Your Review: Participation in Phase I Clinical Pharmaceutical Research

Finalist #10 in the Review Contest

[This is one of the finalists in the 2025 review contest, written by an ACX reader who will remain anonymous until after voting is done. I’ll be posting about one of these a week for several months. When you’ve read them all, I’ll ask you to vote for a favorite, so remember which ones you liked]

If you’ve been following this blog for long, you probably know at least a bit about pharmaceutical research. You might know a bit about the sort of subtle measures pharmaceutical companies take to influence doctors’ prescribing habits, or how it takes billions of dollars on average to bring a new medication to market, or something about the perverse incentives which determine the FDA’s standards for accepting or rejecting a new drug. You might have some idea what kinds of hoops a company has to jump through to conduct actual research which meets legal guidelines for patient safety and autonomy.

You may be less familiar though, with how the sausage is actually made. How do pharmaceutical companies actually go through the process of testing a drug on human participants?

I’m going to be focusing here on a research subject’s view of what are known as Phase I clinical trials, the stage in which prospective drugs are tested for safety and tolerability. This is where researchers aim to answer questions like “Does this drug have any dangerous side effects?” “Through what pathways is it removed from a patient’s body?” and “Can we actually give people enough of this drug that it’s useful for anything?” This comes before the stage where researchers test how good a drug is at actually treating any sort of disease, when patients who’re suffering from the target ailments are given the option receive it as an experimental treatment. In Phase I clinical trials, the participants are healthy volunteers who’re participating in research for money. There are almost no cases in which volunteer participation is driven by motivations other than money, because the attitudes between research participants and clinicians overwhelmingly tend to be characterized by mutual guarded distrust. This distrust is baked into the process, both on a cultural level among the participants, and by the clinics’ own incentives.

All of what follows is drawn from my own experiences, and experiences that other participants in clinical pharmaceutical research have shared with me, because for reasons which should become clear over the course of this review, research which systematically explores the behaviors and motives of clinical research participants is generally not feasible to conduct.

Part 1: What is participating in a clinical study actually like?

You start by looking up the studies available at a particular site. This may involve browsing their website for offerings, or it may involve simply calling up the clinic and asking what’s currently available. Because many research clinics do not actually bother to keep their websites up-to-date, participants are incentivized to do the latter, which applies an asshole filter to clinics’ participant populations. This will be relevant later.

The clinic representative or website will tell you how much the available studies pay and how long you’ll have to stay at the clinic. They usually will not tell you the intended purpose of the study drug; that comes during the phone screening, where they run through a laundry list of exclusion criteria (do you have an appropriate BMI to participate in the study? Do you have any relatives who work at the clinic? Do you have a history of any sort of disease which might appear in your bloodwork? Etc.) Once you make it through the phone screening, they will schedule an in-person screening at the clinic.

At your in-person screening, if it’s your first time at the clinic, they will go over your entire medical history, and ask about your relationship with every sort of disease, disorder and medical event known to man. In defiance of statistical probability, you will tell them that you are in perfect health with no record of medical events whatsoever. You might be tempted to be honest, but as we’ll address later, this is a mistake which the participant population on the whole has been trained out of. You will give them your payment information, so they can pay you for your study participation, and they will subject you to a battery of physical tests (blood tests, urine tests, temperature, pulse and ECGs, plus any tests idiosyncratic to a particular study) which determine whether you meet that study’s eligibility criteria.

You’ll also receive my personal favorite component of the clinical research process, an Informed Consent Form, which details everything the clinic is legally obligated to tell you about the contents of the study so that you can offer your consent to participate. These forms are not in any respect fun; they’re tedious to read, and probably an absolute slog for the clinics to put together. On the odd occasion where the clinic makes any small change to the procedure after you’ve signed, they have to bring you in to receive a whole new copy of the consent form, and point out the changes so you can sign all over again. They have staff on hand to go over them with you to make sure you’ve actually read them and understand the contents. The whole process is frankly a bit obnoxious, but when I compare it to actual employment contracts I’ve signed in the past, I can’t help but appreciate just how much tighter the requirements are in comparison to make sure that research participants fully understand what they’re agreeing to, and aren’t being taken advantage of. In a way, it makes the process feel significantly less exploitative than regular employment. Of course, this does not mean that research clinics will not screw over their participants when given the opportunity to do so; they’re simply operating within tighter restrictions.

Provided you meet all the criteria for the study, you’ll receive a call a few days later telling you you’re eligible to come in. This does not necessarily mean you’ll end up participating. Clinics almost always want to bring in more people than they’ll actually end up using as research subjects, enough to offer a safe margin in case there are any problems with the lab readings of the participants when they’re brought in at intake. Usually, there are no problems. Regular research participants deal with looming anxiety over the prospect of being made “alternates,” people who’re brought in for a study, but not dosed with the study drug, because alternates don’t receive payment for their participation beyond the day or two they’re in the clinic for the study, meaning the time the participant blocked off for involvement in that study is largely wasted.

Most research clinics do not actually randomize the dosing order of their participants, but instead give participants priority based on the order in which they screened for the study. Thus, among regular study participants, who often travel cross-country to make it into clinical studies, the screening process becomes something of a race to secure the earliest slots in order to maximize their chances of actually getting paid to participate.

If you do end up receiving the study drug, you become a valuable data point for the research sponsor, and your participation is secured. You’ll be dosed according to a regimen described in the informed consent (sometimes just once at the very beginning of your stay at the clinic, sometimes several times a day across your entire stay.) The staff will perform occasional medical tests on you throughout your stay, and ask you to report any effects you experience from the medication. In the great majority of studies, you will not experience any noticeable effects from the medication. If you do, you probably will not report them. In fact, in the event that they experience significant symptoms, participants have strong incentives to actively conceal them, and most of them know this. With some notable exceptions, the actual medication is a trivial component of the experience; most of what matters about your stay will be determined by how invasive the testing procedures are for that particular study, and the company you keep.

Part 2: What sort of people participate in clinical research?

Mostly weird ones.

If you do it regularly, clinical research participation pays on a scale comparable to a regular job, but it’s not a regular job. There is no screening for work experience or skills, or for criminal history, something which a not-insignificant portion of the clinical research population has. Officially, the participant population is very healthy, with no recent diseases or drug use of any kind, not just recreational, but prescribed or over-the-counter for any sort of condition whatsoever, and no medical history of any sort of ailments you might think to include on a survey form. In practice, beyond the requirement of being able to pass medical screenings, study participants have every incentive to lie. If you pass screening, you are probably not on drugs at that specific point in time, although according to clinic staff, it’s not particularly unusual for applicants to try to get away with this. In general, the selection process tilts the participant population towards what might broadly be considered shady characters. People who don’t get along well with traditional employment (it’s hard to reconcile with the scheduling commitments of clinic research,) are comfortable pursuing an avenue of income which is widely perceived as dangerous when people think about it at all, and are generally distrustful of and comfortable lying to authority figures (a useful trait for remaining an active participant in clinical research.)

Many research participants have a dubious regard for the whole institution of “mainstream medicine,” mostly, as far as I can tell, due to a ground-in distrust of credentialed experts and authority, rather than an awareness of how much they are personally lying to people responsible for bringing new drugs to market. Conspiratorial or contrarian dispositions are common. In one characteristic experience, I listened to a couple of participants (both black,) discussing a particular high-profile medical practitioner. One claimed that because the doctor in question was white, he couldn’t be trusted, and was probably throwing people’s health under the bus for personal profit. The other insisted that this sort of thing isn’t a matter of race, just about whether the person in question knows what they’re talking about and has reason to be honest, and the doctor in question was clearly a credible expert. Whatever sense of gratification I might have felt at hearing one of them stand up for racial harmony and the universality of scientific knowledge withered on the vine as I continued listening and realized that the “doctor” in question was actually an alternative medicine provider encouraging his audience to reject mainstream treatment in favor of his own personal line of supplements.

You might infer from all this that clinical research participants are mostly also poor, but this is not particularly the case. The payment structure of clinical studies, which offer large lump sums paid out according to the inconsistent and unreliable schedules that participants build around research participation, mean that very few people involved in clinical research are living paycheck to paycheck. I’ve spoken to several who were surprisingly well-off, owning property in multiple states despite spending much of their time traveling between different clinical research centers across the country. Many are apparently adventurous if not particularly cautious investors. Clinical research participants have the highest concentration I’ve personally encountered in real life of investment in cryptocurrency, outside of some rationalist meetup groups, and also the highest rate of investment into NFTs, despite few seeming to have any familiarity with how those technologies work. Whenever I’ve been tempted to develop a low opinion of their judgment, I’ve had to temper that with the knowledge that many of these people have apparently accumulated much more disposable income in the process than I have. I’ve spoken to research participants who’ve discussed sinking tens of thousands of dollars into NFTs, which is not a life decision many people find themselves in a position to contemplate, for better or for worse.

While the participants might make up something of an odd crowd by ordinary sensibilities, most of them are quite well-adjusted to the environment of clinical research, and have been doing it for quite a long time. They tend to share information pretty freely among each other on how to deal with the practicalities of travel between study clinics, how to reliably pass screenings and avoid being made an alternate for studies, and how to handle the idiosyncrasies, and circumvent the rules, of various study locations.

Part 3: Why nobody is actually honest with research staff.

Simply put, the system of paid clinical research is structured to discourage it.

Clinic staff will tell participants that they should be honest for the sake of their own health and safety, but this is a lie intended to appeal to participants’ own self-interest. The requirements clinical researchers are forced to comply with are well in excess of what’s necessary for participants to reliably avoid lasting harm to their health, and the practices of research clinics tend to filter out participants who are honest with them.

The first filter is in the initial screening process which occurs before a participant even shows up at the clinic. During the initial phone screening, a staff member will ask the participant whether they have any of a wide array of health conditions, and if the caller answers yes, the staff member will immediately tell them that they’re not eligible for the study. A stronger filter on participant honesty however is the fact that the staff member will ask if the participant has received any sort of medication in the last month. Not any sort of recreational drug, or any sort of prescription treatment for any of a number of relevant conditions, or even any prescription medication. Any type of medication or supplement whatsoever, prescription or over-the-counter. This includes “supplements” sold at the grocery store, like fish oil, fiber, etc. Are you wondering whether something counts as a food or supplement? The answer is, if you ask a staff member, and you say the word “supplement,” they will tell you you’re not eligible within thirty days of taking it. There is no point trying to negotiate on this, from the perspective of the clinic, it is always better safe than sorry.

This phrase, “better safe than sorry,” overwhelmingly characterizes the protocols of research clinics at every level, except the level where they start to ask whether participants might become more likely to pass through their filters by lying than meeting all their criteria. This is partly because research clinics are forced to comply with safety standards set by people who are not familiar with basic principles of research, and partly because they have an incentive to put the burden of disclaiming anything that might increase the overall level of risk on the participant, so that, in the event that anything does happen, the clinic can avoid legal responsibility, because the participant is the one at fault if they lied and violated the protocol.

For example, every clinical research protocol I have ever encountered includes a stipulation that a male participant must not donate sperm for at least ninety days following their last dosing of the study drug, and if they have sex with a female partner, they must use a condom with spermicide, combined with a hormonal method of birth control on the part of their partner. As far as I’ve been able to find, no drug has ever been discovered to cause birth defects when taken by a male prior to conception, and for most classes of drugs, there is no known plausible biological mechanism by which this could occur. However, in the event that a patient did have a child who was afflicted with some manner of birth defect after participating in a clinical trial, the clinic might have to face a legal battle over whether they held responsibility for that. Rather than face that cost, let alone the risk of actually being held responsible, it’s safer to ensure that the participant cannot become a parent within that window of time without violating the study protocol. If the patient chooses to violate the study protocol, the consequences of that become their own responsibility.

Research participants who disclose information to the clinics too freely tend to learn quickly that this is not in their interests. Admitting to any sort of medical condition, medication use, or history of medical events, tends to result in participants simply being told they are not eligible for the study they wish to screen for. If, at your first in-person screening at a clinic, you provide information about your medical history which qualifies as an exclusion criterion, you may be ruled out from many or all studies at that clinic, and the relevance of any of these criteria to a participant’s health and safety is heavily colored by the principle of “better safe than sorry.” An example from my own experience: At the first clinic where I participated in studies, I disclosed that I was diagnosed with ADHD as a child, and had been medicated for it in my childhood, although I have not been for many years. This did not automatically exclude me from all studies, but before long, I found that many studies at that clinic had “must not be diagnosed with any mental conditions” as an eligibility criterion. I discussed this with a number of members of the medical staff at that clinic, and they told me that this generally occurs in cases where the general class of drugs an experimental medication is in has been found to sometimes have increased risk of suicide as a side effect. In these cases, the people designing the protocols find it expedient to simply rule out anyone who has any diagnosis of any sort of mental condition. Do they have any reason to think that ADHD might be associated with an increased risk? I asked, and their answer was, not at all, but better safe than sorry.

Another factor which incentivizes participants not to be honest with clinic staff is that they simply get paid more if they aren’t. Even for study participants who genuinely meet all the medical criteria in the screening and study protocols, there’s one factor that affects all participants and is consistent between all clinics and studies, which affects participants’ ability to profit from their involvement in clinical studies. Participants are required to observe a washout period (usually at least 30 days, but this varies between study protocols, and may be as much as 90 for some studies) between the last time they were dosed with any experimental medication, and when they’re next able to participate in a study. Most clinical research participants treat studies as a regular source of income, and prefer not to comply with this, as it limits how frequently they’re able to get paid for participating. Staff at an individual clinic won’t let a person enroll in multiple studies too close together at the same clinic, but most research participants travel around the country to enroll in studies at different locations. Participants who’re willing to lie and claim that they haven’t received any experimental medications in the last month when they actually have are simply able to earn substantially more money than participants who’re unwilling to do so.

While clinic staff will tell participants that they should comply with study protocols for their own health and safety, participants share information freely among each other, including information about how to most effectively get away with violating study protocols. The common perception among participants is that there is no real risk in lying to participate in studies more often, and research clinics are inherently obstructionist, and a canny participant is one who knows how to mislead them to his own benefit (or hers, but most research participants are male, partly for cultural reasons, but also because it’s easier for men to meet clinical studies’ eligibility criteria.) The washout period, for most participants, is however long it takes for a study drug to clear from one’s system so that it won’t be detected when they screen at another clinic. Being caught flagrantly violating screening or study protocol, such as by having prohibited drugs in one’s system during screening, will result in a lack of payment for that visit, and may result in a temporary ban from that clinic. But most participants travel around extensively for studies, and many regard occasional temporary bans as just a natural cost of business.

There is one way though that participants may risk being permanently restricted from participating in studies with a particular company- not just a particular clinic location, but all branches associated with that pharmaceutical research company across the country; a risk which substantially shapes the way participants engage with clinical studies. The thing which most participants are truly hesitant to risk is reporting a negative response to a study drug.

To be clear, reporting a negative reaction to a study drug does not necessarily result in consequences for a participant. In many cases, such as when a particular reaction is expected and discussed in advance by the staff, and widely experienced among the study population, participants generally consider that safe to report. Usually, the staff don’t want participants to be on any other medications whatsoever, but in some studies which researchers anticipate to produce particular symptoms, such as nausea, there are allowances written into the protocols for participants to receive over-the-counter medications, and participants will report their symptoms in order to receive them. It’s also not the case that clinical researchers will directly retaliate against participants for reporting adverse reactions. Although research clinics are contracted for work by pharmaceutical companies, they are not directly owned by pharmaceutical companies, and staff will attest that their primary concern is for research participants’ health and safety, not getting favorable results for the pharmaceutical companies they’re contracted by.

From the perspective of the participants though, this concern for their “health and safety” is exactly the problem. A participant who reports an unusual reaction to a study drug may go on the record with that clinic as having an unusual sensitivity or allergy to that medication. And having unusual sensitivities or allergies to any sort of medication is an exclusion criteria for almost all clinical studies. So, a participant who reports an unusual or unexpected reaction to a study drug risks finding himself thanked for his honesty, and then rendered ineligible for all studies with that pharmaceutical research company afterwards. Better safe than sorry. A participant who experiences symptoms which make them genuinely worry about the prospect of receiving more of the study drug can always simply make an excuse and drop out of the study, something all participants are entitled to do as part of the legally mandated protections involved in clinical research. This would come at the cost of the payment for the rest of their involvement in that study, but better that than being permanently barred from all studies with that company.

As a result, research participants commonly discuss among each other their refusal to disclose or discuss symptoms with clinic staff, out of a general understanding that clinical researchers do not have their best interests as participants in mind, and are not to be trusted. Participants commonly see themselves as being in an adversarial relationship with clinic staff, whose jobs are to enforce arcane and unnecessary study restrictions, while the participants’ interests, for their own comfort and profit, are to find ways to avoid complying.

Part 4: How much does this actually matter?

Probably not as much as you might think.

The overwhelming majority of Phase I pharmaceutical trials are almost certainly being performed on participants who’re not in compliance with the study criteria, and who’re not reporting all the symptoms they experience while taking the experimental medications. But many symptoms, most of the ones most directly relevant to participants’ health, can be caught by the regular medical tests which participants undergo throughout their involvement in the clinical studies. Besides which, in most Phase I clinical trials, most or all participants don’t actually experience any noticeable symptoms in the first place. Studies where any participants experience significant reactions are more the exception than the rule, and most of those exceptions are ones which the researchers can already predict based on animal studies and the general class of drugs they’re studying. If you participate in a study on a medication for cancer or heart failure, the drug is probably going to have a noticeable effect on you, and nobody is going to be surprised.

Most of the study criteria which participants habitually violate probably don’t matter very much, in terms of the actual outcomes of the studies. If a participant has other drugs in their system which might interfere with the actual study drug, or result in test readings which could be misattributed to the study drug, that could have a significant confounding effect on the results. But most relevant drugs are likely to be caught by the medical tests conducted at screenings, if not self-reporting by the participants. In most cases, a participant who last received an experimental study drug ten days before screening for a study, by which point it has already fully cleared from their system, is probably not going to show significantly different outcomes from a participant who waits a full thirty days.

Phase I clinical trials are also not the last step before an experimental medication goes to market. Before a drug is made available to the public, it’s also trialed on research participants who actually have the ailment the drug is intended to treat. These research subjects are generally not paid clinical research participants who travel around the country to participate in studies on a regular basis, and consequently, they operate under very different incentives. Participants in later phases of clinical trials probably are exposed to at least slightly greater risks of side effects and adverse reactions than they would be if Phase I clinical trials didn’t feature perverse incentives against reporting, and filter for a population generally disinclined to do so.

It’s difficult to say how much any of the confounding effects or obfuscation from all the perverse incentives in clinical research serve to skew doctors’ understanding of the actual effects of drugs by the time they reach the general population, not just because there are other layers that a drug has to pass through before it reaches that point, but because it would be nigh-impossible to test the existing pharmaceutical research pipeline against another pharmaceutical research pipeline operating under different incentives. Research which probes into the effects of clinical research’s perverse incentives, and the filters it places on its participant population, is largely nonexistent. How do you systematically study the opinions and behavior of a population who mostly don’t see it as being in their interests to be open or honest with researchers in the first place?

It would almost certainly be possible for pharmaceutical research to work at least somewhat better than this. If I were the clinical research czar, this is not a system I’d be proud to have designed. It’s probably not exposing the general public to catastrophic risks that they could be avoiding with a better-designed research pipeline. It’s not exposing Phase I research participants to catastrophic risks either, although they would almost certainly be at least a little safer if the system weren’t designed with such a “better safe than sorry” ethos that it incentivizes them to constantly lie. At least some of the pathologies of this system probably propagate down to later levels though, and it’s difficult to say how much. In general, if you want to study anything at all, it’s better to make sure you have a system for doing so which encourages the people involved to be honest.