The following Insight is a featured article from WCG’s 2025 Trends & Insights Report. If you would like to read more insights from this report, please click here.

Former U.S. President Obama called precision medicine, “Health care tailored to you.”¹ Nowhere is precision medicine more critical than in oncology, where life and death clinical decisions are based on an individual’s genetic or biomarker results. In the last decade, precision medicine approaches made a paradigm shift in the understanding and treatment of cancer.² From “one-size-fits-all” to an individual, biomarker-driven treatment, precision medicine improved treatment outcomes and patient survival rates, while reducing toxicity.³ 

Despite tremendous progress, much is left to do. The number of biomarkers is vast and complex. A disease biomarker may be a combination of factors, such as multiple genes and proteins barely detectable. Research study designs have been evolving to meet these needs, with the classic basket and umbrella master trial designs requiring biomarker validating components. Similarly, increased complexity with changing master trial designs may move science forward more efficiently. For example, NCI-MATCH has evolved into ComboMATCH to address the issues of tumors having more than one gene driver and cancers developing resistance to treatment.⁴ 

Furthermore, biomarkers and precision medicine approaches will evolve as disease treatments evolve. Next-generation, multi-gene DNA sequencing will grow into multi-RNA sequencing and multi-modal panels, including nucleic acid and other omics-based target testing. Precision medicine requires biomarker-driven targeted treatment, and with cancer’s heterogeneous nature, further profiling of patient tumor tissues will be required.  

The standard collection of tissue and blood samples for DNA will commonly add RNA sequencing, gene expression, mutation and deletion profiles, protein expressions, immune repertoires, tumor microenvironment, and metabolic changes to drive cancer treatment’s increased rate of success. The precision medicine approach works hand in glove with drug development. The biomarkers found in tyrosine kinases, EGFR, ALK, KRAS mutations, immune checkpoints, and T-cell targets resulted in the approval of products targeting those biomarkers. That trend will continue and mature.   

Ensuring biomarkers achieve their potential requires the assays to detect them are high quality, accurate and safe and effective. When used to identify patients who are most likely to benefit, be at increased risk, or need monitoring from a particular product, the assay to detect the biomarker is a companion diagnostic device (CDx). These CDx provide information essential for the safe and effective use of a corresponding drug or biological product. As of October 31, 2024, there are 168 FDA-cleared or approved CDx (In Vitro and Imaging Tools).⁵ Out of the 168 FDA-cleared or approved CDx, 164 (97.7%) are for oncology indications and only four (2.3%) are for non-oncology indications. (see Figure 1).  

The FDA, as always, will be advancing with the technology. This started with the 21^st Century Cures Act detailing the Oncology Center of Excellence.⁶ Bringing together the expertise across drug and device realms for the trials testing companion diagnostics and platform treatment approaches will require exemplary coordination. For example, developing the next decade of gene therapy products will mean testing off-the-shelf CAR-T products with biomarker-directed targets. Institutional Review Boards (IRBs) will also need to keep pace and realize last year’s exploratory objectives are next year’s companion diagnostics, staying current on the technology and regulatory components. Only in this way can we all support the true value of precision medicine. 

References:

1. The White House. “Precision Medicine.” The White House, https://obamawhitehouse.archives.gov/precision-medicine. 
2. Rulten, S.L.; Grose, R.P.; Gatz, S.A.; Jones, J.L.; Cameron, A.J.M. The Future of Precision Oncology. Int. J. Mol. Sci. 2023, 24, 12613. https://doi.org/10.3390/ijms241612613 
3. Nature. “Milestones in Cancer.” https://www.nature.com/immersive/d42859-020-00083-8/index.html  
4. ⁴National Cancer Institute. “New NCI Precision Medicine Trials.” Cancer Currents Blog, https://www.cancer.gov/news-events/cancer-currents-blog/2023/new-nci-precision-medicine-trials. 
5. U.S. Food and Drug Administration. “List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools).” https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools. 
6. U.S. Food and Drug Administration. “Oncology Center of Excellence.” https://www.fda.gov/about-fda/fda-organization/oncology-center-excellence.

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Patients and families from minority groups, and those who come from less economically stable environments often face significant barriers to safe and accessible health care. These can include a lack of supportive resources, such as parental education and awareness of diagnosis and treatment options, or available access to ongoing clinical trials for their conditions. Further impacting access is the historical mistrust toward clinical research studies many minority communities hold, a lack of community representation, and limited engagement with patient advocacy groups that provide supportive guidance and direction. These limitations can readily lead to a delay in diagnosis and access to available treatment options, impacting potential outcomes. A further challenge for many families, both in urban and rural areas, can be more limited access to resources and facilities where diagnosis and intervention take place. Together, these contribute to diminished opportunities for care and poorer outcomes for diverse communities affected by rare diseases.  

When we think about social determinants of health-related access barriers, we must consider factors related to healthcare professional education and knowledge regarding rare diseases. It is the case that many families first rely on available sources of primary care, including family and general practice physicians or nurse practitioners, who may not be as informed about current information regarding rare and ultra-rare diseases. Similarly, primary care practices may not have enough resources or advanced technologies available for faster diagnosis and treatment options. These challenges can be further complicated for minority and under-resourced communities when awareness of specialty care and the availability of practitioners versed in understanding the diverse needs of affected individuals is more limited. 

Importantly, it has been recognized that there is a significant need to provide healthcare professionals and clinical trial investigators with relevant continuing education and training about the importance of diversity, equity, and inclusion strategies regarding the diagnosis and treatment of individuals with rare diseases. Starting early with medical and health care training, the integration of curricula regarding the social and behavioral determinants of health has begun to contribute to better coordination of elements of care, leading to faster diagnosis and, when available, access to developing and approved treatments. Furthermore, improving resources and availability of specialist care and adding greater diverse community representation, such as connecting with patient advocacy groups, have improved outcomes for minority persons with rare disease and their caregivers.  

More specifically, sponsors running clinical trials, including pharmaceutical companies and the individual investigators conducting their studies, have been directed to think more clearly and to state explicitly within their study objectives and design how they will directly address diversity and equity considerations. Unique in 2024 is the extent to which emerging practices regarding equitable clinical trials have begun to standardize as drug developers and other stakeholders become familiar with the methods of diversification required of them, which will ultimately lead to a required increase in the numbers of diverse participants who are represented in and serve as beneficiaries of treatment research. 

During protocol development, sponsors and investigators are also encouraged to carefully assess research methodologies and approaches, research outreach and recruitment methods, and improve the availability of adequate resources to accommodate minority populations for ease of recruitment. Community-based participatory research methods can support this effort, ensuring that individuals from minority communities with rare diseases are included in the design and implementation of the research from the start, and by identifying and resolving potential clinical biases. Community-based participatory research uses collaborations between research organizations, investigators, and community members throughout all aspects of a research project. This approach is important given its commitment to engaging and representing intersectionally diverse populations affected by rare and more common diseases and fostering greater engagement across minority communities. 

Trial diversity and rare disease drug development together will benefit from the growing collaboration by the FDA regarding the necessity for diverse and equitable representation in clinical trials and biotech companies’ increasing familiarity with the resulting best practices in development. Tools to reduce the diagnostic odyssey will continue to reduce the cost and burden of rare diseases, while advocates’ work with policymakers will better open access to these tools and investigation strategies.  

The new DEPICT Act passed recently by the U.S. Congress requires the FDA to require sponsors to submit Diversity Action Plans with their Phase III or other pivotal trials. The FDA has urged both large pharmaceutical companies and the growing number of smaller biotech drug developers involved in rare disease research to reach out and work with them early in the investigatory process to develop protocols and find solutions to the challenges this new requirement presents. The DEPICT requirement comes at a time when the industry is a few years further down the road from the events of 2020, including the COVID-19 pandemic, which awakened a new, sincere investment in being more inclusive in health care across all stages of development and ultimate treatment, including clinical research. 2024 is a specific year to watch this investment translate directly into best practices.  

Additionally, better tools in genomic screening are available now, which help reduce the diagnostic odyssey and connect rare disease patients with new treatments and early interventions that can save their lives and prevent unnecessary damage from the disease. Policies to open access to these fresh solutions more broadly across diverse affected communities will remain an active focus for rare disease advocates and collaborating policymakers in 2024.  

A growing body of evidence shared recently has shown how policies that help families of rare diseases also benefit society. Two studies commissioned by the EveryLife Foundation for Rare Diseases^3,4 will be used in dialogue with policymakers: one quantifies the cost burdens on families and society of rare diseases, and the other quantifies the avoidable costs of the diagnostic odyssey. Legislation is in the works to provide access to treatments and diagnostic tools to people regardless of zip code and income level. Watch for legislative efforts to open access to newborn screening, including rapid genome sequencing, genetic counseling, and early intervention services. Small patient populations have always hampered rare disease research. As we expand our definition of who participates in the research and its benefits, the population sizes grow.  

Lastly, and important to how the process regarding greater diversity and equity in clinical research will unfold, the FDA has already issued draft guidance on enhancing the diversity of clinical trial populations, providing recommendations to sponsors to enroll representative numbers of participants from underrepresented racial, ethnic, gender diverse, and economically diverse populations in the United States. This is being further supported by Institutional Review Boards (IRBs) reviewing current research proposals with an eye toward DEI and representative justice. IRBs play a key role in determining the availability of clinical trials for minority populations in rare diseases. One of the criteria for approval is consideration of the equitable selection of research subjects. As per the Belmont Report, no individual group should be absolutely included or excluded from clinical study without justifiable scientific or ethical reasoning. IRBs can review the submitted justification and study design for scientific and ethical validity, and ensure adequate safeguards and protections are in place for the study population more broadly. This will lead to both greater recruitment of diverse participants and clearer knowledge regarding potential outcomes. 

References

1. Bainbridge, M.N. (2020). Determining the incidence of rare disease. Human Genetics, 139, 569-574. DOI: 10.1007/s00439-020-02135-5 
2. Smith, C.I.E., Bergman, P., & Hagey, D.W. (2022). Estimating the number of diseases – the concept of rare, ultra-rare, and hyper-rare. iScience, 25, 104698. DOI: 10.1016/i.isci.2022.104698 
3. The national economic burden of rare disease in the United States in 2019 
4. The Cost of Delayed Diagnosis in Rare Disease – a Health Economic Study 

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1. What factors are causing age-based exclusions to be possibly inappropriate or unnecessary?

Factors which are possibly inappropriate or unwarranted include^1,2,3:

• Exclusions based on arbitrary age-based criteria without any scientific or ethical rationale as a shortcut to reduce risk
• Confounding co-morbid factors that are more prevalent in the disease being researched but may not affect the risk/benefit ratio
• Fear of increased financial burden and time spent in older subjects enrollment, retention, completion of study-related activities, and management of research-related injuries.

2. What is the role of IRBs to ensure older populations are included in clinical trials?

If research is being conducted for an indication that is prevalent in older populations, it is important, scientifically, and ethically, that an attempt should be made to include older populations in the research and not to have arbitrarily restrictive age-based exclusion criteria. These older individuals may have the potential for direct benefit and their participation in the study may provide important knowledge for their representative population. Based on the Belmont report basic ethical principles (Belmont report), and IRB criteria for approval (21 CFR 56.111, 45 CFR 46.111), there should be equitable selection of subjects so that those bearing the burdens of research will have potential for direct benefit and represent those who will benefit from the knowledge gained. IRBs should ensure that the study includes adequate safeguards and protections as well as reasonable accommodation and assistance to allow inclusion of older subjects.

3. What is the role of Sponsors or study investigators? What should they consider about the age-based exclusion criteria in their protocols?

The Sponsor needs to carefully design the study inclusion and exclusion criteria based on justifiable scientific background and objectives of the study without a reliance on arbitrary age-based exclusions. They can also support individual sites to have adequate safeguards, assistance, and provisions in place to conduct the study with older individuals.

Considering an older subject population may have co-morbid conditions, and functional impairments, Site Investigators should endeavor to develop the sufficiency of support staff, funding, and available resources to support older person’s:

• recruitment and retention success,
• safe conduct of study related activities,
• management of adverse events considering possible disabilities, and
• accessibility for those with functional impairments.

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• Minimal risk (21 CFR 50.51, 45 CFR 46.404),
• Greater than minimal risk but presenting the prospect of direct benefit to the individual subjects (21 CFR 50.52, 45 CFR 46.405), or
• No more than a minor increase over minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or condition (21 CFR 50.53, 45 CFR 46.406).

If the IRB finds that the research cannot be approved under one of the above categories, but determines that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, there is a fourth option to obtain approval– referral to the FDA and/or OHRP (21 CFR 50.54, 45 CFR 46.407).

When research is referred under this process, the FDA Commissioner, the Secretary of the Department of Health and Human Services (HHS) (Secretary), or both consults with a panel of experts in pertinent disciplines and provides an opportunity for public review and comment.  Then, a determination is made as to whether the research can proceed.

What is the 21 CFR §50.54, 45 CFR §46.407 referral process?

On March 30, 2023, FDA and OHRP published a Draft Guidance that describes the process for referral of research involving children as subjects and not otherwise approvable by an IRB.  The Draft Guidance describes the required documents that must be provided to FDA and identifies IRBs and institutions as the organizations that are expected to make the 21 CFR 50.54, 45 CFR 46.407 referrals.

Current WCG policy is to encourage sponsors, rather than the IRB, to initiate communication with, and directly interact with, FDA, OHRP or both regarding research on investigational products under an IND or IDE.

When WCG IRB determines that a given protocol involving children is not approvable under21 CFR 50.51, 50.52, or 50.53 for FDA; 45 CFR 46.404, 46.405, or 46.406 for OHRP, our current process is to provide the sponsor with a detailed description of the reasons why the research is not approvable as currently written, and to recommend modifications to the protocol to secure approval.

If the sponsor does wish to make a 21 CFR 50.54/45 CFR 46.407 referral, WCG IRB will provide the sponsor with the IRB minutes, as required in the Draft guidance, and will be available to assist the sponsor as it navigates the referral process.

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During the COVID-19 pandemic (since the start of 2020), WCG IRB has received almost twice the number of single-patient EA requests compared to the prior two years. All EA requests reviewed by WCG IRB were approved. WCG IRB’s experience with EA submissions over the past 4 years is summarized here, with consideration of the impact of the COVID-19 pandemic.

Pre-COVID-19 pandemic (2018-2019):

During this period, most of the requests WCG IRB received were for oncology and oncology-related indications, which accounted for 62% of the total requests. The next most frequent therapeutic area for which single-patient EA was requested was neurology, which accounted for 12% of the total requests, followed by infections and infectious diseases with 9% of the total requests. Many of these requests were for clofazimine for the treatment of mycobacterial infections (leprosy); while clofazimine is FDA-approved for this indication, the incidence of the infection is so low in the United States that it is only available directly from the manufacturer through expanded access rather than by prescription.

All other therapeutic areas contributed less than 3% of the total number of requests. While EA pathways are often thought of as being only for people who are critically ill, the submissions received also included treatments for long-term conditions such as gastroparesis, eczema, and chronic mercury toxicity.

During COVID-19 pandemic (2020 vs 2021):

Requests for COVID-19 therapies or preventative agents accounted for 53% of the total number of requests in 2020-2021 (64% in 2020 and 30% in 2021). The COVID-19 agents for which EA was requested changed over time, as investigational agents became available through either large-scale group EA programs (which are conducted like clinical trials) or through FDA Emergency Use Authorization (EUA) or FDA approval.  For example, remdesivir accounted for 55% of the COVID-19-related requests and convalescent plasma for 27% of the COVID-19- related requests in 2020, but there were no requests for either product in 2021, after they had become available through other routes.  In 2021, most requests (55%) were for the monoclonal antibody cocktail casirivimab and imdevimab. The other requests were for antibody-based antiviral agents, stem cells, antibiotics, synthetic peptides, and for access to COVID-19 vaccines (after EUA, but for people who were not yet eligible according to public health guidelines).

During 2020-2021, 26% of the total requests (59% of the non-COVID-19 requests) were for oncology or oncology-related indications. The next most frequent therapeutic area in which WCG IRB received EA requests was in infections and infectious diseases, which accounted for 6% of the total requests (13% of the non-COVID-19 requests), followed by the environmental therapeutic area (mercury toxicity, for the provision of an investigational chelating agent) which accounted for 4% of the total requests (9% of the non-COVID-19 requests). The next most frequent therapeutic area for which single-patient EA was requested was neurology which accounted for 4% of the total requests (9% of the non-COVID-19 requests).

Though the requests for EA for the treatment of oncology and oncology-related indications seems to have decreased during COVID-19 pandemic (62% vs 26%),  there was no significant decrease in percentage when compared to the total number of non-COVID-19 requests (62% pre-COVID-19 vs 59% during COVID-19) and the absolute number of requests year-to-year were consistent. This pattern was similar for other therapeutic areas such as neurology and infections and infectious diseases.

Learn more about WCG IRB’s review of single-patient EA submissions

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