for noninvasive prenatal
`diagnosis. Am J Hum Genet 1998; 62: 768–75.
`Dhallan R, Au WC, Mattagajasingh S, et al. Methods to increase the
`percentage of free fetal DNA recovered from the maternal circulation.
`JAMA 2004; 291: 1114–19.
`Lo YM, Tsui NB, Chiu RW, et al. Plasma placental RNA allelic ratio permits
`noninvasive prenatal chromosomal aneuploidy detection. Nat Med 2007;
`published online Jan 7. DOI:10.1038/nm1530.
`11 Anon. ACOG practice bulletin no. 77: screening for fetal chromosomal
`abnormalities. Obstet Gynecol 2007; 109: 217–27.
`12 Malone FD, Canick JA, Ball RH, et al. First-trimester or second-trimester
`screening, or both, for Down’s syndrome. N Engl J Med 2005; 353:
`2001–11.
`
`Attention prescribers: be careful with antibiotics
`
`that maintain ambivalence over the consequences of
`inappropriate and uncontrolled antibiotic prescribing.
`Malhotra-Kumar and
`co-workers undertook a
`randomised, double-blind, placebo-controlled study
`designed to satisfy scientists and persuade even the
`most disengaged of clinical readers. The eff ect of two
`macrolide antibiotics, azithromycin (500 mg once
`daily for 3 days) and clarithromycin (500 mg twice
`daily for 7 days), was measured against placebo in four
`groups of volunteers by use of oral streptococci as
`model organisms.1 The researchers recorded a clearly
`defi ned eff ect on commensal pharyngeal streptococci,
`with both drugs selecting for macrolide resistance.
`Additionally, each antibiotic exerted its own distinctive
`selection pressure—azithromycin selected quantitatively
`more resistant organisms in the early post-therapy
`phases, whereas clarythromycin qualitatively selected
`for the higher resistance-conferring erm(B) gene.
`The acquisition of erm(B) represents a more effi cient
`resistance mechanism for the organism. Not only does
`it confer increased resistance to the macrolide group
`of antibiotics, but it also induces resistance to the
`lincosamide, streptogramin B, and tetracycline groups.
`Just as acquisition of the mec(A) gene in Staphylococcus
`aureus wipes out susceptibility to fl ucloxacillin and all
`other β-lactam drugs, clarythromycin also seems to
`aid the acquisition of a whole package of resistance
`advantages for streptococci.
`
`See Articles page 482
`
`Microbiologists have known for some time that exposure
`to antimicrobial drugs leads to antimicrobial resistance.
`But trying to convince our scientifi c colleagues has not
`been easy. Quite simply, antibiotic consumption is
`diffi cult to measure accurately, along with surveillance
`of the corresponding resistance rates
`in diff erent
`populations. These problems have led to the evidence
`being associative and not necessarily causal. The need to
`prove the link between antimicrobial consumption and
`increasing resistance has now gained momentum and
`the report by Surbhi Malhotra-Kumar and colleagues1 in
`today’s Lancet provides a robust challenge to attitudes
`
`The printed journal
`includes an image merely
`for illustration
`
`Science Photo Library
`
`442
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`www.thelancet.com Vol 369 February 10, 2007
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