The Phases Involved In Them, And The Regulatory Oversight That Was Intended To Govern Reporting Compliance (But So Far Hasn’t).
Originally published May 30, 2020
(Update: Based upon the information current to August 22, 2022)
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.
There are no hard and fast rules governing clinical trials, nothing specific as to the required number of participants in a study, and other things of that nature. Clinical trials, in theory, are designed to achieve the best possible result in a best-case circumstance. Many times, the circumstances are far from the best case, particularly when it comes to the number of subjects (people) that are available to participate in a study.
Typically, there are five phases to a clinical trial, though only four are referred to. The first is referred to as the phase zero clinical trial. These trials are different from other clinical trials in that they are exploratory studies used to speed up the approval process of a new drug, and are usually done on only a few patients. Many times these are investigational drugs and are done in exceptional circumstances.
I’m going to save myself some work and just copy and past this next section on human clinical trials from centerwatch.com.
Phase I studies assess the safety of a drug or device. This initial phase of testing, which can take several months to complete, usually includes a small number of healthy volunteers (20 to 100), who are generally paid for participating in the study. The study is designed to determine the effects of the drug or device on humans including how it is absorbed, metabolized, and excreted. This phase also investigates the side effects that occur as dosage levels are increased. About 70% of experimental drugs pass this phase of testing.
Phase II studies test the efficacy of a drug or device. This second phase of testing can last from several months to two years and involves up to several hundred patients. Most phase II studies are randomized trials where one group of patients receives the experimental drug, while a second “control” group receives a standard treatment or placebo. Often these studies are “blinded” which means that neither the patients nor the researchers know who has received the experimental drug. This allows investigators to provide the pharmaceutical company and the FDA with comparative information about the relative safety and effectiveness of the new drug. About one-third of experimental drugs successfully complete both Phase I and Phase II studies.
Phase III studies involve randomized and blind testing in several hundred to several thousand patients. This large-scale testing, which can last several years, provides the pharmaceutical company and the FDA with a more thorough understanding of the effectiveness of the drug or device, the benefits and the range of possible adverse reactions. 70% to 90% of drugs that enter Phase III studies successfully complete this phase of testing. Once Phase III is complete, a pharmaceutical company can request FDA approval for marketing the drug.
Phase IV studies, often called Post Marketing Surveillance Trials, are conducted after a drug or device has been approved for consumer sale. Pharmaceutical companies have several objectives at this stage: (1) to compare a drug with other drugs already in the market; (2) to monitor a drug’s long-term effectiveness and impact on a patient’s quality of life; and (3) to determine the cost-effectiveness of a drug therapy relative to other traditional and new therapies. Phase IV studies can result in a drug or device being taken off the market or restrictions of use could be placed on the product depending on the findings in the study.
It’s clear that it would be extremely difficult to perform the perfectly ideal clinical trial, that is just the way things are. This risk goes with every drug on the market, and we take that risk with every dosage of a new medication. It ultimately comes down to the question of whether or not the reward is worth the risk. Sometimes it is, and tragically, sometimes it isn’t.
On January 18, 2017, a regulation came into effect that is called the “Final Rule for Clinical Trials Registration and Results Information Submission” that greatly expanded the requirements for clinical trial registration and results submission for certain trials.
Of particular importance is the post-marketing surveillance trial data, which will contain information about any reports of adverse reactions patients have had to a drug. A large number of reports could cause a drug’s approval to be revoked pending further safety studies, a move which could prove costly to a manufacturer. It is of the utmost importance that these results are submitted on a timely basis, as patient safety is the primary concern or at least it should be. Some companies might be reluctant to release these results because they will be problematic for them, however, there are fines that can be levied against companies that do not submit results by the required date.
The statutory maximum penalties under the FD&C Act for committing these prohibited acts are not more than $10,000 for all violations adjudicated in a single proceeding, see section 303(f)(3)(A) of the FD&C Act and, if a violation is not corrected within 30 days following notification of such violation, not more than $10,000 for each day that the violation continues after such period until the violation is corrected, see section 303(f)(3)(B) of the FD&C Act.
In determining the amount of civil money penalty under the relevant statutory limits, the following factors are considered: the nature, circumstances, extent, and gravity of the violation(s) and, with respect to the violator, ability to pay, effect on ability to continue to do business, any history of prior such violations, the degree of culpability and such other matters as justice may require. See section 303(f)(5)(B) of the FD&C ActCivil Money Penalties Relating to the ClinicalTrials.gov Data Bank
Given that a $10,000 fine can be levied for each day a drug company is non-compliant the amount can really add up if it remains so for very long. You might expect this would be an incentive for them to be compliant, however, this has not been the case.
The FDAAA Trials Tracker
(Update: based upon the most recent update as of August 22nd, 2022, out of 14,762 trials, only 11,209 were compliant, a rate of 75.7% reported on time. The longest trial is now over 1,600 days late. The amount of uncollected fines has now ballooned to over US$36.5 Billion)
A team at the University of Oxford has put together a website that tracks the compliance rate of FDA trials, and the results were rather shocking. As of May 28th, 2020, out of 6,567 trials that were reported only 70% were compliant. That means that the results of 1,983 have not been reported. It also keeps track of the number of days a trial is late right from day one, and so far the longest is 821 days and counting.
They are also keeping track of the fines, or rather the potential fines, that the FDA could be assessing. To date, that total is over $9.8 BILLION dollars however the FDA has not enforced this legislation and has collected ZERO dollars. You can access their website by clicking the link below.
FDAAA Trials Tracker
Start Enforcing Toothless Legislation
The fact that there are laws on the books somewhere that aren’t being properly applied should come as a surprise to nobody. However, when the health and safety of the public are at risk then there should be absolutely no question as to whether or not a company is fined. The FDA however doesn’t exactly have the best history when it comes to enforcing the laws and regulations under its control.
Canadian clinical drug trials are listed on the ClinicalTrials.gov website however registration is not mandatory, meaning that there could very well be trials conducted in Canada that will not appear on this database.
There is a database that is maintained by Health Canada however, it does not supply nearly the amount of information that ClinicalTrials.gov does, and it is not easy to use. In addition, the Clinical Trials Database is not a registry, and therefore, it does not contain comprehensive information about each clinical trial.
You will need to know a lot of information about the study in order to search it in the database, and most of it is information that you must get directly from the study sponsor. According to the website, The sponsor of the clinical trial should be contacted for more information about a trial’s objectives, patient enrolment criteria, potential clinical trial sites, and to confirm the status of a trial. Health Canada will not be providing detailed sponsor contact information, or any other details about the clinical trial, other than what is found in the database. Sponsor contact information should be obtained through an internet search.
In addition to this, there are a few other things that it is very important to know.
- Clinical trials in healthy volunteers. Health Canada authorizes clinical trials involving healthy volunteers, such as bioavailability or bioequivalence trials, first-in-human trials (that is, when a new drug is administered for the first time in humans), pharmacokinetic studies, drug-drug interaction studies, etc.; however, information about these trials is not included in the database.
- Clinical trials conducted with natural health products and medical devices. Health Canada also authorizes trials involving natural health products and devices; however, information about these trials is not contained within the database at this time.
- Phase IV trials. Phase IV trials are studies carried out with a marketed drug under its approved conditions of use, and a CTA is not required to be filed with Health Canada. Therefore, information about these studies is not reviewed by Health Canada prior to the start of the trial, and is not contained within the database.
The AllTrials Campaign
In 1964 the World Medical Association (WMA) adopted the Declaration of Helsinki which pertains to the ethical treatment of human subjects in medical research. Section 35 and 36 deal with research registration as well as the publication and dissemination of results, specifically:
- Section 35 Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject.
- Section 36 Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the publication and dissemination of the results of research. Researchers have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results must be published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted for publication.
AllTrials is an international initiative aimed at making sure all clinical trials are registered and that the results be made available to the public. There is a petition on their website calling on international governments to act in making sure this gets done and I would encourage you to sign it. It’s about the life and health of you and your loved ones.