Early Clinical Development Stage Drug Development Clinical Setting Biology Essay

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Early clinical development denotes the stage where the drug development enters the clinical setting. Early clinical drug development studies are also known as Phase I and II clinical studies. Phase IA studies are first in human studies. Prior to phase I studies, the investigational medicinal product (IMP) would only have been tested on animal models. Whilst animal models can give an indication of the pharmacodynamics and pharmacokinetics of the IMP it is impossible to predict exactly how a drug will behave in humans. For this reason patient safety is of utmost importance and the trial design must take this into account. The starting dose is calculated using data generated pre-clinical pharmacology and toxicology findings. The No Observed Adverse Effect Level (NOAEL) is an important part of the non-clinical risk assessment; it is defined by Dorato and Engelhardt (2005) as being "a professional opinion based on the design of the study, indication of the drug, expected pharmacology and spectrum of off-target effects" [1] . In determining the starting dose for first in human trials the Minimum Anticipated Biological Effect (MABEL) must be taken into account together with the pharmacology and toxicology data from both in vivo and in vitro studies [2] . The new drug is usually tested in healthy adult volunteers although sometimes patients are used. Healthy adult are preferred in early phase studies as they are less prone to variation. They may also be at less risk than patients who may be prone to adverse events, adverse events may also be easier to detect in healthy individuals because 'background' events are less likely and there is no risk of interference from previous treatment. [3] There is however, always a risk associated with early clinical development studies and it is important that the risk is minimised by comprehensive pre-clinical data. The TGN1412 study epitomises the risk taken when testing an IMP in humans for the first time. TGN1412 had a complex and novel mechanism. "The molecule is a humanised version of the mouse antibody 5.11A1 which is an agonist of the CD28 antigen that activates T cells without specific engagement of the T cell receptor with the antigen presenting cell" (Kenter, MJH, Cohen, AF. 2006) [4] . The trial involved the administration of TGN1412 or placebo to 8 healthy volunteers. The six men who received TGN1412 rapidly developed catastrophic multisystem failure. [5] Tegenero had chosen cynomolgus monkeys as animal models for their toxicology studies, their choice was based on the fact that "extensive homology between human and cynomolgus monkey Fc receptors has been described. All motifs critical for signal transduction are 100% conserved among human and cynomolgus monkey Fc receptors, suggesting that both CD28 and Fc receptors are recognised identically by TGN1412 in human beings and cynomolgus monkeys." [6] (Hanke, 2006). This example illustrates the need for caution in first in human (FIH) testing and why patient safety is paramount.

"The serious adverse events that arose during the very first administration of TGN1412, the so-called CD28 superagonistic antibody, have led to immediate reactions from different regulators, ranging from a moratorium on CD28 research to rules about how many individuals should receive a new compound at the same time." [7] The EMEA published a Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products which aims to assist the sponsor in the transition from non-clinical to early clinical development. [8] 

Phase I clinical trials are usually small (less than 100 subjects). Phase I studies aim to provide an initial evaluation of the efficacy, safety and tolerability of the drug and its pharmacokinetics (absorbtion, distribution, metabolism and excretion). Phase I studies usually test a range of doses to obtain an indication of an appropriate dose to be used in later studies. [9] 

An example of a Phase I study is the Small Ascending Dose (SAD) study, these studies are run in a small population of healthy volunteers, the subject are divided into groups and each group given a single dose of ascending amounts of the IMP.

The ascending dose study of epigallocatechin gallate was "a randomized, double-blind placebo controlled study to assess the safety, tolerability and plasma kinetic behaviour of single oral doses of 94% pure crystalline bulk epigallocatechin gallate (EGCG) under fasting conditions in 60 healthy male volunteers." [10] EGCG is an antioxidant found in green tea leaves and may provide benefits by preventing oxidative damage to cells by free radicals. [11] Having developed a method to purify EGCG from green tea extract, producing a consistent concentration of 94% EGCG across batches [12] , Roche Vitamins Ltd could manufacture hard gelatine capsules containing a defined and stable ECGC content to be used in studies to further investigate the biological effects of the compound. Volunteers received a single oral dose of EGCG at a dose of between 50mg and 1600mg or placebo after having fasted for 10 hours. Plasma levels of EGCG were measured at intervals for the next 26 hours. [13] 

Although EGCG is an antioxidant and probably not considered potentially dangerous, no reliable data was available on the tolerance or half-life [14] and thus a SAD study is possibly the safest way to determine the pharmacokinetic parameters. By starting with a low dose, and with each volunteer only receiving a single dose of IMP the potential to catch any adverse effects early is increased, before the dose is increased for the subsequent group. In a SAD study, the dose of IMP is usually increased until the volunteers experience intolerable side-effects or the predetermined pharmacokinetic safety level is reached. This is referred to as the maximum tolerated dose (MTD)

Phase IB studies are often designed as Multiple Ascending Dose (MAD) studies and further the pharmacokinetics and pharmacodynamics of the IMP. The study design is such that a group of subjects will received multiple low doses of IMP. Blood tests are performed at intervals and the results analysed. Subsequent groups of subjects will receive higher multiple doses. In the MAD study of Teduglutide 'Pharmacokinetics, Safety and Tolerability of Teduglutide, a Glucagon-Like Peptide-2 (GLP-2) Analog, Following Multiple Ascending Subcutaneous Administrations in Healthy Subjects' [15] (Marier, J et al 2008). Sixty four healthy volunteers were subjected to daily injections of Teduglutide over 8 days, the dose ranged from 10mg - 80mg. Blood samples were taken for analysis on day1 and day8. MAD studies are useful in getting a more comprehensive idea of the pharmacokinetic parameters determining whether or not there is accumulation of the IMP. In the Teduglutide study, "mean AUC0-t, AUC0-∞, and Cmax values of Teduglutide were very similar on days 1 and 8, confirming that minimal accumulation of the drug occurs following repeated once-daily subcutaneous administrations." [16] 

Food Effect Studies look at the effect food has on the drug, whether eating before or after the dose with affect the pharmacokinetics of the IMP. Obviously this type of study would only be relevant to drugs delivered by the oral route. The effect of food on the oral bioavailability of sunitinib malate was assessed in an open-label, randomised, two-way crossover study. The study used 16 healthy volunteers, each subject received a dose of the IMP after a 10 hour fast in one period and in the other period, the dose was administered after a high-fat, high calorie meal. [17] The study found that although there was a slight delay in the formation and subsequent absorption of the active metabolite SU12662, exposure remained unaffected and the 90% confidence intervals (CIs) for maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were within the 80-125% bioequivalence range. These results indicate that sunitinib maleate can be taken with or without food. [18] Knowing whether food has an effect on a drug is important when deciding on appropriate dosing intervals for oral drugs and this information will have an effect on the design of later phase trials.

Phase II studies use small groups of patients with the disease for which a new intervention is being developed (usually 100-300) [19] and use a range of doses in the predicted therapeutic range. The aims of Phase II trials are determining safety, tolerability and proof of efficacy (primary end point). If the IMP doesn't display sufficient biological activity it will not usually progress past the early clinical development stage. The designs of phase II trials are more intricate and extensive than the Phase I trials. Phase II trials are sometimes divided into Phase IIA and Phase IIB, where the Phase IIA study is designed to assess and refine the dosing requirements of the IMP and the Phase IIB designed more towards studying efficacy.

A randomized, double blind, placebo controlled design was used in O'Conner et al (2006) Phase II study examining the safety, efficacy and optimal oral administration dose of teriflunomide in patients with relapsing-remitting multiple sclerosis. Double-blinded, placebo-controlled studies are where neither the subject of the investigator is aware of whether the patient is receiving the IMP or a placebo. By doing this, it is hoped that any bias will be eliminated as the researcher won't be able to skew the results with preconceived ideas of the results he hopes to see, nor will he be able to hint to the patient about the results they should expect. Patients were randomised to receive placebo, teriflunomide 7mg/day or teriflunomide 14mg/day for 36 weeks. [20] The duration of a trial depends largely on the indication; a chronic condition will take longer to show improvement than an acute one. Thus a trial for MS such as this, will take place over a number of months. However phase II trials are usually considerably shorter than the phase III program.

In the teriflunomide study, the primary endpoint was "the number of combined unique active lesions per MRI scan. Secondary endpoints included MRI-defined disease burden, relapse frequency, and disability increase." [21] Every six weeks the patients underwent an MRI scan to determine if there was any improvement in their condition. By running a trial with 2 different doses of IMP researchers can determine if the higher dose has a significantly better therapeutic effect, and whether the adverse events are still manageable. This will aid in the determining which dose is more efficient, a high dose with increased therapeutic effect coupled with intolerable adverse effects is not desirable, especially when one takes patient compliance into account. A smaller dose with slightly lesser therapeutic effect (but obviously still significant) that is well tolerated, might be a more acceptable option for patients. In this study, patients on the higher (14mg/day) dose showed trends toward a lower annualised relapse rate and fewer relapsing patients. [22] O'Conner et al (2006) concluded that oral teriflunamide was well tolerated in patients and was effective in reducing MRI lesions. The researchers did point out that in a short-term study such as is, it was unrealistic to expect a significant change in disability, "however, there was a significant reduction (69%) in the number of patients in the teriflunomide 14mg/day group who demonstrated disability worsening at study completion compared with placebo." [23] These results could be expanded on in long term phase III studies where a better indication of any significant change in disability.

In early phase studies, unexpected findings may occur. The original protocol for the study might not accommodate these finding and thus the design should include a degree of flexibility with regards to dose escalation and safety parameters. Biomarkers and signs preceding what are defined as unacceptable effects should be proposed and justified and clear stopping rules should be defined with regards to maximal exposure and adverse effects. [24] Good quality data from early clinical development is pivotal for the success of the IMP in late phase development. Once early phase studies are complete one would expect to have a good understanding of the pharmacokinetics and pharmacodynamics of the IMP together, a more definite dosing range, knowledge of the side effects that might be expected in its use and most importantly proof of efficacy. These results will provide a solid foundation for a successful phase III programme and hopefully for the successful registration of the product.

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