As it has been previously discussed, the development of new treatments is a process that goes through various phases.
The initial phase, Phase zero or Preclinical phase, often involves lab or animal testing.
However, there comes a point when a drug has to be administered to humans. In the past, this was not regulated, and there were cases when un-tested chemicals did more harm than good to patients. Such a case was the sulphanilamide disaster of 1937, which led to the death of over 100 people, when sulfanilamide, a drug used to treat streptococcal infections, than has previously been used in tablet or powdered form, was introduced as a liquid, without being tested for toxicity. [1] This event led to making American drug distribution laws more strict.In Europe, the Nuremberg Code was formulated in 1947, as a response of Nazi doctors' inhumane trials in concentration camps[2].
Now it is clearly stated, according to the Nuremberg Code, that “No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur.” [3]
But these are not solely events of the past, since valporate, a drug introduced in France in 1967, is now being linked to birth malformations.[4]
Phase one is the first phase in which the newly developed drug is tested on humans, with a relatively small population (20-80 subjects) of healthy volunteers (in cancer drugs, it can be also cancer patients).
"In FIH/early CTs subjects are not expected to derive therapeutic benefit, except in certain patient
populations. The aim should always be the safety and well-being of the trial subjects, whether patient
or healthy individuals. " [5]
These tests measure the absorption, metabolism and excretion of novel drugs, in people with normal liver and kidney function.
The aim of this phase is to find the safest dose, the most effective way to deliver the new drug, and to identify side effects.
In the European Economic Area, there are approximately 8000 clinical trial applications, and 4000 authorisations, each year. The sponsors of these trials are mostly the Pharmaceutical industry (61%) and 39% non-commercial sponsors (which is mostly academia).[6]
However, in a 10-year review of IMPs(Investigational medical products), only 60% progressed from Phase 1 to 2, and a mere 11% became a marketed product.
Image source:[7]
While most studies have uneventful outcomes, some cases might happen that go extremely wrong, and stir up the public opinion on the matter. Such a case was the testing of TGN1412 in June 2006, a drug that was aimed to help people with leukemia and MS. Preclinical testing, including tests in rabbits and monkeys that used doses up to 500 times as high as the doses received by the first group of volunteers, reportedly showed no signs of toxicity.[8] The novel drug was administered as a phase I trial to 6 healthy subjects: within 90 minutes, all of them had strong adverse reactions to the drug. Within 12 to 16 hours later, they all became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation. They all had to be transported to intensive care, and put on dialysis and cardiopulmonary support.[9] All six subjects survived; nevertheless, the company went bankrupt one year later [10]
Another such case was the 2017 BIA 10-2474 trial in France, when healthy subjects suffered brain damage as a result of the accumulation of the substance. One subject died, and 5 suffered severe brain lesions; and the dose they received was only 50 mg higher than the previous cohort.[11] Participants in this study received 1900 E for participating, and the sponsors recruited 128 healthy volunteers, aged 18-55. [12] Three of the survivors suffered irreversible brain damage.[13]
One more fatal experiment was carried out in 2001, when a young female subject died as a result of inhaling an experimental compound, which was found in 1950-1960 to cause fatal lung inflammation. Volunteers in that study received 360 USD.[14]
The starting dose is expected to be calculated considering previous studies (ex vivo/in vitro human or animal studies). However, the sensitivity differences between different species should be taken into consideration.
Why the healthy
Firstly, the choice of healthy people can most easily be backed up by the irrefutable fact that they provide the "cleanest" data. Lab results coming from these subjects will mostly show the true effects of the administered drug. [9] Moreover, already sick patients might have to take other drugs, too, which might interact with the tested substance.
Since the purpose of phase one trials is to determine a safe dose, we cannot speak about a health benefit, neither to a sick person, nor to a healthy one. Therefore, the data provided by a healthy person can give more information on the pharmacodynamics and pharmacokinetics of a substance.
Additionally, healthy volunteers are of the highest availability. The recruitment of them is the fastest and cheapest, and as phase I trials aim to find the safest dose in humans, there is no requirement for an existing condition.
The healthy patients will most likely survive long enough that long-term effects of the medication can be studied.
Healthy patients can withstand the side effects of medication more easily, as in patients, these side effects can even make sickness symptoms worse. Moreover, trial of new medication could worsen certain conditions, and could be a bigger health (and life) risk to patients. [9] Additionally, they are more likely to respond uniformly to medicines, and they are better at completing trials that are more complex or spread over a longer period of time. [15]
It has also been argued that volunteers gain some personal fulfilment for helping the advancements of medicine. Altruism might also be a cause for participating, for example when a person participates in a study for a disease somebody close to them suffers from.
Using sick patients could slow down the trials; e.g. if a patient dies during the trial, this would have to be halted until the cause of death is found out.
However, some FIH tests could be more risky for healthy humans (eg monoclonal antibodies can trigger a very dangerous immune response in healthy humans, but a low one in patients with a compromised immune system), and some biomarkers cannot be found in healthy subjects.
Where do we start..
In healthy volunteers, the starting dose should ideally result in an exposure to a subject that is below that which would be expected to produce a PD response. [16]
Preclinical studies might predict nonexistent benefits, but also nonexistent risks.[17] Phase one tests in healthy humans might prove or disprove some risks, but also give some early information on benefits.
However, preclinical research might not provide sufficient information that would predict the risks that a new substance would be to humans[9] . The animal model in TGN 1412 predicted no acute response in humans, since the monkeys on which it was tested have a safe dose of 500 times the one in monkeys. However, the reliance on monkeys was not a wise choice, since the similarities in monoclonal antibody receptors were limited in human and non-huma n primates.[17]
In order to prevent other dose-related problems, the FDA recommends starting experiments with a 'microdose', defined as “less than 1/100th of the dose of a test substance calculated (based on animal data) to yield a pharmacologic effect,”or the “no observed effect level,”[9]
Other methods of increasing safety would be slow infusion of the drugs, and observation periods between the administration of the drug to different subjects. Researchers should also carefully investigate the data from one cohort before proceeding to the following one and the initially worked-out escalation plan should be adjusted accordingly.[9]
The rigorous investigations and procedures usually mean that errors in dosage, manufacturing or administration of drugs are usually rare (that's why pure form is prefered to solutions in administrating these novel substances), making trials relatively safe.[17]
Another strategy to improve safety, proposed by Wood and Darbyshire[7] would be the creation of a central database, where information from all clinical trials would be submitted. By searching in this, officials could find information about what has been done before, and how it was been done, for a specific chemical compound, and what were the outcomes. This would also facilitate the estimation of initial doses, and strategies for escalating the dose.
The professional guinea pig
Until the 1980, in the US, it was common practice to use prison inmates to test new drugs, but the ethical aspects of this practice led to stopping this. The inmates presented an almost perfect population for these studies: they were captive, compliant, available, and in a controlled environment . However, they were deemed unable to give consent. [18]
Image source:[19]
Since then, the most common people used in drug trials are low-income, young and middle-aged white adults - college students, unemployed men, former inmates : people who don't want to, or find it hard to find a job.[9] This process gave rise to a new profession: the professional guinea pig, as payments rise to the level of up to 4 000 USD for 3-4 weeks of participation, being able to earn up to 20 000 USD a year. [18]
A study in Brasil [20] showed that, as expected, the main motivator of healthy subjects for participating in clinical studies is the financial aspect (94.7% of respondents). Other reasons are altruism and access to healthcare.
In Europe, the legislation varies by country. Some countries exclude compensation, others need an approval from the Ethics committee for it. According to the EU Clinical Trial Directive(2001/20/EC)1 and Regulation (536/2014)2, ‘no undue influence, including that of a financial nature, [must be] exerted on subjects to participate in the clinical trial.’[5]
Nowadays, there are clinical trial centres, which make it much easier to become a professional CT volunteer. A description of one of these is below:
"Phase I Clinical Trials Unit, Ltd. (2004), located in Plymouth, England, is a company that specializes in conducting phase one studies for drug companies. The company has a database of about 5,000 regular volunteers and a clinical staff of about 100 employees. It also has 61 beds, 21 monitored beds, a pharmacy, an ethics committee. It advertises that it can recruit many different types of volunteers for drug studies, including older men and women; sterilized men and post-menopausal women; obese subjects; and smokers and non-smokers. Volunteers stay at the company’s facilities overnight or longer. The company claims that its facilities are comparable to a quality hotel, with televisions in every bedroom, lounges, landscaped gardens, and catered food." [21]
As a result, many subjects see their participation as a job, as, in the US, they are required to pay taxes on this income, and they are often referred to as "independent contractors" in their contracts, and their payments "compensation". The payments are often better than in a low-wage job; however, it often doesn't come with the health and disability benefits.[22] One volunteer said 'You are paid to endure' [22]
Another participant said, “I’ve worked as an electrician and seen guys get electrocuted. Being a lab rat is the only work situation where you’ve got round-the-clock medical attention. It’s the safest job I’ve been in.”
"It is not the first time that I have participated. They pay well, and I have confidence in the place and it is good because they do several examinations, and I a find out about how my health is." [20]
A study concerning the pay of subjects asked institutions for reasons of payment and found that subjects are paid for their time (87%), for inconvenience (84%), for travel (68%), as incentive (58%), or for incurring risk (32%).[23] A 2001 study estimated that participants receive around 450 USD for a study, varying depending on time spent, invasiveness and number of tasks carried out by the subject. A person claimed to have earned 7000 USD as a research subject; but since he had to 'work' for 720 hours, this translates to about 9.71 USD per hour.[21]
Some argue that the pay for FIH trials is equivalent to the pay in other jobs, where the subject would carry out a boring, but dangerous task.
While the financial aspect might be attractive, 'professional guinea pigs' feel there is a stigma against them, and they often do not discuss their 'profession', even with family and friends:
This is a very small percentage of people who are A) even thinking about doing it [enrolling in studies], and B) who are willing to do it. You go out on the street, and you tell people you’ re doing medical testing. They’ re like, ‘ Where’ s your third eye?’ or ‘ Are you cutting off an arm?’
I tend to be pretty secretive about the things that I do simply because everybody doesn’ t understand, you know. Everybody isn’ t the type of person who would be in a study for money.[24]
Another negative aspect is dehumanising the participants. Since it is required that personal data is confidential, people often end up to be the equivalent of a commodity, a mere identification number.[18]
Who are these people?
Table source: [24]
As it can be seen from the image above, there is some variety in the race/ethnicity of participants in the US locations researched. However, it can clearly be seen that female subjects are underrepresented. The FDA is currently carrying out campaigns to encourage women to take part in more clinical trials.
In another study on US clinical trial centres [25], it was found that 89% of studies involved both men and women, and women with childbearing potential were involved in 63% of the both gender tests.
Image source:[26]
It is recommended that women take part in trials only if they are not pregnant or at risk of becoming pregnant for a specified interval, they are not taking hormonal contraceptives, and were informed of potential risks to developing children, in case of pregnancy. [15]
However, a highly underrepresented group is the elderly. It is argued that since they are the most rapidly growing population worldwide, and they represent the main patients for medications treating chronic conditions[27].However, the higher probability of diseases and already existent medications might make using this category as subjects a more difficult task.
Since regulations in EU and USA are becoming more strict, it is becoming increasingly popular to 'export' trials to other areas. The statistics showing locations for clinical trials are as follows: Africa (this area provided 2.76% of the patient in total), Middle East/Asia/Pacific (8.7% in total) Australia/New Zealand: this area provides 1.5%, Central/South America (8.5 % in total), Commonwealth of Independent States (3.8 in total) Eastern Europe-non EU (0.5 % in total), North America (34.54% of the total, mainly from USA (29.98%)), EU/EEA (39.4% of the total [11]. The extension to there countries can be motivated by finding more subjects, for cheaper, and getting more rapid approval for tests. However, this might also lead to lower standards.
Such a case could be one from 2005 in Brazil, where a group of people were each paid between 6 and 10 USD/day to capture mosquitoes in rather unsafe conditions, exposing themselves to a higher risk of malaria contamination. The research was promoted by a North American University and Brazilian research institutions, and the process of capturing the mosquitoes was approved by the Institutional Review Board of the University. Even though the participants received some training, this was not at high enough standards and raises the question of ethics of outsourcing trials and experiments to poor or developing countries.[28]
But doctor
It is stated that "Scientific research as well as any preventive, diagnostic or therapeutic medical intervention involving human subjects is only to be carried out with the prior, free, express, specific, documented and informed consent of the person concerned, based on adequate and comprehensible information provided both in writing (or optionally pictorially for illiterate individuals) and orally. Furthermore, consent should, be given, and may be withdrawn, by the person concerned at any time and for any reason without disadvantage or prejudice." [11]. Therefore, subjects are previously informed about the risks and conditions of participation, and can withdraw anytime. Moreover, the sponsors should take care of providing some form of insurance for the subjects in case any wrongs that should result from the tried substance.
However, it was discovered that subjects are not always aware of their rights.
Additionally, even though the purpose of phase I trials is to test drug safety, many sponsors refuse to provide free healthcare to people involved in trials(US - 16% of academic health centres), and not even to lost wages and pain that result from injury. Contracts often include disclaimers that make subject responsible of their own medical care. Subject are also reluctant to complain about conditions or go to lawyers in case of trials going wrong, for fear of being excluded from future trials. [22]
Moreover, it is often the case that the biggest part of the compensation is paid after the study is over, making people be biased to stay in the study for as long as possible, even though the side effect might be quite serious.[18]
All for the money?
As the main incentive for subjects to participate in these studies is the money, it is common that people would lie about participation in previous studies or physical conditions that would make them unfit for a study. Moreover, some would also avoid reporting effects of the tested substance, so as not to be removed from the study, thus both risking their personal health, and providing false data [9].
Participants in studies are most often required to undergo a 30-day washout period between the last day of one study, and the first day of the next one, but subjects often go to different clinics to work around this restriction, risking their health.[24] Additionally, many subjects remain in the 'clinical trial industry' for many years, accumulating possible cross-efects.
Nevertheless, a study by Bentley and Thacker showed that money can influence the decision to participate in research, but up to a point.[18] From some risks, participants are unwilling to risk their life and health. Study [24] also found that volunteers also consider the long-term effects of the studies they are undergoing.
' [The decision to participate] all boils down to dollars and cents ... I normally read the consent form and pretty much do something I wanna do, so that’ s how I figure out what [drug] I wanna take... ‘ Coz a study could pay you six grand, but they might wanna stop your heart beating or something. Nah, I don’ t think I’ ll do that, you know what I mean? So it’ s dollar and sense, have sense [Laughs].' [24]
Among the participants, there are often 'urban legends' circulating, that often have the morale of never lying to the researchers, in order to protect one's health.
'So you really need to be honest before you try to get in here, no matter if you really need the money or not, because it will harm you. I mean, you have to be honest, telling the truth on your health history. That’ s important, right? You know, if you do that [lie], then you basically just cause a problem.'
[About somebody who committed suicide while a participant in a phase I trial]
'Maybe something else was wrong with him. Because when you make out the consent forms, they tell you, ‘ Whatever’ s wrong with you, please be truthful and report it to us because the medication you’ re taking can have a certain effect on your body’ , especially the ones that mess with your central nervous system.'
Image:[30]
However, there are no long-term studies on health of phase one trials: their risk of developing cancer, cardiovascular problems, liver disease and neurological disorder further in life, so there is no clear data on how dangerous phase I trials really are for healthy subjects, and subjects can have no clear overview of the risk they are actually assuming . [31]
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