In part one of this blog series, “The Path to IND Part I: Milestones and Common Roadblocks,” we introduced the FDA’s Investigational New Drug (IND) application and highlighted some of the most common mistakes drug developers make and how to avoid them. Among our keys to IND success in Part 1 were:
- Familiarize yourself with the IND process
- Avoid common mistakes
- Begin with the end in mind (i.e., understand how best to support your early clinical program)
In part two of this blog series, we take a deeper dive into the last point (i.e., beginning with the end in mind) by discussing 1) First in Human (FIH) study designs, 2) how to select an appropriate starting dose, and 3) what types of data you need to support the FIH study.
Objectives of the First in Human Study
Paracelsus (1493-1541), the “father of toxicology” and a medical pioneer during the Renaissance once said, “Whether wine is a nourishment, medicine, or poison is a matter of dosage.”
This was not only an astute 16th century observation but it also hits upon an important tenet of modern drug development. That is, the challenge for drug developers is to identify a dose that is both therapeutic and safe to administer to humans (or at least, of acceptable toxicity).
In this context, we can establish four broad objectives for a FIH study. These are to:
- Safely administer the drug product in humans
- Determine the maximum tolerated dose (MTD)
- Gather information about human pharmacokinetics to inform future dosing decisions
- Collect preliminary evidence of pharmacologic activity (i.e., therapeutic effect)
First in Human Study Designs
The most common study design for FIH studies is the single ascending dose (SAD) study. A SAD study is a type of dose escalation study that involves administering one dose per subject, with increasing doses in subsequent cohorts. One of the primary purposes of a SAD study is to identify the maximum tolerated single dose and any dose limiting toxicities.
During a SAD study, safety and exposure data are collected and these data are often used to generate interim pharmacokinetic assessments to inform dose escalation decisions. These interim analyses also provide an opportunity to confirm or refine the pharmacokinetic sampling schedule that was originally based solely upon nonclinical data.
Sometimes, a SAD study may be paired with a multiple ascending dose (MAD) design to create what is known as a SAD/MAD combination study. The MAD component essentially echoes that of the SAD portion, with the exception that instead of administering a single dose per patient, the MAD component includes multiple doses per patient. This is especially useful for drugs that are designed to be administered repeatedly, but it can also provide vital information for many other drugs.
For example, a MAD design may be appropriate:
- when there is excessive inter-subject variability in bioavailability after a single dose
- when a single dose results in blood concentrations that are too low to be detected
- when the drug product is an extended release formulation.
Regardless of the design, FIH studies are typically conducted in healthy volunteers, although certain indications may necessitate using patients instead. Oncology and certain rare disease indications are examples where patients are favored due in large part to the inherent toxicities of the drugs involved.
Considerations for the First in Human Starting Dose
Selecting a FIH starting dose is a complex process that relies on integrating nonclinical pharmacology, toxicology, and pharmacokinetic/ADME data. Pharmacology data help to establish the intended therapeutic target and confirm that the drug elicits the desired therapeutic outcome. Toxicology data are used to identify potential toxicities and establish the highest dose or exposure where no adverse effects occur (i.e., the no observed adverse effect level, NOAEL).
Pharmacokinetic data provide information about how the drug is absorbed into the bloodstream, how and where it is distributed in the body, and how it becomes metabolized and it is ultimately excreted from the body (also known as ADME).
When thinking about your FIH dose, consider these key questions:
- What doses result in toxicity in nonclinical species?
- What doses are therapeutically effective in nonclinical species?
- Are the toxic effects reversible and/or monitorable in a clinical setting?
- What happens to your compound following administration (i.e., what are the compound’s pharmacokinetic characteristics)?
- What is known/unknown about the disease you are trying to treat and how could these factors affect the safety and/or effectiveness of your drug?
Selecting an Appropriate Starting Dose
The FDA guidance, “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers,” provides a stepwise approach to establishing a safe starting dose in humans. The steps are:
- Establish the NOAEL
- Calculate the Human Equivalent Dose (HED)
- Select the most appropriate nonclinical species
- Apply a safety factor
- Consider the pharmacologically active dose (PAD)
Establish the NOAEL
As stated above, the NOAEL is the highest dose or exposure at which no adverse effects are observed in a nonclinical species.
Calculate the HED
Once the NOAEL is established for each nonclinical species tested, the HED should be calculated for each by using appropriate scaling factors. This is typically accomplished by normalizing the dose to body surface area, although other parameters may be more appropriate based upon the drug. The species with the lowest projected HED is considered to be the most sensitive species.
Select the Most Appropriate Nonclinical Species
While the HED from the most sensitive species is often used to calculate the maximum recommended starting dose (MRSD), this is not always the case. When another species is deemed to be more relevant for assessing human risk (i.e., it is the most appropriate species), the HED for that species may be used instead. This is most common with biologics, where typical toxicology species may not be relevant for the intended therapeutic target.
Apply a Safety Factor
Once the most appropriate nonclinical species has been established, the HED from that species is divided by a safety factor (typically 10) to arrive at the MRSD. This step provides an extra measure of safety, since it is not yet known how the drug will interact with a human body. For example, humans may prove more sensitive to the drug’s known toxicities, the drug’s bioavailability (i.e., how much is absorbed into the bloodstream) could be higher in humans and result in elevated drug exposures, and humans may even exhibit significant toxicities that were not observed in nonclinical species.
Consider the Pharmacologically Active Dose
While the MRSD is almost always calculated based upon the NOAEL HED, there may be instances where the most appropriate HED is based upon an alternative index of effect (e.g., the PAD). Even if the MRSD is based upon the NOAEL HED, it may be useful to compare it to the PAD, which is generally established using pharmacodynamic modeling approaches. If the pharmacologic HED is lower than the MRSD, it may be appropriate to decrease the starting human dose. Furthermore, because toxicities for certain classes of drugs and biologics may stem from exaggerated pharmacologic effects, the PAD may be a more sensitive indicator of potential toxicity than the NOAEL.
The FIH study is the launching point for clinical drug development. The FIH study typically takes the form of a SAD study in healthy volunteers, although there are a number of drug-related and disease-related factors to consider to achieve the best study design. Selecting an appropriate FIH starting dose can be a complex process and requires knowledge of the drug’s activity and effects (toxic and therapeutic), which are typically established during nonclinical studies.
Because of the importance of the FIH study to overall product development, it is crucial to understand the guiding principles that drive a successful drug development program. This includes engaging industry experts across a broad array of specialties, including toxicology, pharmacokinetics and pharmacodynamics, clinical strategy, and regulatory affairs.