Clinical Drug Trials: Part Two, The Databases

Detailed Information On Over 300,000 Clinical Trials Worldwide Including COVID-19 Available Online

As the clinical trials for a treatment and vaccine for COVID-19 continue, the results of concluded studies are being released in the media on an almost daily basis. Last year I wrote a post that explained the processes that are involved in performing these trials as well as the phases of a clinical drug trial. Because trials are now very topical, I decided to republish some information from that post which explains how clinical trials work.

Part two will look at the legislation governing registration and reporting compliance for most clinical trials conducted in the United States. It will also examine the online databases that have detailed information about these trials and the tens of thousands of others conducted in over 200 other countries.

Finally, part three will examine the studies conducted for the antimalarial drugs hydroxychloroquine and mefloquine. These studies will include those for the treatment of COVID-19 along with other off-label uses.

The search for a treatment and a vaccine for COVID-19 has translated into an increased interest in clinical drug trials on the part of the general public. It isn’t uncommon nowadays to learn the results of one particular study or another in the newsmedia. For the most part however this information is of absolutely no interest to the vast majority of the general public, because these results will have no significance to them whatsoever.

But this pandemic has had a major impact on billions of people in one way or another, and so there has been a great deal of interest in clinical trials and studies relating to COVID-19. There are a number of websites available to the public that can provide detailed information on hundreds of thousands of clinical trials.

The average person will find academic research papers difficult to read because of the technical and scientific terminology and concepts within them, and thus they won’t be able to interpret the data. Every research paper however will have a summary, usually at the beginning, that presents the results in language that is easier for the public to understand.

Google Scholar

For a limited period a number of medical and scientific journals are opening up articles on COVID-19 to the public on Google Scholar. You can now access the most up to date information from a dozen sources including the New England Journal of Medicine (NEJM), the Journal of the American Medical Association (JAMA), and The Lancet without a subscription.

Clinical Trial Databases

There are a number of clinical trial databases to be found online when you do a Google search, so I’m only going to discuss the two that will be of the most help. Those being covid-trials.org and ClinicalTrials.gov.

covid-trials.org

This website is strictly dedicated to tracking COVID-19 clinical trials around the world and can be used to track them by country or by treatment. It’s a very informative website and lists the dozens of treatments that are being tested around the world, including a number of anti-viral drugs like remdesivir, biologic response modifiers such as avdoralimab, as well as corticosteroids and a large host of others.

There is also an eclectic mix of proposed therapies that include such things as Traditional Chinese Medicine, and a herbal concotion of marshmallows and licorice from Iran (click on the link to see it).

https://en.irct.ir/trial/46903

The site is fairly straightforward and easy to navigate allowing you to search by treatment, outcome, and country. Detailed information about each study can be found by clicking on the study you want at the bottom of the screen.

http://covid-trials.org

ClinicalTrials.gov

ClinicalTrials.gov is perhaps the most comprehensive with access to over 300,000 clinical trials from over 200 countries. For studies taking place in the United States, it is mandated that all clinical trials, with a few exceptions, be registered on the site as per the Final Rule (42 CFR Pt 11) set forth in FDAAA 801.

https://prsinfo.clinicaltrials.gov/

Purpose Of The Registry

Establishing the registry served several purposes and was of benefit to a number of groups. These are spelled out on the ClinicalTrials.gov website.

Registry Purpose

Registry PurposeGroup That Benefits
Fulfill ethical obligations to participants and the research communityPatients, the general public, the research community
Provide information to potential participants and referring cliniciansPatients, clinicians
Reduce publication biasUsers of the medical literature
Help editors and others understand the context of study resultsJournal editors, users of the medical literature
Promote more efficient allocation of research fundsGranting agencies, the research community
Help institutional review boards (IRBs) determine the appropriateness of a research studyIRBs, ethicists
https://clinicaltrials.gov/ct2/manage-recs/background#WhatIsThePurpose

Results Database Purpose

Results Database PurposeGroup That Benefits
Provide a public record of basic study results in a standardized formatResearchers, journal editors, IRBs, ethicists
Promote the fulfillment of ethical obligations to participants and the overall contribution of research results to medical knowledgePatients, the general public, the research community
Reduce publication and outcome reporting biasesUsers of the medical literature
Facilitate systematic reviews and other analyses of the research literatureResearchers, policymakers
https://clinicaltrials.gov/ct2/manage-recs/background#WhatIsThePurpose

There is without a doubt an enormous benefit to the scientific and research communities in having this database, allowing information to be shared worldwide. However creating a sense of transparency and providing patients with more information was one of the primary purposes for establishing the registry.

Background

ClinicalTrials.gov is a Web-based resource that provides patients, their family members, health care professionals, researchers, and the public with easy access to information on publicly and privately supported clinical studies on a wide range of diseases and conditions. The Web site is maintained by the National Library of Medicine (NLM) at the National Institutes of Health (NIH). Information on ClinicalTrials.gov is provided and updated by the sponsor or principal investigator of the clinical study. Studies are generally submitted to the Web site (that is, registered) when they begin, and the information on the site is updated throughout the study. In some cases, results of the study are submitted after the study ends. This Web site and database of clinical studies is commonly referred to as a “registry and results database.”

ClinicalTrials.gov contains information about medical studies in human volunteers. Most of the records on ClinicalTrials.gov describe clinical trials (also called interventional studies). A clinical trial is a research study in which human volunteers are assigned to interventions (for example, a medical product, behavior, or procedure) based on a protocol (or plan) and are then evaluated for effects on biomedical or health outcomes. ClinicalTrials.gov also contains records describing observational studies and programs providing access to investigational drugs outside of clinical trials (expanded access). Studies listed in the database are conducted in all 50 States and in 214 countries.

ClinicalTrials.gov does not contain information about all the clinical studies conducted in the United States because not all studies are required by law to be registered (for example, observational studies and trials that do not study a drug, biologic, or device). See FDAAA 801 and the Final Rule for more information. However, the rate of study registration has increased over time as more policies and laws requiring registration have been enacted and as more sponsors and investigators have voluntarily registered their studies.

The ClinicalTrials.gov registration requirements were expanded after Congress passed the FDA Amendments Act of 2007 (FDAAA). Section 801 of FDAAA (FDAAA 801) requires more types of trials to be registered and additional trial registration information to be submitted. The law also requires the submission of results for certain trials. This led to the development of the ClinicalTrials.gov results database, which contains summary information on study participants and study outcomes, including adverse events. The results database was made available to the public in September 2008. FDAAA 801 also established penalties for failing to register or submit the results of trials. In September 2016, HHS issued the Final Rule for Clinical Trials Registration and Results Information Submission (42 CFR Part 11) clarifying and expanding the registration and results information submission requirements of FDAAA 801. This regulation takes effect in January 2017.

https://clinicaltrials.gov/ct2/about-site/background

File:Food and Drug Administration logo.svg - Wikimedia Commons

Perhaps the most important pieces are information to be found in this or any database is the results of the clinical trials. It is in these results that the viability of a particular treatment is assessed and could determine whether or not a drug is approved by the FDA. Of particular signifigance are the reports of adverse events. Adverse event reporting is mandated in all clinical trials and any adverse events that occur during a clinical trial must be thoroughly documented and reported to the registry.

After a drug has been approved for use it also must undergo what’s known as post-marketing surveillance studies. These are necessary after a drug goes to market because these are a monitor for adverse event reports, which are relevant to patient safety. A large number of adverse event reports after approval could lead to a suspension of that approval pending further study. Something like this could cause a drug manufacturer to delay submitting the results, which is why they must be submitted by a particular date or face sanction. According to Section 801 they must be reported no more than one year after being approved.

Not Applicable Outside US

These regulations only apply to clinical trials performed in the United States. There is no legal obligation for studies done outside of the country to be registered on ClinicalTrials.gov, however most do in the spirit of scientific cooperation among researchers internationally.

Fraudulent Results

There have been instances in the past where studies have contained fraudulent results. This usually happens by means of omitting or witholding data that would effect the outcome of the study. For example adverse event reports are left out of a study in order for a drug to be approved by the FDA. While the FDA does perform an audit of the data in clinical trials, it doesn’t happen until sometime after a drug has been approved.

The FDA however has approved drugs in the past that it has KNOWN contained fraudulent research. An article in Scientific American from 2013 reads in part:

The health threat was potentially serious: About 100 drugs, including sophisticated chemotherapy compounds and addictive prescription painkillers, had been approved for sale in the United States at least in part on the strength of Cetero Houston’s tainted tests. The vast majority, 81, were generic versions of brand-name drugs on which Cetero scientists had often run critical tests to determine whether the copies did, in fact, act the same in the body as the originals. For example, one of these generic drugs was ibuprofen, sold as gelatin capsules by one of the nation’s largest grocery-store chains for months before the FDA received assurance they were safe.

The rest were new medications that required so much research to win approval that the FDA says Cetero’s tests were rarely crucial.

Stone said he expected the FDA to move swiftly to compel new testing and to publicly warn patients and doctors.

Instead, the agency decided to handle the matter quietly, evaluating the medicines with virtually no public disclosure of what it had discovered. It pulled none of the drugs from the market, even temporarily, letting consumers take the ibuprofen and other medicines it no longer knew for sure were safe and effective. To this day, some drugs remain on the market despite the FDA having no additional scientific evidence to back up the safety and efficacy of these drugs.

FDA Lets Drugs Approved on Fraudulent Research Stay on the Market
https://www.scientificamerican.com/article/fda-let-drugs-approved-on-fraudulent-research-stay-on-market/
Arakoda Now Available for Malaria Prevention - MPR

Then there is the anti-malarial drug tafenoquine, which goes by the brand name Arakoda. In 2018 the FDA approved the drug on the strength of fraudulent and misleading clinical trial data. Critical adverse event reports were omitted from the results of a clinical trial performed on Australian troops in the early 1990’s, and there was evidence that the trial was also performed in an unethical manner. Despite there being a large body of evidence, the FDA ruled that the claims were unsubstantiated and approved tafenoquine for use.

https://onecalgaryvoter.com/2019/08/11/an-advocate-equalizer-international-exclusive-australian-defense-forces-brass-engineer-cover-up-of-a-drug-trial-that-tested-a-controversial-anti-malarial/

No FDA Enforcement

According to information provided by the FDAAA Trials Tracker only 69% of clinical trials have registered their reports on time, translating to over $10 billion in fines. These are only potential fines however since the FDA has not seen fit to levy any, despite having this ability for three years. There’s no fear in flouting regulations when you know you that can get away with it.

https://fdaaa.trialstracker.net/?status%5B%5D=overdue&status%5B%5D=overdue-cancelled&status%5B%5D=ongoing&status%5B%5D=reported&status%5B%5D=reported-late

It goes without saying that the amount of work that needs to be done by regulators during the drug approval process is enormous. That being said cutting corners and approving drugs without the proper reviews is potentially very dangerous for the public, with patient safety being put in jeopardy. We need to trust that the drugs we take are going to be safe and that there are agencies in place that will ensure this happens. Unfortunately consumers can’t entirely trust the regulators to do their job, and so are taking a risk with each prescription drug they choose to take.

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