First-in-Human-Enabling Toxicology Programs: Common Misconceptions by Grace M. Furman

Nomination of a clinical candidate and subsequent conduct of toxicology studies to support a first-in-human (FIH) clinical trial is an exciting milestone for sponsors! While many are highly experienced drug discovery professionals, some may have limited, or even no experience, in early clinical development, including the critical toxicology studies required to successfully support a FIH trial.

Some sponsors, particularly those earlier in their development journey, may bring initial assumptions about certain aspects of a toxicology program. In some cases, these assumptions benefit from clarification. As experienced drug developers and toxicology subject matter experts, we can offer perspective and technical insight to help sponsors distinguish established principles from common misunderstandings in toxicology study design and interpretation.

In this blog, I will outline five commonly encountered misconceptions that arise in consulting discussions, along with clarifying context and evidence-based explanations.*

_{*Please note that since my expertise and practice are limited to small molecule therapeutics and general toxicology, this may not apply to biologics or more specialized areas.}

Myth #1: Target Organ Toxicity Can Significantly De-Value the Compound to Potential Investors

Fact: Target organ toxicity is a key deliverable of a general toxicology study.

Target organ profiles generated in rodent and non-rodent test species form the basis of a successful clinical risk management strategy. These risk management strategies are essential in monitoring for, and hopefully avoiding, adverse effects in humans. 

Without a target organ profile defined in animals, human risk minimization is severely compromised. Additionally, lack of target organ toxicity can leave regulators with insufficient information to assess risks to human subjects; this is a common deficiency cited by the U.S. FDA [per 21 CFR 312.42(b)(1)(iv)] when imposing a clinical hold on an FIH trial. 

Potential investors seeking molecules that lack target organ effects in animal toxicology studies will either be informed of the associated risks by the experienced drug development toxicologist who is (hopefully) part of their due diligence team or will face potential challenges if the asset is licensed for development.

Myth #2: Target Organ Profiles Generated in Animals Predict Safety in Humans

Fact: Toxicology studies are not crystal balls.

In other words, they cannot forecast what will (and will not) happen in humans. However, target organ profiles generated in animals are valuable in anticipating and managing toxicities that may be elicited in humans; these target organ profiles serve to inform the early risk-benefit analysis for new therapeutics, guiding safe dosing and monitoring in human subjects.

In essence, toxicology data provides the scientific data (the "what and how much"); while clinical risk management strategies provide the structured framework (the "how to manage it") that will protect human subjects (and healthcare staff) from drug-induced hazards. 

Target organ effects associated with engagement of the intended molecular target (or exaggerated pharmacology resulting from target modulation at supratherapeutic doses/exposures) will always be considered relevant to human risk since the intent in humans is to engage the molecular target being investigated.

Therefore, these target organ effects should be elicited in toxicology studies conducted at toxicologically relevant doses/exposures, assuming the species are pharmacologically relevant. In contrast, secondary pharmacodynamic effects identified in one or more animal species, as a result of engagement of unintended molecular targets, may or may not be relevant to human risk. For both intended (“on target”) and unintended (“off target”) effects that will prove to be relevant, humans may be more or less sensitive to these effects than animals.

Additionally, some toxicities are specific to humans. For whatever reason, these are not invoked in animals, even at maximally tolerated dose levels, but are sometimes encountered after administration of a single dose, in humans. If these unanticipated human-specific toxicities are severe and/or dose-limiting, clinical development may be discontinued.

Myth #3: Calculated Safety Margins are Required to Support a First-in-Human Trial

Fact: There are no regulatory requirements, or even expectations, relating to safety margins; however, regulatory standards for safety factors do exist.

The uncertainties associated with translation of animal toxicology data into human safety are addressed by safety factors applied when calculating a clinical starting dose. Per the FDA’s 2005 Guidance for Industry, “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers”, a safety factor is applied when calculating the maximum recommended starting dose (MRSD) to provide a margin of safety for protection of human subjects receiving the initial clinical dose. 

This safety factor allows for variability in extrapolating from animal toxicity studies to studies in humans resulting from:

• uncertainties due to enhanced sensitivity to pharmacologic activity in humans versus animals;
• difficulties in detecting certain toxicities in animals;
• differences in receptor densities or affinities;
• unexpected toxicities; and
• interspecies differences in ADME.

The default safety factor normally used is 10; however, this may not be appropriate for all cases. The extent of increasing or decreasing a safety factor is largely a matter of judgment; all available information must be considered. When an applied safety factor differs from the default value of 10, a clear explanation of the reasoning behind the applied safety factor must be provided.

An alternate approach is taken when a FIH trial is being conducted with a small molecule oncology agent in patients with advanced cancer. For these trials, a common approach is to set a start dose at 1/10th of the severely toxic dose in 10% of the animals (STD 10) in rodents or 1/6th the highest non-severely toxic dose (HNSTD) in non-rodents, whichever is lower. 

It’s important to note that safety margins calculated by drug developers are often based on projected/modeled data. While these projections can be very useful for internal decision-making and business-related purposes, they are not relevant to human risk assessment as there is no regulatory consensus on how safety margins should be calculated. More importantly, regulatory decision-making is based on experimental (and not projected) data. 

Myth #4: Toxicology Data Will Define the Maximum Dose That Can be Administered to Humans

Fact: Toxicology data will only limit dosing in humans in certain circumstances, such as when a serious non-monitorable toxicity has been identified in animals. 

An example of this would be convulsions, in which exposure limitations in humans would be imposed based on exposures documented in animals at an no observed effect level (NOEL). In most cases, however, toxicology data will define a starting dose but will not limit the doses or exposures that can be explored in humans. This is particularly true when target organ effects described in animals are deemed to be monitorable and reversible; these types of effects are typically considered manageable in humans, assuming appropriate clinical risk management strategies are included in the clinical trial design. 

That being said, new target organ effects may be appreciated only in longer duration subchronic and/or chronic toxicity studies conducted after FIH has been initiated, in support of later phases of clinical development and/or registration. Clinical risk management strategies will be needed to address any newly-identified target organ effects; these strategies may include associated clinical stopping criteria if the effect in animals is deemed to pose an unacceptable risk to human subjects.

Myth #5: The High Dose in a Definitive Toxicity Study Should Always Establish a NOAEL Above the Anticipated PAD

Fact: While a no-observed-adverse-effect-level (NOAEL) is not required to calculate an MRSD for a FIH trial, there is no regulatory (or scientific) expectation that the NOAEL identified in any given definitive toxicity study will be the highest dose level evaluated.

Toxicology studies with NOAELs identified at the lowest dose level evaluated can still successfully support the calculation of an MRSD and development of an appropriate clinical risk management strategy.

Regulatory expectations regarding high-dose selection for general toxicity studies are provided in the ICH M3(R2) guideline. Generally, a properly justified high-dose level can be a maximum tolerated dose (MTD), a dose at which exposure saturation has been demonstrated, a maximum feasible dose (MFD), or a limit dose of 1000 mg/kg. While the guidance also mentions the option of a 50-fold margin of exposure as a limit dose, this margin is to be calculated against actual—not projected—human exposure data. This “50x rule” would, therefore, not be appropriate for setting high-dose levels in toxicology studies intended to support a FIH trial. 

A pharmacologically active dose (PAD), derived from appropriate pharmacodynamic models, should always be available for comparison against a calculated MRSD. In fact, identification of a PAD is the fifth and final step in the MRSD algorithm, described in the FDA’s guidance document. Once the PAD is converted into a human equivalent dose (HED), the HED value should be compared directly to the MRSD.

If this pharmacologic HED is lower than the MRSD, it may be appropriate to decrease the clinical starting dose for pragmatic or scientific reasons. Additionally, for certain classes of drugs, toxicity may arise from exaggerated pharmacodynamic effects. The PAD in these cases may be a more sensitive indicator of potential toxicity than the NOAEL and might therefore warrant lowering the MRSD. Note that comparison of an HED to a NOEL may result in the lowering of the clinical starting dose but would never result in increasing the starting dose beyond that supported by the toxicology data (i.e., the MRSD). 

For toxicology studies intended to support a FIH trial to be conducted with a small molecule oncology agent in patients with advanced cancer, NOAELs are not considered essential. For these clinical trials to be conducted in patients with advanced disease and limited therapeutic options, the goal of selecting the starting dose is to use all available nonclinical information (i.e., pharmacology, pharmacokinetics, and toxicology) to identify a dose that is expected to have pharmacologic effects and is reasonably safe to use.

Final Thoughts

I imagine many of you have encountered similar myth-versus-fact examples throughout your drug development journeys. It’s also possible that my perspectives may differ from your experience or from the guidance you may have received—and that’s perfectly okay. If you’d like to discuss any of the myth/fact scenarios shared above, please feel free to reach out to me directly.

About the Author: Grace M. Furman, PhD, DABT, BS, President and CEO, Paracelsus, Inc.

With more than 15 years of experience providing professional toxicology services to the pharmaceutical industry, Grace M. Furman is the President and CEO of Paracelsus, Inc. Her expertise is centered on regulatory toxicology, with a particular focus on the development of novel small-molecule therapeutics. As an independent consultant, Grace delivers strategic nonclinical guidance and leadership to oncology and non-oncology programs across all stages of development, from discovery through post-marketing.

Grace has built her career across both small and large pharmaceutical organizations. Prior to founding Paracelsus, she held a senior leadership role within the drug safety department of Pfizer’s Global R&D division in La Jolla, CA. As Senior Director of Regulatory Safety Assessment, she led the team serving as the functional interface between Drug Safety and Worldwide Regulatory Affairs. In 2007, Grace chose to leave Pfizer to return to her professional passion—project team toxicology.

Grace earned her PhD in biomedical sciences with a specialization in toxicology from Northeastern University in Boston, MA, and holds a BS in toxicology. She is also a Diplomate of the American Board of Toxicology (DABT).

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