After basic research and development and preclinical studies establish the fundamental understanding of how a drug impacts a therapeutic target, the challenge remains to translate the findings from in vitro and animal studies into humans. This must be done comprehensively and safely in order to establish the drug’s potential human safety profile before dosing.
First-in-human trials arguably represent the most critical milestone in a drug’s development, and sponsor companies, particularly those who are entering human trials for the first time, need a considerable amount of support to ensure that all necessary preclinical studies have been performed and to carefully design early clinical studies that will satisfy regulatory obligations.
Key Inflection Point
Translational medicine occurs at a key inflection point in the development of novel drugs. At this point, pharmaceutical sponsors move from preclinical research on their drug candidates into first-in-human (FIH) studies to evaluate the safety and efficacy of potential life-saving medicines.
In addition to collecting toxicity data, preclinical studies involve the development of models whose results can in some form be translatable to what might be seen in a clinical setting with respect to safety and efficacy. Pharmacokinetic/pharmacodynamic (PK/PD) modeling is a valuable tool to help in the translation of preclinical results to what might be expected in the clinical setting. PPD can develop models that describe the relationship between the concentration of the drug (PK) and its effect (PD) in preclinical studies. These models are then used to help “translate” the dose, route of administration, and dose frequency in the preclinical to the clinical setting by considering known differences between species.
Essential Toxicity Data
Essential to reaching that inflection point and enabling translational medicine is comprehensive toxicity data for each drug candidate, although different therapeutics (small molecule vs. biologic candidate) will dictate what preclinical components may be required. Regulatory guidelines (i.e., guidance documents) establish the approach and required toxicology studies that may need to be performed before a drug candidate can be deemed suitable for use in human clinical studies.
Genotoxicity and reproductive toxicity are particularly important, given that most FIH studies involve dosing healthy volunteers. Supporting a small molecule single-dose clinical trial in healthy volunteers will require an assessment for gene mutation; additional assessments to assess chromosomal damage are required in order to support multi-dose trials in healthy volunteers. Biotechnology-derived pharmaceuticals (e.g., “biologics” or high molecular weight therapeutic monoclonal antibodies) do not have this same requirement, given that reaction with DNA in the nucleus is unlikely. Anti-cancer therapeutics intended for patients with advanced disease also have designated guidance recommendations separate from FIH trials in healthy volunteers.
Before beginning any clinical projects, PPD first confirms that sponsors have done their due diligence with regard to preclinical studies and toxicity testing. If not, we can take the lead and guide the sponsor on the work required and how it can be completed accurately and efficiently. Once guidance-required recommendations and regulatory expectations have been satisfied, PPD can then support the sponsor in designing, planning, and operationalizing FIH studies.
PK/PD modeling is a valuable tool to help in the translation of preclinical results to what might be expected in the clinical setting. PPD can develop models that describe the relationship between the concentration of the drug (PK) and its effect (PD) in preclinical studies. These models are then used to help “translate” the dose, route of administration, and dose frequency in the preclinical to the clinical setting by considering known differences between species.
Designing FIH Studies Leveraging Therapeutic and Tox Expertise
Pharmacology/toxicology consultants within PPD’s global regulatory affairs department work closely with pharmacokinetics experts in PPD’s clinical pharmacology group to design and implement comprehensive non-clinical plans to enable successful product development.
Our non-clinical development scientists, including American Board of Toxicology–certified and European Registered Toxicologists, provide assistance with program and study design, competitive bids with comparisons based on critical milestones, and oversight and monitoring of non-clinical studies. PPD’s non-clinical team has experience with a variety of compound types (small molecules and biologics, including biosimilars), targets, routes of administration, and therapeutic areas.
Leveraging Data Analysis to Determine First Doses
Selecting the starting dose for FIH studies requires a deep understanding of the PK and PD data generated during the preclinical assessment stage. It is necessary to understand where the drug substance is in the body at any given time, how its levels in the blood change over time, when its maximum concentration is reached, and when it clears the body — and then relate that information to efficacy, which might be observed visually or through the detection of biomarkers.
This data can be analyzed in several ways to provide information, such as exposure versus toxicity or exposure versus efficacy. By modeling PK and PD behavior together, it is possible to predict what the effect of the drug candidate will be in relation to how much drug there is in the blood over time. This capability is important, because both animals used in preclinical studies and people are variable. Not everyone absorbs an orally delivered API at the same rate, for instance.
This information is used to determine how the drug candidate might be dosed in humans to ensure a sufficient therapeutic window. Converting results from animal models into dose levels for human trials is achieved following regulatory guidance, beginning with determination of the no observed adverse event level (NOAEL), or the dosage level at which no adverse events were observed, in the most sensitive preclinical species in which toxicity was observed.
The NOAEL level is reduced by a safety factor, providing a small percentage of that dosage level to use as the initial dose at the beginning of the FIH study. That dosage is then converted to a human equivalent dose level using allometric scaling, in which specific conversion factors based on body surface area are applied depending on the animal model used.
Multiple Approaches to FIH Development Programs
When PPD accepts a project, there are multiple approaches that can be taken to determine the best FIH clinical study design. First, we conduct a gap analysis to determine if data required for investigational new drug (IND) applications are complete.
The U.S. FDA and the European Medicines Agency (EMA) both have guidelines on what transporters and what metabolites and enzymes must be assessed in vitro, including which reporter molecules or drugs should be used for those assessments. They also have guidelines regarding whether a clinical trial is warranted based on the data. We may also need to model the PK and PD in animals and simulate the outcomes in order to update the clinical doses proposed by the study sponsor. The goal is to ensure that all of the data needed for an IND are in hand.
The next step is to design the FIH study. When a candidate moves into the clinic, typically the first tolerability/safety study is a single ascending-dose study for evaluation of the toxicity profile in humans, with the outcome being the dose level at which a certain level of toxicity is reached. A multiple ascending-dose study is often performed next to determine the effects of chronic dosing.
Following these initial studies, there are many different types of clinical pharmacology studies that can be performed, depending on the nature of the drug candidate. Examples include hepatic and renal impairment studies, food effect, drug interaction studies, and absorption, distribution, metabolism and excretion (ADME), otherwise known as human mass-balance studies. The latter provides information about how much of the drug is being excreted in the urine and feces and if unexpected metabolites are produced.
For certain drug candidates, additional studies in specific populations may be necessary, such as in geriatric or pediatric groups or with people of different ethnicities (often due to different absorption behaviors for specific classes of compounds). Most early-phase studies conducted at PPD are predominantly Caucasian (~40%) and African American (~40%), with a smaller percentage (10–15%) of Asian and Hispanic participants. Some health authorities have more specific requirements. For instance, Japan’s Pharmaceutical and Medical Device Agency (PMDA) requires ethnic PK data in a first-generation Japanese population for studies that may eventually have a patient efficacy component conducted within Japan.
The Role of PPD’s Human Safety Committee
When a sponsor presents a project to PPD, a team of experts analyzes the available preclinical data to determine whether the information necessary for moving into FIH studies is available. If sufficient data has been generated, a study investigator will then present the study to PPD’s Human Safety Committee (HSC), chaired by PPD’s chief medical officer and comprising several voting members, all senior executives with either medical or pharmacology backgrounds. Appropriate specialists are also invited to this meeting, depending on the indication targeted by the drug candidate.
The HSC discusses each project in detail, makes recommendations regarding risk mitigation and safe study conduct, and ultimately votes on whether PPD should proceed with the project as written or only proceed with the study with suggested recommendations or inclusion and exclusion restrictions to ensure the safest study conditions possible. For the investigators within PPD’s early development group, the HSC provides tremendous support in the decision to dose.
In the rare situation where a study is declined, the sponsor will be provided with recommendations and support regarding study design and alternate conduct that may be beneficial to the sponsor’s program. We often involve our late-phase group in these situations to provide the best available information.
There is always some anxiety when the first patient in the first phase I trial is dosed with a novel drug candidate. Assessing safety is paramount, whether the drug is administered orally or via injection, intravenously, or other delivery route. Is the drug tolerated locally and systemically? Is there any type of reaction? How do the vitals respond? What do the lab parameters look like?
Monitoring the First-in-Human Doses
There is always some anxiety when the first patient in the first phase I trial is dosed with a novel drug candidate. Assessing safety is paramount, whether the drug is administered orally or via injection, intravenously, or other delivery route. Is the drug tolerated locally and systemically? Is there any type of reaction? How do the vitals respond? What do the lab parameters look like?
All of those questions must be answered for each individual trial recipient, some of whom may have received a placebo. The collective safety data is used to determine whether to move to the next dose level. Tolerability cannot be easily quantified or measured; for example, there might be no effects on laboratory values, but the patient could experience systemic effects (i.e., changes in vitals, ECG parameters, rash, allergic response or infusion reaction). Visual cues and direct interviews must be included in these evaluations, in addition to lab analyses.
For the projects PPD accepts, our experience working on hundreds of FIH studies makes it possible for us to build the most appropriate mathematical models and identify all the possible “what if” scenarios that are needed to thoroughly understand how the drug candidate is working — information critically important for preparing a successful IND.
From Healthy Volunteers to Patients
Since the goal of drug development is to bring efficacious products to market that address unmet patient needs, those drug candidates must ultimately be dosed into patients. Early-phase research in healthy volunteers is largely designed to assess tolerability and safety but not necessarily efficacy. Whenever possible, biomarker and other pharmacodynamic assessments are included to give some indication of potential efficacy.
An acceptable approach taken by some study sponsors in order to gather efficacy data is to include a patient cohort within the FIH trial. Adding a patient cohort to the multiple ascending-dose portion of study conduct and selecting a dose that is expected to be similar to the anticipated therapeutic dose level, with clinical conduct that matches the healthy volunteer cohorts (e.g., domiciling and frequent study procedures) accomplishes this objective. This becomes a tremendous benefit for the sponsor in order to begin to assess efficacy while continuing to add to the data supporting tolerability and safety. This data supports the sponsor as they plan for and transition into later-phase efficacy studies.
PPD provides comprehensive regulatory and consulting support throughout the preclinical development stage, beginning even before a drug candidate is close to being ready to move into the clinic. With our thorough gap analyses, we also ensure that all necessary preclinical data is collected before moving to FIH studies. Similarly, the use of PPD’s HSC ensures that only drug candidates that are safe to administer to healthy volunteers advance to that development stage.
For the projects PPD accepts, our experience working on hundreds of FIH studies makes it possible for us to build the most appropriate mathematical models and identify all the possible “what if” scenarios that are needed to thoroughly understand how the drug candidate is working — information critically important for preparing a successful IND.
PPD designs streamlined, efficient pharmacology/toxicology programs relevant for the type of drug substance and the intended dose, patient population, route of administration, and duration of treatment in the clinic. PPD’s non-clinical regulatory team also works with clients to improve their protocols in ways that will ensure they are compliant and yield robust, reliable results yet save time and money.