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Clinical Trials

Are Phase I Trials Ethical?

It’s been a year since the clinical trial disaster in France that led to several participants being hospitalized with brain damage. Back in November, the New England Journal of Medicine had an article about the affair, summarizing what was known:

The healthy volunteers described in this article participated in a phase 1 study of BIA 10-2474, a new FAAH inhibitor. They had received the highest cumulative dose (250 to 300 mg) administered to humans. A total of 84 healthy volunteers had previously received cumulative doses of up to 200 mg of BIA 10-2474. No clinical severe adverse event had been reported. The product contained in the capsules administered to all the volunteers was the same as that used for the toxicology studies, and assays confirmed that it was of high purity.These data suggest that the toxic effects we observed were related to drug accumulation. This hypothesis is supported by the nonlinear pharmacokinetics of BIA 10-2474 for doses higher than 40 to 100 mg.

MRI studies and others showed many lesions (microhemorrhages or edema) in the hippocampus and pons of each affected patient, but the exact mechanism for these is still not known. FAAH itself is not expressed in the pons region, and endocannabinoids have not been associated with this sort of toxicity. Whether this was something new in that line, an off-target effect of the compound or a metabolite, or something we haven’t even thought of yet is still unknown.

The latest issue of the journal has a number of letters to the editor prompted by the earlier article. Among them is this from Irwin Nash at Yale, and it’s an idea whose time may be coming:

Kerbrat et al. and Bonini and Rasi describe a phase 1 study that underwent review by an institutional review board. Nevertheless, I question whether it is ethical to enroll healthy persons in phase 1 (toxicity) trials.

According to the principle described in the Belmont Report,1 beneficence implies a reasonable risk-to-benefit ratio. For a healthy volunteer enrolling in a toxicity trial, there is clearly risk but no medical benefit. Monetary compensation or appeals to altruism in the name of humankind are only avenues for ethical abuse. The only cohort that can be considered to derive at least a modicum of medical benefit from volunteering in a phase 1 trial consists of patients who have the condition for which the drug is being developed as a treatment. They should be the only persons who are asked to volunteer for a phase 1 trial.

This sounds a bit radical to people in drug development, but there’s definitely a case to be made. I don’t expect this to change overnight, but it wouldn’t surprise me if Phase I populations do start to shift over. Failing that, we need to get better at estimating pharmacokinetics and pharmacodynamics, because otherwise we may be running greater-than-acceptable risks when drugs go in for first-in-man studies. This topic has certainly come up before (here’s a 2004 articlea clinician’s view from 2008, and another piece from 2011). You’ll notice that all of these assume that there are indeed ethical questions about Phase I trials in healthy volunteers, and work from there to try to find ways to minimize or mitigate the problems.

But problems there are, in any case. How bad would it be, and how much would it slow things down, to go into the intended population in Phase I instead? Thoughts?

42 comments on “Are Phase I Trials Ethical?”

  1. Anon says:

    Irwin Nash’s position is pretty much the norm already in oncology, both because of the higher potential for toxicity and the life-or-death desperation of the patients. It also has the advantage of giving a trial sponsor some early insights into patient selection for Phase II. Arguably Nash is right that this mindset should be extended to other indications. The risk/benefit of dosing healthy volunteers has never been especially clear to me. We’ve gotten a lot better at screening out tox liabilities preclinically, but cases like the one cited make you wonder.

    1. Noeasypath says:

      While the events of the Bial study are tragic, we must be careful to drive changes in FIH studies based on science not emotion. There have been 2 very tragic events in FIH trials since 2004 but, as EMA pointed out when they released the revised guideline, thousands of healthy subjects had safely completed FIH studies in that timeframe. I would not feel any better ethically about the tragic outcome of this trial had the people impacted been patients with knee osteoarthritis, migraines or Parkinson’s disease rather than healthy subjects.
      Further, as a patient, why would I volunteer for a FIH or dose finding multiple dose trial when I have other options for longer term therapy and/or therapy at a dose that has been shown to provide some evidence of a potential benefit?

  2. myma says:

    I think it is worth considering for certain therapies. For example, for rare disease with a missing enzyme, and 10-20-50 patients total worldwide, why bother with any Phase of the trial, why not do some kind of Phase A (for All) study on all the patients?
    On the other hand, vaccine phase 1 are typically in seronegative naïve populations so that they can measure interesting biomarkers as an exploratory endpoint, so this kind should be a phase 1 in healthy populations.

  3. mallam says:

    “Failing that, we need to get better at estimating pharmacokinetics and pharmacodynamics, ”
    You should know that many people and groups have been working toward this for a long time. Further, as someone with your experience, the problem is with both the PK and the PD….so when there is nonlinear, accumulation in kinetics, animal models don’t accurately predict humans, so there is some roll of the dice involved. Kinetic modelling is now very good either since there are too many in vivo unknowns (eg transporters, metabolism, saturations, distribution etc). As for PD, there also are many problems in having biomarkers and outcome measures for human disease changing potential drugs moving into Phase 1 and beyond.
    It’s good to wish, but there’s not going to be a breakthrough in this type of need soon. What we can do is be extra cautious, does one patient at a time when going to higher doses to not too many will suffer ill-effects, make sure the subjects are WELL informed, have safety protocols in place, and a guaranteed financial safety net in case of terrible debilitating event occurs. The public needs to know there is no guarantees in the discovery process of finding and making new drugs, and also needs to know the vast negatives if there are no new drugs made in the future.

  4. anon says:

    I’m sure this will not be an popular idea, but what about a good citizen requirement for micro-dosed PK/PD studies for all able bodied people, like jury duty. With increased detection sensitivities and instruments, you can get lots of information from small drug doses directly from humans. Skip the animal suffering and poor correlation to humans. Then go to Phase III directly for efficacy with ill patients.

    1. David says:

      Or use prisoners, immigrants? Pretty sure you’d wind up with Human Rights issues?

      1. Anonymous says:

        We used to joke that the only people legally forbidden to participate in clinical trials are prisoners and drug company employees. Then someone noticed that the barbed wire on the fence surrounding the facility pointed inwards, so we’re uncertain to which group we belonged.

        1. schinderhannes says:

          I´ve heard that in the old days it was common to once in a while do PK in “naked apes” early on to weed out uncertainty in PK. Usually the chemist who first synthesized a compound and was convinced of its powers was picked,

          Those were the days..

          1. Anonymous says:

            Pretty much everyone I know who has gotten a drug they synthesized on to the market has gone back and secretly tried it.

        2. Isidore says:

          I do not believe that drug company employees are not allowed to participate in clinical trials, there are no regulations to that effect.

          1. Anonymous says:

            Drug company employees, like prisoners, are not capable of giving informed consent. So there are ethical requirements which make it impossible to use them in phase 1trials.

          2. Nelson says:

            I run phase 2 & 3 trials in psychiatry. Every protocol has an exclusion criteria item barring employees and family members of the drug company sponsoring the trial.

    2. Mol Biologist says:

      Well, *someone* has to fund basic science or try to identify biological mechanism of action. The probability that this particular compound is blocking FAHH receptor indirectly is very high that contradict the mainstream perspective. It may interfere with other metabolic pathways.
      Small dosages may help out but “healthy” patients with slightly impaired liver function still will be outlines for the study.

    3. Dr. Manhatten says:

      Microdosing has its place, but nonlinear PK, etc. can throw a curve ball into the evaluation. You will always need animal testing to establish toxicity limits and toxicokinetics as well before going into man.

      Good citizen requirement reminds me of Eddy Izard’s “Cake or Death” routine.

    4. WishIwasanonenough says:

      This is a common underground sentiment amongst a few pharma people I know. I, for one, am all for it. In fact, I’m going to try it.

    5. Linda Matthews says:

      Mandatory? Isn’t Informed Consent the primary hallmark of our industry?

  5. Billy says:

    Why would it be more ethical to enroll patients who have the condition for which the drug is being developed? If there are tox effects like the ones described here, why is it ok for sick patients to develop the resulting brain lesions? Clinical trials are investigational. I don’t think choosing sick patients (except for certain indications, e.g. cancer) mitigates risk or makes it any more ethical.

    1. J.S. Mill says:

      Getting the ill effects is certainly no better in the target population than in volunteers; however, I think that the ethical description comes in the utilitarian calculus: the target population could (in principle) see some benefit while healthy volunteers will at best see no ill effects. In essence, it is a draw/lose scenario for volunteers in a medicinal sense.

  6. Ian says:

    In the article from a year ago, you mentioned canine fatalities in animal trials. Has there been any further information on the cause of those deaths?

    1. Noeasypath says:

      That was mentioned in the TSSC expert report. The canine deaths were unrelated to the brain injury in humans. There were no results from the tox studies that, even in hindsight, would have been a signal of the events to come in the trial subjects.

  7. DanielT says:

    Why is it ethical to employ someone to do a dangerous job (say coal mining), but unethical to employ them to do the far less risky job of phase 1 testing of pharmaceuticals? When some poor person dies testing a new drug it is international news, when a coal miner or construction worker dies it barely makes the local news.

    1. zero says:

      This is an interesting idea. Professional phase 1 subjects would have training, long-term monitoring, good vocabulary for communicating medically-relevant effects and probably a dozen other things that might be useful. Investigators would be able to see their subjects’ full medical history with details like monthly metabolic panels, diet and exercise history, drug use, etc.
      That makes a lot of sense to me, and as you pointed out a job like this would be safer than many existing jobs.

  8. tnt says:

    Swings and roundabouts – my previous unit ran some early phase 1/2a for HepC antivirals (Sofosbuvir et al), and the problem with using patients is that you only need/want a short course of dosing to check if the drug is (reasonably) safe, but it’s not long enough to eradicate the virus. So you run the risk of promoting viral resistance, and also making it harder for those subjects to get into other curative trials, as they have already been exposed to a similar drug.

    1. AR says:

      It’s a shame it’s being perceived as a false dichotomy then, maybe it wouldn’t be a good idea in your scenario, but for others it would be. Analgesics for migraines for example

  9. patently says:

    Would it be practical to require the exec who authorised the trial to be a participant?

  10. anon says:

    This trend to patients in phase 1 has started a long time, and is entirely dependent on the specific target and patient population. It’s not a question of whether, it’s just a question of when it’s appropriate. The reasons have not been entirely about the ethics, but also about getting data, particularly PD data, in a patient population. So nothing really newsy or original here.

    1. Fraz Ismat says:

      True! But it is good that this issue is being raised out in the open, outside of industry.

      Moreover, with the possibility that more folks may be able to access not-yet-approved (more likely never-to-be-approved) compounds following Phase 1, it is not a bad idea to show people what they may be getting into.

  11. Noeasypath says:

    I don’t think this can so readily be considered a result of simply drug accumulation or the steepness of that accumulation would be remarkable. Still can’t wait to see the PK published. The subject that died and the 5 subjects severely injured received a total dose of 250 mg (50 mg, 5 doses). The subjects in the prior cohort received 200 mg over 10 doses (20 mg/day) and had no notable adverse events (or brain injury when later scanned). That is a steep toxicity curve if it is accumulation based.

  12. Flem says:

    Crazy thought…how about doing PhI in brain dead subject organ volunteers…just before (or after harvesting)? I don’t see anything ethical about but can’t speak to usefulness of PK/PD in a living but brain dead subject.

    1. drsnowboard says:

      I think you might struggle to get consent from the family for that one, unless the living will of the volunteer expressly allows it. Why just one study? Why not keep farming them for multiple PK experiments? Obviously, the organs would no longer be donatable….

      1. drsnowboard says:

        BTW, in case the irony wasn’t evident, I think that’s a vile idea

        1. flem says:

          I apologize if the actual use of dead volunteers is vile compared to the current practice of paid live volunteers for drug studies. Please help a non-scientist understand how offering the use of one’s body after death for drug study is any less ethical than offering one’s organs? If one wishes to make best use of their body after death why shouldn’t they consider consenting to medical experimentation in addition to donating organs?

    2. cynical1 says:

      Personally, I think we should do all of our Phase I studies in politicians. After all, they ran for office to serve the public, right?

      Let’s start at the top and work down.

      1. Anonymous says:

        Unfortunately the PK data won’t translate into normal human beings. The super levels of both bile and BS impact liver function, so the clearance rates will be far too low.

  13. Adam Shapiro says:

    It’s one thing to contemplate doing phase 1 trials in patients for drugs to treat chronic conditions that aren’t immediately life threatening, but it’s difficult for me to imagine conducting an ethical phase 1 trial of an antibacterial drug for life-threatening infections in patients. They must be treated immediately with a drug that has already been shown to be effective for the condition, they may already have received multiple drugs, they may have comorbidities, and so forth.

  14. Yes, phase I trials can be ethical. Ethical issues with subclinical start dose can sometimes be mitigated by intra-patient dose escalations. Risk/benefit uncertainty and low rates of benefit, are mitigated by eligibility that requires that no satisfactory regular treatment exists for the eligible participants. On recall, safety for phase I dose-finding cancer trials is better than for phase II trials. While the chance for a response was low in 1991 (~6%), the era of targeted agents and immunotherapy has increased the chance to benefit.

  15. Cymantrene says:

    A month ago a letter in Nature told that pharmacodynamic data were not used in designing the Phase I study
    I’m not familiar with clinical studies. However, it is strange to me that the single dose experiments revealed that the compond acts at much lower levels in humans than in animals (about one tenth or even less), the applied levels were not adjusted. I don’t remember the exact numbers, but the 40 mg/day dose was designed as about 4 times of the intended daily dose of about 10 mg/day. Then it turned out that in humans even ~1 mg saturates the FAAH, so 40 mg was an overkill.

  16. Scott says:

    I would be concerned about … what’s the technical term, comorbidities(?) from having sick patients in a First in Man trial.

    Sick patient dies from SOMETHING, trial stops until autopsy/determination of death happens. Does that stop the trial permanently? *I* can probably come up with a list of potential trials where that would be the case, and I’m not even a medical professional. I’m sure the actual medical professionals can come up with a much longer list of things that need to be continued to the end of the trial or we are harming the sick patients.

  17. tangent says:

    “The only cohort that can be considered to derive at least a modicum of medical benefit” – that modicum of benefit, is that enough to make it ethical here either? The practical benefit is really very small, in most situations. The affected-patient volunteers would be doing it for altruism or money, just like healthy volunteers, it’s just that they feel more altruism because they know the issue personally.

    If you require any identifiable modicum of medical benefit, you seem to rule out all Phase I for conditions that aren’t long-term chronic or recurring. Or you end up concluding that the benefit is “well, they might come down with it in a few years”, which could equally well apply to anybody.

    I agree that toxicity studies are inherently a little sketchy. There is risk to the subjects, or you wouldn’t need the study, right? I don’t have a solution though. Aren’t enough researchers to dose them…

  18. Samuel Zagarella says:

    Of course Phase 1 trials in healthy volunteers are unethical.
    If anyone argues against this I would ask them one question: would you be happy for your son, daughter or loved one to participate in a Phase 1 trial?

    I rest my case

Comments are closed.