Introduction

Clinical development is the art of turning science into medicine. It is the point at which all the data from basic science, preclinical pharmacology and safety are put into medical practice to see whether scientific theory can translate into a valuable new medicine for patients. The fundamental purpose of the clinical development programme is to provide the clinical information to support the product labelling, which ultimately tells the healthcare professional and patient how to use the drug effectively and safely.

The segments of product label coming from clinical trials are the pharmacokinetics, the dosing regimen in the main population and in special populations, e.g. the elderly or those with hepatic and renal impairment, the clinical pharmacology/mechanism of action in man, drug interactions, contraindications, warnings, precautions, efficacy in the indication, safety and side effects. All this information has to be generated from a development programme designed to investigate these specific properties.

Clinical development has to satisfy the demands of regulators who will grant product approval, government organizations responsible for reimbursement in countries where healthcare is state subsidized, managed care organizations in the USA and also the marketing team who will sell the product. The needs are sometimes conflicting and a challenge of clinical development is to design a trials programme that not only demonstrates that the new drug is effective and safe, but also balances the various desires and requirements of the different parties, for the product profile.

Bringing new drugs to the market is not only complex but also costly, time and resource consuming. Taking into account failure of drugs in development to make it to market, Di Masi (2003) estimated the costs to be around US$802 million and Adams and Brantner (2006) made an estimate of US$868 million but within a range of $500 million to $2 billion, depending on the indication pursued and the company performing the development. Of this total amount the clinical development accounts for just over half, i.e. about US$480 million.

In spite of heavy investment in research and development, new product approvals have been decreasing in the last 10 years (Woodcock and Woosley, 2008). Pipelines of large pharmaceutical companies have been declining and the productivity of large pharmaceutical companies in new drug development has been diminishing in an environment of increasing costs of clinical development and increasing risk aversion of companies, regulators and the general public. New strategies are needed to overcome this problem, both in the way companies source and develop new drugs and also in the way regulators approach the evaluation of efficacy and safety of new medicines.

This new environment is leading to an evolution in clinical development strategy, with the type of indications being pursued and in the sourcing and development of new compounds. There is a move away from blockbuster medicines, i.e. ‘one size fits all’ in major indications, towards more specialized unmet medical needs and patient-tailored therapies, i.e. personalized medicine. The success of the human genome project was supposed to have heralded a new era for patient-specific drug development. However, for now, the art of medicine appears to continue to outwit the theory of basic science and drug development based purely upon genomic approaches has yet to live up to its promises.

There is an increasing trend for large pharmaceutical companies to collaborate with small pharmaceutical companies and biotech companies in order to enhance discovery pipelines and drug development productivity. Large companies have a great deal of resources to put behind development programmes but internal competition for resources, risk aversion and political pressures within these organizations can mean they are less flexible and creative in clinical development. Small pharmaceutical companies can provide the flexibility, innovation and creativity to complement the large pharmaceutical company development activities and there is an increasing trend for new drug development to be performed in partnership.

In the United Sates the Food and Drug Administration (FDA) published a white paper in 2004 (FDA, 2004a) that identified that the current methods of drug development were partly behind the decline of new drug applications and has set up the Critical Path Initiative (FDA, 2004b) in order to address some of the problems of low productivity and high late-stage attrition rates, the idea being to encourage novel approaches to clinical development in trial design and measuring outcomes. The Innovative Medicines Initiative (EFPIA, 2008), underway in Europe, is also looking to encourage public and private collaboration with small and large enterprises and academia, to share knowledge, enhance the drug discovery and development process, reduce late-stage attrition and, ultimately, bring good medicines to patients in a cost- and time-effective manner.

These factors are changing the way clinical development is being performed and will be performed in the future. In this chapter the conventional path of clinical development will be explained along with the new strategies for merging phases and using adaptive trial design to enhance the development of new medicines.

Clinical development phases

The conventional path of clinical development involves four phases:

A summary of these phases is given in Table 17.1.

Table 17.1 Phases of clinical development

Traditionally these phases have been conducted in a step-wise manner with decisions to proceed to the next stage being made once the preceding stage was completed. However, more recently, the margins between phases are becoming less distinct as more seamless drug development programmes are being performed and adaptive trial designs adopted. Therefore, it may be more appropriate to describe the phases as: clinical pharmacology, including first in man – Phase I; exploratory, proof of concept – Phase IIa; confirmatory efficacy and dose range finding – Phase IIb; confirmatory, large scale efficacy and safety – Phase III; marketing authorization application, license extension and post-marketing surveillance – Phase IIIb/IV.

Phase I – Clinical pharmacology

Phase I is somewhat of a misnomer for, although the first studies in man are performed as part of Phase I, many of the other components of Phase I, for example drug–drug interactions, special populations and human radiolabelled studies, are conducted in parallel with later phase studies. Hence it is probably more appropriate to call these ‘clinical pharmacology studies’.

A typical Phase I programme may contain around 20 clinical pharmacology studies. The main objectives of the programme are to define the pharmacokinetics, metabolism and safety of the intended formulation given alone and with other drugs that have potential to interact either kinetically or dynamically with the new drug. How the drug is handled by certain populations, such as the elderly, ethnic groups or those with hepatic or renal impairment, is also studied. All of this information goes into the prescribing information to guide the safe and effective use and dosing of the drug. Some efficacy information can also be gathered in human pharmacological models in order to assist dose selection for trials in patients. The principal components are as follows:

• First in man single ascending dose pharmacokinetics and safety

• Multiple ascending repeat dose pharmacokinetics and safety

• Pharmacodynamic studies

• Bioavailability absolute and bioequivalence of new formulations

• Absorption distribution metabolism excretion in man (radiolabelled studies)

• Drug–drug interaction studies

• Safety pharmacology, e.g. thorough QT studies and abuse liability studies

• Elderly pharmacokinetics and safety

• Ethnic groups pharmacokinetics and safety

• Hepatic and renal impairment, pharmacokinetics and safety.

Clinical pharmacology studies and in particular ‘first in man’ studies are conducted by specialist medical staff, trained in clinical pharmacology, in specialized units either within or close to a major hospital. The units are specifically equipped for the preparation and correct administration of the test drugs (and in some cases manufacture of the drug product), collection and storage of biological samples and management of subject safety, including full resuscitation facilities. The subjects selected for studies are usually enrolled from the unit’s subject volunteer panel. Typically a clinical pharmacology unit will advertise for subjects to join their database. People who are interested in taking part in trials are then carefully screened for their physical health, their ability to comprehend the requirements of taking part in the studies and their motivation to comply with the constraints of the studies, to check whether they are suitable to join the volunteer panel. In some countries (e.g. France), the subjects have to be registered on a national database to make sure they comply with laws governing participation in clinical trials. For most large professional units, the database will comprise a variety of healthy subjects including young men and women (18–45 years), older healthy subjects (over 55 years), subjects of non-Caucasian origin (e.g. Japanese) and subjects with genetic polymorphisms for CYP metabolism. As the subjects gain no medical benefit from taking part in the studies and have to undergo procedures which can be mildly unpleasant or inconvenient, they are paid for taking part. However, the amount they can be paid is restricted to be commensurate with the inconvenience and discomfort of the study and is not so high as to be an inducement to take part. The subjects’ reimbursement is reviewed and has to be approved by the ethics committee, before the study can go ahead. The number of studies that subjects can take part in annually is also restricted. Most protocols demand that a subject cannot be exposed to another investigational drug within 90 days of taking part in a study and so that limits how many studies in which a given subject can participate, in any one year.

First in man, single ascending dose, pharmacokinetics and safety

First dose in man (FDIM), also known as single ascending dose (SAD), is a red-letter day for the drug development team, when single doses of the drug are given to small cohorts of subjects in a sequential manner until the maximum tolerated dose is achieved.

Objectives

The objectives of the SAD study are to evaluate the safety (physiological effects on body systems), tolerability (occurrence of side effects) and pharmacokinetics of different doses of the test drug, and to identify the maximum tolerated dose (MTD). That is the dose at which either the occurrence of intolerable side effects and/or unacceptable safety findings are encountered. The MTD is important to identify for estimation of the therapeutic window, which is the dose range within which the drug is effective but safe and well tolerated. In some cases it is not possible to achieve the MTD, perhaps if the drug is very well tolerated, or has poor bioavailability, in which case the maximum feasible dose can be used to estimate the therapeutic window.

Subjects

In most cases the subjects in first in man studies will be conducted in healthy young men usually aged 18–45 years. The idea behind this is to have a fairly homogeneous population in which to study the effects of the new drug and so limit variability, and also to have a population who will be more able to withstand any unexpected toxicity caused by the test drug. Healthy subjects are those who have no underlying diseases that could interfere with the conduct of the study or confound the interpretation of the safety or pharmacokinetic data. Criteria for inclusion into the study based upon medical history, physical examination, use of concomitant medications, alcohol, cigarettes and recreational drugs, as well as the results of blood testing 12-lead ECG, blood pressure heart rate are laid out in the study protocol. Male subjects are generally preferred, because at this early stage of development, reproductive toxicology testing in animals will not have been completed and the risk to the fetus of female subjects who might be pregnant or become pregnant shortly before or after the study, has not been characterized. Once the segment 2 reproductive toxicology has been completed (see Chapter 15), female subjects of non-childbearing potential, i.e. post-menopausal, surgically sterilized, sexually abstinent or using effective methods of contraception, may be included in European studies. In the USA, female subjects may be included prior to reproductive toxicology data being available if they are of non-childbearing potential. In some cases it is not appropriate to use healthy young men, for example, studies of female hormone products or products for oncology, and in these cases the subjects will be selected from the appropriate population.

Design

The classical design of the SAD study is a double-blind, placebo-controlled sequential cohort design; where the first cohort takes the lowest dose and then the dose is escalated through subsequent cohorts, provided the tolerability and safety in the preceding cohort are acceptable. The size of each group is usually six to eight subjects, with two of the subjects being randomized to placebo. The use of placebo and the double-blinding, where neither the investigator nor the subject knows the treatment being taken, allows for a more objective evaluation of the safety and tolerability of the test drug.

The choice of doses to be administered in the SAD trials should be based on the highest dose at which no adverse effects were seen in the most sensitive species tested in toxicology studies (the no observed adverse effect level, or NOAEL; see Chapter 15) and on the nature of the toxicity observed. The starting dose should be at least 10-fold lower than the NOAEL, but specific guidelines exist for the accurate determination of the starting dose on a case-by-case basis (FDA; http:www.fda.gov/cber/gdlns/dose.htm).

The dose escalation plan will depend on the characteristics of the drug and its metabolites, and especially on the nature of any toxicity seen in preclinical toxicology testing at doses above the NOAEL. It will also be influenced by the relationship between dose, systemic exposure as determined by its pharmacokinetic (PK) profile in animals, and the pharmacodynamic (PD) effects observed in preclinical pharmacology studies. Each dose escalation step will be dependent on satisfactory safety data from the previous dose level, according to the clinical judgment of the investigator.

Usually the drug is administered only once to each subject so that each dose group comprises separate subjects. This has the advantage of maximizing the population exposed to the test drug. Sometimes, however, it may be appropriate for each subject to receive two or three of the planned doses at successive visits, with the proviso that each dose is administered only after the response to the preceding dose in the series has been evaluated. In this way the required number of subjects is reduced, but each has to attend more than once.

Typical dose escalation schedules from a starting dose of X are:

• Dose escalation schedule 1: X, 2X, 4X, 8X, 16X, 32X

• Dose escalation schedule 2: X, 2X, 4X, 6X, 8X, 10X.

The dose escalation schedule is guided primarily by safety considerations. Dose escalation schedule 1, where the dose is increased exponentially, would be appropriate for a drug that has shown low toxicity in animal testing. Schedule 2, where the dose increments are constant, is more conservative and might be more appropriate for a drug which has a toxicology profile that calls for a more cautious approach to dose escalation in man. There are many other possible dose escalation patterns, and each is considered on its own merits. The ideal is to exceed the dose predicted to effective from preclinical pharmacology studies, by a good margin. A drug for which the MTD is close to the dose predicted for therapeutic effect is less likely to be successful than one that has a wide therapeutic margin.

As it is common for the PK profiles of orally administered drugs to be affected by the presence or absence of food in the stomach at the time of dosing, the food effect is usually investigated at the end of the SAD study. A dose level that is safe and well tolerated (e.g. one-quarter of the MTD) will be given to healthy subjects on two occasions once in the fed state (following a standard high-fat breakfast) and once fasted (overnight fast). The order of fed and fasted administration is randomized among the subjects and the two dose periods are separated by an appropriate washout period, so that the results of the second period are not affected by the drug administration on the first period. The results of the fed/fasted comparison will form the basis of the dosing instructions for all future studies with the drug.

Outcome measures

In the SAD study the principal outcome measures are safety, tolerability and pharmacokinetics.

Throughout the study, for an appropriate period after each dose, the subjects are intensively monitored for signs and/or symptoms of toxicity (adverse events). The safety parameters measured include, blood pressure, heart rate and rhythm, 12-lead ECG (intervals and morphology), body temperature, haematology, liver function and renal function, as well as observation for any other unwanted effects. Tolerability is evaluated by the documentation of adverse events which are collected throughout the study and then categorized by severity, duration, outcome and causality. If an adverse event meets certain specific criteria (for instance if it is life-threatening or necessitates hospitalization) it is classified as a serious adverse event (SAE) and must be reported without delay to the ethics committee, and usually also to the regulatory authority.

Whereas assessment of safety and tolerability is the primary objective, pharmacokinetic evaluation is the secondary objective of a SAD study. Blood samples will normally be taken before dosing and at specified intervals after dosing to measure the amount of drug in the blood or plasma at various time points after each dose. A typical sampling schedule is shown in Figure 17.1A. In addition, urine and/or faeces may be collected to measure the excretion of the drug via the kidneys and/or liver (in bile). The results enable the rate of absorption, metabolism and excretion of the drug to be explored, and the PK parameters to be estimated (see also Chapter 10).

Fig. 17.1A, B A, A typical sampling schedule. B, A typical Phase MAD blood sampling schedule.

The plasma or serum PK parameters usually derived are:

• C_max: peak drug and/or metabolite(s) concentration

• T_max: time to peak drug and/or metabolite(s) concentration

• AUC_0–∞: area under the concentration–time curve of the drug and/or metabolite(s), extrapolated to infinity

• AUC_0-T: area under the concentration–time curve of the drug and/or metabolite(s), calculated to a specific time point T

• t_1/2: time taken for levels of drug and/or metabolite(s) to decrease by half (a measure of the rate of elimination of the drug from plasma).

Other PK parameters may also be determined, including:

• V_D: volume of distribution of drug and/or metabolite(s)

• Cl: clearance of drug and/or metabolite, i.e. the volume of plasma/serum cleared of drug and/or metabolite(s) per unit time, e.g. mL/min, L/h

• MRT: mean residence time, i.e. the average time a drug molecule remains in the body after rapid i.v. injection.

Specialist pharmacokineticists perform the calculation of these parameters.

A comparison of the PK parameters at each dose level, e.g. AUC_∞′, C_max, will indicate whether they increase proportionately (linear kinetics) or disproportionately (non-linear kinetics) with increasing dose. This information will influence the selection of dose levels, regimen and duration of dosing for the multiple, ascending repeat-dose study (MAD). The single-dose PK data can also be used to predict the drug/metabolite(s) concentrations expected on repeated dosing, based on the assumption that the kinetics do not change with time.

Multiple ascending repeat-dose studies

After review of the safety data and the single-dose PK profile, two or three safe and well-tolerated dose levels are chosen and the multiple ascending (repeated-dose) study (MAD) is designed. Its purpose is to test safety, tolerability and PK when the drug is given repeatedly.

Design

A typical MAD study design will be double-blind, placebo-controlled with two or three cohorts of eight (six active two placebo) to 12 (eight active four placebo) subjects taking successively higher doses for several days. As for the SAD, the decision to escalate to the next dose level is based upon the safety and tolerability of the preceding dose level. The dose regimen in the MAD study is based upon the PK characteristics seen in the SAD and designed to give the PK profile necessary to allow the drug to exert its therapeutic effect and to achieve ‘steady state’ in which the drug’s input rate is balanced by its rate of elimination. The duration of the dosing is based upon the desire to achieve steady state but also to collect sufficient safety information to support use in Phase II studies. For indications where chronic dosing is required a duration of around 7–10 days is usual in MAD studies.

Outcome measures

Safety assessment is necessary under these conditions, as steady-state blood levels are usually higher than blood levels following a single administration. It is also important to know whether the PK of the drug and/or metabolite(s) changes on repeated dosing. For instance, saturation of elimination pathways (e.g. metabolizing enzyme systems) could cause the drug to accumulate to toxic levels in the body, or alternatively stimulation (induction) of drug-metabolizing enzyme systems could cause the levels of drug and/or metabolite(s) to decrease to subtherapeutic levels. A comparison of the predicted and observed plasma–serum concentration time curves will provide evidence of any such non-linear or time-dependent kinetics for the drug and/or metabolite(s).

The general requirements and procedures for MAD studies are the same as those for Phase I SAD. A typical Phase MAD blood sampling schedule is shown in Figure 17.1B. Blood samples for PK profiling will generally be taken on the first and last days of dosing, with additional single samples taken immediately before the first morning dose each day, to measure the levels of drug remaining in the blood immediately before the next dose is administered, i.e. the trough level.

The results of the Phase I SAD and MAD studies together support the decision as to whether to administer the drug to patients and, if so, at what dose and regimen and for how long.

Pharmacodynamic studies

Pharmacodynamic (PD) assessments may be included in the MAD studies, or specific PD studies can be performed separately. Usually prior to Phase IIa, the objective of these studies is to establish whether the drug has some pharmacological effect in man that may be relevant to its therapeutic effect, and to determine at what doses and plasma concentrations the effects are seen, with a view to optimizing dose selection for Phase IIa. Such studies are termed PK/PD studies.

This approach must still be treated with some caution, as the physiology in patients may differ from that in healthy subjects, and clinical efficacy may therefore not be reliably predicted from Phase I results. It is not uncommon for drugs that are highly effective in patients suffering from a certain condition to have little or no effect on the same body system in healthy subjects. This is particularly true of drugs acting on psychiatric diseases as these conditions are very difficult to emulate in healthy subjects. The ideal PD assessments in Phase I are those that have biological or surrogate markers that are measurable in healthy subjects and are relevant to drug’s mechanism of action and/or therapeutic effect. For example, the ability of a β-adrenoceptor antagonist to inhibit exercise-induced tachycardia, or the effect of a proton pump inhibitor on acid gastric secretion are relevant effects that can easily be measured objectively in volunteers. However, such markers are not always available (e.g. in the case of many psychiatric diseases) or may be misleading (pain is a good example because the endpoints are subjective rather than objective), and the interpretation of such data is usually approached with care. Nonetheless, Phase I PK/PD studies can be very useful to confirm that a new drug is actually having the pharmacological effect in man that was predicted from animal studies. As well as studying pharmacodynamics in healthy subjects, patients with a mild form of disease can be studied. An example is asthma, where a new drug could be studied for a short period of time in mild asthmatics to observe a pharmacological response, without necessarily intending to provide a long-term therapeutic benefit. Such subjects are known as patient volunteers and, like healthy subjects, as they are not entering the study to seek a cure for their disease, they can receive some financial compensation for their time and inconvenience.

Drug–drug interaction studies

The objective of drug–drug interaction studies (DDI) is to determine whether the test drug’s efficacy, safety or pharmacokinetics will be altered if it is given with other drugs that the target patient population may also be taking. The timing of drug interaction studies depends partly on the importance of understanding interactions prior to treating patients. Some DDIs may need to be performed prior to Phase IIa if the patient population in the study cannot be excluded from taking concomitant medications that might interact with the test drug. Otherwise DDIs can be conducted later in the development programme when more is known about the target treatment population and the efficacy and safety of the new drug. The choice of which DDI studies to perform is based on the following: the metabolism of the new drug (for example if it inhibits, induces or is metabolized by certain cytochrome p450 enzymes – see Chapter 10); the pharmacodynamic action of the drug; and which drugs the target population may be taking concomitantly. Drug interactions can occur on a metabolic level, so that the exposure to a certain dose may be changed by a drug interaction or on a pharmacodynamic level so that pharmacological effects may be increased or diminished by the interacting drug. It is important to known whether co-administration of the relevant drugs leads to a change in exposure or a change in pharmacodynamic effect of either the test drug or the interacting drug.

In a typical DDI study, subjects are dosed with the interacting drug until steady state is achieved and then a single dose of the test drug is given and the PK, safety, and sometimes PD effects are evaluated. The information from the DDI studies gives guidance as to whether any dose alterations are necessary when the new drug is co-administered with a drug with which it interacts and the information is included on the product label.

Absolute bioavailability and bioequivalence of new formulations

Absolute bioavailability studies are performed to compare the exposure of an intravenous preparation of the study drug which has 100% bioavailability, with the formulation intended for clinical use which is to be given by another route, e.g. oral or subcutaneous. The absolute bioavailability information is needed for the product label, but also assists further formulation development as modifications to the formulation can be made in order to optimize exposure to the drug. The studies are conducted in healthy subjects in a crossover fashion where each subject receives an intravenous dose and then one or more doses of the study drug given by its intended clinical route of administration. Standard pharmacokinetic parameters are measured and the absolute bioavailability calculated by comparing the pharmacokinetics of the intravenous and non-intravenous doses.

In the initial clinical pharmacology trials and in the exploratory efficacy studies it is not usual to use a formulation that would be the final commercial formulation. Development of a commercial formulation is performed in parallel with the early phase studies and the data from those studies guides the formulation development activity. Once a commercial type formulation or formulations has been identified, the safety and pharmacokinetics are compared with the prototype formulation in comparative bioavailability studies. As for absolute bioavailability, the studies are conducted in healthy subjects in a crossover fashion. If there is no more than 5% difference in exposure (AUC) between two formulations, they are considered to be bioequivalent. Dosing information obtained from exploratory efficacy studies using a prototype formulation which is bioequivalent to the commercial type formulation, can, therefore, be applied directly to confirmatory efficacy dose range finding studies. If the formulations are not bioequivalent, further multiple dose pharmacokinetics and pharmacodynamic studies may be needed to determined dosing regimens for the dose range finding studies. Depending on the intricacy of the formulation development, comparative bioavailability studies may need to be performed on more than one occasion.

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