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Human Challenge Studies for Vaccine Development: Regulatory Aspects of Human Challenge Studies

September 21, 2021  •  Blog  •  Norman Baylor, President & CEO
Posted In Biologics News & Insights – Biologics Consulting  •  Tagged FDA, clinical trials, vaccine, human trials


The traditional regulatory pathway for the evaluation of new vaccine candidates generally proceeds from preclinical through three successive phases of human trials. Study phases may overlap, and the clinical testing may be highly iterative because multiple Phase 1 or 2 trials may need to be performed as new data are obtained. In each phase of investigation, the protection of human subjects is of utmost impor­tance. Phase 3 trials may involve anywhere from thousands to tens of thousands of volunteers across multiple study sites and are considered the pivotal efficacy trial. Efficacy is demonstrated ideally in randomized, double-blind, well-controlled trials. For some diseases, vaccine field trials present potential limitations when the inci­dence of disease is low and outbreaks of disease decline before the study can be completed. Oftentimes, Phase 3 vaccine clinical trials may be based on an immune biomarker. The endpoints will be product specific. If the measurable immune biomarker fails to correlate with clinical benefit or reliably predict protection from disease, the trial may be considered a failure.

Human challenge trials have been used for testing vaccines and therapeutics in early stage research for the selection of candidate interventions, as well as for investigating host-pathogen interactions, identifying protective immune responses in humans, and determining efficacy of investigational vaccine candidates against challenge strains. Moreover, well-designed human challenge studies may also lead to expediting significant public health benefits of medical interventions. Infecting humans purposely with infectious microorganisms to protect or prevent more severe disease has been done for centuries throughout the world (Jarnrozik and Selgelid 2021).

Early challenge studies have provided important knowledge and contributed to the successful development of vaccines against smallpox, malaria, cholera, influenza, typhoid, and other infectious diseases; however, some methodologies applied in these studies as well as the study populations, e.g., prisoners, institu­tionalized patients as well as persons from disenfranchised communities, have been questionable and considered unethical (Semin Immunol 2020). Albeit, with a few exceptions human challenge trials have had a good safety profile. Through scientific advancements as well as strengthened regulatory and ethical requirements, modem human challenge trials (HCTs) or sometimes called controlled human infection models (CHIMs) have become a key component in vaccinology over the last few decades. The aim of this chapter is to provide an overview of the current knowl­edge, guidance, and interpretations of regulatory authorities on human challenge studies.

Regulatory Recommendations

There are no codified regulations from national regulatory authorities (NRAs) that specifically address HCTs; however, all NRAs would agree that challenge studies, as all human clinical trials must be done within an ethical framework whereby participants provide clear informed consent. The World Health Organization (WHO), although not an NRA, has published generalized guidance for NRAs, manufacturers, vaccine developers, and others on the use of HCTs in vaccine development (World Health Organization 2017). This guidance primarily focuses on issues relevant to the design and performance of HCTs/CHIMs enrolling healthy adults. WHO recommends evaluating the benefit of the information to be gained by HCTs against the risks to human subjects to assure that this information clearly justifies the potential risks to human subjects. One must consider whether the infectious disease for which a vaccine may be developed is suitable for conducting a human challenge trial. The use of a virulent challenge organism may be unsafe or unethical. For example, if an organism causes a disease with a high case fatality rate ( or there is a long and uncertain latency period) and there are no existing rescue therapies to prevent or ameliorate disease and preclude death, then it may be considered unethical to use such a challenge organism. On the other hand, a HCT may be feasible if the disease caused by the challenge organism has an acute onset, and can be readily and objectively detected, and existing efficacious treatments can be administered if needed to prevent significant morbidity or mortality (World Health Organization 2017).

The WHO guidance also emphasizes the importance of considering the regu­latory framework in which a HCT will be conducted because the requirements differ between countries. In some countries such as the USA, challenge stocks are reg­ulated in the same manner as vaccines and are expected to be studied in accordance with clinical trial regulations, whether or not an investigational vaccine is to be used in the same clinical investigation protocol (World Health Organization 2017). When clinical trial regulations apply, there is generally more clarity about the requirements for the preparation of the challenge stock. This is not the case in countries where the challenge stock is not considered to be a human medical product and therefore would not be subject to review by the country’s NRA resulting in less clarity on the regulatory expectations for quality of the challenge strain.

The US Food and Drug Administration (FDA) considers challenge agents as meeting the definition of a biologic and a drug as per the US Food, Drug and Cosmetic Act, and thus, the FDA has regulatory oversight for challenge studies. Moreover, in the US HCTs must be done under an investigational new drug (IND) application.

An IND is required for challenge studies in which a live organism (e.g., virus, bacteria, or fungi, whether modified or wild-type) is administered to subjects to study the pathogenesis of disease or the host response to the organism (see part 312). Although the challenge organism is not intended to have a therapeutic purpose, there is intent to affect the structure or function of the body. Thus, the organism is both a biological product (see 21 CFR 600.3 (h )(1)) and a drug, and an IND is required for the clinical investigation, unless the criteria for exemption in 21 CFR 312.2 are met or the product meets the definition of a dietary supplement or is an article used for food or drink (i.e., primarily for taste, aroma, or nutritive value, rather than for some other effect on the structure or function of the body) in the study. Similarly, an IND is required for a clinical investigation designed to evaluate whether colonization with a strain of bacteria can treat or prevent disease in patients with a chronic immune disorder (Guidance for Clinical Investigators 2013).

US Federal Regulations regarding the safety and protection of human subjects as well as the provisions of good clinical practice (GCP) requiring systematic moni­toring, recording, and reporting of safety data following challenge also apply to conducting HCTs.

The US FDA recently published a manuscript discussing US regulatory con­siderations for CHIMs to support vaccine development (Ramanathan et al. 2019). Although the authors clearly state that this publication does not establish data requirements or agency policy or guidance regarding specific vaccine development programs of CHIMs, it does provide regulatory considerations related to (i) Chemistry Manufacturing and Controls (CMC) for challenge inocula, (ii) the conduct of CHIMs under US IND, and (iii) the use of CHIMs to support clinical development of investigational vaccines. The FDA’s CMC guidance applies to the production of challenge strains in regard to strain characterization, purity, potency, stability, and viability. Information on strain selection must include the passage history of the challenge strain, full genomic DNA sequencing as well as phenotypic analyses to determine the presence of virulence factors and antimicrobial suscep­tibility, adventitious agent testing for virus-based challenges, and compendial tests for contaminants in bacterial challenge strains. Establishment of a stability program is also important to assess the purity and potency of the challenge inoculum. Facilities for production of challenge agents should comply with cGMP appropriate to the phase of the clinical study.

The US FDA recommends that pregnant women as well as women who are trying to become pregnant generally be excluded from HCTs, and screening and counseling should be provided to women of child-bearing age prior to enrollment in an HCT. The risk of environmental transmission and ethical considerations must also be considered in conducting an HCT. The decision to develop a HCT to provide primary or supportive evidence of effectiveness of a product may depend on the feasibility of conducting a field efficacy study and on the strengths and limitations of the challenge model. Because of the complex considerations related to the use of HCTs to support development of investigational vaccines, the US FDA recommends early and frequent interactions with vaccine sponsors (Ramanathan et al. 2019).

In the UK and European Union, the regulatory authorities do not consider challenge agents to be drugs (Catchpole et al. 2018). The European Medicines Agency (EMA) does not approve HCTs nor clinical trials. Clinical trials are approved by individual EU member states, and they consider challenge organisms as a Non-lnvestigational Medicinal Product (NIMP) not subject to rules for manufacturing of medicinal products. While NIMPs do not have a marketing authorization in the EU, they must be manufactured under GMP guidelines, such that they are as safe for subjects as an IMP would be (European Commission Health and Consumers Directorate-General 2011). Consequently, there are no universally agreed-upon regulatory requirements for the review and approval of HCTs in the EU. The challenge virus, once manufactured and having undergone safety testing and released by a qualified person, can be used in a controlled infection trial (European Commission Enterprise Directorate-General). Trials such as dose rang­ing studies to determine the optimal dose of a challenge virus for use in an inter­vention study do not require MHRA notification or approval by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK.

Outcome of International Alliance for Biological Standardization Workshops

There is a resurgence in the desire of investigators to conduct HCTs for the advancement of vaccine development around the world in both high-income and low- and middle-income countries. Given the variability in the regulatory requirements or lack thereof, the lack of consensus on ethical considerations, as well as the lack of standardization of methodologies and clinical endpoints, the International Alliance for Biological Standardization (IABS) convened three sep­arate workshops in 2014, 2017, and 2020 (Sheets et al. 2016; Baay et al. 2019; Pollard et al. 2020). These workshops brought together international representatives from academia, industry, and regulatory and public health agencies to discuss the scientific, ethical, and regulatory framework required for safe and ethical conduct of challenge trials. Some of the recommendations that came out of the consultations included development of globally aligned guidance documents for CHIM studies; further definition of a CHIM, based on the challenge agent used; and standard­ization of methodology and study endpoints. The development of a manufacturing guidance for challenge agents by regulatory authorities is currently under prepa­ration with support from the Wellcome Trust and HIC-Vac (Sekhar and Kang 2020).

COVID-19 Human Challenge Studies

There is much discussion about using HCTs to accelerate or improve the devel­opment of vaccines against COVID-19 (Jamrozik et al. 2021; Nguyen et al. 2021). The COVID-19 pandemic raises the possibility of using HCTs in which well-informed volunteers would consent to be deliberately infected with the SARS-CoV-2 virus to test and speed the development of candidate vaccines. HCTs present some advantages over traditional clinical trials, especially for situations like addressing an infectious disease pandemic such as COVID-19. HCTs offer the use of fewer test subjects, faster readouts of vaccine safety and efficacy, monitoring of participants in real time, quicker de-selection of the less promising candidates, the potential ability to elucidate functional immune correlates of protection with immunological assays, and potentially shorter times to regulatory approval. However, each instance of an HCT poses unique ethical and regulatory issues that must be carefully weighed by experts and regulators to justify acknowledged risks to participants. Above all, HCTs of COVID-19 candidate vaccines are controversial and will likely remain so for the present time because there are currently no proven effective rescue treatments immediately available.

Now that there are authorized and approved vaccines (in some parts of the world) the question arises in reference to whether there is still a role for COVID-19 HCTs. Moreover, does the potential risk of COVID-19 HCTs outweigh the potential benefit. HCTs could be used to identify correlates of protection against disease endpoints and perhaps expediting licensure of the currently authorized vaccines as well as the next generation of vaccines against COVID-19. There is a precedent for use of HCTs to support many vaccine candidates including licensure of Vaxchora by the FDA. FDA states in their guidance for COVID-19 clinical development that if it is no longer possible to demonstrate vaccine effectiveness by way of conducting clinical disease endpoint efficacy studies, the use of a controlled human infection model to obtain evidence to support vaccine efficacy may be considered (Food and Drug Administration 2020). However, the US FDA is clear that many issues, including logistical, human subject protection, ethical, and sci­entific issues, would need to be satisfactorily addressed, and presently no controlled human infection models for SARS-Co V-2 have been established or characterized in the USA. The UK is further ahead than the USA and has moved ahead with allowing an HCT for COVID-19 to proceed.


Human challenge studies have been used for decades, inter alia, for vaccine development as models of early vaccine efficacy, natural history of disease pathogenesis, identification of immune correlates, down selection of advancement of vaccine candidates, potentially de-risking overall vaccine development as well as to support licensure in one case. HCTs have improved with significant modifica­tions and been recognized as acceptable for use in the study of multiple infectious diseases; however, the regulatory assessment of HCTs by NRAs varies by country, and there are no codified regulations specific to the conduct of HCTs. Albeit, other regulations for conducting human clinical trials such as good clinical practices (GCPs) and protection of human subjects do apply. There have been many work­shops and papers published on the conduct and ethical standards such as assuring informed consent for HCTs; however, clear regulatory guidance is needed as the desire and interest in conducting these studies increase. Only the US FDA requires challenge agents to be produced under CGMPs; however, there are discussions on developing guidance and standards for manufacturing challenge agents among regulatory authorities that will assist developers in adhering to quality and safety standards.


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Baylor N. W. (2021). Human Challenge Studies for Vaccine Development : Regulatory Aspects of Human Challenge Studies. Current topics in microbiology and immunology, 10.1007/82_2021_239. Advance online publication. Retrieved from source.