Contributed Commentary by David S. Weiss, Cognivia 

December 6, 2024 | While randomized clinical trials (RCTs) have rightly long been considered the gold standard for establishing the safety and efficacy of new medications, their strict inclusion and exclusion criteria narrow participant types. For example, RCTs tend to exclude certain patient sub-groups, especially those with specific comorbidities. The scientific rationale behind these practices results from a desire to assess the benefit/risk ratio in a stepwise fashion, starting with the most homogenous population to more heterogeneous ones as development of a therapeutic progresses.  

The recent progress made in diversity, equity, and inclusion (DEI) supported by guidelines from the FDA, which aims to include underrepresented populations in clinical trials, encourages a more in-depth review of common practices to adjust to today's reality and more quickly match the real-world populations. 

While there are a number of comorbidities potentially unnecessarily excluded from participating in clinical trials, I’m going to focus mostly on HIV patients in this article because December 1 was World AIDS Day, a day that serves as a reminder of the global struggle to end HIV-related stigma—a goal the medical field can help reach by reviewing past practices and accepting a new development pathway paradigm of accelerated inclusion of HIV positive patients in clinical trials. 

Consequences of Exclusion

The decision to exclude patients living with HIV from participating in clinical trials was based on the significant immunosuppression associated with untreated HIV, which raised concerns about increased susceptibility to adverse events and unpredictable responses to investigational drugs. However, with the introduction of antiretroviral therapy in 1987 and later highly active antiretroviral therapies, HIV became a manageable condition, allowing patients to lead largely normal and healthy lives. 

Clearly, drug-drug interaction between antivirals and test drugs will remain a challenge and should be monitored in RCTs, but assuming those are minimal and/or predictable, HIV patients could be included in clinical trials much earlier than in clinical development.  

A recent paper from Uldrick et al., in the prestigious Journal of Oncology has reviewed the potential inclusion of HIV patients in cancer trials. Cancer trials represent more than 30% of the clinical studies run globally, and they have historically excluded HIV patients. In this review, the authors provide specific recommendations for the inclusion of HIV patients in these trials, and they conclude, “Expanding clinical trial eligibility to be more inclusive of patients with HIV is justified in most cases and may accelerate the development of effective therapies in this area of unmet clinical need.” This is clearly a very positive endorsement for more inclusivity of this patient population.  

When Inclusion is Prioritized

Diversity, equity, and inclusion efforts aren’t just feel-good recommendations; implementing these initiatives has proven real-world advancements. The landmark 1993 NIH Revitalization Act is a powerful example of such advances. Prior to this legislation, women and underrepresented racial and ethnic minority populations were often excluded from clinical research due to the belief that hormonal differences, different metabolisms, and/or comorbidities could skew results.  

Although some legacy issues persist, the mandate to include women and minorities in clinical trials have seen substantial progress in aligning research study populations with the broader patient population. This has led to critical insights that improve health outcomes across diverse groups. For example, heart attack symptoms in women differ from those in men. Women often experience chest pain accompanied by flu-like fatigue, nausea, night sweats, and stomach discomfort. The inclusion of women in cardiovascular research allowed for more accurate evaluations of treatment efficacy in women. This is especially important, given that cardiovascular disease is the leading cause of death among women. 

With the new FDA mandate to include more heterogeneous patient populations in clinical trials, we could anticipate more nuanced data on treatment efficacy and safety, leading to better-informed healthcare decisions and reduced health disparities.

The Role of Tech in Drug Adherence 

One of the reasons often cited for excluding HIV patients from trials is concerns about drug adherence, which is paramount when evaluating the effectiveness and safety of investigational medications. Historically, drug adherence has been challenging for many HIV patients due to existing complex medication regimens, side effects, and socioeconomic barriers. But treatments have improved, and we now have the technology to predict, reduce, and potentially eliminate non-compliance. 

Additionally, tech companies propose patient engagement strategies, and some companies go even a step further by leveraging predictive behavioral models to reduce non-compliance, anticipating when patients may struggle, why, and proactively providing support that lead to tailored patient engagement. 

What Now? 

Embracing diversity and including those with manageable conditions like HIV, will make clinical trials more representative and effective. Updating exclusionary policies doesn’t just help us understand how diverse populations respond outside of controlled settings, it also helps reduce stigma and bias, advance Health Equity initiatives, and achieve better real-world outcomes.  

David S. Weiss is an experienced business strategist and legal expert who serves as Cognivia's Chief Strategic Officer and General Counsel, overseeing the company’s long-term vision and legal affairs. David supports work to modernize trial design and address complex issues around data variability and drug adherence in trial and managed care, focusing on health equity processes and policies. He holds a J.D. from New York Law School, a Bachelor’s in Political Science and Government from Drew University, and studied International Law and Legal Studies at Sorbonne University in Paris. He can be reached out at david.weiss@cognivia.com.