Showing papers by "Peter C Gøtzsche published in 2018"

The Cochrane HPV vaccine review was incomplete and ignored important evidence of bias.

Abstract: In May 2018, the Cochrane Collaboration published its review of the human papillomavirus (HPV) vaccines.1 The review primarily assessed the vaccines’ effect on precursors to cervical cancer. Cochrane has high standards for its reviews2; however, there were important limitations in its HPV vaccine review, which we address in this paper. The Cochrane review conducted trial searches up until June 2017 and included 26 randomised trials with 73 428 women.1 In January 2018, we published an index of the study programmes of the HPV vaccines that included 206 comparative studies.3 As of June 2017, about one-third of the 206 studies were not published and half of the completed studies listed on ClinicalTrials.gov had no results posted.3 Although we sent our index to the Cochrane group handling the Cochrane review, the review stated that, ‘nearly all end-of-study reports have been published in the peer-reviewed literature’. When we applied the Cochrane review’s inclusion criteria to the 206 studies, we identified 46 completed and eligible trials. The number of randomised participants could be assessed for 42 of the 46 trials and was 121 704. With nearly half of the trials and half of the participants missing, the Cochrane authors’ conclusion, ‘that the risk of reporting bias may be small’, was inappropriate. Fifteen of the 20 additional trials were listed on ClinicalTrials.gov; the Cochrane authors would therefore have identified more trials if they had searched ClinicalTrials.gov in more depth and searched additional trial registers (we searched 45 trial registers3). The Cochrane authors stated that they ‘did not include …

Collaboration between academics and industry in clinical trials: cross sectional study of publications and survey of lead academic authors

Abstract: Objectives To determine the role of academic authors, funders, and contract research organisations in industry funded trials of vaccines, drugs, and devices and to determine lead academic authors’ experiences with industry funder collaborations. Design Cross sectional analysis of trial publications and survey of lead academic authors. Eligibility criteria for selecting studies The most recent 200 phase III and IV trials of vaccines, drugs, and devices with full industry funding, at least one academic author, published in one of the top seven high impact general medical journals (New England Journal of Medicine, Lancet, JAMA, BMJ, Annals of Internal Medicine, JAMA Internal Medicine, and PLoS Medicine). Results Employees of industry funders co-authored 173 (87%) of publications; 183 (92%) trials reported involvement of funders in design, and 167 (84%) reported involvement of academic authors. Data analysis involved the funder in 146 (73%) trials and the academic authors in 79 (40%). Trial reporting involved the funder in 173 (87%) trials and academic authors in 197 (99%). Contract research organisations were involved in the reporting of 123 (62%) trials. Eighty (40%) of 200 lead academic authors responded to the survey. Twenty nine (33%) of the 80 responders reported that academics had final say on the design. Ten responders described involvement of an unnamed funder and/or contract research organisation employee in the data analysis and/or reporting. Most academic authors found the collaboration with industry funder beneficial, but 3 (4%) experienced delay in publication due to the industry funder and 9 (11%) reported disagreements with the industry funder, mostly concerning trial design and reporting. Conclusions Industry employees and academic authors are involved in the design, conduct, and reporting of most industry funded trials in high impact journals. However, data analysis is often conducted without academic involvement. Academics view the collaboration as beneficial, but some report loss of academic freedom.

Index of the human papillomavirus (HPV) vaccine industry clinical study programmes and non-industry funded studies: a necessary basis to address reporting bias in a systematic review.

Abstract: Unabridged access to drug industry and regulatory trial registers and data reduces reporting bias in systematic reviews and may provide a complete index of a drug’s clinical study programme. Currently, there is no public index of the human papillomavirus (HPV) vaccine industry study programmes or a public index of non-industry funded studies. By cross-verification via study programme enquiries to the HPV vaccine manufacturers and regulators and searches of trial registers and journal publication databases, we indexed clinical HPV vaccine studies as a basis to address reporting bias in a systematic review of clinical study reports. We indexed 206 clinical studies: 145 industry and 61 non-industry funded studies. One of the four HPV vaccine manufacturers (GlaxoSmithKline) provided information on its study programme. Most studies were cross-verified from two or more sources (160/206, 78%) and listed on regulatory or industry trial registers or journal publication databases (195/206, 95%)—in particular, on ClinicalTrials.gov (176/195, 90%). However, study results were only posted for about half of the completed studies on ClinicalTrials.gov (71/147, 48%). Two thirds of the industry studies had a study programme ID, manufacturer specific ID, and national clinical trial (NCT) ID (91/145, 63%). Journal publications were available in journal publication databases (the Cochrane Collaboration’s Central Register of Controlled Trials, Google Scholar and PubMed) for two thirds of the completed studies (92/149, 62%). We believe we came close to indexing complete HPV vaccine study programmes, but only one of the four manufacturers provided information for our index and a fifth of the index could not be cross-verified. However, we indexed larger study programmes than those listed by major regulators (i.e., the EMA and FDA that based their HPV vaccine approvals on only half of the available trials). To reduce reporting bias in systematic reviews, we advocate the registration and publication of all studies and data in the public domain.

Challenges of independent assessment of potential harms of HPV vaccines

Abstract: After three years of trying to access trial data for HPV vaccines, Lars Jorgensen and colleagues find current transparency policies unfit for their purpose

Patients not patents: Drug research and development as a public enterprise.

Abstract: The current system for drug innovation and usage has generally failed public health. Only 11 (1%) of 1032 new drugs approved in France between 2005 and 2014 were considered real advances, and 54 of the 87 analysed drugs or indications in 2014 were no better or actually worse than existing treatment options. Drug harms are so prevalent that studies in high-income countries have shown that drugs are the third leading cause of death, after heart disease and cancer. The European Commission has estimated that adverse reactions kill about 200 000 EU citizens annually at a cost of €79 billion. Many of these deaths are avoidable. Our for-profit system encourages overprescribing, and many patients could have fared well without the drug that killed them, for example a nonsteroidal anti-inflammatory agent or a psychoactive drug. Meanwhile, many important health problems do not receive the attention they deserve, for example to address antimicrobial resistance. The main problem is that the current system is based on patents and monopolies, which allow companies to set their price as they want. This system is unethical, as people may die if they cannot get access to the drug they need. It is also inefficient, as research knowledge is not shared, for example about toxicology and failed projects. Furthermore, the TRIPS-plus provisions prohibit generic manufacturers from using clinical trial data submitted by brand manufacturers. I propose a radically different approach in which the current drive of profit maximization via patents is replaced by a public interest-driven system that is not for profit. I hope this paper can be a starting point for a much-needed discussion.

Redactions in protocols for drug trials: what industry sponsors concealed.

Abstract: Objective To describe the redactions in contemporary protocols for industry-sponsored randomised drug trials with patient relevant outcomes and to evaluate whether there was a legitimate rationale for the redactions. Design Cohort study. Under the Freedom of Information Act, we requested access to trial protocols approved by a research ethics committee in Denmark from October 2012 to March 2013. We received 17 consecutive protocols, which had been redacted before we got them, and nine protocols without redactions. In five additional cases, the companies refused to let the committees give us access, and in three other cases, documents were missing. Participants Not applicable. Setting Not applicable. Main outcome measure Amount and nature of redactions in 22 predefined key protocol variables. Results The redactions were most widespread in those sections of the protocol where there is empirical evidence of substantial problems with the trustworthiness of published drug trials: data analysis, handling of missing data, detection and analysis of adverse events, definition of the outcomes, interim analyses and premature termination of the study, sponsor's access to incoming data while the study is running, ownership to the data and investigators' publication rights. The parts of the text that were redacted differed widely, both between companies and within the same company. Conclusions We could not identify any legitimate rationale for the redactions. The current mistrust in industry-sponsored drug trials can only change if the industry offers unconditional access to its trial protocols and other relevant documents and data.

A totally new system is needed for drug research and development.

Abstract: In response to my paper, where I call for abolishment of patents and for drug research and development as a public enterprise, Raj asserts that there is an increase in novel drug discoveries. The fact is that even the drug industry laments that drug innovation has dried out, which is why they buy start-up companies. Big Pharma doesn’t invest in innovative research, as it is far more profitable to have creative marketing and legal departments than creative research divisions and to develop an endless array of “me too” products. I referred to France because Prescrire is one of the very few journals where none of the editors or authors are allowed to have conflicts of interest in relation to the drug industry. The French results have global value, as the drug market is global, and I believe it is clear that I have tried to address the global problems we are facing with development, pricing and usage of drugs and not only those in high-income countries. Since 1981, Prescrire’s Pilule d’Or (Golden Pill) has been granted to drugs that constitute a major therapeutic advance in a field in which no treatment was previously available. There was no worthy candidate for 1982, 1984, 1985, 1990, 1991, from 1993 to 1995, for 1997, from 1999 to 2005, from 2008 to 2013, and for 2015. The statement by Raj that novel drugs for infectious diseases come second after cancer drugs among new FDA approvals is not reassuring. Everywhere, people complain about antibiotic resistance and the lack of innovative antibiotics, and no matter how many “novel” drugs FDA has approved, the clinical situation has not improved during the last 20 years. Patients die in huge numbers because we do not have effective antibiotics against tuberculosis, methicillinresistant staphylococci, beta-lactamase-producing E. coli, carbapenemase-producing organisms and so forth. The paper Raj refers to only says that 14% of the novel drugs were for infections, not whether these drugs were antibiotics, immunoglobulins, vaccines, or something else, or whether they were simply “me too” drugs with no added value. It is similarly misleading when Raj praises progress against cancer because extremely few cancer drugs add anything of value. Raj asserts that around half of the newer drugs were approved for acute and intermediate disease conditions and argues that this contradicts my statement that the industry tends to focus on drugs to treat chronic conditions that affect many people. Raj seems to have a naive view about what the drug industry does and why. Illegal marketing is one of the most common and profitable crimes the drug industry commits, and many drugs that should only have been used short-term end up being used for life, for example psychiatric drugs, although the long-term use of these drugs causes vastly more harm than good. Raj believes I underestimate the importance of adaptive trial designs. These designs allow drugs to be approved based on observational data only, which is a disaster for public health. Our drugs are already the third leading cause of death after heart disease and cancer, and the lowering of regulatory standards for new cancer drugs and other drugs has increased the rate of drug withdrawals because of safety issues and has undoubtedly increased the death toll further. Considering all the unnecessary deaths we cause with drugs most people don’t really need, we must require that trials submitted for obtaining marketing authorization are large enough and have run for sufficient lengths of time to capture rare but lethal harms and we should avoid approving drugs based on surrogate outcomes. We do not approve cars based on the fact that we can start the engine. We require more than this, in particular safety studies. But with drugs, which kill about 10 times more people in my country than cars do, we do not care that we have not requested adequate safety data. This is insane. Raj argues for a holistic approach where nondrug and drug therapies complement each other rather than considering them as mutually exclusive components. Fine, but first we must stop the lethal drug epidemic, which means using drugs far less than we do today. Whenever we can, we should prefer nondrug therapies, as they don’t kill people. [The copyright line for this article was changed on 25 July 2018 after original online publication.]