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presidente Prof. Nelson Fernando Pacheco Rocha Professor Catedrático da Secção Autónoma de Ciências da Saúde da Universidade de Aveiro Prof. Doutor Luís Almeida
Professor Associado Convidado da Secção
Autónoma de Ciências da Saúde da Universidade de Aveiro
Prof. Doutor Patrício Soares da Silva
Professor Catedrático da Faculdade de Medicina da Universidade do Porto
Prof. Doutor Vítor Manuel Sousa Félix Professor Associado com Agregação do Departamento de Química da Universidade de Aveiro
Agradecimentos Ao Grupo BIAL, do qual me orgulho pertencer, agradeço a oportunidade e o apoio sempre demonstrado.
Ao Sr. Professor Patrício Soares da Silva pela oportunidade concedida, por toda a confiança e apoio demonstrado, bem como a serenidade incutida.
Ao Sr. Professor Luís de Almeida pelo permanente incentivo, entusiasmo e disponibilidade em todas as fases que levaram à concretização deste trabalho. Aos meus colegas Rui Sousa, Katya Lemos e Ana Barrias pelo ânimo e amizade .
E muito especialmente aos meus maravilhosos marido e filhos, pela minha frequente presença ausente, por toda a tolerância e carinho.
palavras-chave: Desenvolvimento de fármacos, desenvolvimento pré-clínico, toxicidade de medicamentos, biomarcadores
resumo: A toxicidade é uma das principais razões para o insucesso do desenvolvimento de novos fármacos. Esta monografia descreve o conjunto de estudos de toxicologia necessário para o desenvolvimento de um novo fármaco. É colocado especial ênfase nos estudos de toxicologia requeridos para compreender e identificar os potenciais riscos associados aos novos medicamentos antes da primeira administração no ser humano.
Identificam-se estratégias para a transição da fase do desenvolvimento pré-clínico para a fase clínica inicial, com vista a tornar os estudos de toxicidade mais preditivos de segurança nos seres humanos, encurtar o período de desenvolvimento e reduzir os recursos necessários, incluindo o número de animais envolvidos.
Destaca-se o papel dos biomarcadores preditivos de segurança como uma das abordagens emergentes para a redução das elevadas taxas de insucesso durante o desenvolvimento, a melhoria da eficiência e a redução do tempo de desenvolvimento de novos medicamentos.
keywords: Drug development, preclinical development, drug toxicity, biomarkers
abstract: Toxicity is one of the major reasons for drug development attrition.
This monograph describes the toxicology package required for the development of a new drug candidate. It is placed special emphasis on toxicology studies required to understand and identify the potential risks associated with new drugs before the first administration in humans. From preclinical development to clinical early phase in order to make the most predictive toxicity studies of safety in humans, shorten the development period and reduce the required resources, including the number of involved animals.
It was also highlight the role of predictive safety biomarkers as one of the emerging approaches to reduce high failure rates during development, improving efficiency and reducing the development time of new medicines.
CONTENTS
LIST OF FIGURES ... 6
LIST OF TABLES ... 7
LIST OF ABBREVIATIONS ... 8
1. INTRODUCTION ... 9
2. NONCLINICAL DEVELOPMENT PLAN ... 11
2.1. Safety Pharmacology ... 12
2.1.1. Central Nervous System ... 13
2.1.2. Cardiovascular System ... 13
2.1.3. Respiratory System ... 14
2.1.4. Supplementary studies ... 14
2.2. Toxicity studies ... 14
2.2.1. Genotoxicity ... 14
2.2.1.1. Bacterial mutation assay (AMES test) ... 16
2.2.1.2. Chromosomal aberrations assay ... 16
2.2.1.3. Mouse micronucleus test ... 16
2.2.2. Toxicology ... 16
2.2.2.1. Acute toxicity studies ... 17
2.2.2.2. Repeated-dose toxicity (subacute and chronic toxicity studies) 19 2.2.2.3. Reproductive toxicity ... 23
2.2.2.4. Carcinogenicity ... 25
3. NEW DRUG DEVELOPMENT STRATEGIES 3.1. Current status ... 27
3.1.1. PSTC - Predictive Safety Testing Consortium ... 32
3.1.2. SAFE-T consortium ... 34
3.1.3. Biomarkers ... 36
4. NEW DRUG DEVELOPMENT PARADIGMS ... 40
LIST OF FIGURES
Figure 1: Phase II clinical trial failure rates according to the therapeutic area:
2007-2010 ... 28
Figure 2: Phase III clinical trial failure rates according to the therapeutic area: 2007-2010 ... 28
Figure 3: Phase II and submission failures: 2007- 2010 ... 29
Figure 4: Phase III and submission failures: 2007- 2010 ... 29
Figure 5: PSTC Milestones ... 33
Figure 6: The “quick win/ fast fail” drug development paradigm ... 41
LIST OF TABLES
Table 1: Nonclinical repeated-dose toxicity studies to support phase I clinical trials ... 21
Table 2: Desirable biomarker profile for drug-induced kidney, liver and vascular injuries ... 37
LIST ABBREVIATIONS
ADI Acceptable Daily Intake
ADME Absorption, Distribution, Metabolism and Excretion ADR Adverse Drug Reaction
CNS Central Nervous System C-PATH Critical Path Initiative DILI Drug-induced liver injury DIKI Drug-induced kidney injury DIVI Drug-induced vascular injury DNA Deoxyribonucleic acid ECG Electrocardiogram EMA European Medicines Agency FDA Food Drug Administration FIH First-in-Human GLP Good Laboratory Practice
ICH The International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use
IMI Innovative Medicines Initiative MFD Maximum Feasible Dose
MTD Maximum Tolerated Dose NIH National Institutes of Health
NOAEL No Observed Adverse Effect Level NOEL No Observed Effect Level
PD Pharmacodynamic PK Pharmacokinetic
PMDA Japanese Pharmaceutical and Medical Devices Agency PSTC Predictive Safety Testing Consortium
QT QT interval
QTc Corrected QT interval
TSBMs Translational safety biomarkers R&D Research & Development
1. INTRODUCTION
The research and development (R&D) of new drugs is an expensive and high-risk process. Thousands of new compounds need to be synthesised and tested to find one that can achieve marketing approval and clinical use.
Despite the scientific and technological advances and the increase of R&D expenditure in recent years, the number of applications for marketing authorization submitted by the pharmaceutical industry to the competent authorities remained stable or even declined.1
Since the 70s of the XXth Century, the number of new approved drugs remained relatively constant, although some studies evidence that the average number of molecules studied by scientists increased approximately from 75,000 to 2.5 million between 1990 and 1997, showing that the rate of abandonment of drugs during their development has significantly increased.1
Although about half of the molecules in development are abandoned due to the lack of efficacy, one third are abandoned due to safety issues.2 Thus, toxicity is a significant cause of attrition during drug development.
Toxicology is the science that studies the harmful effects resulting from the interaction between a substance and a biological system. Toxicity studies aim to determine the concentration of substance that cause harm, through safety studies performed in vitro and in vivo in experimental animals and, in some cases, in clinical trials in human beings .3
As previously mentioned, one of the major reasons for drug failure is safety. However, several circumstances have been identified that limit the predictive value of animal safety data to humans4:
− Toxicity observed in animals or in in vitro systems is not completely understood, therefore the potential risk for human cannot be adequately evaluated;
− Toxicity observed on animals or in in vitro systems is understood and its relevance to humans is known or suspected, but the potential risk is considered unacceptable;
− Inability to establish safety boundaries in animals and/or in humans; − Animal studies do not predict the toxicity observed in clinical trials.
Therefore, a multiple and integrated approach should be envisaged for the evaluation of a new drug before its potential study in humans is considered.
2. NONCLINICAL DEVELOPMENT PLAN
The drug development process is generally divided into three main steps: discovery, preclinical/nonclinical development and clinical studies.
Preclinical or nonclinical development encompasses all activities that link drug discovery to human clinical trials. Nonclinical studies are performed to characterize the pharmacology and toxicity of a drug in in vitro models or laboratory animals. The details of each preclinical development package can vary, but all share the same goal: to design and conduct a set of studies aiming to evaluate the safety and to explore the efficacy of a new drug to ensure a quick and safe route to start studies in humans.
The nonclinical development of a new drug is supported by a set of guidances issued by The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). In its guidance for industry M3(R2) - “M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals”, ICH outlines the nonclinical information needed to support human clinical trials. This guidance is complemented by a group of specific guidance’s, each one detailing a given area of nonclinical development.
The purposes of a nonclinical development program are: − To identify the potential target to obtain benefit;
− To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile;
− To characterize the target-organ toxicity;
− To predict possible serious adverse drug reactions (ADRs) in First-in-Human (FIH) studies;
− To understand the relationship between dose or exposure and response for any effects on the most important physiological systems that may be predictive of ADRs in humans;
− To identify potential parameters for monitoring adverse effects in clinical studies;
− To select the starting dose for FIH studies;
− To support mechanistic understanding of ADRs in clinical trials; and − To understand the safety risk in populations of patients with high risk on
long-term therapy.5
Herein, the main requisites and aims of a safety and toxicology nonclinical development plan will be presented and discussed.
2.1. Safety Pharmacology
Safety pharmacology studies seek to predict the potential risks and effects of the test substance on vital functions.
The main objectives of safety pharmacology studies are:
− To identify undesirable PD properties of a substance that may have relevance to human safety;
− To evaluate adverse PD and/or pathophysiological effects of a substance observed in toxicology and/or clinical studies; and
− To investigate the mechanism of the adverse PD effects observed and/or suspected.
To meet these objectives the investigational plan should be clearly identified and delineated. 6
Human diseases are complex and cannot be truly modeled in animals; despite this, safety pharmacology studies are of peculiar interest because they show a good predictive potential for humans. The ICH, in its guidance documents S7A and S7B, details a core battery of safety pharmacology studies on three vital organs or systems prior to human exposure: central nervous system (CNS), cardiovascular, and respiratory systems. Other supplemental tests may be
conducted to assess the repercussion on other organ systems if a need is identified. 6
2.1.1. Central Nervous System
The CNS primary studies look for effects on general behavior, locomotion, neuromuscular coordination, convulsive threshold, and vigilance. A functional observation battery (FOB) or modified Irwin’s system test can be used.
Results of these assays are used to detect the potential toxicity, the active dose-range and the principal effects of test substance on behavior and physiological function. It can also be used for detecting untoward effects of a new molecule on general behavior, and to evaluate its acute neurotoxicity. The Irwin Test can provide a first orientation towards a specific therapeutic indication, mechanism of action or a specific physiological function.6,7
2.1.2. Cardiovascular System
The basic cardiovascular system assessment evaluates the proarrhythmogenic risk using in vitro approaches (hERG K+ channel in the Purkinje fiber assays) and
in vivo measurements (ECG: QTc interval for example) in conscious animals via
telemetry. These studies are performed in a complementary approach to achieve an integrated risk assessment.7 Blood pressure, heart rate and ECG (by telemetry) are the parameters measured in conscious or anaesthetized animals. Those assays intend to “identify the potential of a test substance and its metabolites to
delay ventricular repolarization, and relate the extent of delayed ventricular repolarization to the concentrations of a test substance and its metabolites. The study results can be used to elucidate the mechanism of action and, when considered with other information, estimate risk for delayed ventricular repolarization and QT interval prolongation in humans.”8 If a drug and/or its
metabolites increase the QTc interval to more than 500 ms the risk to induce ventricular arrhythmias (torsade the points and ventricular fibrillation) also increase substantially. This indicates the risk to induce sudden death in humans and
supports drug development cancellation, especially if the new drug is intended for chronic use.
2.1.3 Respiratory System
The effects of a test substance on the respiratory system should be also assessed. These effects are best studied by whole-body plethysmography test in conscious animals (usually in rats or guinea-pigs). Whole-body plethysmography is a non-invasive technique for assessing the respiratory function. Respiratory rate and tidal volume are the basic parameters measured. However other parameters such as hemoglobin oxygen saturation, expiratory time, peak inspiratory and exploratory flow and resistance, can also be evaluated. Whole-body plethysmography assay can explain if a new drug may affect respiratory control and/or change in lung mechanical properties and sensitivity to respiratory-depressant effects.7
2.1.4. Supplementary Studies
Other supplementary safety pharmacology studies may be required if some concerns may arise from the core battery or other studies. Based on current knowledge of the test drug, no follow-up or supplemental safety pharmacology studies are expected to be required in an early phase but may be required on a later phase of development.8
The ICH S7A guidance encourages “the use of new technologies and methodologies in accordance with sound scientific principles”. But future of safety pharmacology will depend, in part, upon the scientific and technological advances and regulatory challenges that surround pharmaceutical development.
2.2. TOXICITY STUDIES
2.2.1. Genotoxicity
Genetic toxicology studies are conducted early in a safety evaluation program to assess the potential for induction of genetic mutations or chromosomal damage.
The characterization of the toxicity of a drug on genetic material (DNA) is performed using in vitro and in vivo tests with the aim to observe the onset of genetic changes, direct or indirectly, by several mechanisms (mutations, DNA injuries, numerical changes or recombination of chromosomes). These changes are often interpreted as predictors of carcinogenesis, since the results from dedicated carcinogenicity studies are generally not available until the time of product approval when human subjects, including healthy volunteers, will be exposed to pharmacologically active doses. Carcinogenicity could take several years to be manifest.4,9 Therefore, data from genotoxicity studies are used as a surrogate for carcinogenicity during development, i.e. during clinical trials.10
A standard battery of tests to characterize the genotoxicity is mandatory for almost all drugs. Accordingly to the ICH guidelines it is recommended a minimum of 3 mutagenicity studies (standard battery) for a novel pharmaceutical:
1. An in vitro bacterial mutation assay (Ames test);
2. An in vitro chromosome aberration assay or in vitro mouse lymphoma assay; 3. An in vivo micronucleus test.9
Studies typically follow a tiered approach beginning with an in vitro Ames test and progressing to short term in vitro assays including the mouse lymphoma and chromosomal aberrations assays, and in vivo assays such as the rodent micronucleus assay.9
The emergence of positive results on standard battery tests is one of the main reasons for the abandonment of the development of a drug. However, not all genotoxic drugs are flatly rejected; this decision depends on the proposed therapeutic use. For example, many of the drugs used in the treatment of cancer are genotoxic.9
A complete standard battery must be conducted prior to initiate Phase II clinical trials.9
2.2.1.1. Bacterial mutation assay (AMES test)
In vitro bacterial mutation assay (Ames test) is required for all new drugs. The test exposes bacteria (e.g.: Salmonella and or E. coli) to the drug candidate and evaluates for changes in the way bacteria grow. These changes result from mutations that occur when the structure of DNA is altered in certain regions. Many chemicals that cause mutations can cause cancer in animals or in humans. Consequently, this test determines if a chemical is a mutagen.9
Results concerning gene mutation assay must be available before the first clinical trials in humans.5
2.2.1.2 Chromosomal aberrations assay
Chromosomal aberrations assay evaluates the compound, or its metabolites, for the ability to induce chromosome aberrations in cultured mammalian somatic cells. It is an in vitro mammalian cell genotoxicity test, which evaluates the carcinogenic potential of the compound.9
Results must be available before conduction of multiple-dose clinical studies.9
2.2.1.3 Mouse micronucleus test
Mouse micronucleus test is an in-vivo test that detects injury to the chromosomes (resulting in micronucleus formation) in the bone marrow cells of the animals exposed to the compound.9
Supplementary genotoxicity tests, with appropriate models, may be conducted for compounds that were negative in the standard 3-test battery but which have shown effects in carcinogenicity bioassay(s) with no clear evidence for a non-genotoxic mechanism.9
2.2.2. Toxicology
Accordingly to the Food and Drug Administration (FDA), the rationale of general toxicity studies is to:
‐ Determine whether it is safe to administer drug candidate to humans ‐ Determine an initial safe dose for human clinical trials
‐ Help to determine a safe stopping dose (if necessary)
‐ Identify dose limiting toxicities (what should be monitored in clinical trials) ‐ Assess potential toxicities that cannot be identified in clinical trials.15
Toxicological studies include tests that assess general toxicity (acute and chronic), mutagenicity, carcinogenicity, toxicity on reproductive function and risk of fetal malformations, among others. General toxicity studies should be conducted according to Good Laboratory Practice (GLP) regulations.5
On these studies, rodent and non-rodent mammalian models are used to delineate and identify toxicity patterns. More than one species must be used to establish the fate of the drug in the body, i.e., PK: absorption, distribution, metabolism and excretion (ADME). For drugs that are intended to treat CNS diseases, the ability of the drug to cross the blood-brain barrier is a key issue.11
2.2.2.1. Acute toxicity studies
In the evaluation of safety profile of a new drug candidate the acute toxicity is usually determined first.
These are the first in vivo studies in order to predict future use in humans. An acute toxicity test evaluates the toxic syndrome produced by a single or a few doses over the course of a day.5
Accordingly to regulatory guidelines the main objective of these studies is to determine the dose that causes major adverse effects after administration of a single dose. Generally, these studies identify adverse effects observed after a short time administration. They also provide information regarding the possible health hazards that are likely to occur if humans are exposed to a single dose of a substance. By this way, they can help select the level of usage of that substance.5
Data from acute toxicity studies helps to determine the doses for animal repeated dose tests and in human Phase I studies. Information on the acute toxicity of drug could be also useful to predict the consequences of human overdose situations and should be available to support Phase III.5
Usually, acute toxicity studies are tested on at least two mammalian species: one rodent (e.g. rat or mice) and one non-rodent (e.g. rabbit or dog).13
Single-dose toxicity study
The requirement for single-dose studies is based essentially on the need of evaluation of acute toxic reactions. These studies are usually performed in a very early phase of development before a bioanalytical method has been developed and toxicokinetic monitoring of these studies is therefore not normally possible.12 The single-dose toxicity test is designed to obtain acute toxic effects after administration of a single dose of a substance.5 Its major objective is to establish the toxicity profile and to investigate adverse effects, which can follow within a short period of time after a single oral, dermal or inhalation administration of the new drug candidate in equal number of male and female (in at least two mammalian species of known strain) and to establish the maximum tolerated dose (MTD).13
The MTD is defined as the dose below the lower dose that produces severe clinical signs. This assay intends to identify the target organ of toxicity and also to establish the doses for future toxicology studies and for the first in human clinical study. In the toxicity studies, normally the effects that are potentially clinical relevant can be adequately characterized using doses up to the MTD. Other equally limiting doses include those that achieve large exposure or saturation of exposure or use the maximum feasible dose (MFD). Nevertheless, MTD is not essential to be demonstrated in every study.5
Single-dose toxicity tests ought to be conducted in such a way that signs of acute toxicity are revealed and the mode of death determined. In suitable species a quantitative evaluation of the approximate lethal dose and information on the dose-effect relationship should be made, but a high level of precision is not required. This study also determine the No Observed Effect Level (NOEL).13
The information obtained from single dose toxicity assays is very important to select the doses for repeat-dose studies. With this information preliminary identification of target organs of toxicity is possible, and delayed toxicity is frequently revealed.5
The results from these studies usually help to choose the formulation and to predict the rate and duration of exposure during a dosing interval.13 They also establish the doses for next toxicology studies or even first in humans’ studies. In 2008, authorities recognized that the value of information of single dose toxicity studies is limited, considering that the same information can be obtained from other types of toxicity studies, namely a dose-escalation study, which is considered an acceptable alternative to the single-dose design.5
Reflecting this development, where data from conventional single-dose studies were formerly required, information on MTD from other studies is now acceptable.5 Therefore, when acute toxicity information is available from any study, separate single-dose studies are not recommended, thus reducing the number of animals used for testing and contributing to the 3R’s principles (to reduce-refine-replace the use of animals).
Despite the recent initiatives to move away the single-dose toxicity studies there are companies that continue to perform this type of studies.
2.2.2.2. Repeated-dose toxicity (subacute and chronic toxicity studies)
Repeated-dose toxicity studies are carried out after initial information on toxicity has been obtained from acute toxicity tests.
The repeated dose toxicity studies are designed to determine the toxic effect of a drug on repeated exposure of several weeks to several months. It also gives the precious information about the delayed effect that might be the result for cumulative effect of chemicals.14
The main objectives of repeat dose studies are the following:
‐ Establish a No Observed Adverse Effect Level (NOAEL) dose; ‐ Determine safety factors, identify target organs or systems; ‐ Determine Acceptable Daily Intake (ADI);
‐ Identify materials that may require special investigation for neurotoxicity; reproductive toxicity, ocular toxicity or immunotoxicity;
‐ Establish dose levels for long-term tests; ‐ Assess toxicokinetic profiles.
These studies are used to assess chronic toxic profile that develops only after repeated administration of the drug, the characterization of physiological and pathophysiological effects that are induced by continuous administration and the detection of the most potential affected organs of toxicity and exposure/response relationship. They also provide important information about the delayed effects that might be the result for accumulative effect of the drug.4,14
Repeated-dose toxicity studies are used to support clinical studies as well as to qualify impurities.
As all preclinical studies, repeated-dose toxicity studies ought to be tested in species with similar PK profile as humans.14
Toxicity studies by repeated administration must be performed in at least two species: one species of rodent (e.g. rats or mice) and one non-rodent (e.g. beagle dog, pig or monkey). Testing on both sexes is required.14
Duration of exposure normally depends on nature of the drug and on its proposed therapeutic use.14
Depending on the duration of the studies, repeated dose studies, accordingly to the regulatory guidelines, may be referred to as subacute (14 days to 4 weeks), subchronic (3 to 6 months) or chronic (9 to 12 months). The specific duration should anticipate the length of the clinical trial that will be conducted on the new drug. Again, two animal species are typically required.14
Subacute, subchronic or chronic studies all fall into the general category of repeated-dose toxicity studies. The terms “subacute”, “subchronic” or “chronic” are vague and often source of confusion about the precise length and purpose of the study. It is more informative to refer to a repeated-dose toxicity study by the duration of administration of the drug and the type of study (e.g., referred to as 4-week, 3-month, 6-month, 9-month or 12-months toxicity studies).
A repeated-dose toxicity study with a minimum duration of 2-4 weeks would support Phase I studies up to 2 weeks in duration. Beyond this, 1-, 3-, or 6-month
toxicity studies would support Phase I human clinical trials for up to 1, 3, or 6 months, respectively.5
Table 1: Nonclinical repeated-dose toxicity studies to support phase I clinical trials
Duration of Clinical Trial Duration of Repeated-Dose Toxicity Studies
Rodent Non-rodent
Single dose 2-4 weeks 2-weeks
Up to 2-weeks 2-4 weeks 2-weeks
Up to 1-month 1 month 1 month
Up to 3-months 3 months 3 months
Up to 6-months 6 months 6 months
More than 6 months 6 months 6-9 months
Source: ICH M3
14-days repeated-dose toxicity test
The 14-days repeated-dose subacute toxicity study generally supports any clinical development trial up to 2 weeks of duration.
For a new compound projected for short-term use (e.g. less than 7 days) and for acute life-threatening diseases, repeat-dose studies up to 14-day duration may be considered appropriate.14
These studies are also carried out when toxicity studies of 3-month or longer duration are needed, in such a way that it can serve as a dose-finding study for long-term investigation. 14
It is also important to refer that generally a 14-day repeated-dose toxicity test is conducted with a dose below those employed in single dose or acute studies.5 Single- and repeated-dose toxicity studies (14 days) can be merged, in order to reduce the need to conduct unnecessary tests on animals.12
4-week repeated-dose toxicity test
The purpose of 4-week repeated-dose toxicity is to show the signs of toxicity of the test substance by observing the changes that emerge in bodily functions and forms when the test substance is repeatedly administered to animals every day.5 Repeated-dose toxicity 4-week study is carried out in such a way that it can serve as a dose-finding study for long-term investigation.
The 4-week toxicity study is usually recommended before initiation of repeated-dose Phase I studies.14
3-month and 6-month repeated-dose toxicity test
According to the pertinent FDA Guideline, subchronic toxicity studies are generally conducted for 3 months, but they may proceed for up to 12 months.16 Obtained results from these studies can be used to support predicting appropriate doses of the test substance for future chronic toxicity studies, to be used to establish NOELs for some toxicology endpoints, and to allow future long-term toxicity studies, to be designed with special emphasis on identified target organs, in rodents and non-rodents.16
12-month repeated-dose toxicity test
Chronic toxicity tests determine toxicity from exposure for a substantial portion of a subject's life. They are similar to the subchronic tests except that they extend over a longer period of time and involve larger groups of animals.
However after a review undertook by ICH to determine whether a harmonized duration for chronic toxicity testing in non-rodents should be recommended, it was concluded that toxicity findings are usually detectable following drug administration up to 6 months in rodents and up to 9 months in non-rodents. Therefore, it was recommended that studies in rodent should have a 6-month duration and studies in non-rodents should have a 9-month duration.14,17
Chronic studies are conducted to fulfill the registration requirements for drugs that are intended for continuous long-term use or frequent intermittent use.18
2.2.2.3. Reproductive toxicity
Toxicity problems related to reproduction and development systems have been recognized for centuries, but reprotoxicity has received huge attention since the thalidomide tragedy, where thousands pregnant women received thalidomide for morning sickness, and consequently thousands of children exposed in utero during the first trimester of gestation were born with a variety of severe birth defects.19 For that reason, ICH issued a guideline that defines the way new drugs have to be tested for reprotoxicity effects. It is intended that these assays, in which animals are treated during defined stages of gestation, reflect better human exposure to drug compound and permit more detailed identification of stages at risk.20
Reproductive toxicity has been defined as "any effect of chemicals that would interfere with reproductive ability or capacity," including effects on lactation.19
Since, drugs can cause reproductive toxicity by acting on the mother, father, feto-placental unit and the fetus directly, the main objective of reproductive toxicity studies is to “reveal any effect of one or more active substance(s) on mammalian
reproduction,” therefore they are conducted to evaluate the potential detrimental
effects of test items on the reproductive process.20
Basically, they are expected to explain the effects of the tested compounds on reproduction and fertility stage since there are many compounds that have the capacity to affect the reproduction and fertility (females and males both can be affected). There can also be adverse effects on the new developing embryo or foetus that might be also result of the chemical exposures.
The evaluation of a new chemical compound for effects on reproduction must take into account that mammalian reproduction is a complex process.
Reproductive toxicity studies are performed in rodents and rabbits using appropriate routes of dose administration including oral, parenteral and special dose routes such as inhalation and infusion.
General reproductive toxicity and development toxicity are the two main areas of animal reproductive process evaluation.
The general reproductive toxicity (embryotoxicity, fetotoxicity, embryo-fetal toxicity) is defined as “any adverse effect on the conceptus resulting from prenatal
exposure, including structural or functional abnormalities or postnatal manifestations of such effects. Terms like "embryotoxicity", "fetotoxicity" relate to the timepoint/period of induction of adverse effects, irrespective of the time of detection”, and development toxicity is designed as “any adverse effect induced prior to attainment of adult life. It includes effects induced or manifested in the embryonic or fetal period and those induced manifested postnatally.”20
The actual reprotoxicity assays should be determined by: ‐ anticipated drug use especially in relation to reproduction ‐ the form of the substance and route(s) of administration ‐ intended for humans and
- making use of any existing data on toxicity, PD, PK, and similarity to other compounds in structure/activity. 20
Guidelines suggest that for most medicinal products the following 3-study design will be adequate: 20
- Fertility and early embryonic development
- Pre- and postnatal development, including maternal function - Embryo-fetal development
Fertility and early embryonic development studies detect toxic effects resulting from treatment before mating, through the mating and the implantation process. Pre- and postnatal development, including maternal function, evaluates adverse effects on prenatal and postnatal development. Embryo-fetal development tests determine adverse effects on the development of the embryo and fetus by focusing on the identification of external, visceral and skeletal anomalies. 20
According to circumstances, other strategies or combination with these 3 studies could be as valid or even more valid. The main factor is that, in overall,
they do not leave knowledge gaps and allow direct or indirect evaluation of all stages of the reproductive process. 20
2.2.2.4. Carcinogenicity
Carcinogenicity potential of a drug is only evaluated after the acquisition of basic information that includes genotoxicity results, intended patient population, clinical dosage regimen, PD in animals and in humans (selectivity, dose-response) and repeated-dose toxicology studies.21
Long-term carcinogenicity studies aim to observe test animals for the development of neoplastic lesions during or after long-term exposure, to various doses of a test substance.22
These studies identify if a new drug have tumorigenic potential in animals and assess the possible risk in humans. 22
Unlike to what happens with the characterization of genotoxicity studies, this study is not mandatory for all drugs. The decision to require the study should take into account if the new drug raises a concern about its carcinogenic potential.22 When a positive result is observed in the tests for carcinogenicity, the conclusion to be drawn is that the drug is tumorigenic in rodents, because generally this study is conducted initially in rodent, which does not automatically mean that the drug is of carcinogenic potential in humans. Additional studies are usually performed to clarify the relevance of that result to man.
The selection of the species for long-term carcinogenicity study should be based on considerations that include the data observed in pharmacology, repeated-dose toxicology, metabolism, toxicokinetics and the route of administration. In absence of clear evidence favoring one species, it is recommended to select the rat. 21
An alternative for safety evaluation studies is the use of new in vitro methods. There exists some evidence that in vitro studies are able or potentially able to provide more precise, rapid, and relevant information than studies performed with animal studies. All ICH regulatory authorities accept and validate these alternatives to replace the current standard methods.5
3. NEW DRUG DEVELOPMENT STRATEGIES
3.1. Current status
One of the most important challenges in drug development is the accurate assessment of human drug toxicity. Though, over the last decades, a number of drugs have been withdrawn or have required special labeling due to adverse effects observed post-marketing, the majority of new drugs fail at the initial stages of development, such as pre-clinical phase and clinical phases I to III.
In the development of drug discovery pipeline, preclinical studies provide information about toxicity, kinetics and metabolism in animal administered with the new compound. They are also very important to determine the “safe” starting dose for FIH clinical studies.5
A recent Trial Watch study, carried out by the Centre for Medicines Research in the UK, concluded that, since 2007, the failure rate for drugs in Phase II and III clinical trials has been rising. This study analyzed, between 2007 and 2010, 108 Phase II clinical trials failures for new drugs or new indications of existing drugs, and 83 Phase III clinical trials or submission failures.23 The analysis included failures across all therapeutic areas. Figures 1 and 2 show the major proportions of these failures by therapeutic areas.
Figure 1: Phase II clinical trial failure rates according to the therapeutic area: 2007-2010.
Source: Adapted from Nature Reviews. Drug Discovery (10):1; Feb. 2011
The analysis revealed that 70% percent of the failures in Phase II clinical trials fell into only four therapeutic areas: alimentary/metabolism (including diabetes) - 23%, anticancer - 20%, nervous system - 16%, and cardiovascular diseases - 11%.23
Figure 2: Phase III clinical trial failure rates according to the therapeutic area: 2007-2010
Source: Adapted from Nature Reviews. Drug Discovery (10):1; Feb. 2011 20% 16% 23% 11% 32% 0% 5% 10% 15% 20% 25% 30% 35%
108 failures divided according to therapeutic area
Anticancer Nervous System Alimentary / metabolism Cardiovascular Others 28% 18% 13% 13% 0% 5% 10% 15% 20% 25% 30%
83 failures divided according to therapeutic area
Anticancer Nervous System Alimentary / metabolism Anti-infectives
With respect to Phase III clinical trials, failures occurred by the following order of magnitude: anticancer - 28%, nervous system, which includes neurodegenerative disorders - 18%, alimentary and/or metabolism, which includes diabetes and obesity - 13%, and anti-infectives - 13%.23 Reasons of failures are demonstrated on figures 3 and 4.
Figure 3: Phase II clinical trials: 2007- 2010.
Source: Adapted from Nature Reviews. Drug Discovery (10): 1. Feb. 2011
Figure 4: Phase III and submission: 2007- 2010.
Source: Adapted from Nature Reviews. Drug Discovery (10): 1. Feb. 2011 19% 29% 51% 1% Reason of failures Safety concerns Strategic reasons Insufficient efficacy Not disclosed 21% 7% 66% 6% Reasons of failure Safety concerns Strategic reasons Insufficient efficacy Not disclosed
These data show that safety issues represent the second most important reason for clinical development discontinuation: 19% in Phase II and 21% in Phase III. The occurrence of unexpected adverse effects at this stage reveals that previous nonclinical and clinical studies were unable to predict such safety issues.
The preclinical studies are limited because the extrapolation of toxicity data from animals to humans is not completely reliable, and relatively rare adverse effects are unlikely to be detected. Hence, it must be considered that traditional preclinical toxicology approaches have limited power to detect adverse effects in human and to evaluate relevance of preclinical findings to the clinical setting.
Thus, different species used in preclinical toxicity and safety tests and the lack of sensitive biomarkers and non-representative patient population in clinical trials are potential reasons for the failures in predicting human drug toxicity.23
However, changes in drug discovery practices and the development of specific and sensitive safety biomarkers, more predictive models (in silico and in vitro), ‘omics’ approaches, translational methods and studies are expected to reduce these failures considerably. 23
Drug development programs are often abandoned after high investment of time and resources. The failure rate of testing new drug therapies is socially unacceptable, approximately 95%. 24; 25
As the increase of expenditure and challenges of drug development maintain, innovation may continue to stagnate or decline, and therefore, many medical needs will remain unmet.
The assays used to determine drug safety have not changed since decades. The development of new safety testing methods requires its acceptability by the regulatory agencies, such as FDA or EMA. This raise the extreme need to improve the efficiency and the predictability of the drug development, thus providing better
conditions for projects with high probability of success. Hence, there is an important need for more powerful and predictive methods such as new animal models of disease, in vitro tests, biomarkers for safety and efficacy and new clinical evaluation technique of drug development.
Currently, pharmaceutical companies attempt to decrease uncertainty around a compound before it goes in on the most expensive stages of development, essentially in phases II and III, where the costs are very high.
Therefore, preclinical safety drug and efficacy methods are needed to build a link between disease models and human experience, since unexpected toxicity from marketed drugs continues to cause 2-3% of approved drugs to be removed from the market each year.24
To answer the current deceleration in innovative therapies, the regulatory authorities introduced some initiatives, such as the FDA Critical Path Initiative (C-Path) in the US, and the Innovative Medicines Initiative (IMI) in Europe, with the purpose of expediting the development of better and safer medicines for patients.
The C-Path declared aim is “to improve the efficiency of product development
industry-wide and to identify and prioritise the most pressing development problems for new drugs and therapeutic agents and a strategy to drive innovation in the scientific processes through which medical products are developed, evaluated, and manufactured”.26
Consistently, the IMI purpose is “to speed up the development of better and
safer medicines for patients”.27
These Initiatives,which join the regulatory agencies and the research-based industry, are trying to draw the attention to new scientific research tools that may revolutionize the regulatory and scientific process for new drug development evaluation and approval. And they also intend to modernize the drug development
by incorporating recent scientific advances, such as genomics and advanced imaging technologies, into the process. 26
As previously referred, it is urgently mandatory to develop better predictors of human major drug safety issues, such as immunogenicity, liver toxicity and kidney toxicity, among others.28 To better support these challenges, consortia of scientists from public entities and private companies have been implemented and supported. Key consortia are the US-based Predictive Safety Testing Consortium and the EU-based SAFE-T Consortium, which are working on key areas such as nephrotoxicity, hepatotoxicity, carcinogenicity, myopathy, and vascular injury.
3.1.1. PSTC - Predictive Safety Testing Consortium
The PSTC brings together pharmaceutical companies that share and validate each other's safety testing methods under the advisement of the FDA, EMA and Japanese Pharmaceutical and Medical Devices Agency (PMDA).29
Although pharmaceutical companies have traditionally been reluctant to give too many details about their own R&D development, the PSTC determine which of the lab tests that they developed individually should be recommended by the FDA to screen drugs. 25
PSTC has been created as a neutral ground where scientists from pharmaceutical companies and academia can share and test new methods that are more trustworthy predictors of human safety. The principal objective is to develop adequate evidence to qualify new predictive safety tests for regulatory use that may improve the safety of new drugs that reach the market.29 The PSTC’s intends also to qualify new biomarkers for the detection and monitoring of drug-induced toxicity in preclinical and clinical studies that includes:
‐ Qualification of biomarkers of toxicity to use as experimental systems to predict the possibility of toxicity in humans.
‐ Sharing preclinical and clinical data for genomic, proteomic and metabolomic biomarkers of drug-induced nephrotoxicity, hepatotoxicity, vascular injury,
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toxicity, and vascular injury. All biomarker research programs have a strong translational focus to select new safety tools that are applicable across the drug development spectrum.29
Accordingly to the Consortium, the following biomarkers were submitted to FDA:
‐ Hepatotoxicity Working Group of PSTC - submitted a briefing package for qualification of four biomarkers for detecting drug-induced liver toxicity.29 This investigation took an innovative genomics-based approach to investigate drug-induced liver injury by comparing molecular events produced in vivo by compound pairs that are: similar in structure and mechanism of action; associated with few or no signs of liver toxicity in preclinical studies; and show marked differences in hepatotoxic potential.30
- Nephrotoxicity Working Group (NWG) of PSTC - evaluated the utility of the following urinary kidney biomarkers (KIM-1, albumin, total protein, β2-microglobulin, cystatin C, clusterin, trefoil factor-3) known as Rat KidneyMAP® that can be tracked in the urine in early-stage, to determine of acute drug-induced nephrotoxicity in rats and to be included along with traditional clinical chemistry markers and histopathology in toxicology. This set of biomarkers has been qualified by regulators in the US, the EU, and Japan.29; 30
- Myopathy Working Group - has submitted a briefing package of data that support eight novel biomarkers for detecting and monitoring drug-induced skeletal muscle injury in the rat. 35
3.1.2. SAFE-T – Safer and Faster Evidence-based Translation Consortium
The Safer and Faster Evidence-based Translation (SAFE-T) consortium is a project with public-private partnership between the European Commission and the European research-based pharmaceutical industry (EPFIA). The aim of this European initiative is the revitalization of the biopharmaceutical sector in Europe and overcome the research in the drug development process through the
discovery of changes in drug discovery practices with a specific and sensitive safety biomarkers to consequently result in a considerably decrease of drug development failures.30
Patient safety is one of the target areas of this project, which has established a standard qualification strategy for new translational safety biomarkers that will allow early identification, assessment, and management of drug-induced injuries throughout research and development.30
The objectives of the SAFE-T Consortium are:
- To evaluate utility of safety biomarkers for detecting, assessing, and monitoring drug-induced kidney injury (DIKI), drug-induced liver injury (DILI), and drug-induced in vascular injury (DIVI) in humans;
- To develop assays and devices for clinical application of safety biomarkers; - To compile enough evidence to qualify safety biomarkers for regulatory
decision making in clinical drug development and in a translational context; - To gain evidence for how safety biomarkers may also be used in the
diagnosis of diseases and in clinical practice.27
Currently, SAFE-T has approximately 150 potential biomarker candidates for drug-induced injury of the kidney, liver and vascular system) have been evaluated and currently undergoing in clinical evaluation.27
In general, the composition and goals of SAFE-T are similar to the PSTC.
PSTC and SAFE-T, are working on a number of projects with others institutions to advance the scientific understanding of drug-induced toxicities.
C-Path and IMI made that industry, academia and government agencies work together to share the information, technology and expertise to modernize and transform the approach to drug development. These collaborations, mainly the public-private partnerships and consortia, have been sharing data, establishing data standards, and facilitating collective tool development. 28
The role of both Initiatives is extremely important for safety Biomarkers development.
Biomarkers are the stepping-stones for modern drug discovery and those are developed and implemented, in medical practice, in parallel process with drug development. The discovery and development of biomarkers has a huge potential to revolutionize the diagnosis and treatment of a disease in early stage.
They are the main focus in patient selection, PD responses as efficacy and safety target validation and compound-target interaction.30
3.1.3. Biomarkers
Accordingly to the National Institutes of Health (NIH) Biomarkers Definitions Working Group a biomarker is defined as “a characteristic that is objectively
measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”32
In the context of research, biomarkers can be used to understand the mechanism wherebydrug works, to screen compounds for toxicity before they get into clinical trials, they can also provide indications of the potential hazards, and to forecast adverse events resulting from wider exposure. Thus, biomarkers can improve the safety of drugs, speed the progress of drugs to market and potentially reduce the costs of new drugs.31
Biomarkers can take several different forms and have several potential valuable applications in medicine in general. These applications can include:
- diagnosis and differential diagnosis;
- screening potential new therapies either in vitro or in vivo;
- measuring severity, progression of disease, and responses to therapy; - predicting prognosis and
As discussed before, one of the major potential uses of biomarkers is the monitoring of toxicity of a drug in preclinical and clinical studies, and this has been the major reason for the high attrition rate of the traditional drug development process. Therefore, a move to new paradigms is welcome.
Bellow are listed some of the desirable biomarkers profile for drug-induced kidney, liver and vascular injuries.
Table 2: Desirable biomarker profile for drug-induced kidney, liver and vascular injuries Drug-induced kidney injury (DIKI) Drug-induced liver injury (DILI) Drug-induced vascular injury (DIVI) Type of biomarkers to be clinically qualified
Preclinically qualified and
exploratory biomarkers Exploratory preclinical and clinical biomarkers Exploratory biomarkers for DIVI and biomarkers for human vascular disorders
Definition of purpose Risk prediction
Early diagnostic Prognostic Risk prediction Early diagnostic Prognostic Risk prediction Early diagnostic Prognostic
Contexts of use Preclinical, early clinical
and clinical
Candidate TSBMs will be evaluated in clinical studies
Preclinical, early clinical and clinical
Candidate TSBMs will be evaluated in clinical studies
Preclinical, early clinical and clinical
Parallel ‘forward and reverse qualification’ required
Current standards Specific but not sensitive
enough, lack of predictivity Current standards include serum creatinine and blood urea nitrogen
Sensitive but not specific enough, lack of
predictivity and prognostic value Current standards include liver enzymes and bilirubin
Not sensitive nor specific enough
Absence of standards for preclinical
DIVI DIVI-like pathologies in human are diagnosed using clinical, pathological and biological criteria
Source: Adapted from Matheis K in Drug Discovery Today.16: Jul. 2011
Industry recognizes that there are major efficiency gains in access to secure decision-making tools that inform about safety at an early stage of drug
development. Qualified safety biomarkers provide the promise of an important predictive tool.33
Thus, we will focus our attention on safety biomarker where the advances in molecular biology, molecular medicine, and associated technologies (genetics, genomics and proteomics) resulted in its qualification (biological and clinical evidence, relevance, utility and limitation).34
Safety biomarkers can be applied in different phases of drug development, so they can allow the advancement of new drugs with preclinical or clinical safety liabilities, evidence based and hypothetical. 34; 35
In preclinical development the applicability in the use of safety biomarkers consists in assisting the selection of drug candidates that are more likely to be tolerated in humans, reducing the time and cost of preclinical safety evaluation.35
One example of these approaches is the evaluation of first new set of nephrotoxicity biomarkers, based on studies performed in rats using known nephrotoxic such as gentamicin and cisplatin. These biomarkers reveal toxicity in different anatomical regions of the kidney and they intend to provide earlier warning signs of drug-induced toxicity.35
As mentioned before, in clinical studies biomarkers can be used in early or late drug development to increase the probability of detecting clinical safety signs. Currently they are being developed to identify patients at risk for disease and to predict potential treatment responders, adverse event occurrence, and favorable clinical outcomes for many diseases states, in particular in cancer.
In the context of clinical development biomarkers applicability in the different stages of the clinical development is essentially as follows:
‐ Phase I studies represent the first opportunity for new safety biomarkers to be tested in humans;
‐ Phase I and II studies safety biomarker data with early events leading to dose limiting toxicities will impact the dosing or schedule regimen and establishing stopping criteria for subsequent studies:
‐ Phase II biomarkers may help to establish safe treatment regimens for diseased patients, who typically are more susceptible to develop drug-induced adverse events than healthy volunteers;
‐ Phase III biomarkers may allow to identify adverse events affecting only a low proportion of the treated population;
‐ Phase IV trials and post-marketing surveillance programs may be used to detect idiosyncratic toxicities (rare SAEs in a very low proportion of treated patients).
The development of new biomarkers is an imperative need, since they have an especial value, as they can help to prioritize drug discovery resources by enabling early proof-of-concept studies for novel therapeutics target.
Consortia are making progress toward developing knowledge and tools that can reduce uncertainty in drug development. As trusted and neutral third parties, US C-Path and EU IMI may play an important role to bring more and safer products to market faster.
4. NEW DRUG DEVELOPMENT PARADIGMS
The way to get new products out quickly involves the minimization of the complexity by moving in short and simple steps.
The most important goal is to identify a molecule with the desired effect in the human body and to establish its quality, safety and efficacy for treating patients. In this context, new development strategies are being combined with integrated, multidisciplinary approach to accelerate the processes of chemical and pharmacological characterization, toxicological investigation, and clinical testing. In complement to these strategies, sophisticated new technologies in the discovery and design of new drugs are replacing the traditional methods of discovery and development.
To reach new patterns we will handle with difficult questions, such as:
‐ Can we change the template of medical research in ways that reduce the cost of innovation without risking the patient safety?
‐ Can we improve incentives between industry and academia so that investigators interested in translation can be rewarded for it?
‐ Can we create an infrastructure that supports collaboration among sectors while guarding against conflicts of interest?
The process of accelerated drug development, however, presents unique challenges as well as opportunities.
This approach can include the use of appropriate biomarkers during preclinical and clinical drug development.
Accordingly to the approach previously discussed, the current model of non-clinical development is not sufficiently predictive of safety in humans due to the significant rate of attrition during clinical phases (including post-marketing) related to safety reasons.
Thus, it urges to refine the non-clinical development paradigm. One of potential processes is the development of predictive biomarkers for the most common problems and most serious safety events.
One way to reduce the failure rate and the considerable costs of new drug candidate development is the determination of the mechanism of drug interaction during preclinical stages, i.e., establishment of proof-of-concept, with the new concept ‘quick win/ fast fail’.
The new paradigm known as “quick win/fast fail” (Fig.6), is an alternative to the traditional development method shifts the in proof-of-concept stage from Phase II to just after the start of clinical development. 36
Figure 6: The “quick win/ fast fail” drug development paradigm
Legend: CS-candidate selection; FED-first efficacy dose; FHD-first human dose; PD-product decision
Accordingly to Steven P. and colleagues36, figure 6 illustrates the traditional paradigm of drug development (a) contrasted with an alternative development paradigm referred to as “quick win/fast fail” (b). In this alternative, technical uncertainty is intentionally decreased before the expensive later development stages (Phase II and III) through the establishment of proof-of-concept. This results in a reduced number of new molecular entities advancing into Phase II and III, but those that do advance have a higher probability of success and launch. The
savings gained from costly investment in late-stage R&D failures are re-invested in R&D to further enhance R&D productivity.36
Adopting the ”quick win/fast fail” approach researches can remove some of the doubts and concerns in the outcomes of the research and can improve the probability that a therapy will perform in the real world the expected desire, without unforeseen risks.
This model estimate that, fewer new drugs advance to the later phases, but those that do, have a higher probability of success and launch.
”Quick win/fast fail” paradigm evidence that investments made in the process sooner, increase the information available on which focused the key decisions, allowing the earlier termination and prevent of a project of new drug prior to huge investments being made for a late-stage development program.
5. CONCLUSION
The failure of a new drug to reach the therapeutic arsenal is an issue that has long attracted considerable attention; toxicity is one of the major reasons for drug development attrition and medicines market withdrawal.
Drug development attrition in late stage or market withdrawal causes significant financial losses and burden. So, new approaches to identify as earlier as possible drug candidates with safety issues are hugely necessary.Public-private partnerships and consortia aiming to improve the safety assessment tools, namely the development and validation of biomarkers predicitive of safety in humans are thus very welcome and holds the promise that the future will bring us better and safer medicines.
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