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International Clinical Trials

Phase I Efficiency

Mario Tanguay of Anapharm examines new trends in the design and conduct of Phase I studies

Phase I trials are a crucial step in the drug development process as they represent the first opportunity to obtain information on an investigational product with regards to its safety, pharmacokinetics and pharmacodynamics in humans. Pharmaceutical and biotechnology companies are being subjected to increasing pressure to produce clinical data and obtain proof-of-concept as early as possible during the drug development process. At the same time, the very serious adverse reactions that occurred in March 2006 during the TGN412 firstin- human (FIH) trial has had a significant impact on how we approach Phase I trials. This event led to the publication of the EMEA Guidance related to strategies to identify and mitigate risks for FIH clinical trials (1). Therefore, a good understanding of both the regulatory framework and new trends in the design of FIH studies is essential in order to conduct safe and efficient Phase I programmes. To better describe the new trends observed in various aspects of the design and conduct of Phase I trials, we have compiled some statistics from a total of 27 FIH studies over the last two and a half years.


Formulation Development Strategy
There is evidence that most sponsors have a good understanding of the toxicology programme that is required to bring a product to Phase I. However, formulation development is an aspect that is often neglected. Indeed, as illustrated in Figure 1, 25 per cent of FIH trials conducted in the represented Phase I clinics involved powder-in-a-bottle products, which corresponds to approximately 50 per cent of oral products. Moreover, capsule products often simply consisted of encapsulated active pharmaceutical ingredients (that is, API-in-a-capsule). This may represent a challenge as it is estimated that approximately 60 per cent of new chemical entities are poorly soluble compounds (2). Poorly soluble compounds clearly deserve more attention in order to ensure that formulations are developed that circumvent potential bioavailability issues. Many of the powder-in-a-bottle and API-in-a-capsule products that were administered during the Phase I studies were actually poorly soluble compounds, some of which unfortunately lead to nonoptimal results. The bioavailability of a drug substance can be limited due to poor solubility, which can result in a less than proportional increase in drug exposure (AUC) with increasing doses, as illustrated in Figure 2, page 12. In such cases, no clear conclusions can be drawn from the Phase I study since the systemic exposure associated with the desired pharmacological effects cannot be attained. In addition, the maximum tolerated doses (MTD) cannot be identified if a plateau in bioavailability is observed as the dose is increased. This explains why certain pharmaceutical companies have implemented more robust formulation strategies in preclinical and early clinical development when dealing with poorly soluble compounds (for instance, micronised API, solid dispersion, liquid or semisolid filled capsules, and so on), taking into consideration the physico-chemical properties of the drug substance and using tools such as the biopharmaceutical classification system (3).

Determination of the First Dose
Determining the first dose to be administered to humans is another important step in the transition to Phase I. The FDA has put forth a methodology to determine the maximum recommended starting dose (MRSD) in FIH studies that is based on the ‘no observed adverse event level’ (NOAEL) determined in non-clinical toxicology studies performed in the most sensitive and relevant animal species (4). More recently, the EMEA Guidance on FIH studies introduced the concept of minimum anticipated biological effect level (MABEL) as an alternative approach to calculate the starting dose (1). The calculation of MABEL is based on any pharmacokinetic/pharmacodynamic data derived from in vitro and in vivo non-clinical studies. The use of MABEL for determining the MRSD is recommended for investigational products that may be associated with higher risks (for example, drugs affecting the immune system or with a novel mode of action, drugs with a steep dose-response relationship, when the nature of the target is not well known, when the relevance of animal models is questionable, and so on) (1). It is to be noted however, that based on the FIH trials included in the analysis, the NOAEL approach remains the methodology that is most commonly used for the determination of the MRSD (see Figure 3).


FIH Study Population
Healthy volunteers generally constitute the population of choice in FIH studies, unless considered unsafe or unethical. However, there is a clear trend towards enrolling patients much earlier during Phase I, especially in the multiple-ascending dose portion of Phase I, where an effect on a clinical endpoint or a biomarker is more likely to occur. Table 1 provides some examples of target populations enrolled in the Phase I trials included in the analysis.

 Table 1: Examples of target populations enrolled in Phase I studies

 Target population  Proposed indications of study drugs may be better
 Overweight/obese subjects  Metabolic syndrome, diabetes 
 Elderly subjects  Cognitive disorders, Alzheimer’s disease
 HCV or HIV patients  Antivirals
 Type II diabetes subjects  Hypoglymecic agents
 Asthmatic subjects  Bronchodilators

Most regulatory agencies have encouraged the enrolment of female subjects earlier on in the clinical development process. Based on recent FIH studies that were conducted, sponsors clearly follow recommendations to include women in Phase I studies, as 89 per cent of the studies included both men and women. Moreover, women of childbearing potential were enrolled in 63 per cent of studies that included both genders. However, it is important to examine carefully the specific characteristics of the investigational drug to determine if women of childbearing potential should be enrolled. For example, drugs that have a long half-life can still remain in the body after the subject has left the clinical unit, therefore increasing the risks related to non-compliance with the recommended contraceptive methods.

Sample Size
There are no clear requirements from regulatory agencies with regards to the number of subjects required in FIH trials, and sample size rationale is not frequently provided in FIH study protocols. However, in 67 per cent of the studies conducted over the last two and a half years, each dose level cohort consisted of six patients who received the active treatment and two subjects who received the placebo. Even though this approach is generally accepted, it is worth considering if this is a sufficient number of subjects to evaluate the safety of each dose level. Figure 4 illustrates the minimum incidence of an adverse event that is required to be detected in relation to the number of subjects exposed; for example, with six subjects, the detection of an adverse event that has an incidence of at least 25 per cent, with an 80 per cent probability. Even though an increase in sample size may increase the chance of detecting adverse events that have a lower incidence, the potential benefit is not very high compared to the risk of exposing too many subjects to a drug that has an unknown safety profile. On the other hand, a very low number of subjects per cohort may be associated with an increased risk of missing an adverse event that possibly has a high incidence.

Staggered Dosing Approach
One precaution of great interest that has been put forth by the EMEA Guidance on FIH studies is to use a staggered dosing approach rather than dosing all subjects from a cohort at once (1). A frequent approach in the studies is to dose two subjects (for example, one active and one placebo) at least 24 to 48 hours before the remaining subjects of the cohort. Even though this approach was used for only 40 per cent of the studies included in the analysis, there is clearly a trend towards staggered dosing in the most recent studies.

Dose Escalation Scheme
The dose escalation scheme must be justified based upon the risks identified from non-clinical studies (for example, steep dose-response curve, nature of the toxicity observed in animal studies, and so on). Based on studies that have been conducted at the clinic, the dose-escalation scheme tends to be more aggressive in the lower dose ranges (for example, at least by two-fold increments), especially if the first dose was calculated based on a more conservative approach (for example, MABEL or NOAEL are associated with a higher safety factor). On the other hand, doses were escalated in a more conservative manner as higher dose levels were reached (Fibonacci-like dose increments). An interim blinded pharmacokinetic (PK) evaluation between each cohort of subjects could help with the justification to proceed to the next dose level. It may also allow us to adjust the dose to be administered to the next cohort should the exposure be lower or higher than expected. Interim PK data would also allow us to terminate the trial in cases where the absorption process appears to be saturated, such as the one depicted in Figure 2. Such interim PK evaluation was performed in approximately half of the studies we have conducted. In any event, the decision-making process and stopping rules should be well-defined and justified a priori in the protocol.


Use of More Complex Integrated Protocols
Considering the increasing pressure for sponsors to produce clinical data and obtain proof-of-concept as early as possible during the drug development process, FIH studies must be designed in an efficient manner in order to obtain as much information as possible from a single trial. A frequent strategy is to integrate the single and multiple ascending dose (SAD/MAD) studies into a single trial. Indeed, this approach has been used in 44 per cent of the FIH studies included in this analysis. SAD/MAD integrated studies can result in significantly reduced timelines. However, study protocols should allow for more flexibility and should include welldefined safety measurements and clear stopping rules. They should also include proper justification for the provision to start the MAD portion of the study.

In an attempt to obtain more information from FIH trials, approximately half of the studies performed with orally administered products included a food-effect evaluation, which consisted of one cohort of subjects, at a predetermined dose level, which was brought back to the clinic to receive the study drug with a high-fat meal. Even though this cannot replace a formal food-effect study, this provides some early indication of any possible food interaction. Finally, 48 per cent of the studies conducted included some pharmacodynamic evaluation in an attempt to obtain a proofof- concept much earlier in the clinical development process. This was performed mostly during the MAD portion of the study and was achieved through the use of certain biomarkers, either in healthy volunteers or in patients with the targeted indication.

QT Evaluation in Phase I
There is also an increased interest in obtaining more exhaustive cardiac safety information (QT data) as part of the FIH study (5-7). Since Phase I studies are designed to identify the maximum tolerated doses, the effect on the QT interval can be assessed during SAD or MAD studies at doses that are often much higher than those that could be studied in a formal, thorough QT study. Earlier detection of a cardiac safety issue can also help in the decision-making process as it may, for example, lead to conducting a thorough QT study much earlier during the clinical development process or lead to a termination of the programme, thereby saving time and money. It is to be noted, however, that the absence of QT prolongation in Phase I would generally not waive the need for a thorough QT study later on, as it would not be conducted in an optimal fashion (for example, there would be an absence of positive control, insufficient power and so on). However, this may constitute convincing data in the case of drugs that do not generally require thorough QT studies, such as large molecules or cytotoxic drugs.


Sponsors should implement a formulation development strategy that would ensure that a suitable product is administered in their Phase I trials. While assuring the safety of study subjects, there is clearly a trend towards more complex integrated FIH protocols that provide more information from a single trial. A thorough knowledge of the regulatory framework and extensive experience in innovative Phase I study designs can certainly contribute to streamlining the early clinical drug development process and improving the go/no-go decision-making process.


  1. Committee for Medicinal Products for Human Use (CHMP), Guidelines on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products, The European Medicines Agency, September 2007
  2. Dubin CH, Formulation strategies for poorly soluble drugs, Drug Del Technol 6: pp34-38, 2006
  3. Ku MS, Use of the biopharmaceutical classification system in early drug development, AAPS J 10: pp208- 212, 2008
  4. Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, mation/Guidances/ucm065014.htm, July 2005
  5. Malik M, Hnatkova K, Ford J and Madge D, Nearthorough QT study as part of a first-in-man study, J Clin Pharmacol 48: pp1,146-1,157, 2008
  6. Shah RR, If a drug deemed ‘safe’ in nonclinical tests subsequently prolongs QT in Phase 1 studies, how can its sponsor convince regulators to allow development to proceed? Pharmacol Therap 119: pp215-221, 2008
  7. Salvi V, Karnad DR, Panicker GK and Kothari S, Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development, Br J Pharmacol 159: pp34-48, 2010

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Mario Tanguay is Vice President of Scientific and Regulatory Affairs at Anapharm, a subsidiary of the PharmaNet Development Group. Mario has 15 years of experience in the drug development industry, including 10 years with major contract research organisations, and five years at Wyeth-Ayerst and Pharmacia in the field of clinical research. Throughout his career, he has served as co-investigator in over a 1,000 pharmacokinetic and Phase I trials, including first-in-human, drug-drug interactions and bioavailability/bioequivalence studies. Mario holds a BSc in Pharmacy and obtained an MSc and a PhD in Pharmacology from the University of Montreal. In addition to his current position at Anapharm, Mario is a guest professor at the Faculty of Pharmacy of University of Montreal, being involved in their post-graduate programme on drug development.
Mario Tanguay
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