120 Researchers Question Integrity of the Anti-Chloroquine Lancet Study

A recent study from The Lancet found hydroxychloroquine or chloroquine to be ineffective, and even increase mortality. As a result, the WHO immediately paused all the trials until a “committee reviews all available data on COVID-19 and hydroxychloroquine.”

The study concludes:

Compared with the control group (0·3%), hydroxychloroquine (6·1%; 2·369, 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983), chloroquine (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.

We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.

This sounds like the other study the news media was touting as proof that HCQ was unsafe and was killing people quicker than not using it. I’ve talked about that flawed study before. This one comes from a highly respected publisher, The Lancet. They tout themselves as providing “the best science for better lives”. Is that really the case here?

It turns out there are a lot of issues with the study. The popularity and impact of the study caused many researchers to take a closer look. The result of the scrutiny is 120 researchers signing an open letter to the editor of The Lancet raising concerns about the methodology and data integrity.

Here are some of the points raised:

  1. There was inadequate adjustment for known and measured confounders (disease severity, temporal effects, site effects, dose used).
  2. The authors have not adhered to standard practices in the machine learning and statistics community. They have not released their code or data. There is no data/code sharing and availability statement in the paper. The Lancet was among the many signatories on the Wellcome statement on data sharing for COVID-19 studies.
  3. There was no ethics review.
  4. There was no mention of the countries or hospitals that contributed to the data source and no acknowledgments to their contributions. A request to the authors for information on the contributing centres was denied.
  5. Data from Australia are not compatible with government reports (too many cases for just five hospitals, more in-hospital deaths than had occurred in the entire country during the study period). Surgisphere (the data company) have since stated this was an error of classification of one hospital from Asia. This indicates the need for further error checking throughout the database.
  6. Data from Africa indicate that nearly 25% of all COVID-19 cases and 40% of all deaths in the continent occurred in Surgisphere-associated hospitals which had sophisticated electronic patient data recording, and patient monitoring able to detect and record “nonsustained [at least 6 secs] or sustained ventricular tachycardia or ventricular fibrillation”. Both the numbers of cases and deaths, and the detailed data collection, seem unlikely.
  7. Unusually small reported variances in baseline variables, interventions and outcomes between continents (Table S3).
  8. Mean daily doses of hydroxychloroquine that are 100 mg higher than FDA recommendations, whereas 66% of the data are from North American hospitals.
  9. Implausible ratios of chloroquine to hydroxychloroquine use in some continents
  10. The tight 95% confidence intervals reported for the hazard ratios are unlikely. For instance, for the Australian data this would need about double the numbers of recorded deaths as were reported in the paper.

Some of the data used for the study is being kept secret by a US company called Surgisphere, who said “Our data sharing agreements with the various governments, countries and hospitals do not allow us to share data unfortunately.” Researchers want to review the data themselves, and are asking:

  1. The company Surgisphere provides details on data provenance. At the very minimum, this means sharing the aggregated patient data at the hospital level (for all covariates and outcomes)
  2. Independent validation of the analysis is performed by a group convened by the World Health Organization, or at least one other independent and respected institution. This would entail additional analyses (e.g. determining if there is a dose-effect) to assess the validity of the conclusions
  3. There is open access to all the data sharing agreements cited above to ensure that, in each jurisdiction, any mined data was legally and ethically collected and patient privacy aspects respected

Other issues raised by a French reviewer of the study soon after it came out had others concerns. Such as:

  • Inaccuracies on the treatments analyzed: we are talking about macrolides. Impossible to know who received azithromycin
  • Unspecified doses and durations of treatment
  • A prescription sold as early (less than 48 hours after hospitalization) which obscures the date of the first symptoms and makes people believe in an early prescription!

Understanding that testing a treatment recommended at an early stage of the disease on hospital patients with advanced serious illness simply does not answer the question of the effectiveness of the treatment as proposed

A former editor of the New England Journal of Medicine, Arnold S. Relman, spoke of the corruption in medical studies due to big pharma having bought out so many researchers:

“The medical profession is being bought by the pharmaceutical industry, not only in terms of the practice of medicine, but also in terms of teaching and research. The academic institutions of this country are allowing themselves to be the paid agents of the pharmaceutical industry. I think it’s disgraceful.”

Is this why the study didn’t do a proper analysis of the data wit respect to a proper treatment protocol of COVID-19?

The Lancet study didn’t evaluate previously proposed therapies that were said to work. One was by Didier Raoult, a French microbiologist. Another was by Anthony Cardillo, an ER specialist in Los Angeles. Both had 99% success rate. They both used HCQ with zinc.

Zinc is a crucial component. The HCQ apparently opens up the cells for the zinc to get in and do the work. All the data the Lancet analyzed make no mention of zinc. The study also apparently looked at people who received HCQ later on in their illness. And without zinc, it wasn’t that effective indeed.

The HCQ treatment isn’t about HCQ alone, but HCQ with zinc to treat people with COVID-19. This doesn’t seem to be understood, or they don’t care and just report a failure of HCQ and even leading to more fatalities. It’s not a very good study.

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