What are the potential risks and benefits of participating in a clinical trial?

Potential risks and benefits to participating in clinical trials vary based on the focus area and intervention being tested in the study. Clinical trials are required by law to have informed consent, which is designed to inform participants of potential risks so that they can weigh them against the benefits of trial participation.¹ Types of clinical research can include trials examining treatment, prevention, diagnosis, screening, quality of life, genes, epidemiology, medication, and medical devices.

Medication Research Phases

For research on new medications, potential risks and benefits of participation vary based on phase. Clinical trials studying the efficacy of new medications follow a federally regulated four-phased design to maximize patient safety and minimize health risks.

After discovery of a new potential treatment modality, compounds go through development in the laboratory setting to understand the underlying mechanism of the medication as well as begin to understand its effectiveness and ideal dosage. Before being allowed to go to human trials in the United States (US), the Food and Drug Administration (FDA) requires that the toxicity of new compounds is established in preclinical research.² Preclinical research can either be done in vitro in or in vivo using non-human subjects.

Once approved by the FDA for testing in human subjects, new medications are tested through clinical research following a four phase design:³

• Phase 1: The treatment is tested on 20-100 volunteers to assess its safety, determine the correct dosage, and identify side effects. For most medications, Phase 1 is done with healthy volunteers. The exception is for cancer treatments, which are tested on patients with the type of cancer the medication targets.
• Phase 2: The treatment is then given to a larger group of up to several hundred people with the targeted disease or condition to further evaluate its safety.
• Phase 3: The treatment is tested on 300-3,000 volunteers with the targeted disease or condition to evaluate its efficacy and monitor side effects.
• Phase 4: After FDA approval, post-marketing studies are conducted on several thousand volunteers with the targeted disease or condition to gather more information about the treatment's risks, benefits, and optimal use as well as continue to monitor its safety.

In general, lower phase trials infer greater risk than higher phase trials due to the relatively limited knowledge of the medication and its effects.

Risks of Clinical Trials

The primary risk for participating in clinical trials is adverse effects, especially for early-phase drug trials. The purpose of drug trials is to test the efficacy and tolerability of medications, meaning that their efficacy and tolerability at the time of testing isn’t well established. Medications must be shown to be safe in the laboratory setting before being allowed to be tested on humans, but the only way to know for sure how the medication affects humans is through these trials.

The exact risk being taken on by participants varies based on the intervention. For example, chemotherapy medications, which are known to be cytotoxic, carry more risk than other relatively more well-tolerated drugs. A 2024 meta-analysis of 128 cancer trials found that patients in experimental groups had a median increase in progression-free survival of 1.25 months (95% CI [0.80-1.68]) and median increase in overall survival by 1.18 months (95% CI [0.72-1.71]).⁴ However, those in experimental groups also experienced significant increase in serious adverse events (36.96% for intervention groups vs 29.56% for comparator groups).

However, even among drug trials classified as highest risk, the risk of serious adverse events has been trending downward. A 2004 meta-analysis of 213 studies involving 6,474 cancer patients found that safety and tolerability in phase 1 trials of cancer drugs has improved from 1991 to 2002.⁵ Treatment-related death rates fell from 1.1% from 1991-1994 to 0.06% from 1999-2002. Rates of serious adverse events fell from 4.2% from 1991-1994 to 3.1% from 1999-2002, with about 85% of all events reported to be partly or completely reversible.

In addition to potential adverse events, any potential benefit is also uncertain. There is no guarantee that the intervention will be effective, and it can even end up being found to be less effective than other treatment options available. There’s also a chance that participants are randomized to the control arm, meaning they would not receive any of the potential benefits of the new treatment.

Additionally, participation in a clinical trial is a time investment sometimes requiring frequent visits and tests, which can be burdensome for participants. A 1993 survey of women participating in a dietary intervention (n=66) found that the most reported disadvantage to participating was having to attend additional appointments for the study (26%).⁶

Benefits of Clinical Trials

The primary benefit to participating in clinical trials is being able to experience any benefits from the treatment being offered. This is particularly beneficial to those with conditions that have limited treatment options as clinical trials allow access to new treatments not yet available to the public. A 2016 study (n=396) asked participants in phase 1 oncology trials to rank their motivations for enrolling on a Likert scale, and 56% of participants ranked “no alternative treatment options” highest.⁷

Participants in trials also receive more care than the general population consisting of regular monitoring and follow-up. A 1985 study found (n=608) found that the leading perceived benefits of trial participation were increased knowledge (76%) and the enhanced treatment and information from specialists (72%).⁸ In 2009, a follow-up survey was performed with participants of a study examining Interleukin-2 (IL2) in HIV asking about benefits and burdens of participating in the trial.⁹ Participants from the intervention (n=292) and control arm (n=290) were surveyed. A majority of participants in both arms reported medical benefits from participation in the study (91% in IL2 arm, 79% in control arm). Both arms cited better access to healthcare services and improvement in their emotional condition in the top three perceived medical benefits.

Additionally, participants in clinical studies sometimes exhibit the “healthy adherer” effect, where trial participants have improved overall health regardless of trial arm, although it is difficult to ascertain whether this is due to trial participation or because those who participate in trials tend to have healthier behaviors.^10,11

Another benefit to participation is a positive feeling of altruism from contributing to scientific discovery. Participants have reported feeling that they have contributed to the state of medical research by participating in clinical trials.¹² In the same 2016 study as above examining participants of phase 1 oncology trials, 38% ranked “the research would benefit others” highest on a Likert scale.⁷ A 1993 survey of participants in a cardiovascular health study (n=3,522) found that 20% of participants reported that their primary motivation for participating was contributing to medical science.¹³

Studies sometimes also offer incentives to participants, such as monetary compensation or gift cards. A 1994 study (n=195) found financial compensation was among the reported motivations for participating in a drug trial in addition to the potential to improve their health and contribute to science.¹⁴

References

1. Informed Consent FAQs. U.S. Department of Health and Human Services. Accessed 11 December 2024, https://www.hhs.gov/ohrp/regulations-and-policy/guidance/faq/informed-consent/index.html
2. Step 2: Preclinical Research. U.S. Food & Drug Administration. Accessed 11 Dec 2024, https://www.fda.gov/patients/drug-development-process/step-2-preclinical-research
3. Step 3: Clinical Research. U.S. Food & Drug Administration. Accessed 11 Dec 2024, https://www.fda.gov/patients/drug-development-process/step-3-clinical-research
4. Iskander R, Moyer H, Fergusson D, McGrath S, Benedetti A, Kimmelman J. The Benefits and Risks of Receiving Investigational Solid Tumor Drugs in Randomized Trials : A Systematic Review and Meta-analysis. Annals of internal medicine. Jun 2024;177(6):759-767. doi:10.7326/m23-2515
5. Roberts TG, Jr., Goulart BH, Squitieri L, et al. Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. Jama. Nov 3 2004;292(17):2130-40. doi:10.1001/jama.292.17.2130
6. Sutherland HJ, Carlin K, Harper W, et al. A study of diet and breast cancer prevention in Canada: why healthy women participate in controlled trials. Cancer Causes Control. Nov 1993;4(6):521-8. doi:10.1007/bf00052427
7. Dolly SO, Kalaitzaki E, Puglisi M, et al. A study of motivations and expectations of patients seen in phase 1 oncology clinics. Cancer. Nov 15 2016;122(22):3501-3508. doi:10.1002/cncr.30235
8. Mattson ME, Curb JD, McArdle R. Participation in a clinical trial: the patients' point of view. Control Clin Trials. Jun 1985;6(2):156-67. doi:10.1016/0197-2456(85)90121-7
9. Lazovski J, Losso M, Krohmal B, Emanuel EJ, Grady C, Wendler D. Benefits and burdens of participation in a longitudinal clinical trial. J Empir Res Hum Res Ethics. Sep 2009;4(3):89-97. doi:10.1525/jer.2009.4.3.89
10. Simpson SH, Eurich DT, Majumdar SR, et al. A meta-analysis of the association between adherence to drug therapy and mortality. BMJ (Clinical research ed). Jul 1 2006;333(7557):15. doi:10.1136/bmj.38875.675486.55
11. Ladova K, Vlcek J, Vytrisalova M, Maly J. Healthy adherer effect - the pitfall in the interpretation of the effect of medication adherence on health outcomes. J Eval Clin Pract. Apr 2014;20(2):111-6. doi:10.1111/jep.12095
12. Natale P, Saglimbene V, Ruospo M, et al. Transparency, trust and minimizing burden to increase recruitment and retention in trials: a systematic review. J Clin Epidemiol. Jun 2021;134:35-51. doi:10.1016/j.jclinepi.2021.01.014
13. Henzlova MJ, Blackburn GH, Bradley EJ, Rogers WJ. Patient perception of a long-term clinical trial: experience using a close-out questionnaire in the Studies of Left Ventricular Dysfunction (SOLVD) Trial. SOLVD Close-out Working Group. Control Clin Trials. Aug 1994;15(4):284-93. doi:10.1016/0197-2456(94)90044-2
14. Cunny KA, Miller HW. Participation in clinical drug studies: motivations and barriers. Clin Ther. Mar-Apr 1994;16(2):273-82; discussion 271-2.