First-in-human (FIH) studies are a critical step in the development of new therapeutic interventions, providing the initial opportunity to assess their Safety, tolerability, and pharmacokinetics in humans. However, these studies can pose various challenges and risks, making them a complex endeavor. Some potential issues in Fih Studies may include unpredictability of Drug behavior in humans, adverse reactions, unexpected pharmacokinetic profiles, and participant dropout. 

For instance, the TGN1412 trial in 2006 resulted in serious adverse events in healthy volunteers due to unforeseen immune responses, and the BIA 10-2474 trial in 2016 led to one death and multiple hospitalizations because of unexpected neurotoxicity.

To ensure the success of FIH studies, it is crucial to carefully plan and execute these trials by addressing the inherent challenges and uncertainties. Key aspects to consider include a thorough understanding of the investigational drug’s mechanism of action, its pharmacokinetics (pharmacokinetic) and pharmacodynamics (PD), and the selection of appropriate study design and endpoints. 

Furthermore, it is essential to implement stringent safety monitoring measures, maintain effective communication with regulatory agencies, and ensure ethical considerations are taken into account. By focusing on these critical elements, researchers and clinical trial sponsors can minimize the risks associated with FIH studies, maximizing the chances of successfully bringing new therapeutic interventions to the market.

Here we have collected and highlighted some important tips and tricks when conducting a FIH study.

Should healthy volunteers vs patients be recruited?

Traditional FIH studies for systemic drugs are often conducted on healthy volunteers. However, they can be conducted on patients as well. Deciding whether to recruit healthy volunteers or patients for FIH studies requires careful consideration of various factors. The following guidelines can help researchers make an informed decision about the most appropriate population for their investigational drug.

Consider Healthy Volunteers:

• If the investigational drug’s safety profile is reasonably predictable and the risk of adverse effects is low, conducting FIH studies in healthy volunteers may be appropriate.

Example: a drug that has been extensively studied in animal models and has a known mechanism of action that does not pose significant safety concerns may be tested in healthy volunteers as the first step in clinical development.

• If the drug’s mechanism of action or pharmacokinetic and pharmacodynamic properties are not disease-specific, testing the drug in healthy volunteers can help establish a baseline understanding of the drug’s behavior in the absence of the disease.

Example: a drug that targets a common protein in the body and is not specific to any particular disease may be tested in healthy volunteers to establish how it is absorbed, distributed, metabolized, and excreted by the body. This information can then be used to inform the dosing and administration of the drug in subsequent studies in patients.

Consider Patients:

• If the investigational drug’s mechanism of action or its effect on disease-specific biomarkers can only be accurately assessed in patients with the targeted condition, conducting FIH studies in patients may be more suitable.

Example: a drug that targets Alzheimer’s disease may only show its full effects on biomarkers and cognitive function when tested in patients with Alzheimer’s disease.

• If there are disease-specific safety concerns or potential pharmacokinetic or pharmacodynamic differences between patients and healthy volunteers, testing the drug in patients can provide a more accurate assessment of the drug’s safety and efficacy in the intended population.

Example: a drug that is metabolized differently in patients with liver disease may need to be tested in that patient population to ensure its safety and effectiveness.

• If there are safety concerns related to the on-target effects of the drug, which could normalize values in patients but result in abnormal values in healthy volunteers, patients may be the more appropriate population to evaluate the drug’s safety and efficacy.

Example: a TNF-alpha is normally expressed at higher levels in patients with rheumatoid arthritis (RA) compared to healthy individuals and plays a role in promoting inflammation and joint damage. Drugs that target TNF-alpha, such as TNF inhibitors, aim to regulate its expression could potentially alleviate symptoms and reduce inflammation. However, this regulation may lead to adverse effects or imbalances in healthy volunteers. Therefore, patients diagnosed with RA may be the more appropriate population to evaluate TNF inhibitors targeting RA.

Balancing these factors, researchers can determine the most appropriate and ethically sound approach for their FIH studies, whether in healthy volunteers or patients.

Choosing the starting dose, dose increment and dose range

The aim of FIH studies is to find the right balance between efficacy and safety by starting in the right range of doses. This requires careful consideration of the animal data, the pharmacological properties of the drug, and the potential risks and benefits for human subjects.

When translating drug doses from animals to humans, differences between species necessitate dose adjustments. These differences encompass diverse aspects, including variances in metabolic processes, elimination kinetics, distribution patterns and overall physiological characteristics.

Additionally, factors, such as body weight and organ size, can differ between animals and humans, giving rise to variations in drug response and pharmacokinetic. These dissimilarities highlight the importance of dose scaling and adjustments to ensure safety and achieve similar drug plasma levels in humans as seen in animal studies without exceeding or falling short of the intended therapeutic range. Determining the appropriate starting dose, dose increment, and dose range in FIH studies requires careful consideration of animal data, pharmacological properties, and potential risks and benefits for human subjects.

For systemic drugs, the traditional way to do the dose extrapolation is to follow the FDA guidance for estimating a maximum safe starting dose by converting no observed adverse effect level (NOAEL) obtained from the most sensitive animal toxicology test to human equivalent dose (HED) based on body surface area (BSA)-related scaling or similar mathematical paradigms. 

Based on our experience, this tends to be a sufficient approach for most straightforward drugs, allowing for the identification of a safe starting dose. However, in cases where the extrapolation to the human dose is complicated by factors such as unusual absorption, metabolism, or expected compartmentalization, alternative modeling approaches may need to be considered, including physiologically based pharmacokinetic (PB/PK) modeling.

A careful balance should be sought to optimize dosing in FIH studies. The dose range must be sufficiently high to produce the desired drug effect while minimizing the risk of adverse events. It is important to avoid excessively low starting doses, which would offer limited potential for gathering meaningful information while necessitate multiple cohorts and prolong the time and cost to reach the target concentration.

In a typical FIH study, sentinel dosing is used to mitigate safety risks. This means two subjects receive an active drug and placebo at a 1:1 ratio, followed by the remaining subjects in the respective dose cohort. Regulatory agencies and ethics boards typically require sentinel dosing, which helps ensure safety throughout the trial. The dose escalation scheme can be fixed or flexible. A flexible dosing scheme is a common feature of an adaptive design in a Phase I clinical trial, which can allow for changes in the dose level, frequency, or even route of administration based on the observed safety and pharmacokinetic data.

Overall, it is necessary to have careful planning and execution of the dose escalation process, with close monitoring and prompt management of adverse events. It’s also important to establish clear stopping rules for individual subjects, dose escalation, or terminating the trial.

Closely monitor adverse events (AEs) occurring on the participants

There have been a few cases where safety signals observed in Phase 1 trials have led to the termination of drug development:

• In 1993, a Phase 1 trial of the drug Fialuridine, which was being developed as a treatment for hepatitis B, resulted in the death of five of the 15 participants due to severe liver toxicity. The trial was halted, and the drug’s development was terminated.
• In 2006, a Phase 1 trial of the drug TGN1412, which was being developed as a treatment for autoimmune diseases, resulted in a serious adverse event in all six healthy volunteers who received the drug. The participants developed a severe systemic inflammatory response, leading to multi-organ failure. The trial was immediately halted, and the drug’s development was terminated.
• In 2016, a Phase 1 trial of the drug BIA 10-2474, which was being developed as a painkiller, resulted in the death of one volunteer and serious neurological symptoms in five others. The trial was stopped, and the drug’s development was terminated.

The examples of Fialuridine, TGN1412 and BIA 10-2474 highlight the importance of monitoring drug safety in clinical trials, as unexpected safety concerns can emerge even after extensive preclinical testing. Safety monitoring should start with Phase 1 trials and include routine monitoring of vital signs, ECGs, physical exams and clinical lab values. The monitoring period should be long enough to eliminate the possibility of serious toxicity going undetected, especially since there is usually no clear information about a drug candidate’s prolonged effect or off-target effects in FIH studies.

Care and accuracy when collecting and organizing trial data

Proper data collection and management are particularly essential for a FIH studies where safety is of utmost importance.

A well-written protocol should provide clear instructions on important endpoints and outline the specific data that will be collected, how and when it will be collected, and how it will be managed.

Specific techniques and equipment may be needed for certain endpoints, such as pain relief, which requires tests like the pinprick or von Frey test to assess an individual’s perception of pain or tactile sensitivity. Protocols should provide precise instructions on timing, techniques, and equipment to ensure accurate measurement for these specific tests. 

Routine measurements, such as vital signs and physical exams, may rely on standard operating procedures from the clinical research organization. Regardless, all staff involved in the trial should be trained on the study protocol and data collection procedures to ensure consistency and accuracy.

A centralized database or cloud-based system can help ensure consistency in data collection and management across multiple sites.

Setting clear pharmacological endpoints

Assessing the pharmacological responses of an investigational product in a FIH studies requires a comprehensive approach that considers multiple factors, including safety/ Pharmacokinetics (pharmacokinetic)/ Pharmacodynamic (PD) endpoint determination and statistical analysis.

How safe the investigational product is for people to use (Safetly)

The primary objective in a FIH study is to assess the safety and tolerability of the investigational product. Therefore, a conventional systemic safety evaluation should include assessments of AEs, lab data, physical examination, vital signs and ECG when appropriate.

In addition, it is essential to consider additional safety monitoring based on preclinical data to ensure the safety of study participants. For example,

• for drugs that have the potential to affect cardiac function, it may be appropriate to add specific monitoring on serum cardiac troponin I and creatine kinase;
• for drugs that are metabolized by the liver, it may be appropriate to add specific safety monitoring on liver enzymes, bilirubin, albumin and coagulation parameters etc.;
• for drugs that are excreted through the kidney, it may be appropriate to add specific safety monitoring on renal biomarkers in urine samples.

It is also important to be aware of potential adverse events that may arise during the study. Involving appropriate specialists in the study team should be considered to ensure that any potential adverse events are managed properly, and the safety of study participants is ensured.

Here are some specific examples for adding additional safety measures based on known adverse effects.

• Reversible hair loss is a potential side effect associated with Nonalcoholic Steatohepatitis (NASH) drugs such as fibrates and statins by lowering cholesterol and fatty acids in the body. Some NASH drugs may also cause inflammation in the scalp or alter hormone levels, which can contribute to hair loss. If we are conducting a trial on NASH, as hair loss is not an unexpected adverse event, it is important to involve a dermatologist to assess if the hair loss is a result of damage to the hair follicle or not.
• DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) is a severe and potentially life-threatening drug reaction characterized by a widespread rash, fever, lymphadenopathy (swollen lymph nodes), which can be caused by a variety of drugs, such as proton pump inhibitors, antibiotics and anticonvulsants. As DRESS is known for some drug categories, if we are going to conduct trials on similar drugs, specific instructions should be given to the Principal Investigator (PI) and study staff to monitor for signs of DRESS. Additionally, it is essential to incorporate information about DRESS in the Informed Consent Form (ICF) and educate participants about monitoring for symptoms associated with this condition. By taking these measures, diligent observation and early detection of potential DRESS symptoms can be facilitated, enhancing participant safety and the overall quality of the trial.
• Infusion reaction is a recognized potential adverse effect associated with intravenously administered SiRNA drugs. If we are conducting trials on SiRNA drug, to minimize the risk of this adverse event, various safety measures can be implemented such as premedication with corticosteroids or H1 blockers, stepwise infusion approach with initial low-dose infusion rates, and administration of the drug in a setting where emergency equipment and personnel are readily available.

With regard to topically applied drug candidates, site reactions such as dryness, erythema, burning, and discoloration are also important assessments to be considered into the FIH study design.

How the body absorbs and eliminates the investigational product (pharmacokinetic)

Generally, the systemic exposures to the active ingredients or clinically relevant metabolites should be evaluated by using standard pharmacokinetic parameters, such as Cmax, Tmax, AUC and T1/2 and the link between the systemic exposure and the systemic AEs observed at a certain dose level can help to define the maximum acceptable systemic exposure and identify stopping criteria from pharmacokinetic perspective.

It is important to carefully evaluate the pharmacokinetics of investigational drugs early in development, even if there are no safety signals. Sponsors should not decline or delay pharmacokinetic evaluation, as failure to achieve target concentrations could impact the efficacy of the drug.

In the case of plasma drug levels are unexpectedly low, compounding and the use of alternative formulations of the drug may need to be considered to improve the absorption and achieve higher plasma concentrations. Proactively including provisions for compounding and formulation optimization in the protocol will enable different formulations implemented in the trial without extensive GMP activities on the drug product.to optimize drug delivery in response to emerging data and helps to ensure that the study remains on track and is aligned with its objectives.

The importance to have a careful assessment of the drug metabolism in preclinical data should also be highlighted. If there is a potential impact of genetic variation on drug metabolism, especially if there is evidence that the drug primarily undergoes metabolism through a single enzyme, variants or polymorphisms that affect this pathway could result in significant differences in pharmacokinetic parameters. For example, if a drug is primarily metabolized by the CYP2D6 enzyme and a participant is a poor metabolizer due to a genetic variant, they may have slower drug clearance and higher drug exposure, potentially leading to toxic levels of the drug in the body.

How the investigational product affects the body’s functions (PD)

FIH studies have clinical and PD endpoints that align with proposed indications, such as HbA1c level reduction for antidiabetic drugs and anesthesia duration for anesthetics.

It is worthy to note that the implementation of a biomarker in a FIH study can benefit not only a single drug development, but also a disease indication for which multiple drugs will be developed. Examples include prostate-specific antigen (PSA) for prostate cancer, carcinoembryonic antigen (CEA) for colorectal cancer, and CA 125 for ovarian cancer.

While biomarkers, PoC or PoM outcomes can be valuable tools in assessing the effectiveness of a drug, caution should be exercised when interpreting these outcomes. A lack of signal does not necessarily indicate that the drug is not working, and additional evidence and a broader understanding of the overall efficacy and safety of the drug should be sought before making any go/no-go decisions. 

One illustrative example is the cold pressor test, which evaluates the body’s response to pain and stress by immersing the hand in ice water for 2–3 minutes while monitoring physiological measures. It induces a brief period of reduced blood flow in the hand, triggering a stress response characterized by increased blood pressure and heart rate. The test is used to evaluate pain medication efficacy but has limited sensitivity and high variability. Negative outcomes may not indicate the drug’s effectiveness.

Considering regulatory feedback

Lastly, taking a proactive approach to engage with regulatory agencies before submitting a clinical trial application can yield significant benefits from a regulatory perspective. Not only does it minimize the risk of clinical hold, but it can also maximize the return on investment. Therefore, it is essential to give careful consideration to regulatory feedback.

It is essential to give careful consideration to regulatory feedback. In our experience, regulatory agencies often provide comments on the protocol based on their access to information from other similar drugs. While they may not be able to disclose the data, their recommendations, including specific safety monitoring measures, are critical to implement. Incorporating these recommendations can not only improve the chances of regulatory approval, but also enhance patient safety and overall study outcomes.

Why Choose BioPharma Services?

Effective FIH studies rely on cross-functional cooperation. The clinical pharmacology team must consider all preclinical data when designing the FIH study to minimize uncertainties, such as the drug’s pharmacological and toxicological profiles, preclinical pharmacokinetic data, safety and efficacy biomarkers, and potential drug-drug interaction risks. The physician and clinic operation teams must focus on safety monitoring plans, study startup activities, and study oversight to ensure the quality of the study. Proactively engaging with regulatory agencies before submitting a clinical trial application and considering regulatory feedback can minimize clinical hold risks and enhance patient safety and overall study outcomes. By following these tips and tricks, researchers can prioritize safety and ethics in their FIH studies, leading to meaningful outcomes.

Written by: Vivian Zha, Clinical Pharmacology Scientist

BioPharma Services, Inc., a Think Research Corporation and clinical trial services company, is a full-service Contract Clinical Research Organization (CRO) based in Toronto, Canada, specializing in Phase 1 clinical trials 1/2a and Bioequivalence clinical trials for international pharmaceutical companies worldwide. BioPharma has clinical facilities both in the USA and Canada with access to healthy volunteers and special populations.