PracticalDermatology

In the context of clinical care, physicians navigate ethical dilemmas on a regular basis. Those venturing into the realm of clinical trials, however, face a whole new set of ethical challenges that can sometimes feel contradictory to the usual goals of medicine. It’s definitely an adjustment: If you’re used to seeing regular clinic patients and then you become a clinical trial investigator, you now have a responsibility to the ethics of performing the trial, and there are a lot of moving parts involved – through the study protocol, the study design, the outcomes, and your study team.

Disclose and Be Discreet

Outside of the trial, the credibility of the investigator is important. When you’re doing research, the ethical thing to do is be discreet about your prescription habits. As an example, let’s say I’m doing a trial for Company X, but I’m also writing a ton of prescriptions for Company X’s biologic drug and I’m out there doing promotional work for the drug and being very vocal about it. That’s going to raise a lot of flags, and that’s an ethical issue.¹

It’s a very real phenomenon to see someone who has their name on industry-sponsored research papers as an author or an investigator, but then you see how much work they’re doing for the company, and it makes you take a step back and wonder if there’s something going on that needs to be disclosed.² If someone is very upfront about their disclosures, that’s one thing, but based on FDA requirements, if you have a relationship that brings you more than $25,000 from that sponsor, that not only has to be disclosed, it might disqualify you from being in the trial.³

Don’t Play Savior or Take Hostages

To remain ethical and effective as an investigator in a clinical trial, following the rules is the top priority. The protocols are written for patient safety, for operational guidance, and for leveling the playing field of how research is conducted. For most physicians, when they’re making decisions, they’re trying to do the best thing for the patient in front of them, but in a research trial, they’re obligated to follow the rules whether patients get better or not, and that can present dilemmas.

Under Pressure

In industry-sponsored clinical research, you won’t be dealing with pharmaceutical reps, so sales pressure is out of the equation. Typically, most salespeople don’t even know about these trials. It’s been in very rare in my career that I’ve had sales personnel come to me and ask how a trial’s going, and we can’t talk about it anyway.

From the sponsorship side, however, there’s a lot of pressure to enroll certain numbers of patients per month, and they obviously want to see good enrollment numbers early on because they want to report that to their shareholders.

There’s also – and this is where it gets a little dicey – this whole diversity of trials issues, and you’ll get pressure from certain corporate people who will say the trial needs to enroll a certain number of skin of color patients or a certain number of ethnic patients. That can become a problem because then you may be discriminating against others to pull a quota that is based on diversity, equity, and inclusion (DEI) and social issues.

I’ve actually turned down trials because of the pressure to enroll skin of color patients. I’ll get a call from these corporate reps, asking what our strategy is for recruiting skin of color patients, and I’ll say, “Our recruitment efforts are based on the recruitment strategies that you gave us, so if you want recruitment of skin of color patients, you have to give me the tools to recruit them.”

If a patient answers the ad for a trial, I just want to know if they match what I need for the trial – the protocol-mandated inclusion and exclusion criteria – and if they’re willing to be in the trial.

Some trial sites will just look the other way and agree to take these patients on, and then they under-enroll them and don’t satisfy the requirements because the reality is that a lot of patients with certain diseases are of certain skin colors. Plus, if I’m in rural Nebraska, for instance, then the odds of me getting a different mix of ethnicities are much lower than if I’m in San Diego or New York City.

Some companies will do subset trials where they have enough budget to run a separate skin of color trial after the main trial. Eventually, a lot of those trials don’t come to fruition because it’s unreasonable to expect a trial site to say, “We’re recruiting for a trial, and we only want skin types IV, V, and VI, but you have skin type III. I know you want to be in this trial, but we can’t put you in.” What does that say? That’s the ethical question. Did you just deprive somebody of the chance to be in a trial because they’re not of a certain color, race, or ethnicity?

The protocol mandates all, and then the disease state mandates all. If it’s built into the protocol – for example, “This trial design is only for assessment of response of atopic dermatitis in skin types IV, V, or VI” – then at least everyone’s upfront about it. But if that’s the case, then the sponsoring company needs to provide the tools to enable investigators to recruit ethically without looking discriminatory.

For example, if a participant isn’t responding to a treatment and you know that others are, you can’t go to the unmarked bottles and say, “Well, I’m just going to find the right drug for the patient to get better” when they’ve been assigned a placebo. Patients sign consent forms to participate in research knowing full well that they could be getting a placebo or that they could be receiving a treatment that’s not effective.

Let’s say I have an eczema patient in a trial, and they just keep getting worse after two weeks, and I know that the treatment should be working within two or four weeks and I see other patients who are responding but that particular patient is like, “I’m miserable. I can’t keep this up.” It’s their absolute right to decide they don’t want to be involved in the trial anymore and to go seek treatment.

The ethical course of action is to allow them to withdraw from the trial, but there are some investigators who would insist on the patient staying in the trial because the trial sites get paid for participants to stay on for the duration of the trial.

Some trials allow for what’s called “rescue therapy.” If there’s someone who’s really getting bad and it’s a long trial, they’re allowed a course of rescue therapy and can stay in the trial, depending on the trial design and the product involved. Otherwise, the right thing to do is, the minute the patient says they want treatment or a different course of action, then you have to let them walk away from the trial and go get treatment.

Don’t Fudge the Data

Within the body of the trial, it is critical to remain ethical not just in how you perform the trial, but in ensuring that the data you’re working with is sound. There’s a phenomenon called “investigator creep.” Let’s say a patient comes in after 12 weeks of acne treatment, and 20 acne papules is the cutoff for being considered a treatment success. If the patient has 21 papules, the investigator may end up biasing against them and say they have 20 papules.

Or, if the investigators try to enroll a patient in a trial with a minimum cutoff of 20 papules and the patient has 18, the investigators might falsely report that the patient has 20 papules. That phenomenon does occur, maybe without intent in some cases and with intent in other cases, but that can happen in trials quite a bit.

Another common scenario involves failure to report adverse events observed in the trial because the investigator thinks they’re trying to protect the drug. If a study participant keeps saying they’re experiencing headaches and it’s not being adequately reported, that could raise a flag ethically. If you’re observing adverse events and you’re underreporting or not reporting them, you’re not doing anyone a service. In any case, if you’re fudging data to get the drug across the goal line, that’s complete fraud.

Report Questionable Activity

If you suspect or learn of an ethical violation occurring within a trial you’re involved in, then you have to report that to the institutional review board – they’re like the referees of the trial.4 If there’s something shady going on, whether it’s from the sponsor or one of the research subjects or anyone else involved in the trial, it’s your ethical responsibility to report that. It comes back to just doing the right job for the trial.

Clinical research isn’t for everybody. It may be appealing because it can be very lucrative and it’s a good alternative to seeing patients for some physicians who are burned out or want a career change, but it’s a different game. There are lots of details to manage on the business end, and many aspects of working on trials vary considerably from the work we do in the clinic. That doesn’t make it better or worse; it’s just very different.

Overall, you have to know what you’re getting yourself into, and you must have the character and integrity to do it the right way.

1. Breault JL, Knafl E. Pitfalls and safeguards in industry-funded research. Ochsner J. 2020;20(1):104-110. doi:10.31486/toj.19.0093

2. Johnston J, Brumbaugh. Conflict of interest in biomedical research and clinical practice. The Hastings Center. Published June 3, 2022.

3. US Food and Drug Administration. Financial disclosures by clinical investigators. Last reviewed March 30, 2018. Accessed October 10, 2023.

4. Slade KL, Carreau NA, Heald P. Ethics of clinical trials in dermatology. Clin Dermatol. 2012;30(2):226-30. doi:10.1016/j.clindermatol.2011.06.012