Special Edition 2021

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Prescrire International • 2021 • SPECIAL EDITION

Specially selected to introduce you to this wholly independent monthly drug bulletin , written by and for healthcare professionals

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Who are we? Prescrire is a French non-profit continuing education organisation, committed to better patient care Prescrire International is a monthly drug bulletin with selected texts translated from the French journal La Revue Prescrire

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President of Association Mieux Prescrire: Pierre Chirac, pharmacist ASSOCIATION MIEUX PRESCRIRE “To work, in all independence, in favour of quality healthcare, first and foremost in the interest of patients (...)” (Article 1 of the Association Mieux Prescrire bylaws). Prescrire International is published 11 times a year by Association Mieux Prescrire, a non-profit continuing education organisation (N° 11 711 075) under the French law of 1901. EDITORIAL STAFF Members of the Prescrire Editorial Staff sign a yearly declaration of absence of conflicts of interest, in accordance with Prescrire’s “Non merci...” Charter. Members are free from any interest contrary to Association Mieux Prescrire’s objectives (the Charter and the Declaration are available online at english.prescrire.org). Publishing reliable reviews that are easy to use and adapted to readers’ needs depends upon complex editorial procedures, all initiated and overseen by the members of Prescrire’s Editorial Staff. Members of the Editorial Staff define editorial goals.They oversee the literature search, the writing and rewriting of texts, and the review by a panel of outside experts (medical specialists, methodologists, representatives of Prescrire’s subscriber base…).They organise internal and external quality control procedures, and edit the final copy. Every draft is submitted, before publication, to a large number of external reviewers. Copyright Prescrire www.prescrire.org Registered address: 83, bd Voltaire 75011 Paris France Tel.: 33 01 49 23 72 80 E-mail: contact@prescrire.org Postal address: Prescrire - 83, bd Voltaire 75558 PARIS CEDEX 11 - FRANCE - Around 150 members of the Prescrire team - Around 100 external reviewers, experts in the subjects discussed and practising healthcare professionals For each issue, readers are provided with a list of the contributors to that issue. Around 250 people participate in the production and distribution of every issue of La Revue Prescrire , including:

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Editorial Doing one’s job TOP TEXTS OF 2021 SPECIAL EDITION How we work Prescrire’s rigorous, collective editorial process has been fine-tuned over the years NEW PRODUCTS

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Ebola vaccine rVSV-Zebov( ervebo °) in an outbreak of Ebola virus disease Major reduction in incidence among those at risk for this often-fatal infection Fexinidazole ( fexinidazole winthrop °) and sleeping sickness caused by Trypanosoma brucei gambiense Effective and more convenient than injectable treatments Polatuzumab vedotin ( polivy °) and large B-cell lymphoma Remdesivir ( veklury °) and covid-19 Too many uncertainties over its efficacy as well as its harms Authorisation of remdesivir in the European Union: EMA needs to prioritise patients’ interests Dasatinib in children ( sprycel ° and other brands ) with acute lymphoblastic leukaemia Failure to demand solid evidence for marketing authorisation spells danger for patients ADVERSE EFFECTS VEGF inhibitors : arterial aneurysm and dissection Apixaban, edoxaban, rivaroxaban: situations with a high risk of bleeding or thrombosis Liposomal forms of drugs: now specified in the brand name, but no improvement to the INN REVIEWS Medical cannabis in chronic pain An option for some types of pain, while awaiting further evaluation Hydrochlorothiazide in hypertension An acceptable first choice OUTLOOK Towards better patient care: drugs to avoid in 2021 Drugs in 2020: a brief review Drug shortages : a (big) thorn in the side of pharmacists Towards transparency in the research costs of new drugs

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Prescrire’s reviews, written by specially trained health professionals, are based on an exhaustive search of the literature, and undergo scrutiny by a large panel of outside reviewers plus rigorous quality-control procedures.

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Editors free from conflicts of interest The absence of any direct or indirect financial links to the pharmaceutical industry is an absolute requirement to be a member of the Prescrire team. Any such link would be cause for dismissal from the Prescrire Editorial Staff. A vast network of reviewers Once they are in an advanced stage of editing and quality control, all draft reviews are sent to outside reviewers (10 to 40 reviewers read each draft at this stage). These reviewers critique each article in terms of content, style, relevance, newsworthiness, presenta- tion of arguments and usefulness in daily practice. The reviewers are spe- cialists in the subject being discussed, methodologists, or healthcare profes- sionals representative of Prescrire’s readers (and chosen from their midst).

All the reviews published in La Revue Prescrire (aside from a few clearly labelled exceptions, such as readers’ letters) are written by Prescrire’s Edi- torial Staff. Prescrire does not publish unsolicited manuscripts from outside contributors. The production of reviews draws upon a wide range of skills, all exer- cised under the supervision of Prescrire’s editors. This team approach is reflected in the collective byline “©Prescrire”. Written and edited by healthcare professionals Most of Prescrire’s editors are physicians (both in individual prac- tice or on hospital staff), pharma- cists (working in pharmacies or hos- pitals), nurses and dentists. A few are economists or journalists with specific expertise in the area of health- care. All Prescrire editors have received extensive in-house training in Prescrire’s editorial production process.

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P rescrire I nternational S pecial E dition 2021 • P age 1

Doing one’s job

Patients and healthcare professionals need to be able to count on an effective pharmaceutical industry. On pharmaceutical companies that market thoroughly evaluated drugs. Drugs that are more useful than dangerous and represent a tangible therapeutic advance in the indications for which they have been approved. Patients and healthcare professionals should be able to count on pharmaceutical companies to consistently produce drugs that meet high quality standards. At the right strength. Easily stored. Available on demand, supplied reliably and predictably, without delays, shortages or stockouts. Patients and healthcare professionals should be able to count on pharmaceutical companies to supply their drugs in safe, informative and functional packaging that does not take up more of their time than necessary. In which the drug is clearly identified with its international nonproprietary name (INN), dose strength, and so on. In which the drug is accompanied, where appropriate, by a suitable device for its accurate preparation and administration. Together with a patient leaflet containing all the information patients need to have about their treatment, without alarming them, so that they can understand, monitor and benefit from it. And all this must be achieved at prices that are reasonable, affordable and sustainable for health insurers and society as a whole. Without harming the environment. It’s a valuable job that requires expertise. Every year, the Prescrire Awards honour specific pharmaceutical companies that did their job, in a responsible manner, and provided a valuable service to healthcare professionals and patients (see Prescrire Int n° 224, pp. 77-81). But what a shame it is when pharmaceutical companies stray beyond their remit! When they take control of the most critical clinical research, influence the initial and continuing education of healthcare professionals in universities and healthcare establishments (see Prescrire Int n° 224, pp. 82), openly or surreptitiously advertise their products directly to patients, draining the resources of health insurers at the risk of compromising patients’ access to health care, or put pressure on health authorities to rush their drugs onto the market despite the risks. The entire health system should be able to count on pharmaceutical companies to do their job, no more, no less. When the roles within the system become blurred, the quality of health care and patients’ freedom to choose according to their needs both suffer. Prescrire ▶ Translated from Rev Prescrire February 2021 Volume 41 N° 448 • Page 81

EDITORIAL

Prescrire Int • March 2021

P age 2 • P rescrire I nternational S pecial E dition 2021

NEW PRODUCTS

Ebola vaccine rVSV-Zebov ( ervebo °) in an outbreak of Ebola virus disease Major reduction in incidence among those at risk for this often-fatal infection

BRAVO The evaluation data on Ebola vaccine rVSV-­ Zebov show that, during an outbreak of Ebola virus disease, vaccinating those who have been in contact with infected patients great- ly reduces the number of new cases, from day 10 after vaccination onwards.The report- ed adverse effects are acceptable given the severity of the disease, and include those common to all vaccines, as well as joint and skin disorders. The vaccine must be kept frozen, which complicates its use. In practice, this vaccine is a useful complement to the strict protective and hygiene measures that must be implemented around a patient infect- ed with Ebola virus. ERVEBO° - Ebola vaccine rVSV-Zebov solution for intramuscular injection • at least 72 million pfu (plaque-forming units) of live atten- uated rVSVdeltaG-Zebov-GP (recombinant vesicular sto- matitis virus expressing a Zaire Ebola virus surface glyco- protein) per vial in 1 ml of solution, corresponding to one dose of vaccine ■ Ebola vaccine ■ Indication : “ active immunization of individuals 18 years of age or older to protect against EbolaVirus Disease caused by Zaire Ebola virus ”. [EU centralised procedure]

of the fever after 6 to 11 days usually means that the patient will survive.The convalescent period is long and sometimes associated with sequelae, in- cluding neurological and hepatic disorders. In fatal cases, death occurs between 6 and 16 days after the onset of symptoms, in a context of generalised haemorrhage and multiorgan failure (1-5). Most outbreaks of Ebola virus disease have oc- curred in Africa, including in the Democratic Repub- lic of the Congo, Sierra Leone, Liberia and Guinea. The Zaire strain of the virus was usually involved. The proportion of infected patients who died (the case fatality rate) ranged from 30% to 90%, depend- ing on the outbreak (1,2,4). Transmitted through exposure to body fluids and excreta. According to epidemiological studies, Ebola virus is mainly transmitted from person to person through contact between a healthy person’s skin or mucous membranes and an infected person’s body fluids (including blood, tears, saliva, semen, amniotic fluid or breast milk) or excreta (faeces, urine, vomit or sweat), or through injuries with contaminated equipment. Airborne transmission seems unlikely. In non-fatal cases, the Ebola virus appears to persist in certain organs (including the testicles, eyes and central nervous system) and some body fluids (including semen), occasionally up to 2 years after the infection. In pregnant women, the virus persists in the placenta, amniotic fluid and breast milk, as well as in the fetus (1-4). Healthcare professionals are at particularly high risk of acquiring the infection. Between 1 January 2014 and 31 March 2015, during the epidemic in Guinea, Sierra Leone and Liberia, the incidence of Ebola virus infection per 1000 health workers was evaluated at 30 for doctors, 43 for nurses and 40 for laboratory technicians, versus 1.4 for non-health workers (4). In addition to health workers, anyone else in close contact with infected patients or who handles in- fected cadavers is also at high risk of contracting and spreading the virus. Infected patients do not appear to be contagious during the incubation period, when the virus is not detectable in blood (1,2).

Compare before deciding

Ebola virus disease, in brief

Ebola virus disease is caused by a virus belonging to the filovirus family. The main reservoir of this virus is a bat found in the forests of equatorial Africa. The infection is sometimes transmitted to other mammals, including humans (1,2). A serious and often fatal infection. After an incu- bation period of 2 to 21 days, Ebola virus disease presents with non-specific flu-like symptoms, in- cluding fever.This is followed by signs of multiorgan damage, including respiratory, gastrointestinal, hepatic, renal, neurological and cutaneous disorders. About half of patients develop bleeding. Resolution

Full review (5 pages) available to subscribers at english.prescrire.org ▶ Translated from Rev Prescrire December 2020 Volume 40 N° 446 • Pages 885-887

Prescrire Int • February 2021

P rescrire I nternational S pecial E dition 2021 • P age 3

NEW PRODUCTS

fexinidazole ( fexinidazole winthrop °) and sleeping sickness caused by Trypanosoma brucei gambiense Effective and more convenient than injectable treatments

A REAL ADVANCE Fexinidazole is the first drug for patients with trypanosomiasis caused by Trypanosoma brucei gambiense that can be taken orally and has high efficacy in both stages of the disease and acceptable adverse effects. Com­ pared with pentamidine and NECT ( nifurti- mox + eflornithine combination therapy), which require daily injections or infusions for 7 days, oral administration is a major advan­ tage for patients living in countries with limit­ ed health infrastructure, often in rural areas, and sometimes far from a healthcare facility. However, NECT remains the first choice for patients with the most advanced forms of the disease and who have access to this treat­ ment, as it is probably more effective in this situation. FEXINIDAZOLE WINTHROP° - fexinidazole tablets • 600 mg of fexinidazole per tablet ■ antiparasitic drug; 5-nitroimidazole derivative ■ Indication : “ first-stage (haemo-lymphatic) and second-­ stage (meningo-encephalitic) of human African tryp­ anosomiasis due toTrypanosoma brucei gambiense in adults and children ≥ 6 years old and weighing ≥ 20 kg ”. [Euro- pean Medicines Agency (EMA) evaluation procedure for drugs intended exclusively for use outside the European Union (Article 58 of European Regulation EC No 726/2004)] Human African trypanosomiasis (or sleeping sick- ness) is caused by a parasite of the genus Trypano- soma , usually T. brucei gambiense . The disease is endemic in many countries in sub-Saharan Africa, and is transmitted to humans through the bite of the tsetse fly (genus Glossina ), a haematophagous insect. It typically affects people living in rural or periurban areas. After an incubation period, sometimes lasting several years in the case of T. brucei gambiense , sleeping sickness progresses through two phases or stages: the haemolymphatic stage, followed by the more advanced meningoencephalitic stage. If left untreated, the disease is almost always fatal, within 2 to 3 years on average from the start of an infection caused by T. brucei gambiense (1,2).

The standard treatments for T. brucei gambiense infection are pentamidine during the haemolymph­ atic stage, and nifurtimox + eflornithine combination therapy (NECT) during the meningoencephalitic stage.These treatments are highly effective, with a cure rate of over 95%.They involve daily injections or infusions for 7 days (2).

What’s new?

An oral antiparasitic drug

Fexinidazole is a 5-nitroimidazole derivative, like metronidazole (3,4). Its mechanism of action in sleeping sickness is thought to involve conversion of the drug by parasite enzymes into metabolites that are toxic to trypanosomes. Nifurtimox is thought to have a similar mechanism of action (3). Fexinidazole (Fexinidazole Winthrop°, Sanofi Aventis) has been evaluated by the European Medi­ cines Agency (EMA) as a treatment for both stages of sleeping sickness due to T. brucei gambiense , in adults and children aged 6 years or more and weighing at least 20 kg. The evaluation was con- ducted through a European procedure for drugs intended exclusively for use outside the European Union (see also the inset “Development of fexini- dazole”, p. 289) (3,5). Is fexinidazole more effective than the standard treatments for sleeping sickness due to T. brucei gambiense ? Does it have fewer adverse effects? Is it easier to use? Fexinidazole has not been compared with penta­ midine in patients with haemolymphatic-stage human African trypanosomiasis due to T. brucei gambiense . Clinical evaluation of fexinidazole at this stage of the disease is based on two non-­ comparative trials (3,6). Fexinidazole was evaluated inmeningoencephalitic-­ stage disease in a randomised trial versus NECT (3,6,7). Full review (5 pages) available to subscribers at english.prescrire.org ▶ Translated from Rev Prescrire August 2020 Volume 40 N° 442 • Pages 565-567 Is it effective? Highly effective

Prescrire Int • December 2020

P age 4 • P rescrire I nternational S pecial E dition 2021

NEW PRODUCTS

polatuzumab vedotin ( polivy °) and large B-cell lymphoma

NOT ACCEPTABLE A single randomised comparative trial with numerous methodological flaws evaluated the addition of polatuzumab vedotin to a drug combination which is relevant in this situation.

patient characteristics and the imbalance between the groups favoured polatuzumab vedotin (espe- cially with regard to the reasons for ineligibility for transplantation and factors linked to disease prog- nosis); and there were no statistical hypotheses in the trial protocol, reducing the reliability of the statistical tests performed. After a median follow-up of 22 months, median survival appeared longer in the polatuzumab vedotin group. But given the comparator that was chosen, this finding does not show whether or not polatuzumab vedotin is useful in this clinical situation (6,7). The main adverse effects of microtubule-disrupting cytotoxic drugs, such as taxanes, are: neuropathy; haematological, cutaneous and gastrointestinal disorders; and arthralgia and myalgia (5). Allergic reactions are likely due to the protein portion (the monoclonal antibody) of polatuzumab vedotin . In the trial mentioned above, serious adverse events were reported in 64.4% of patients in the polatu- zumab vedotin group, versus 61.5% of those in the comparator group. The adverse events reported more frequently with polatuzumab vedotin than with the comparator were mainly: anaemia (47% versus 26%), thrombocytopenia (47% versus 28%), neutropenia (47% versus 39%), diarrhoea (38% versus 28%), infusion reactions (33% versus 23%), peripheral neuropathy (20% versus 3%) and pneu- monia (16% versus 10%) (6). Polatuzumab vedotin is metabolised by the cytochrome P450 isoenzyme CYP3A4. It is also a P-glycoprotein substrate. Numerous pharmacokinetic interactions are to be expected (6). ©Prescrire ▶ Translated from Rev Prescrire December 2020 Volume 40 N° 446 • Pages 893-894 Literature search up to 7 October 2020 In response to our request for information, Roche provided us with administrative documents, published articles and packaging items. 1- Prescrire Editorial Staff “Axicabtagene ciloleucel - Yescarta°. In certain types of lymphoma when other treatment options have been exhausted: a CAR T-cell therapy that increases the chances of sur- vival but frequently provokes serious adverse effects” Prescrire Int 2019; 28 (208): 229-231. 2- BMJ Best Practice “Non-Hodgkin’s lymphoma” 15 March 2019: 96 pages. 3- Freedman AS et al. “Treatment of relapsed or refractory diffuse large B cell lymphoma” UpToDate. www.uptodate.com accessed 2 October 2020: 46 pages. 4- Tilly Het al. “Diffuse large B-cell lymphoma: ESMOClinical Practice Guidelines” Ann Oncol 2015; 26 (suppl. 5): v116-v125. 5- Prescrire Rédaction “Brentuximab védotine (Adcetris°). Un intérêt à mieux cerner” Rev Prescrire 2012; 32 (349): 814-818. 6- EMA - CHMP “Public assessment report for Polivy. EMEA/H/ C/004870/0000” 14 November 2019: 159 pages. 7- HAS - Commission de laTransparence “Avis-Polivy” 10 June 2020: 29 pages.

POLIVY° - polatuzumab vedotin powder for concentrate for solution for intravenous infusion • 140 mg of polatuzumab vedotin per vial ■ antineoplastic; cytotoxic drug conjugated to an anti-CD79b monoclonal antibody ■ Indication : relapsed or refractory diffuse large B-cell lymph- oma, in combination with bendamustine and rituximab, in adults who are not candidates for haemopoietic stem cell transplantation. [EU centralised procedure - orphan drug] Diffuse large B-cell lymphoma is an aggressive form of non-Hodgkin lymphoma.The first-line treatment is R-CHOP chemotherapy, a combination of rituximab + cyclophosphamide + doxorubicin + vincristine + prednisolone . If the disease is refractory to or relapses after this first line of treatment, a second chemotherapy regimen is used, often containing a platinum compound and rituximab . A haemopoi- etic stem cell transplant is sometimes offered.There is no consensus over which chemotherapy regimen to use after several successive relapses. CART-cell therapy (a type of immunotherapy in which patients are injected with their own T cells that have been genetically modified to destroy the malignant cells) is sometimes an option in this situation (1,2). The bendamustine + rituximab combination has not been evaluated in comparative randomised trials in this situation. It has not been shown to extend survival. And, as of autumn 2020, it is not included among the options recommended in European guidelines (2-4). Polatuzumab vedotin is an anti-CD79b monoclo- nal antibody conjugated to monomethyl auristatin E, a drug, like the taxanes, whose cytotoxic action is based on microtubule disruption. Polatuzumab vedotin (Polivy°, Roche) as an adjunct to benda- mustine + rituximab has been granted conditional European marketing authorisation for use in adults with relapsed or refractory diffuse large B-cell lym- phoma who are not candidates for haemopoietic stem cell transplantation (5,6). Clinical evaluation of polatuzumab vedotin in this situation is mainly based on one non-blinded ran- domised trial in 80 patients that compared polatu- zumab vedotin + bendamustine + rituximab versus bendamustine + rituximab .The strength of evidence provided by this trial was greatly reduced by its numerous methodological flaws: an irrelevant comparator was used; the highly heterogeneous

Prescrire Int • March 2021

P rescrire I nternational S pecial E dition 2021 • P age 5

NEW PRODUCTS

remdesivir ( veklury °) and covid-19

Too many uncertainties over its efficacy as well as its harms

JUDGEMENT RESERVED The results of the main randomised placebo-­ controlled trial of remdesivir in adults hospi- talised for Sars-CoV-2 infection affecting their lungs (usually severely) showed no reduction in mortality, despite the inclusion of about 1000 patients. In this trial, remdesivir short- ened the “recovery” time in patients whose condition warranted supplemental oxygen or mechanical ventilation. Remdesivir can provoke hypersensitivity reactions and pos- sibly kidney and liver damage. The decision to authorise this product in July 2020, while so many uncertainties surrounded its harms and benefits, due to gaps in its evaluation, was very premature, if not reckless. Remde- sivir is still an experimental treatment; its evaluation in clinical trials should continue. VEKLURY° - remdesivir concentrate for solution for intravenous infusion, or powder for concentrate for solution for intravenous infusion • 100 mg of remdesivir per vial (both forms) ■ antiviral; adenosine nucleotide analogue ■ Indication : “ covid-19 in adults and adolescents (aged 12 years and older with body weight at least 40 kg) with pneumonia requiring supplemental oxygen ”. [EU centralised procedure]

Abstract

● The severity of covid-19, the disease caused by infection with the Sars-CoV-2 virus, varies greatly between patients. Most patients have a mild form that resolves without treatment. Other patients develop serious, and sometimes fatal, respiratory disorders and complications. ● Standard care as of mid-2020 mainly consists of treatments to relieve symptoms and other treatments to prevent certain complications. In a non-blinded randomised trial, 6 mg of dexa- methasone per day for up to 10 days, added to usual care, reduced mortality in patients receiv- ing invasive mechanical ventilation and, to a lesser degree, in those receiving oxygen . ● Remdesivir (Veklury°, Gilead Sciences) is a drug that disrupts the replication of viral RNA. It has been authorised in the European Union for use in adults and adolescents with covid-19 that is sufficiently severe to warrant supplemental oxygen . ● One double-blind placebo-controlled trial in 1062 adults hospitalised for covid-19 with pul- monary involvement found no statistically sig- nificant difference in mortality between the rem- desivir and placebo groups. ● In this trial, the median time to clinical improvement, mainly defined as the time to clinical discharge, was 10 days in the remdesivir group versus 15 days in the placebo group (p<0.001). Remdesivir had no effect on this end- point in patients with covid-19 considered mild or moderate. Remdesivir showed no efficacy in another double-blind placebo-controlled clin­ ical trial that included only 237 adults. ● The data concerning the drug’s adverse effects are extremely limited, leaving many questions unanswered. Remdesivir can provoke hyper- sensitivity reactions and possibly liver and kid- ney damage. ● As remdesivir is a substrate for various enzymes in vitro, many pharmacokinetic inter- actions are to be expected. Little is known about remdesivir’s potential effects on the metabolism of other drugs. No interaction studies have been conducted in humans.

©Prescrire ▶ Excerpt from Rev Prescrire November 2020 Volume 40 N° 445 • Pages 808-811

P age 6 • P rescrire I nternational S pecial E dition 2021

NEW PRODUCTS

EDITORS’ OPINION

Authorisation of remdesivir in the European Union: EMA needs to prioritise patients’ interests

Some of the reactions to the covid-19 pandemic have been irrational and harmful to society, particularly in the field of health care: reliable methods for evaluating drugs have been challenged; crackpot theories have been widely circu- lated; study results have been released prematurely with no quality control; poorly designed studies and trials abound, and so on. On 19 March 2020, the EMA rightly urged the scientific community to conduct randomised comparative trials, designed to generate robust evidence, when evaluating potential treatments for covid-19 (1). Yet on 25 June 2020, the EMA recommended the authorisation of remdesivir for certain covid-19 patients, despite the absence of robust evi- dence and many deficiencies in the data submitted by the pharmaceutical company: no detailed reports of the clinical trials; tenuous results; unknowns concerning the drug’s metabolism and potential interactions; incomplete toxicol­ ogy study results; etc. (2). Expedited analysis of drug evaluation data makes sense in a pandemic, so that a decision can be reached on its harm-benefit balance before all the usual data have been collated. But only if the preliminary clinical evaluation data available suggest that the drug is sufficiently effective to justify taking a certain amount of risk. This is certainly not the case for remdesivir .The data provided by the company point only to the need to continue its evaluation until its

harm-benefit balance is sufficiently clear (see “Remdesivir (Veklury°) and covid-19” p. 14). By granting marketing authorisation, the EMA might give some people the impression that it has fulfilled its role by expediting authorisation for a drug against a disease that is a major public health problem. But the reality is quite different. By accepting this unsound evaluation from Gilead, the company that markets remdesivir , and granting condi- tional marketing authorisation, EMA has hindered its evalu­ ation. Although it is conditional and will be reviewed in a year’s time, this authorisation removes the company’s main incentive to thoroughly evaluate the drug in comparative randomised trials, using clinically critical endpoints (inten- sive care procedures and mortality). Yet again, the EMA lacked rigour in its relationship with a pharmaceutical com- pany, and the price will be paid by patients and healthcare professionals, left in the dark over the harms and benefits of this treatment. ©Prescrire ▶ Translated from Rev Prescrire November 2020 Volume 40 N° 445 • Page 810 1- Prescrire Editorial Staff “Evidence required: for covid-19 too” Prescrire Int 2020; 29 (218): 199. 2- EMA - CHMP “Summary of opinion (initial authorisation) for Veklury” 25 June 2020: 1 page.

Prescrire Int • March 2021

COVID-19 UPDATE

Follow Prescrire’s independent, evidence-based analysis of the pandemic

Recent subjects include: • “Covid-19 vaccine Ad26.CoV2S (by Janssen): as with the other covid-19 vaccines, effective in the short term but unknowns remain” (23 March 2021) • “The AstraZeneca covid-19 vaccine: British epidemiological data on the vaccination of older adults, and reassuring pharmacovigilance data” (15 March 2021) • “Messenger RNA covid-19 vaccines: Prescrire’s in-depth analysis as of end February 2021” (2 March 2021)

english.prescrire.org/covid

P rescrire I nternational S pecial E dition 2021 • P age 7

NEW PRODUCTS

dasatinib ( sprycel ° and other brands ) in children with acute lymphoblastic leukaemia

NOTHING NEW Bias in the comparison with imatinib makes the favourable results obtained for dasatinib impossible to intepret. More than two years after its authorisation, the oral liquid form of dasatinib , for children unable to swallow tab- lets, is still not marketed in France. SPRYCEL° - dasatinib tablets and powder for oral suspension • 20 mg , 50 mg , 70 mg , 100 mg or 140 mg of dasatinib per tablet • 10 mg of dasatinib per ml of reconstituted suspension. The tablets and oral suspension are not bioequivalent. ■ antineoplastic; tyrosine kinase (including BCR-ABL) inhibitor ■ New indication : newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia in combination with chemotherapy in children. [EU centralised procedure] Acute lymphoblastic leukaemia is the most common childhood cancer and accounts for about 80% of childhood leukaemias. In about 5% of cases, the malignant cells contain an abnormal chromosome called the Philadelphia chromosome. Its presence is associated with a poor prognosis. First-line treat- ment in this situation is generally chemotherapy divided into several phases (induction, consolidation, maintenance) with imatinib , a tyrosine kinase in- hibitor that includes the kinase BCR-ABL among its targets (1-3). Dasatinib (Sprycel°, Bristol Myers Squibb) is another tyrosine kinase inhibitor that includes BCR- ABL among its targets. It has been granted market- ing authorisation in the European Union as first-line therapy added to chemotherapy for children with Philadelphia chromosome-positive acute lympho- blastic leukaemia (3,4). The application to obtain marketing authorisation for dasatinib in this situation was based on data from a non-comparative trial. An indirect compari­ son of these data with those from a cohort of his- torical controls who received imatinib added to chemotherapy did not show dasatinib to be an advance over imatinib (4). Since this evaluation, additional data have become available from a ran- domised, non-blinded, head-to-head trial of dasat- inib versus imatinib , added to chemotherapy (see “Failure to demand solid evidence for marketing authorisation spells danger for patients” p. 13). This comparative trial included 189 children (me- dian age 8 years) with Philadelphia chromosome-­

positive acute lymphoblastic leukaemia (5).The daily dose of imatinib in this trial was 300 mg/m 2 , which is less than the minimum dose of 340 mg/m 2 per day recommended in the European marketing author­ isation.This biased the comparison in favour of da- satinib and weakens the quality of the evidence (3,5). After a median follow-up of about 26 months for the 161 patients still alive at the time of the analysis, the estimated 4-year overall survival was about 88%with dasatinib versus 69% with imatinib (p=0.04) (5). The known adverse effects of dasatinib are similar to those of imatinib and include: bleeding events, gastrointestinal disorders, sodium and water reten- tion and oedema, pleural effusion, haematological disorders, myalgia, heart failure, arrhythmias, infec- tions (including hepatitis B reactivation), dyspnoea, interstitial lung disease, pulmonary arterial hyper- tension, hepatic and pancreatic disorders, and skin disorders (including Stevens-Johnson syndrome). There have also been reports of nephrotic syndrome, thrombotic microangiopathy and, in children, abnor- mal bone growth or development.The trial compar- ing dasatinib versus imatinib added no new infor- mation to this adverse effect profile (3,5,6). For children who find it difficult to swallow tablets, imatinib tablets can be dispersed in water or apple juice, which is not the case with dasatinib tablets. If tablets of differing strengths are present in the home (due to the dose adjustment required as the child’s body weight increases), it is important to warn the child’s carers about the risk of dosing errors. The different packaging colours for the various dose strengths help to distinguish between doses (3). More than 2 years have elapsed since the oral liquid form of dasatinib was authorised in the Euro­ pean Union in mid-2018, yet it has still not been marketed in France (3). ©Prescrire ▶ Translated from Rev Prescrire October 2020 Volume 40 N° 444 • Pages 734-735 Literature search up to 31 July 2020 In response to our request for information, Bristol Myers Squibb provided uswith no documentation on its product. 1- Prescrire Editorial Staff“Imatinib and acute lymphoblastic leukaemia in children. Prolonged survival in Philadelphia chromosome-positive cases” Prescrire Int 2015; 24 (157): 38-39. 2- National Comprehensive Cancer Network“Pediatric acute lympho- blastic leukemia” 25 November 2019: 118 pages. 3- European Commission “SPC-Sprycel” 13 February 2020 + “SPC- Glivec” 3 April 2020: 150 pages. 4- EMA - CHMP “Public assessment report for Sprycel. EMEA/ H/C/000709/II/0059” 13 December 2018: 80 pages. 5- Shuhong S et al. “Effect of dasatinib vs imatinib in the treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia. A randomized clinical trial” JAMAOncol 2020; 6 (3): 358-366 + supplementary material: 53 pages. 6- Prescrire Rédaction “Dasatinib (Sprycel°) et leucémie myeloïde chronique chez certains enfants et adolescents” Rev Prescrire 2019; 39 (433): 816-817.

P age 8 • P rescrire I nternational S pecial E dition 2021

NEW PRODUCTS

EDITORS’ OPINION

Failure to demand solid evidence for marketing authorisation spells danger for patients

In order to minimise the dangers of drugs, marketing author­ isation should be granted on the basis of a rigorous evalu- ation, which in most cases will involve double-blind ran- domised trials comparing the drug against a standard treatment, showing that the drug represents a tangible therapeutic advance for patients. And at least two trials are required to ensure that the findings are reproducible (1,2). Unfortunately, in 2020, it is clear that pharmaceutical com- panies generally do not respect these requirements, and the European Medicines Agency (EMA) does not insist that they do so. Consequently, most applications are based on a single clinical trial. The application to extend dasatinib ’s indications to include children with acute lymphoblastic leukaemia illustrates this issue: the extension of indication was approved on the basis of non-comparative data alone, without the EMA demand- ing more information (see “Dasatinib in children with acute lymphoblastic leukaemia” p. 12). In certain very specific situations, non-comparative data are sometimes acceptable, for example in a condition for which an urgent, unmet medical need exists or a serious condition that is so rare that it is impossible to recruit enough patients for a comparative trial (1). The use of dasatinib in children with acute lymphoblastic leukaemia does not meet these criteria. A treatment of the same type with a favour- able harm-benefit balance is already available for these

children. Furthermore, a randomised comparative trial ver- sus imatinib has now been conducted. Its results were pub- lished just a few months after dasatinib was granted mar- keting authorisation in this situation, thus proving that a comparative evaluation would have been feasible (3). In March 2020, the EMA rightly urged the scientific com- munity to conduct randomised comparative trials designed to generate robust evidence on covid-19 (4). It would be helpful if the EMA adopted the same attitude towards other clinical situations, to better serve patients and build con­ fidence in its work. ©Prescrire ▶ Translated from Rev Prescrire October 2020 Volume 40 N° 444 • Page 735 1- Prescrire Editorial Staff “Adaptive pathways: EMA’s dangerous plan” Prescrire Int 2016; 25 (174): 223. 2- Prescrire Rédaction “Évaluer le progrès thérapeutique: avec méthode, au service des patients” Rev Prescrire 2015; 35 (382): 565-569. 3- Shuhong S et al. “Effect of dasatinib vs imatinib in the treatment of pedi- atric Philadelphia chromosome-positive acute lymphoblastic leukemia. A randomized clinical trial” JAMAOncol 2020; 6 (3): 358-366 + supplementary material: 53 pages. 4- Prescrire Editorial Staff “Evidence required: for covid-19 too” Prescrire Int 2020; 29 (218): 199.

Prescrire Int • January 2021

PRESCRIRE’S RATINGS Our judgement is based on the therapeutic advance of the new product. It considers not only the inherent value of each product in terms of its harm-benefit balance, but also its advantages and disadvantages relative to existing products available in France. Note that the relative value of new products can vary from one country to another.

Quality of information from pharmaceutical companies In response to our systematic requests

BRAVO The product is a major therapeutic advance in an area where previously no treatment was available.

NOTHING NEW The product is a new substance but with no evidence that it has more clinical value than other substances of the same group. It can be a me-too or a near me-too.

Company provided detailed information including unpublished

data and packaging items.

A REAL ADVANCE The product is an important therapeutic advance but has certain limitations.

Company provided information limited to published administrative data or packaging items.

NOT ACCEPTABLE Product without evident benefit but with potential or real disadvantages.

OFFERS AN ADVANTAGE The product has some value but does not fundamentally change the present therapeutic practice. POSSIBLY HELPFUL The product has minimal additional value, and should not change prescribing habits except in rare circumstances.

Company provided minimal information, mainly administrative

JUDGEMENT RESERVED The editors postpone their rating until better data and a more thorough evaluation of the drug are available.

and packaging items.

Company provided no information.

P rescrire I nternational S pecial E dition 2021 • P age 9

ADVERSE EFFECTS VEGF inhibitors:

arterial aneurysm and dissection

exposed patients (10 cases). The median time to onset was 105 days (range: 4 days to 1363 days) (7). A retrospective study conducted in Latin America in 1173 patients treated with intravitreal bevacizumab for eye disorders identified 2 iliac artery aneurysms (5). Disruption of vessel remodelling. VEGF induces the formation of new blood vessels by stimulating endothelial cell proliferation. VEGF inhibitors on the other hand contribute to endothelial cell apoptosis (genetically programmed cell death).VEGF inhibitors can therefore alter the structure of vascular endo­ thelium, exposing patients to the risk of haemor­ rhagic and thrombotic complications (6). Hypertension, which can be caused by VEGF in­ hibitors, is another major risk factor for aortic dis­ section (7,8,10). In practice VEGF inhibitors can cause arterial an­ eurysm and dissection.This risk should be taken into account and warrants careful monitoring of exposed patients, especially those with other cardiovascular risk factors. Urgent investigation is required when a patient receiving aVEGF inhibitor develops abdom­ inal or chest pain or signs of ischaemia. ©Prescrire ▶ Translated from Rev Prescrire May 2020 Volume 40 N° 439 • Page 353 Literature search up to 20 January 2020 1- PrescrireRédaction“Médicaments anti-VEGF: deseffets indésirables cardiovasculaires et rénaux fréquents” RevPrescrire 2015; 35 (375): 30. 2- EMA“Minutes of PRACmeeting on 26-29November 2018” 17 Janu­ ary 2019: 105 pages. 3- EMA “Scientific conclusions and grounds for the variation to the terms of themarketing authorisation(s). Active substance(s): sunitinib” 13 December 2018: 2 pages. 4- Wiegering A et al. “Early development of a celiac trunk aneurysm during anti-vascular endothelial growth factor receptor therapy” Surgery 2014; 155 : 729-730. 5- Wu L et al. “Twelve-month safety of intravitreal injections of bevaci- zumab (Avastin): resultsof thePan-AmericanCollaborativeRetinaStudy Group (PACORES)” GraefesArchClinExpOphthalmol 2008; 246 : 81-87. 6- Baxi SS et al. “Hemorrhagic pseudoaneurysm in a patient receiving aflibercept formetastatic thyroid cancer” Thyroid 2012; 22 (5): 552-555. 7- OshimaY et al. “Association between aortic dissection and system- ic exposure of vascular endothelial growth factor pathway inhibitors in the Japanese Adverse Drug Event Report database” Circulation 2017; 135 : 815-817. 8- Aragon-Ching JB et al. “Acute aortic dissection in a hypertensive patient with prostate cancer undergoing chemotherapy containing bevacizumab” Acta Oncol 2008; 47 (8): 1600-1601. 9- Serrano C et al.“Acute aortic dissection during sorafenib-containing therapy” Ann Oncol 2010; 21 : 181-190. 10- Edeline J et al. “Aortic dissection in a patient treated by sunitinib for metastatic renal cell carcinoma” Ann Oncol 2010; 21 (1): 186-187. 11- FormigaMN et al. “Aortic dissection during antiangiogenic therapy with sunitinib. A case report” Sao PauloMed J 2015; 133 (3): 275-277. 12- TakadaMet al.“Aortic dissection and cardiac dysfunction emerged coincidentally during the long-term treatment with angiogenesis inhibitors for metastatic renal cell carcinoma. A case report of onco-­ cardiology” Int Heart J 2018; 59 : 1174-1179.

● Cases of arterial aneurysm or dissection have been reported withVEGF inhibitors, such as beva­ cizumab , used to treat cancer. Systemic adminis- tration and hypertension, a known adverse effect of these anti-angiogenic drugs, are risk factors. ● In practice, monitoring is warranted for patients treated withVEGF inhibitors, especially those with cardiovascular risk factors. D rugs that target vascular endothelial growth factor (VEGF) inhibit angiogenesis and are mainly used to treat diseases involving vas­ cular proliferation, in particular cancer and certain eye conditions (by intravitreal administration).They can provoke cardiovascular disorders such as hyper­ tension, heart failure and arterial or venous thrombo­ embolic events (1). In 2019, the European Pharmacovigilance Risk Assessment Committee (PRAC) reported arterial dissections or aneurysms linked to the use of VEGF inhibitors (2). Hundreds of cases, sometimes fatal. In late 2018, the European pharmacovigilance database contained several hundred cases of arterial dissection or an­ eurysm, recorded since the market introduction of the variousVEGF inhibitors: 256 cases were report­ ed with bevacizumab , 249 with ranibizumab , 79 with sunitinib and 43 with sorafenib. Fewer cases were described with other VEGF inhibitors (2). A PRAC report published in late 2018 mentioned 26 fatal cases of aortic dissection or aneurysm at­ tributed to sunitinib (3). Our literature search identified about 15 case reports of arterial aneurysm, pseudoaneurysm or dissection in patients treated with aVEGF inhibitor.They occurred at various sites: the coeliac trunk, inferior pancreatico­ duodenal artery, aorta or cervical artery (4-12). In most cases, theVEGF inhibitor had been used to treat cancer. Some patients had no history of cardiovas­ cular disease, but at least two patients had hyper­ tension before exposure to the VEGF inhibitor. The time to diagnosis of the disorders ranged from about 20 days to several months after startingVEGF inhibi­ tor therapy; in several cases, the disorders resolved after discontinuing the VEGF inhibitor (4-11). 20-fold risk of aortic dissection. In a study based on data froma Japanese pharmacovigilance database, 91 055 patients were identified as having undergone treatment for cancer; 16 441 of these patients had been treated with at least one VEGF inhibitor, and 74 614 of them had not been exposed to this type of drug.The risk of aortic dissection was about 20 times greater (95% confidence interval: 10-41) in patients exposed to VEGF inhibitors (49 cases) than in un­

Prescrire Int • September 2020

P age 10 • P rescrire I nternational S pecial E dition 2021

ADVERSE EFFECTS

Apixaban, edoxaban, rivaroxaban: situations with a high risk of bleeding or thrombosis

ABSTRACT

available to quantify the anticoagulant effect of xabans.This effect is achieved within 2 to 4 hours. Their plasma half-life is about 12 hours (1,3). This relatively short duration of effect is an advantage in the event of overdose or bleeding, but a disad- vantage when patients are underdosed or miss a dose. As of 2020, which situations are associated in practice with a particularly high risk of bleeding or thrombosis during treatment with apixaban , edo­ xaban or rivaroxaban ? This review is mainly based on data provided in documentation published by drug regulatory agen- cies and on the results of clinical trials and pharma­ coepidemiological studies identified through our literature search (see “Literature search and meth- odology” p. 241). Thousands of cases of sometimes fatal bleeding or thrombosis linked to xabans have been reported since the late 2000s in France and other countries. The French Health Products Agency (ANSM) con- ducted a national pharmacovigilance survey on rivaroxaban between 2009 and 2015. 2989 cases of serious adverse effects were recorded (5,6). 1911 cases (64%) were bleeding events, 1131 of which were serious, mainly involving the digestive tract or the central nervous system. Among the 548 cases of thrombosis, 360 cases were serious, and included venous thromboembolism, pulmonary embolism, and ischaemic stroke. 250 of the 324 deaths were linked to bleeding. The ANSM conducted a national pharmacovigi- lance survey on apixaban between 2012 and 2017. Among the 1296 cases of serious adverse effects recorded, 60% were bleeding events, mainly involv- ing the central nervous system or digestive tract. 115 of the 149 deaths were linked to bleeding (5-10). Bleeding has also accounted for a large proportion of the adverse effects reported with xabans in other countries (the Netherlands, Norway, Australia, Canada, the United States, and Japan) (11-15). Reports: mainly bleeding

● Apixaban , edoxaban and rivaroxaban are direct oral anticoagulants that inhibit factor Xa. No rou- tine laboratory tests are available to quantify their anticoagulant effect as of mid-2020, whereas the effect of the standard oral anticoagulant, warfarin , can be easily monitored using the INR. ● Data from clinical trials, cohort studies and pharmacovigilance can be used to identify situ­ ations that increase the risk of bleeding or throm- bosis, some of which involve medication errors. ● The main situations and errors known to increase the risk of bleeding with xabans are: advanced age; renal or hepatic impairment; low bodyweight (body mass index (BMI) less than 18.5 kg/m²); certain conditions that increase the likelihood of bleeding; and drug interactions that increase blood xaban levels or involve drugs with additive bleeding effects. ● The main situations and errors known to increase the risk of thrombosis with xabans are: missed or delayed doses; drug interactions that lower blood xaban levels or involve drugs with antagonistic effects; a period of under-anticoagulation when switching to a vitamin K antagonist; and, in the case of edoxaban , creatinine clearance greater than 95 ml/min. ● In practice, as of mid-2020, when using xabans, it is essential to take into account the situations that increase the risk of bleeding or thrombosis, and to monitor the patient for any change in these risks, such as new comorbidities, new drugs, or discontinued drugs. Rev Prescrire 2020; 40 (441): 506-509 A pixaban , edoxaban and rivaroxaban (also called xabans) are direct oral anticoagulants that inhibit factor Xa, hence the stem -xaban in their international nonproprietary names (INNs). They are authorised for the prevention or treatment of thrombosis in various medical and surgical set- tings. As with all anticoagulants, their main adverse effect is the risk of potentially severe or even fatal bleeding through over-anticoagulation. Conversely, under-anticoagulation carries the risk of throm­ bosis (1-4). The management of xaban therapy is challenging. As of mid-2020, no routine laboratory tests are

Full review (4 pages) available to subscribers at english.prescrire.org ▶ Translated from Rev Prescrire July 2020 Volume 40 N° 441 • Pages 506-509

Prescrire Int • October 2020

P rescrire I nternational S pecial E dition 2021 • P age 11