Early Phase Research – The Problem, the Pathway, and the Higher Value Outcome

By Royce Morrison, MD, Director of Clinical Strategy at Charles River Laboratories

Members of product development teams typically visit the Phase I-II world every few years. Increasingly, however, they are finding it a different world at each visit, due to a variety of trends. To these visits they bring lists of concerns and expectations, and the up-front unresolved issues are often numerous and mission-critical. They need a business partner who can help them reliably navigate this ever-changing landscape.

Despite the fact that Phase I-II CRO teams live in this world continuously, they are constantly challenged by the rate of change in therapeutic science, project requirements, research design, and conduct. Therapeutic targets and drug classes are proliferating at the speed of bioscience. Simultaneously, the drug development industry is continually undergoing major changes, creating substantial shifts in the nature and range of client/sponsor characteristics.

The Problem - Pressures, Expectations, Scope

Throughout drug development, cost is a primary concern. But the average cost of a single-ascending-dose, First-in-Human (FIH) study has approximately tripled since 2005. The immediate question is "Why?" Is this driven by a seller's market - a shortage of Phase I capacity? No - Phase I capacity has actually significantly increased in all major early-phase CRO market areas. Is there a dominant line-item product/service cost driver? No, but there is an identifiable thematic pressure driving this trend. The complexity and cost of FIH studies is driven by our increasing ability to make a wide range of useful measurements in FIH, and by the mandate to employ those measurements in correspondingly more complex studies; to ascertain drug development risks; and to make go/no-go decisions earlier in the development process.

These trends are increasing expectations of product development teams and their consultants, and of the consultative arms and investigators of early-phase CROs. The scope of all stakeholders' concerns is widening to include the insight they offer and value they add to the entire development process.

To successfully plan and conduct early-phase research, one must be prepared to deal with increasing complexity. Becoming skilled in coordinating the contributions of multiple topic specialists at the point of transition from preclinical to clinical research has become essential to providing a solid scientific foundation for the development program and to optimizing study design. In parallel, increasing expertise is required of teams in early-phase CROs. The value gained is in reaching appropriate go/no-go decisions earlier in the development process and in providing information to enable optimizing subsequent development

The Pathway - Science, Design, Conduct Optimized

Years ago, Phase I study objectives were purely safety and PK, with designs created from pre-existing templates and study conduct a matter of reliably re-running the same drill. No more. Yes, there are still vanilla bioequivalence studies to be conducted, but the real action in Phase I springs from the recognition that complex information can be harvested in early development. Doing so requires complex studies comprising the "old standard" Phase I elements and aspects customized for the drug, its metabolites, and their targets and interactions.

Participants - Including Women, Older Adults

Increasingly, FIH studies are designed to include female participants. To go beyond what have traditionally been truly "First-in-Man" studies, we must absolutely avoid drug exposure in pregnancy if preclinical reproductive toxicity work is not completed and sufficiently favorable. One limiting factor is finding eligible participants, as recruitment of specified numbers of women of non-childbearing potential may be challenging. Given this challenge, it may be necessary to enroll women of childbearing potential. Risk of pregnancy may be essentially eliminated by in-house confinement (i.e., supervised sexual abstinence) between successive pregnancy tests done ten days apart, prior to dosing. In planning for inclusion of women in FIH studies, be aware that subjective adverse events and objective study parameters may vary significantly with phases of menstrual cycle - e.g., in cardiac safety, the ECG QT-RR relationship, and magnitude of drug effect on repolarization/QT.

In addition to the inclusion of female participants, increasing numbers of FIH studies are now calling for enrollment of healthy older adults to ascertain both safety and PK characteristics. Historically, these tended to be separate studies, with the studies in healthy young adults preceding those in older adults. When it is necessary to combine the studies, we take care to reduce impact on recruitment and timelines. This requires clearly separate age ranges for "healthy normal" and "healthy older" volunteers, and recruitment will be facilitated by setting the lower age limit of the older group as low as is allowed by science, marketing plans, and regulatory advice.

Terminology can significantly affect recruiting. Think twice about advertising for "elderly" volunteers; "older," or a simple statement of age range will feel and work better. Still, recruiting sufficiently healthy older adults, free of concomitant medications, OTC drugs, herbs, vitamins, and supplements is predictably challenging. What questions need to be answered by the study? If older adults do not need to be exposed to all dose levels, it may be optimal to conduct the basic, sequential-cohorts FIH study with younger adult participants. During conduct choose a dose level at which an additional cohort of older adults will be enrolled as they are available, admitting/dosing them in synchrony with the remaining escalation cohorts of younger adults. This provides a full cohort of older adult PK information at a single-dose level, for comparison with younger adult PK at the same level.

Again, consider whether an older cohort is truly necessary at the FIH stage of testing. A group of "healthy older" volunteers will have a higher prevalence of undiagnosed disease (e.g., heart disease, atherosclerosis, cancer) than a younger group. An undiagnosed condition can become evident during or shortly after the FIH study. Whether truly drug-related or random, such apparently dose-emergent adverse events will be taken seriously by investigators and regulators, and the subsequent development program may be burdened by mandated, detailed, expensive testing and surveillance for possible drug-relatedness.

Safety First

The first objective in FIH studies is maintaining strict safety criteria and reducing, or eliminating, adverse events. There are several standardized toxicity scales for assigning grades to adverse events, which are always useful and in some circumstances even required. However, they should be critically examined and sensibly customized, stating exceptions in detail. Otherwise, Murphy's Law will prevail, and dose escalation or study termination may be dictated by the occurrence in one cohort of two Grade 2 adverse events for even the most inconsequential symptoms or signs. Envision Grade 2 flatulence triggering several weeks' delay for FDA review and protocol amendment.

Related to the impact of adverse events, but on a higher level, is the prevention of disastrous results. The TeGenero experience demonstrated important lessons in disaster prevention. When the drug class suggests the possibility that serious, nonidiosyncratic human toxicity at usual starting doses may not be confidently predictable by preclinical experience, Phase I teams can optimize FIH design to minimize the risk. Also, the study conduct team can be prepared to provide maximal immediate support, in the appropriate clinical care setting, to a study participant.

At the preclinical-clinical transition, there is the specific problem of determining starting doses and escalation multiples. These decisions may not be entirely straightforward, even with the "Guidance for Industry - Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers" (http://www.fda.gov/cder/guidance/5541fnl.pdf) in hand. An experienced CRO with integrated preclinical and clinical teams can contribute substantially to the discussion.

Pharmacokinetic & Metabolite Measures

FIH or other early clinical studies can yield absolute bioavailability and additional ADME information by administering small doses of radiolabeled investigational product, with or without larger dose(s) of unlabeled ("cold") product. When 14-C labeled API (active pharmaceutical ingredient) is available and suitable (by manufacture and preclinical work) for human IV microdose administration, it can be given as independent microdose or simultaneously with administration of "cold" API by other route (e.g., oral, subcutaneous) and, combined with highly sensitive analytic techniques (e.g., AMS [accelerator mass spectrometry], LC/MS/MS) to compare bioavailabilities and contribute to understanding metabolite formation processes.

Drug-Drug and Drug-Food Interaction

Paralleling the proliferation of drug classes, formulations, and known interaction mechanisms, and with emphasis on developing drugs for chronic use in populations using other drugs, increasing numbers of DDI studies have become necessary. Standard interaction studies between new and reference drugs can present significant design problems from both safety and PK perspectives, making it necessary to plan ahead. 

"Cocktail" combinations of "probe" drugs can be administered simultaneously to investigate multiple interactive mechanisms in one study. Importantly, this method is still in active development, and the design of such studies will always be compound-specific, requiring consultation between the development team, PK-metabolism specialists, and bioanalysts responsible for measuring levels of multiple drugs and metabolites in the same specimen matrices.

Though the two-way crossover "food-effect study" has traditionally followed FIH single ascending dose (SAD) and multiple ascending dose (MAD) studies of orally-administered drugs, a preliminary indication of food effect can be achieved by adding a one-way crossover (from fasting to fed) into the SAD design, at one or two dose levels.  

Pharmacodynamic Measures

Increasing scientific complexity drives greater complication of study design and conduct. The details require discussion and planning with the early-phase CRO. Current FIH study designs may incorporate testing for CYP and other metabolic genotype/phenotype characteristics at screening, on admission to study, or electively when PK data suggest atypical results. This can affect screening efficiency and timelines. Better understanding of subcellular target specificities and biosystem interrelationships is driving inclusion studies of specific laboratory PD measurements of both on-target effects and off-target adverse effects in FIH. The biomarker analyses can require additional complexity in study design and conduct, sample processing, storage, and shipping.

Cardiac Safety

According to the E-14 guidance, a remarkably expensive "thorough QT study" to evaluate the potential for inducing Torsade de Pointes (TdP) dysrhythmia will be required in mid-course of a successful drug development program. The FIH SAD and MAD escalation studies offer a distinct opportunity for acquiring ECG data that can later greatly assist in designing and powering the definitive study. In the FIH studies, the range of measured exposures may be greater than will ever again be achieved, especially if the highest tested dose is determined to be above maximum tolerated dose (MTD). At low additional expense, continuous ECG data can be acquired and saved for later detailed analysis, if the drug's development proceeds as hoped. Design the FIH study to include 24-hour baseline and post-dose ECG data collections, with supervised, quiet rest periods preceding each PK timepoint (the "extraction windows" of a QT study, during which high-quality ECGs can be extracted for detailed analysis by cardiac core lab). Ensure archiving of the entire acquired set of continuous data.

The E14 guidance articulates today's regulatory requirement for basic clinical assessment of a drug's tendency to alter QT interval duration and to pose a risk of precipitating Torsade de Pointes (TdP). At present, guidance requires detailed, extensive, expensive studies generally following a standard design, and FDA provides a focused point of contact (the Interdisciplinary Review Team) for discussion of protocols proposed for assessment of TdP risk. This is easily the subject of whole books and long review articles. For now, it is important to recognize that the science, methods, protocol designs, and regulatory context are changing literally from month to month. Great progress is being made in driving down the cost per delivered useful information. There is little doubt that QT interval measurement will eventually be supplanted as the best method for assessing TdP risk. Already, the delta-delta-QTc approach is substantially augmented by other ECG analytic methods. Be aware that the methods of data acquisition and conditions of study conduct can contribute significantly to data quality and study power. Also, commonly a "pilot" study may be necessary to establish an appropriate supratherapeutic dose and to ascertain any suggestion of drug-induced QT effect; both factors greatly influence TQT study design and required enrollment numbers.

A high-quality 12-lead telemetric ECG data system (e.g., the Mortara Surveyor System) can accomplish this while also providing real-time safety monitoring without committing to the cost of Holter recording rental. Such data can be analyzed by standard methods to yield an estimate of "central tendency" in delta-delta-QTc information (as defined in the E14 guidance) and by alternative methods to yield higher-sensitivity, highly useful information (T-wave morphology, beat-to-beat methods, concentration-effect modeling) despite the low N typical of FIH studies

This information will be highly valuable in designing and powering the cardiac safety study that will be required farther down your product's development path. Additionally, the collection of baseline continuous 12-lead information enables elective Holter-equivalent analysis of the baseline when the study participant's post-dose ECG data are found to suggest an abnormality. In most cases, such analysis will show that the observed finding is not new but existed prior to dosing. Often, the findings are relatively minor and would not necessarily be exclusionary per standard screening criteria, but the need is to be confident that the finding is not dose-emergent.

While TdP liability has received justified emphasis, the histories of Fen-Phen and Vioxx have forced us all to recognize the breadth of the cardiac safety problem. Most "hard outcomes" evidence of drug liability for other cardiac safety problems (atherothrombotic events, myocardial function, valvular damage, etc.) will necessarily come from Phase III and IV research. In parallel with the general trend to increasing emphasis on understanding mechanisms and identifying signals of adverse effects in the earliest clinical studies, there is increased emphasis on detecting cardiac safety signals at the FIH stage of development.

Troponin measurements are becoming essentially standard in FIH studies. Echocardiography is employed in Phases I and II. ECG monitoring is more sophisticated in data acquisition (e.g., the Mortara Surveyor System) and data analysis (e.g., the iCardiac analytic toolbox). Noninvasive measures of cardiovascular dynamics - thankfully beyond simple static and postural vital signs - are in use and increasingly sophisticated.

The Desired Outcome - A Higher Value Study & Development Program

Overall, sponsors and CROs are better at working faster. Because specific outsourcing needs vary from case to case, the CRO will work with the sponsor to help determine what is essential to accelerate drug development at the critical preclinical-clinical transition. In the current life sciences environment, it is critical to demand and expect more from the CRO - in outcome accuracy, efficiency, and cost, or, more accurately, in value gained per cost.

To help optimize costs, sponsors can plan the transition from preclinical-to-clinical well in advance. In addition, continual attention to and adaptation of trials will help preserve resources and produce results that are both intended and, most importantly, accurate. One of the keys is to book all or most of the product's Phase I-II development with the same CRO. Booking with a consistent partner will decrease the per-study investment of most senior CRO staff time for IB, protocol, and ICF development and will produce the most efficient working relationships. Additionally, with a set of studies in queue and a set of dates for deliverables, the CRO can most efficiently manage timelines at a site. In other words, optimized planning, adaptive responsiveness of the CRO's expert team, more cohesive teamwork between sponsor and CRO, and CRO responsibility for a series of studies with latitude for time management will all help achieve project objectives while the CRO achieves efficiencies and reduces project cost.

This is the strategic calculation driving change in early-phase research - while the cost of FIH studies has risen substantially, complexity and information value have increased, and the cost per value has decreased. Stated again, the value gained is in reaching appropriate go/no-go decisions earlier in the development process, and in providing information to enable optimizing subsequent development.