Tag Archives: EMEA

Drug Regulators EMEA Publish Concept Paper on the Need to Revise the Guidlines on the use of Transgenic Animals in Biological Manufacture.

Posted on August 18, 2009 by admin| Leave a comment

Drug Regulators, Manufacturing, EMEA publish concept paper on using transgenic animals for biological manufacturing.

Following rapid changes in the area and products making it to the market (related article) The EMEA has published the following “CONCEPT PAPER ON THE NEED TO REVISE THE GUIDELINE ON THE USE OF TRANSGENIC ANIMALS IN THE MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE (3AB7A OF JULY 1995)”

Introduction to Regulations

Recombinant proteins for medicinal use are routinely produced in bacterial or mammalian cell lines. The regulatory requirements to make and test the production lines and cell banks, and the subsequent manufacture and testing of the medicinal product are well established. Many relevant Guidelines are available for production in cell lines. An alternative production platform for recombinant proteins is transgenic animals, where a foreign gene, which codes for a therapeutically useful protein, is inserted into the genome of the chosen
species and is expressed under the close control of a promoter. The recombinant protein is generally expressed in some easily harvested body component such as milk or eggs and does not harm the animal.

The Problem to Tackle

A guideline was prepared by CPMP and entered into force in July 1995 (3AB7A). Although it contains advice which was useful for a technology platform which was in its infancy, since it came into force, this production method has progressed significantly and the guidance has not been revised to take account of these advances. The current guideline was prepared at a time when the scientific possibilities for transgenic animals were being investigated and no product had been generated for commercial or clinical trial purposes. In addition, many relevant guidelines, such as the ICH Q5 series had not been prepared.

Discussion on the Problem

It is proposed that the scope of the guidance covers the quality issues regarding biological active substances produced by the expression of one or more transgenes stably located in the genome of animals. Production using cloned animals falls outside the scope.

The following improvements to the published guideline have been identified:

  • The current document contains too many references to the benefits of transgenic technology but is not sufficiently detailed technically. A complete re-write to bring the structure of the document in line with the current format of CHMP guidance documents is needed.
  • The lay-out of the document is not logical or easy to follow. It is not broken down into logical sections which follow CTD headings and concepts.
  • There is no specific section on pathogen safety.
  • There is no discussion of specific Quality systems, particularly for generation of transgenic lines, breeding and maintenance of production animals.
  • A discussion on product characterisation is omitted.
  • Breeding strategy is not mentioned, nor the concept of master and working cell/transgenic banks.
  • Control of active substance or raw material is not adequately covered.
  • Advice on residual Host Cell Proteins and DNA is incomplete.
  • Since products from transgenic animals are (to date) the product of sexual reproduction, and not of cloned animals, the potential inherent variability of transgenic proteins needs to be explicitly discussed and the regulatory requirements to map this variability should be updated.
  • Advice on the information which is required regarding development genetics is confusing and should be clarified.
  • Advice is given that material from different genetic lines should not be mixed when producing product for a single license. This advice needs to be reviewed in light of more recent regulatory considerations.

The Biologics Working Party recommends developing a guideline on the use of transgenic animals in the manufacture of biological medicinal products for human use to replace the existing guideline.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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Posted in biotechnology, formulation, manufacturing

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Drug Development Guidance – EMEA for Medical Products for Term and Preterm Neonates

Posted on August 17, 2009 by admin| Leave a comment

Drug Development Guidance Published by EMEA on New Medicinal Products for Term and Pre-term Neonates

EMEA publishes “GUIDELINE ON THE INVESTIGATION OF MEDICINAL PRODUCTS IN THE TERM AND PRETERM NEONATE”. This guideline addresses the considerations and requirements for the design and conduct of clinical trials in premature and term neonates using medicinal products of relevance for the use by this population. It includes background information on the maturation of organs and of body functions.

Introduction to EMEA Guidelines

Neonates are the group of children from birth up to and including the age of 27 days, including term and preterm neonates. They represent a particularly vulnerable subgroup of the paediatric population. Whilst they account for a low percentage of the total use of medicines in childhood, up to 90 % of medicinal products are used unauthorised or off-label in this population, especially if treated on Neonatal Intensive Care Units (NICUs).

There are several reasons as to why few clinical trials of medicinal products have been performed in neonates (e.g. feasibility difficulties linked to: age, small patient group and uniqueness of their diseases.) The Regulation on Medicinal Products for Paediatric Use (Regulation (EC) 1901/2006) creates obligations with regards to conducting clinical trials in paediatric patients including neonates in order to meet the recognised need for authorised medicinal products and the information on the use of medicinal products in children. Therefore clinical trials to investigate medicinal products in the neonatal population have to address the needs of this population (section 9.1).

Scope of EMEA Guidance

The guideline aims to provide guidance for the development of medicinal products for use in the neonatal period, defined as from birth up to 27 days post-natal age in term neonates and from birth up to a post-menstrual age of 40 weeks and 27 days in preterm neonates.

Organ Maturation in the Neonate

Most organ functions are physiologically immature in the neonatal period. The degree of immaturity may be aggravated due to prematurity, intrauterine growth retardation or any potential pathologic condition affecting the neonate. Functional immaturity of physiological processes and organ function predispose neonates to altered pharmacokinetics and pharmacodynamics, leading to potential inefficacy or reduced safety of a medicinal product in the neonate.

Maturational changes are rapid in the post-natal period, and the resulting high variability of the neonates (both inter-individually and intra-individually) has to be considered when investigating medicinal products for use in the neonatal population. Additionally, any medicinal product administered to the neonate may affect the ongoing maturation processes. Major developmental changes should be identified that could significantly influence exposure, safety and efficacy for a given medicinal product. If adequate and possible, not only pharmacokinetic changes due to ongoing maturation but also pharmacodynamic changes as a function of maturation itself should be investigated.

Heart and Lung

The post-natal cardiopulmonary system adaptation marks the most prominent changes during and after birth. Some of these changes occur instantaneous with the first breath, whereas others occur within hours or days after birth. In general, the impact of lung and heart maturation on PK/PD relationship (e.g., closure of the ductus arteriosus) has to be considered.

Cardiopulmonary monitoring of hospitalised neonates is carried out on a routine basis and these findings should be used and documented for the purpose of a clinical trial as appropriate. Less or non-invasive measures should be used whenever possible (e.g., measurement of blood pressure, heart rate, respiratory excursions and rate; pulse oximetry in at least one site, transcutaneous pO2 and / or pCO2 measuring, electrocardiogram [ECG], echocardiography, and Doppler sonography). Radiologic (e.g. X-ray, MRI) and laboratory (e.g., blood gases, haematocrit) assessments may additionally be required and would need to be synchronised with routine assessments and limited as much as possible.

Central Nervous System (CNS)

Critical processes of brain development consist of neuronal proliferation, migration, organisation and myelination. Two main phases can be distinguished with the first occurring between the 8th and 16th week of gestation, consisting of neuronal proliferation and generation of radial glia, and the second phase between 5 months and 1 year of life, consisting of glial multiplication (with neurogenesis and neuroproliferation continuing).

Even if a medicinal product is not primarily developed for an indication related to the CNS, the distribution and penetration into the CNS and the potential effects and neuro-developmental sequelae should be addressed.

Hypoglycemia is an important risk factor for perinatal brain injury. Due to the high metabolic rate and the dependence on glucose as unique source of energy of the brain, any medicinal product affecting glucose metabolism in the neonate may have an effect on the developing brain. This should be carefully taken into consideration when planning a neonatal study.

Measures to monitor brain function include EEG (electroencephalography), amplitude-integrated EEG (aEEG), ultrasonography, Doppler sonography, auditory and visual evoked potential measurements (AEP, VEP), cerebrospinal fluid (CSF) sampling, near-infrared spectroscopy (NIRS), (functional) magnetic resonance imaging (MRI) and positron emission tomography (PET). These measures have different utility, e.g. NIRS allows to continuously assess brain perfusion and oxygen consumption in neonates.

Kidney and Renal Function

Renal clearance mechanisms include glomerular filtration (GFR), tubular secretion and reabsorption. Glomerular filtration matures faster than the tubular function, and both depend not only on age and maturational status but also on adverse factors occurring in the pre- and post-natal period, including for example intrauterine growth retardation or administration of nephrotoxic drugs to the mother and the neonate.

Serum creatinine is elevated in the first days of life and reflects maternal creatinine and low GFR in the neonate. In premature neonates, the persistence of an elevated serum creatinine during the first weeks of life is the result of a transitory process of tubular creatinine reabsorption. Therefore, to monitor renal function serum creatinine is used after the first week of life in term neonates and after 4 weeks in premature neonates. Before these times, intra-individual changes (related to post-menstrual age) in serum creatinine are used as a guide to renal function.

Liver and Hepatic Function

Hepatic blood flow, plasma protein binding and intrinsic clearance determining hepatic clearance undergo significant post-natal changes. Most enzymatic microsomal systems responsible for drug metabolism are present at birth and their activities increase with advancing post-natal and gestational age. Rapid maturational changes occur during the first weeks of life. Hepatic clearance may be influenced by premature birth, pathologic conditions of the neonate or administration of drugs to the mother or to the neonate.

To predict the exact nature of these consequences requires an understanding of post-natal maturation and main involved enzymes. The ontogeny of specific enzymes is partly described in the scientific literature and may allow estimations of drug metabolism in the neonate. These data should be considered when planning neonatal studies.

If the medicinal product investigated is likely to be eliminated mainly through hepatic metabolism, markers of reduced/normal hepatic function could be included as covariates in the pharmacokinetic data analysis (e.g., in population PK analysis) as well as included in the safety assessment. Monitoring could include standard laboratory and imaging procedures.

Gastrointestinal System

Data concerning maturational changes of the neonatal gastrointestinal tract that may influence bioavailability are still limited.

Immune System

Lymphoid stem cells develop from precursors and differentiate into T, B or NK cells, as well as Antigen presenting cells (APCs) depending on the organs or tissues to which the stem cells traffic. Indeed, both the initial organogenesis and the continued immune system cell differentiation occur as a consequence of the interaction of a vast array of lymphocytic and microenviromental cell surface molecules and proteins secreted by the involved cells. De novo T-cell generation requires a functional thymus. The current paradigm is that the human T-cell repertoire is established during late foetal development and that, by the time of birth, thymectomy does not cause immediate immune deficiency. Thymic epithelial cells – the component of the thymus relevant for T-cell production and selection – involute rapidly after birth. Compared with adult T cells, neonatal T cells secrete increased levels of interleukin-10 (IL-10) following stimulation, but reduced levels of many other cytokines, including IL-2, IL-4, IL-8, interferon gamma (IFN-gamma), transforming growth factor beta (TGF-beta) and tumor-necrosis factor alfa (TNF-alfa).

Antibody response can readily be detected upon challenge in neonates provided to take into account the presence of interfering maternal antibodies. Modern multiparameter cytofluorimetric technology can be employed to assess not only the number of immune cells but also some immune functions such as cytokine production or cytolytic activity. However an effort to develop microassays has to be done to truly assess the different pattern of immune responses in the neonate and in infants in the first years of life. Molecular techniques such as spectratyping for T and B cell repertoire assessment can also be of value.

Body Composition

Changes in body composition during the neonatal period are important factors for altered pharmacodynamic and pharmacokinetic characteristics. Body composition correlates with both gestational and post-natal age, and it continues to change significantly during the first years of life. Age related changes in fat, muscle and total body water composition may produce significant quantitative changes in pharmacokinetic parameters such as volume of distribution. For instance, total body water is highest in the newborn and decreases substantially in the first 4 months of life therefore high water soluble drugs will present a larger Volume of Distribution in the neonatal period potentially requiring larger doses than older children in order to achieve the same desired therapeutic plasma concentrations. On the contrary, the amount of body fat is low at birth and increases progressively in the first months of life. Iatrogenic interventions in neonates could also significantly shift body composition characteristics.

Conditions Affecting Specifically the Neonatal Population

Neonates frequently suffer from conditions that are specific for this subset of the paediatric population, for example respiratory distress syndrome (RDS) or patent ductus arteriosus (PDA). In addition, neonates hospitalised on NICUs often suffer from multiple concomitant conditions, requiring administration of a combination of medicinal products resulting in a high risk of drug interactions. Additionally, adverse reactions in neonates, especially in preterms may trigger specific complications, as for example in relation to susceptibility to necrotising enterocolitis (NEC) or retinopathy of prematurity (ROP). As a further complicating factor, in utero growth retardation may affect pharmacokinetics and pharmacodynamics of drugs at birth and therefore may change the safety and efficacy profile of drugs used in the neonatal period.

Timing of Development of Medicinal Products in Neonates

The timing of studying a medicinal product in the neonate will depend on the seriousness and uniqueness of the condition to be treated as well as on the availability of alternative treatment options, the potential benefit of a new product, and the target population. Sponsors should refer to ICH Guideline E11.

Data Required Before the First Administration to a Neonate in a Clinical Trial

If possible, clinical data should always be obtained in the least vulnerable population. Depending on the condition, the new product, the target population and further factors according to section 2.1 of the ICH Guideline E11, initial tolerability, PK and safety data should be collected in adults before initiating studies in the neonatal population.

If older children are affected by the same disease or another disease for which the medicinal product may be of use, in general older (less vulnerable) paediatric age groups should be studied before studying the product in the neonatal population.

For conditions exclusively found in neonates, the development should primarily be made in neonates. However, also in such condition, the first studies in man should, if possible, be done in healthy adult volunteers. Sponsors should refer to the ICH Guideline E11.

In-Vitro Data

In order to predict the in vivo situation as much as possible (i.e., as regards efficacy, pharmacokinetics, safety), in vitro studies on human biomaterial, (e.g., on human non-terminally differentiated cells or, if relevant, foetal or neonatal cell cultures) may provide relevant additional information. Examples include enzyme activity, receptor expression and mediator modulation.

Animal Data

The conventional nonclinical studies should be performed including pharmacokinetic, primary pharmacodynamic, safety pharmacology, single- and repeated dose toxicity, genotoxicity, reproductive and developmental toxicity, including peri-/post-natal toxicity testing (e.g., transplacental exposure) and local tolerance studies.

In addition to these conventional non-clinical studies, juvenile animal data should be provided if needed. Juvenile toxicity studies will be necessary if available human safety data and previous animal studies are considered insufficient for a safety evaluation in the intended paediatric age group. If such studies are considered to be not relevant or not feasible, a scientifically data based justification should be provided.

Formulation and Route of Administration

The choice of formulation and route of administration depend on the condition to be treated and the clinical state of the neonate. Age-appropriate formulations and strengths using appropriate excipients must be developed to avoid extemporaneous preparations, even more so for neonates. Novel formulations should be evaluated through preclinical studies and in adults or older children as appropriate before consideration for administration to neonates.

Intravenous (IV)

The intravenous route will normally be used in clinically unstable term and preterm neonates. Neonates have a fragile vasculature system, and it may be very difficult to obtain appropriate peripheral or central access. Most common IV routes are peripheral veins (limbs, feet, hands or scalp), umbilical vein, or “long” peripheral lines that can be considered central, whereas internal jugular vein or femoral vein access is uncommon. Neonates may only have a small number of IV lines to administer all medicines as well as blood products, total parenteral nutrition (TPN) and fluid maintenance.

Oral

Oral administration should be used when possible and appropriate in the neonatal population, but there is still lack of data on absorption and safety. The way of enteral feeding (e.g., feeding tube, sucking), the time intervals (e.g. continuous, hourly feeds) and amounts of feeding have to be considered and specified.

Rectal Use

Rectal administration is not commonly used in this age group, and it is associated with erratic absorption. If considered it must be fully evaluated for safety and efficacy in addition to the appropriate bioavailability studies.

Topical Use

Topical administration may be necessary or suitable for local or systemic effect. Account must be taken of skin immaturity, especially in preterm neonates, and the large and more permeable and moisturised surface area to weight ratio which all predispose to an increased systemic absorption that could lead to toxicity.

Intramuscular (IM) use

Intramuscular administration is not usually a route of choice for neonates because absorption may be slow and unpredictable, varying with postnatal age and clinical state; injections may be painful and cause tissue damage. If the intramuscular route is considered its use must be justified.

Other Routes

Other routes of administration may be required or may be suitable (e.g., endotracheal, inhalation etc). Their use should be justified.

Dose Finding

In general, most drugs are developed for adults and older children before they are developed for the neonatal population. All relevant pre-clinical and clinical data in adults and children, or in adults and juvenile animals, should be taken into consideration to find a safe starting dose in neonates. PK / PD modelling techniques, using age appropriate and validated biomarkers, need to be considered to find the optimal dose. For a new medicinal product, the optimal dose has to be clinically verified. Existing physiologically based pharmacokinetic models to predict pharmacokinetic characteristics in the neonatal population may be considered if appropriate.

Pharmacokinetic Studies and PK/PD studies

Pharmacokinetic information is important to support adequate dosing in subpopulations of the clinically studied population and to assess the potential for clinical relevance of toxicity findings in the preclinical studies. However, pharmacokinetics alone is of limited value for extrapolating efficacy and safety from other patient groups, and extrapolation of efficacy will in general need pharmacodynamic data and PK/PD monitoring.

A population PK approach is preferable due to the importance of finding covariates related to dose-individualisation between individuals and over time in the maturating individual. The analysis can be made on rich and/or sparse data depending on the number of patients available and the possibility of developing highly sensitive analytical methods where very small sample volumes could be used.

Specific Aspects of Clinical Trial Design in Neonates

As for all clinical trials all measures to avoid bias should be included in trials performed in neonates. Therefore uncontrolled trials should be avoided in principle for demonstration of efficacy. They have limited usefulness for the demonstration of safety. On the other hand for randomised trials, in particular those using a placebo, there should be equipoise (genuine uncertainty) at the beginning of the trial and no participants should receive care known to be inferior to existing treatments.

The size of a trial conducted in neonates should be as small as possible to demonstrate the appropriate efficacy with sufficient statistical power. Adaptive, sequential, Bayesian or other designs may be used to minimise the size of the clinical trial. However, a balance between the need to stop recruitment early and the need to obtain reliable safety information should be aimed at.

In addition, clinical trials in neonates should be carried out in experienced neonatology centres with relevant expertise and with appropriate resources, in order to ensure optimum professional conditions for the protection and medical support of the neonates.

Age and Further Stratification Criteria

Taking into account age classes is of particular importance when recruiting patients within the clinically relevant age interval to optimise the evidence the potential influence of maturation. However, during data analysis, the use of age as a continuous co-variable is recommended whenever possible for the same reason.

The following subgroups within the neonatal population should be recognised as distinct, and the use or not-use of these criteria for stratification should be justified accordingly.

  • SGA or not; hypertrophy or not
  • ELBW, VLBW, and LBW
  • GA (for example, < 26 weeks, 26 – 29 weeks, 30 – 33 weeks, 34 – 36 weeks, >= 37 weeks)

Endpoints and Outcome Measures

For use in clinical trials in neonates, there is a need to elaborate clinically relevant primary endpoints, linked to the conditions and prospects specific to preterm and term neonates. In addition, the need for establishing age appropriate surrogate endpoints should be considered.

Pharmacogenetics and -genomics

The relationship between phenotype and genotype may be completely different in the neonate as compared to other patient groups. Genetic testing like other tests is subject to prior informed consent. If target genes of interest can be identified, pharmacogenetic analyses of these genes are encouraged. If there are important pharmacogenetic differences affecting pharmacokinetics, efficacy and safety of the medicinal product in the adult populations, pharmacogenetic analysis of the target genes is recommended in neonates. In such cases, the time-dependency (maturation) of the relationship between genotype and phenotype may need to be described.

Dosage Adjustment over Time

Within days in the life of preterm and term neonates, there may be large physiological and / or pathological changes in body weight, BSA, and body composition, as indicated above. For example, physiological post-natal weight loss may be more than 10 % of birth weight, and body weight in preterm neonates may increase rapidly, up to threefold during post-natal medical care.

Consequently, there is a need to continuously re-calculate and adjust dosages of investigational medicinal products on the basis of actual weight (or other relevant covariates) or on the basis of results from therapeutic drug monitoring, because fixed or perpetuated dosages are most probably inadequate in terms of efficacy and safety.

Placebo and Active Comparator

Use of placebo in neonates is more restricted than in adults and older children, as neonates are even more vulnerable. Placebo can be used on top of best standard of care, as placebo use does not imply the absence of treatment. The use of placebo may be needed for scientific reasons, for example to quantify variability and to determine treatment effects. Placebo may be warranted in children as in adults when evidence is lacking. As the level of evidence in favour of an effective treatment increases, the ethical justification for placebo use decreases. In all cases, placebo use should be accompanied by measures to minimise its use and to avoid irreversible harm, especially in serious or rapidly evolving diseases.

Blood Sampling

Preterm and term neonates have very limited blood volume, are often anaemic due to age and frequent sampling related to pathological conditions. The fact that they receive blood transfusions (or iron or erythropoietin supplementation) must not be used as a convenience for increased volume or frequency for blood sampling. The number of samples and/or sample volume should be kept to a minimum.

Study Analysis

As in any clinical trial, the study analysis should be carefully planned in advance, taking into account the limited amount of data that may be available with this patient population. The Guideline on Clinical Trials in Small Populations (CHMP/EWP/83561/2005) is fully applicable to studies with term and preterm neonates, and it therefore needs to be taken into consideration for the planning of the study and of the analysis.

Pain and Distress

As most investigations and procedures carry the risk of pain for the neonates, pain should be prevented, and if unavoidable evaluated, monitored and treated appropriately. Evaluating and monitoring the level of pain may be difficult in the neonate, as scales are based on physiological parameters that can be affected by concomitant diseases and procedures. However, the development and / or use of validated scales is recommended, for example, the Premature Infant Pain Profile (PIPP) or the Neonatal Infant Pain Scale (NIPS) scale for the assessment of pain.

Safety Monitoring

As a general recommendation for hospitalised neonates in a trial, vital signs should be monitored continuously, and related events should be registered according to neonatal definitions (apnea-bradycardia; sustained bradycardia, tachycardia, desaturation, hypotension; fever, hypothermia etc.). Specific age and/or gestation appropriate (e.g., laboratory) reference values and ranges should be used.

Pharmacovigilance and Long-Term Follow up of Safety

The challenging task of pharmacovigilance and follow-up in terms of duration and type depends on the product itself, the target organs, the duration of exposure and other risk factors for sequelae. The potential for adverse drug reactions occurring later in life should be monitored as neonates may have been exposed to medicinal products at a sensitive period in terms of organ maturation. Only a small number of neonates is likely to be included in rather short term trials, thus long-term adverse reactions may not be detected and would require additional appropriate pharmacovigilance approaches and particularly pharmacoepidemiological studies.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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ICH M3 (R2) Non-clinical Safety Studies Guidance updated by EMEA

Posted on July 28, 2009 by admin| 2 Comments

Drug Regulators, EMEA, update ICH M3 (R2) Non-Clinical Safety Guidlines.

The EMEA published new guidance on ICH Topic M 3 (R2) Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals

Regulatory Guideline Introduction

The purpose of this document is to recommend international standards for, and promote harmonisation of, the nonclinical safety studies recommended to support human clinical trials of a given scope and duration as well as marketing authorization for pharmaceuticals. This guidance should facilitate the timely conduct of clinical trials, reduce the use of animals in accordance with the 3R (reduce/refine/replace) principles and reduce the use of other drug development resources.

The nonclinical safety assessment for marketing approval of a pharmaceutical usually includes pharmacology studies, general toxicity studies, toxicokinetic and nonclinical pharmacokinetic studies, reproduction toxicity studies, genotoxicity studies and, for drugs that have special cause for concern or are intended for a long duration of use, an assessment of carcinogenic potential. Other nonclinical studies to assess phototoxicity, immunotoxicity, juvenile animal toxicity and abuse liability should be conducted on a case-by-case basis.

The development of a pharmaceutical is a stepwise process involving an evaluation of both animal and human efficacy and safety information. The goals of the nonclinical safety evaluation generally include a characterisation of toxic effects with respect to target organs, dose dependence, relationship to exposure, and, when appropriate, potential reversibility.

Pharmacology Studies

Safety pharmacology and pharmacodynamic (PD) studies are defined in ICH S7A (Ref. 5). The core battery of safety pharmacology studies includes the assessment of effects on cardiovascular, central nervous and respiratory systems, and should generally be conducted before human exposure, in accordance with ICH S7A and S7B (Refs. 5 and 6).

Toxicokinetic and Pharmacokinetic Studies

In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials. Further information on pharmacokinetics (PK) (e.g., absorption, distribution, metabolism and excretion), in test species and in vitro biochemical information relevant to potential drug interactions should be available before exposing large numbers of human subjects or treating for long duration (generally before Phase III).

Nonclinical characterization of a human metabolite(s) is only warranted when that metabolite(s) is observed at exposures greater than 10% of total drug-related exposure and at significantly greater levels in humans than the maximum exposure seen in the toxicity studies.

Acute Toxicity Studies

Historically, acute toxicity information has been obtained from single-dose toxicity studies in two mammalian species using both the clinical and a parenteral route of administration. However, such information can be obtained from appropriately conducted dose-escalation studies or short-duration dose-ranging studies that define an MTD in the general toxicity test species (Refs. 8 and 9). When this acute toxicity information is available from any study, separate single-dose studies are not recommended.

In some specific situations (e.g., microdose trials)  acute toxicity or single-dose studies can be the primary support for studies in humans.

Information on the acute toxicity of pharmaceutical agents could be useful to predict the consequences of human overdose situations and should be available to support Phase III.

Repeated-Dose Toxicity Studies

The recommended duration of the repeated-dose toxicity studies is usually related to the duration, therapeutic indication and scope of the proposed clinical trial. In principle, the duration of the animal toxicity studies conducted in two mammalian species (one non-rodent) should be equal to or exceed the duration of the human clinical trials up to the maximum recommended duration of the repeated-dose toxicity studies.

table1 300x96 ICH M3 (R2) Non clinical Safety Studies Guidance updated by EMEAEstimation of The First Dose in Humans

The estimation of the first dose in humans is an important element to safeguard subjects participating in first-in-human studies. In general, the No Observed Adverse Effect Level (NOAEL) determined in nonclinical safety studies performed in the most appropriate animal species gives the most important information. The proposed clinical starting dose will also depend on various factors, including PD, particular aspects of the molecule, and the design of the clinical trials.

Exploratory Clinical Trials

It is recognized that in some cases earlier access to human data can provide improved insight into human physiology/pharmacology, knowledge of drug candidate characteristics and therapeutic target relevance to disease. Streamlined early exploratory approaches can accomplish this end. Exploratory clinical studies for the purpose of this guidance are those intended to be conducted early in Phase I, involve limited human exposure, have no therapeutic intent, and are not intended to examine clinical tolerability. They can be used to investigate a variety of parameters such as PK, PD and other biomarkers, which could include PET receptor binding and displacement or other diagnostic measures. The subjects included in these studies can be patients from selected populations or healthy individuals. Five different examples of exploratory clinical approaches are summarized below:

Microdose Trials

The first approach would involve not more than a total dose of 100 μg that can be administered as a single dose or divided doses in any subject. This could be useful to investigate target receptor binding or tissue distribution in a PET study.

A second microdose approach is one that involves < 5 administrations of a maximum of 100 μg per administration (a total of 500 μg per subject). This can be useful for applications similar to the first microdose approach described above, but with less active PET ligands.

Single-Dose Trials at Sub-Therapeutic Doses or into the Anticipated Therapeutic Range

The third approach involves a single-dose clinical study typically starting at subtherapeutic doses and possibly escalating into the pharmacological or anticipated therapeutic range.

The maximum allowable dose should be based on the nonclinical data, but could be further limited based on emerging clinical information obtained during the course of the study. This approach could allow, for example, determination of PK parameters with non-radiolabeled drug at or near the predicted pharmacodynamically active dose.

Multiple Dose Trials

These approaches support up to 14 days of dosing for determination of PK and PD in human in the therapeutic dose range, but are not intended to support the determination of maximum tolerated clinical dose.

Approach 1 involves 2-week repeated-dose toxicity studies in rodents and non-rodents where dose selection in animals is based on exposure multiples of anticipated AUC at the maximum clinical dose.

Approach 2 involves a 2-week toxicity study in a rodent species and a confirmatory non-rodent study that is designed to investigate whether the NOAEL in the rodent is also not a toxic dose in the non-rodent.

A detailed description of the non-clinical requirements for each study is given in the guidleins

Local Tolerance Studies

It is preferable to evaluate local tolerance by the intended therapeutic route as part of the general toxicity studies; stand alone studies are generally not recommended. To support limited human administration by non-therapeutic routes (e.g., a single i.v. dose to assist in the determination of absolute bioavailability of an oral drug), a single dose local tolerance study in a single species is considered appropriate.

Genotoxicity Studies

An assay for gene mutation is generally considered sufficient to support all single dose clinical development trials. To support multiple dose clinical development trials, an additional assessment capable of detecting chromosomal damage in a mammalian system(s) should be completed. A complete battery of tests for genotoxicity should be completed before initiation of Phase II trials.

Carcinogenicity Studies

If carcinogenicity studies are recommended for the clinical indication, they should be conducted to support the marketing application. Only in circumstances where there is a significant cause for concern for carcinogenic risk should the study results be submitted to support clinical trials.

Reproductive Toxicity Studies

Men can be included in Phase I and II trials before the conduct of the male fertility study since an evaluation of the male reproductive organs is performed in the repeated-dose toxicity studies. A male fertility study should be completed before the initiation of large scale or long duration clinical trials (e.g., Phase III trials).

Women not of childbearing potential (i.e., permanently sterilised, postmenopausal) can be included in clinical trials without reproduction toxicity studies if the relevant repeated-dose toxicity studies (which include an evaluation of the female reproductive organs) have been conducted. Postmenopausal is defined as 12 months with no menses without an alternative medical cause.

For women of childbearing potential (WOCBP) there is a high level of concern for the unintentional exposure of an embryo or fetus before information is available concerning the potential benefits versus potential risks. The recommendations on timing of reproduction toxicity studies to support the inclusion of WOCBP in clinical trials are similar in all ICH regions.

Before the inclusion of pregnant women in clinical trials, all female reproduction toxicity studies  and the standard battery of genotoxicity tests (Ref. 10) should be conducted. In addition, safety data from previous human exposure should be evaluated.

Clinical Trials In Pediatric Populations

When pediatric patients are included in clinical trials, safety data from previous adult human experience would usually represent the most relevant information and should generally be available before initiation of pediatric clinical trials. The appropriateness and extent of adult human data should be determined on a case-by-case basis. Extensive adult experience might not be available before pediatric exposures (e.g., for pediatric-specific indications).

Immunotoxicity

As stated in the ICH S8 guidance, all new human pharmaceuticals should be evaluated for the potential to produce immunotoxicity using standard toxicity studies and additional immunotoxicity studies conducted as appropriate based on a weight-of-evidence review, including immune-related signals from standard toxicity studies.

Photosafety Testing

The appropriateness or timing of photosafety testing in relation to human exposure should be influenced by: 1) the photochemical properties (e.g., photoabsorption and photostability) of the molecule, 2) information on the phototoxic potential of chemically related compounds, 3) tissue distribution, and 4) clinical or nonclinical findings indicative of phototoxicity.

Non-clinical abuse liability

For drugs that produce central nervous system activity, regardless of therapeutic indication, it should be considered whether or not an evaluation of abuse liability is warranted. Nonclinical studies should support the design of clinical evaluations of abuse potential, classification/scheduling by regulatory agencies, and product information. There are regional guidance documents on the conduct of nonclinical abuse liability assessment that can be helpful in designing specific abuse liability packages.

Other Toxicity Studies

Additional nonclinical studies (e.g., to identify potential biomarkers, to provide mechanistic understanding) can be useful if previous nonclinical or clinical findings with the product or related products have indicated special safety concerns.

Combination Drug Toxicity Testing

Combinations covered might involve: (1) two or more late stage entities (defined as compounds with significant clinical experience (i.e. from Phase III studies and/ or post marketing)); (2) one or more late stage entity(ies) and one or more early stage entities (defined as compounds with limited clinical experience (i.e. Phase II studies or less)); or (3) more than one early stage entity.

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If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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Drug Regulators, EMEA, Publishes Q&A on ICH M2 eCTD

Posted on July 18, 2009 by admin| Leave a comment

The Drug Regulators, EMEA, has published Q&A paper on ICH M2

The EMEA publishes ICH Topic M 2 Question and Answer Common Technical Document for the Registration of Pharmaceuticals for Human Use

Its a huge document that I would recommend you reading as its too big and varied to summarise here, but the document reference so you can search for it is CPMP/ICH/820/03.

This question and answer document is a summary of questions reviewed by the eCTD Implementation Working Group (IWG) on the eCTD Specification. The questions answered here relate to common questions that relate to the eCTD in all three ICH regions. Many of the questions received on the Step 2 specification were addressed in Step 4 and do not appear in the list. Questions concerning the timeframe for implementation of region-specific application types, module 1 implementation, lifecycle management and those questions that relate to items in the specification that direct the reader to each region are answered in guidance documents published for each region.

Questions related to the table of contents for the Common Technical Document (CTD) should be directed to the CTD question and answer section of the ICH Website.
Some of the questions posed so far address change requests to the eCTD Specification. The change request section of this document addresses all those items received by the eCTD IWG and indicates their status.

This document will be updated as the specification undergoes change control or as new questions are submitted to the eCTD IWG.

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Drug Development Regulations – Q4B Annex

Posted on July 16, 2009 by admin| Leave a comment

Drug Regulator, EMEA, publishes input into ICH Q4B Tablet Friability

EMEA publishes ANNEX 6 TO NOTE FOR EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS ON TABLET FRIABILITY GENERAL CHAPTER (EMEA/CHMP/ICH/379801/2009)

Analytical Procedures

The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that the analytical procedures described in the official pharmacopoeial texts, Ph.Eur. 2.9.7. Friability of Uncoated Tablets, JP General Information 26. Tablet Friability Test, and USP <1216> Tablet Friability, can be used as interchangeable in the ICH regions.

Acceptance Criteria

For interchangeability, the loss of mass for a single determination should be not more than 1.0 percent, unless otherwise specified in the dossier. When three determinations are conducted, then the mean loss of mass for the three determinations should be not more than 1.0 percent, unless otherwise specified in the dossier.

EMEA publishes input into ICH Q4B Polyacrylamide Gel Electrophoresis

EMEA publshes ANNEX 6 TO NOTE FOR EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS ON POLYACRYLAMIDE GEL  ELECTROPHORESIS GENERAL CHAPTER (EMEA/CHMP/ICH/381133/2009)

Analytical Procedure

The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that the official pharmacopoeial texts, the section in Ph.Eur. 2.2.31. Electrophoresis entitled “Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis (SDS-PAGE)”, JP General Information 23. SDS-Polyacrylamide Gel Electrophoresis, and USP <1056> Biotechnology-derived Articles – Polyacrylamide Gel Electrophoresis, can be used as interchangeable in the ICH regions.

Acceptance Criteria

The texts evaluated did not contain acceptance criteria

EMEA Publishes ICH input Q4B Sterility Test

The EMEA Publishes ANNEX 6 TO NOTE FOR EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS ON STERILITY TEST GENERAL CHAPTER (EMEA/CHMP/ICH/645592/2008)

Analytical Procedure

The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that the official pharmacopoeial texts, Ph. Eur. 2.6.1. Sterility, JP 4.06 Sterility Test, and USP <71> Sterility Tests, can be used as interchangeable in the ICH regions subject to the conditions detailed below. Testing conditions for medical devices, such as sutures, are outside the scope of the ICH recommendation.

  • Diluting and rinsing fluids should not have antibacterial or antifungal properties if they are to be considered suitable for dissolving, diluting, or rinsing an article under test for sterility.
  • When testing liquid parenteral preparations with a nominal volume of 100 milliliters in batches of more than 500 containers, the test is considered interchangeable if the minimum number of containers selected is either 20 or is 2 percent of the total number of containers, whichever is lower.

Acceptance Criteria

The acceptance criteria are harmonized between the three pharmacopoeias.

EMEA Publishes ICH input on Q4B Disintigraion Test

The EMEA Publishes ANNEX 5 TO NOTE FOR EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS ON DISINTEGRATION TEST GENERAL CHAPTER (EMEA/CHMP/ICH/308895/2008)

Analytical Procedure

The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that for tablets and capsules, the official pharmacopoeial texts, Ph. Eur. 2.9.1. Disintegration of Tablets and Capsules, JP 6.09 Disintegration Test, and USP <701> Disintegration, can be used as interchangeable in the ICH regions subject to the conditions detailed below. Testing conditions for specific dosage forms are outside the scope of the harmonization of this chapter.

  • For tablets and capsules larger than 18 millimeters (mm) long for which a different apparatus is used, the Disintegration Test is not considered to be interchangeable in the three regions.
  • The Disintegration Test is not considered to be interchangeable in the three regions for dosage forms referred to in the regional compendia as delayed-release, gastro-resistant, or enteric-coated.
  • Product-specific parameters such as media and the use of discs should be specified in the application dossier.

Acceptance Criteria

Acceptance criteria are outside the scope of the harmonization of this chapter and should be specified in the application dossier.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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Herbal Drug Regulations – EMEA Draft Guidance on Genotoxicity Testing for Traditional Herbal Medicinal Products

Posted on July 14, 2009 by admin| 1 Comment

Drug Regulators, EMEA, Publish Draft Guidance on Genotoxicity Testing for Traditional Herbal Medicinal Products.

Inclusion in the Community list of a herbal substance/preparation represents a significant advantage to applicants seeking registrations for traditional herbal medicinal products. This is because once a herbal substance/preparation is included in the Community list an applicant will not be required to provide evidence of the safe and traditional use of a medicinal product for which he seeks a traditional use registration if he demonstrates that the proposed product and related claims in the application comply with the information contained in the list.

Progress with the development of Community list is being hampered by the absence of genotoxicity data. Experience to date confirms that many well known traditional herbal substances/preparations, already widely available within the Community, will be excluded from the Community list solely as a consequence of absence of genotoxicity data and thus any potential benefits of the list to applicants will be lost.

The stepwise approach described in the guideline sets out a pragmatic approach to address both scientific aspects of genotoxicity testing and the special needs of herbal medicinal products within the current regulatory framework applicable to these products.

Strictly speaking, genotoxicity testing should be carried out by individual applicants on their specific materials and it is recognised that this represents a major task and considerable duplication of effort particularly for applicants seeking registrations for traditional herbal medicinal products. Industry has therefore been encouraged to consider undertaking collaborative research on genotoxicity and one such study is underway within some Member States.

This guidance offers a strategy to reduce the number of test materials such that a representative range of herbal preparations is tested rather than requiring individual manufacturers to undertake their own testing on specific preparations.

Scope

This guideline addresses the selection of materials for genotoxicity testing in support of applications for traditional herbal medicinal products/ herbal medicinal products.

This guideline provides possible approaches to what types of materials should be subjected to testing for genotoxicity bearing in mind that different herbal preparations may have different toxicological profiles.

The main objective is to achieve consensus on a standard range of test materials which could be considered representative of the commonly used herbal substances/preparations with the intention of facilitating entry to the Community list.

Selection of Materials for Genotoxicty Testing

The concept of applying a reduced design approach such as ‘bracketing/ matrixing’to the selection of samples for genotoxicity testing is proposed. Using the ‘bracketing’ concept, only samples on the extremes of certain design factors would be tested. The reduced design assumes that the genotoxic potential of any intermediate preparation is represented by the test results of the extremes tested. Where a reduced testing design is proposed, evidence (usually chromatographic data) should be provided to demonstrate that the samples to be tested represent the phytochemical profile of all materials to be covered by the genotoxicity testing.

Herbal Substance Used in Herbal Medicinal Products

Where the entire herbal substance is incorporated directly into the herbal medicinal product, e.g. in capsules, tablets, the test material for genotoxicity testing, should, in theory, cover the entire spectrum of phytochemical constituents, including polar and non-polar constituents. Test materials for genotoxicity testing should therefore include extraction solvents which encompass the entire phytochemical profile. The choice of solvents should be justified. Consideration should be given to including an extract mid-range e.g. 50% water.

Fixed oils/essential oils/extracted juices etc

Where the herbal preparations include for example fixed oils, essential oils, expressed juices etc these should be addressed on a case by case basis. Some materials may need to be tested individually as part of the genotoxicity test programme. In the case of expressed juices, it may be possible to demonstrate that the material is covered by testing of, for example, an aqueous extract.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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Drug & Biotech Regulations – EMEA Transparency Policy, Draft for Public Consultation

Posted on July 10, 2009 by admin| Leave a comment

EMEA publishes Draft Transparency Policy

Drug and Biotechnology Regulatory Agency, EMEA, Publishes a draft Policy on Transparency. The EMEA in its longer term vision indicated that its stakeholders would see over the next few years a gradual and stepwise increase in the Agency’s level of transparency, both in the field of non-product as well as product related activities. In order to achieve this objective the EMEA stated that it would involve its partners and stakeholders in discussions on how to meet the increasing demands of civil society (in particular patients/users of medicines as well as healthcare professionals) for earlier information whilst respecting commercial confidentiality of proprietary information.

Rational and Scope of The EMEA Transparency Policy

Rational

The rationale for the development of an EMEA Transparency Policy is:

  • To be able to better address the increasing need for information from civil society
  • To provide for more openness on the various activities undertaken by the EMEA (in particular its opinion/decision-making process),

Transparency is a pivotal element in building trust and confidence in the Agency’s operation and in addition it fulfils the right of EMEA stakeholders for impartial and comprehensible information about the medicines regulated by the Agency and their use for the benefit of public and animal health.

Scope

Transparency implies openness, communication and accountability, whilst respecting the protection of both personal data as well as commercially confidential information. The EMEA embraces these concepts in the development of its Transparency Policy. The scope of the EMEA Transparency Policy covers medicines for both human and veterinary use, addressing the particularities of each field. Furthermore, the Policy is not restricted to measures arising from currently applicable Community legislation, but it will provide the Agency’s stand on its level of openness toward stakeholders. It is not limited to the level of transparency applied to documents produced by the EMEA, but it will also address other aspects such as the level of interaction with its stakeholders, including involvement in opinion/decision-making.

Objectives of the EMEA Transparency Policy

Three important objectives have been identified:

  1. To apply a more proactive approach towards transparency in the daily operation of the EMEA
    1. Finding the right balance between transparency and protection of commercial confidentiality
    2. Increasing the understanding of activities undertaken by the EMEA, including the Agency’s opinion/decision-making.
    3. Promoting good administrative and regulatory practices
  2. To further strengthen interaction with EMEA stakeholders
  3. To enhance and promote closer interaction with the NCAs within the frame of the EU Regulatory System Network on transparency related aspects

Proposed Way Forward

Objective 1

  • Review the balance between transparency and the protection of commercial confidentiality of proprietary information by redefining the notion of commercially confidential information and subsequently arriving at a harmonised EU view on this topic.
  • Gradually improve, once the decision-making process has been concluded, the proactive disclosure of EMEA documents/information throughout the lifecycle of medicines for human and veterinary use
  • Improve the visibility of the Agency and undertake efforts to better explain how conclusions are being reached at the EMEA as well as the (scientific) rationale for these conclusions.
  • Embed a culture of transparency in the Agency’s operations in order to achieve a consistent approach in the application of the various principles of the EMEA Transparency Policy.

Objective 2

Over the next years the EMEA will further progress existing interactions with civil society representatives (in particular patients, but also healthcare professionals), especially at the level of the EMEA Scientific Committees

Objective 3

Further work in this field will focus on identifying where it would be of benefit for the efficiency of the EU Regulatory System Network to arrive at a harmonised approach on transparency related aspects for medicines regulation throughout a product lifecycle. In addition, efforts should also be directed on achieving as much as possible a consistent implementation across the EU.

Next Steps

The draft EMEA Transparency Policy is subject to public consultation until 25 September 2009. In addition, a 2nd Workshop with EMEA partners and stakeholders on the development of the EMEA Transparency Policy is scheduled to take place at the EMEA on 19 October 2009. Following an analysis of the comments received and subsequent adoption by the Agency’s Management Board, the EMEA will publish the final Transparency Policy.

The document then goes on to give examples of the strategies being pursued, its a good start in a process that should make the EMEA more open and accountable, which is good for all involved.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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Guidline on Quality, Non-Clinical and Clinical Aspects of Live Recombinant Viral Vectored Vaccines

Posted on June 19, 2009 by admin| Leave a comment

EMEA publishes new guidelines, “Guideline on Quality, Non-Clinical and Clinical Aspects of Live Recombinant Viral Vectored Vaccines” . Vaccines against infectious diseases based on a viral vector expressing the antigen infectious agent have been under development for some time.This guideline ap pplies to such live recombinant vaccines for the prevention and treatment of infectious disease, and provides guidance on quality, non-clinical and clinical aspects.

The objective of this guideline is to provide recommendations on the quality, nonclinical and clinical studies should be performed in order to obtain marketing authorisation of a live recombinant viral vector vaccine intended to use in the prophylaxis of infectious disease in humans. This guideline is intended products entering the marketing authorisation procedure. However, the principles laid down in this guideline should be considered by applicants entering into clinical trials.

In this guideline, the emphasis is placed upon safety issues, such as:

  • The phenotype of recombinant virus
  • The extent of pre-immunity to the vector, the extent of community induced to the vector and the potential for reuse of the vector,
  • Genetic stability of the recombinant virus, reversion to the virulence or the combination with wild type strains
  • Clinical follow up in healthy patient populations
  • Chromosomal germline integration.

These aspects will drive the selection a number of different relevant toxicological pharmacological models. Emphasis is also placed on first in man studies as the vaccines within the scope of this guideline and novel laboratory derived viruses obtained by recombinant DNA technology and clinical assessment will represent their first contact with humans.

The guideline goes on to give detailed descriptions of what is expected in the following areas:

  • Quality aspects
    • General considerations
    • Genetic development
    • Vaccine seed lots
      • General
      • Characterisation of vaccine seed lots
      • Adventitious agent safety
    • Vaccine manufacture
      • Vaccine production
      • Harvesting
      • Virus pools
      • Final bulk vaccine (drug substance)
    • Control of final vaccine (drug product)
      • Identity
      • Potency assays
      • Stability
      • Consistency of production
  • Nonclinical immunological and safety requirements
    • General considerations
    • Pharmacodynamic studies (protection and immunogenicity)
    • Nonclinical safety studies (toxicity testing)
      • Single and repeated dose toxicity
      • Distribution studies
      • Reproduction and development toxicity studies
      • Local tolerance
  • Clinical
    • Immunogenicity
    • Safety

These are a detailed set of guidelines that cover most of the process of development and are required reading for anybody working in the area.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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IDA consultants Provides Regulatory Roadmap

Posted on June 8, 2009 by admin| Leave a comment

IDA consultats has been approached to provide a couple of slides that outline a regulatory roadmap, I thought I woudl share them with my readers as well, along with the notes that I provided to the speaker, I hope you find them helpful.

slide1 IDA consultants Provides Regulatory Roadmap

slide2 IDA consultants Provides Regulatory Roadmap

The pathway through MHRA/EMEA drug approval process

Speaker notes for slides

The first step is to put together your development plan, in the first instance you will require clinical trials outlines nonclinical outlines nonclinical safety outlines and GMP manufacturing plans. It is advised that you seek scientific advice at this stage unless your program is very much a vanilla program. This process of gaining a regulatory rubberstamp can prove very valuable in terms of de-risking your project and make you more attractive to investors.

In order to get your clinical trial program approved there are two routes that you can take:

There is a central review process that is run by a subcommittee of the EMEA, where you can submit your development plan and clinical trials protocols for central review this is not an approval process, it enables European wide feedback and comments upon your plans. It is voluntary for most programs however it is mandatory for biotech products and high-tech products for multinational phase 3 programs . You still need to apply for local approval after this and local ethics approval however it gives you an opportunity to countries that have a positive opinion about your program.

Most companies chose to go down the national procedure route, in which you have your clinical trial approved by the appropriate authorities in the UK this is the MHRA, you will then require local ethics approval, we advise you apply for both your CTA and your local ethics simultaneously in order to save time.

If your product is a high risk product such as monoclonal or similar, you will require an extra stage of approval by the EAG this will come before your standard CTA approval program.

You can then initiate your clinical trials programme.

For the scientific meetings and advice you will need a regulatory briefing book, this should be ideally no more than 20 to 50 pages 20 pages of the new programs 50 pages the programs are gone through a number of clinical trials, this should be very brief and to the point.

To start your official CTA process you will require full protocols, full case report forms, and a much more detailed briefing book.

In order to undertake your clinical trial you will require a CRO to manage it, it is recommended that you undergo a CRO selection process at a very early stage, you will require insurance, again the cost of insurance can be much reduced if you speak to your insurance company at a very early stage. You will require ongoing Pharmacovigilance cover, in most of the world pre-clinical and clinical trials programmes will require GMP clinical trial stock however there are a number of countries were full GMP is not required and “in the spirit of GMP” may be acceptable. This includes the USA Belgium and Holland.

I would recommend that you seek regulatory scientific advice between each of your clinical trials in order to establish that the results seen have not impacted on the regulatory acceptance of the overall design. This is probably not required if your results are exactly as you have predicted they would be.

Second slide

Once you have completed your development programme will require a product licence to sell your product in Europe. There are many routes for this: there is a central process run by the EMEA, a national process, the national process followed by mutual recognition, and decentralised process for products that are already on the market in the country.

There are many factors that go into the choice of routes to many to be discussed here. Whichever route you decide upon it is well advised to seek meetings with the regulators well before submission of your application in order to confirm acceptance of your planned route.

With the central process your application is made to the EMEA who then have it reviewed by two representative national bodies, if this is acceptable then Central European approval is granted and your product can be sold anywhere within the union.

In the national process you gain national approval with the body of your choice then you can sell your product in that country. At this point you can start a mutual recognition process where you use your existing approval to springboard approval into other selected states.

The decentralised procedure is the products are being on the market and have a market history in one or more European states, you can then proceed to gain regulatory approval in national states based upon that national approval.

Whichever route you take your require a common technical document or a an eCTD as they are known, this will ensure that your documentation is in a state that is acceptable in all this national states and also in the USA.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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EMEA publishes concept paper on the development of guidlines on the use of Pharmacogenomic Methodogologies in PK evaluation

Posted on June 4, 2009 by admin| 1 Comment

The EMEA has published concept paper on the development of the guidelines on the use of pharmacodynamic methodologies in the pharmacokinetic evaluation of medicinal products.  In recent years there has been a rapid development regarding our understanding of the genetics behind interindividual differences in drug response. This development encompasses the area of pharmacodynamics where individual variability in genes encoding drug transporters, and drug metabolising enzymes affects the systemic and target organ exposure as as well as the occurrance of adverse drug reactions to pharmacologically active substances.

A reflection paper on the use of pharmacokinetics in the pharmacokinetic evaluation of medicinal products was published by the EMEA in May 2007. Since the drafting of this reflection paper, progress in the field has been considerable. In the light of evolution and broad acceptance of genotyping methods, as well is increased experience in the use of such pharmacognomic methodologies during drug development, it was considered appropriate to update aline this progress in the guidance on the topic.

The fundamental issues to be discussed in a proposed CHMP guideline is how to implement pharmacogenetics affecting PK in drug development, and the pharmacokinetic variability arising from pharmacogenetic differences may best be determined, how to assess clinical relevance of this pharmacokinetic differences and recommendations on how to reflect these data in the labelling.

The main additional topics to be addressed in the proposed guideline as compared to reflection paper are:

  • Clarifications regarding how and when to apply genotype during clinical development.
  • Data needed for evaluating the clinical relevance of  pharmacogenetic effect on drug exposure as well as the benefits of applying genotyping during clinical use.
  • Recommendations regarding pharmacokinetic studies investigating the effect of polymorphisms at transport level.
  • Guidance on specific technical aspects to be considered in accessing clinically relevant polymorphism (e.g. impact of different allelic variants).

Timetable for drawing up this guidance is as follows; it is anticipated that the guidance will be available nine months after adoption of this concept paper on purely six months external consultation, before finalisation within six months. External consultation from the pharmaceutical industry and academics and professional networks is welcomed by the EMEA.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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EMEA issue draft guidance on plasma-derived medicinal products

Posted on June 2, 2009 by admin| Leave a comment

EMEA has issued guidance on plasma derived medicinal products. This guidance lays down the requirements of the collection of starting material, the manufacturing and the quality control of plasma derived medicinal products. Specific attention will be given to the viral safety of these products.

This is the fourth edition of the guidelines to be published, and include an update on the legal framework as well is an update on specific guidance.

Human plasma contains many proteins, extraction and purification of which are of great medicinal importance. Improvements in protein purification and molecular separation technology has made available a wide variety of products, with medicinal applications covering a large field, the therapeutic value of these products is unquestioned. However, the potential for viral transmission is well recognised, and because of the large number of donations which are pooled, a single contaminated batch of plasma drug product, with the contamination possibly originating from a single source donation, and transmit viral disease to a large number of recipients.

The prevention of such contamination is the main focus of these guidelines. They cover the whole process from the collection and testing of the starting material through quality-control manufacturing and preparation processes, a great deal of emphasis is put upon donor selection, traceability and post collection measures including look-back procedures. Process validation during manufacturing is also covered in the guidance, as well as quality control. These products have specific requirements for stability which are also covered.

This guidance is essential reading than anybody developing plasma derived therapeutic products.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug  development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

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EMEA Guidlines on Clinical Investigation of Medicinal Products for The Treatment of Ankylosing Spondylitis.

Posted on June 1, 2009 by admin| Leave a comment

The EMEA has published guidance on the clinical evaluation of new medical products the treatment and ankylosing spondylitis (AS), a chronic inflammatory disease that affects primarily sacroiliac joints and the axial skeleton. The prevalence has been estimated at between 0.1 and 1.1% of the population.

The guidance describes the patient characteristics/selection criteria that should be considered for inclusion of patients into clinical trials. This is of particular importance in order to establish the correct diagnosis, distinguish patients with AS from those suffering from other subtypes of spondyloarthritis, and appropriately assess the severity and extent of the disease at baseline.

The different domains to assess efficacy and medicinal product are described as well is the therapeutic claims that are distinguished from the regulatory perspective:

  1. improvement of symptoms and signs such as pain and stiffness or enthesopathy
  2. improvement of physical function
  3. slowing or prevention of structural damage
  4. prevention of disability

The guidance, furthermore, outlines strategies for early studies in man (does response trials) as well as therapeutic complimentary trials including acceptable primary and secondary endpoints to assess efficacy. Specific aspects of evaluation of clinical safety are also highlighted, specifically a need for long-term safety data in the treatment of this chronic disease.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug  development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

ida consultants freestrategyconsultation 515x64 EMEA Guidlines on Clinical Investigation of Medicinal Products for The Treatment of Ankylosing Spondylitis.

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EMEA re-posts Points to Consider on Missing Data

Posted on May 29, 2009 by admin| Leave a comment

The EMEA has re-posted points to consider on missing data, this points to consider was formally adopted in 2001, however the EMEA has chosen to re post this on the website. It does not appear to have changed since its last posting.

The EMEA a considered missing data as a potential source of bias when analysing clinical trials, interpretation of the results of a trial is always problematic when the number of missing values is substantial. There are many possible sources of missing data, affecting either complete subjects or specific items, missing data violate the strict Intend To Treat principals: measurement of patient outcomes regardless of protocol adherence and analysis performed by treatment assigned, regardless of which treatment patients actually received.  If missing values are handled simply by excluding any patients with missing outcomes from analysis, the following problems may affect the interpretation of the trial results.

The sample size and variability of outcomes affects the power of the clinical trial, power is greater the larger sample size and smaller variability. The reduction in the number of cases available for analysis, completeness of data add ot the resulting reduction of the statistical power.

Bias is the most important concern resulting from the missing data may affect: Designation of the treatment effect, The comparability of the treatment groups, The representativeness of the study sample in relation to the target population. Bias occurs in the estimation of the treatment effect when the relationship between missing this treatment outcomes exists. In most cases it is difficult or impossible to elucidate whether the relationship between missing values and unobserved outcome variable is completely absent. Thus it is sensible to adopt a conservative approach, considering missing values as potential sources of bias.

A possible way of handling incomplete data is to ignore them and perform statistical analysis with complete data only. However, complete case analysis violates intention-to-treat principal. More importantly it is subject to bias, and thus cannot become recommended as the primary analysis confirmatory trial.

The statistical analysis of the clinical trial requires imputation of values to those data that have not been recorded. Many techniques have been used for the imputation of missing data, but none of them can be considered as the gold standard in every situation. The guidance goes on to discuss the many options available:

To cope with situations where response collection is interrupted at one point, the widely used method is last observation carried forward. This method is likely to be acceptable if measurements are expected to be relatively consistent over time.

Best worst case imputation, assigning the worst possible value of the outcome to dropouts are a negative reason (treatment failed) and the best possible value to positive dropouts (kills), is another approach that can be considered, provided it is applied conservatively.

Another simple approach of inputting missing data is to replace the unobserved measurements by values derived from other sources. Possible sources include information from the same subject, from other subject of similar baseline characteristics, the predictive value from an empirically developed model, historical data, etc.

Most methods faced the risk of bias in the standard error downwards by estimating central value and ignoring its uncertainty. This risk can be avoided by some techniques based upon maximum likelihood methodology and with multiple imputation methods. Maximum likelihood methodologies have been proposed that imputation of missing values, as have multiple imputation methods. Maximum likelihood method strategies fit the model by an iterative process. Multiple input methods generate multiple copies of the original dataset replacing missing values by randomly generated values, and analysing is complete sets.

Unfortunately, there is no universally accepted methodological approach and the missing values.the best process of all is the avoidance of missing data in the first place.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug  development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

ida consultants freestrategyconsultation 515x64 EMEA re posts Points to Consider on Missing Data

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EMEA republish points to consider on clinical investigation of medicinal products used in the treatment of osteoarthritis

Posted on May 28, 2009 by admin| 1 Comment

The EMEA has republished points to consider on the clinical investigation of medicinal products used in the treatment of osteoarthritis, this was originally published in July 1998 however the EMEA has recently re-posted it on their website. The publication has not been altered since 1998. This concept paper presents guidance for clinical studies addressing pharmaceutical treatment of osteoarthritis only systemic products are addressd, topical remedies in particular and not dealt with in this paper and other rheumatic diseases are also not considered.

The concept paper starts by outlining the classification of anti-osteoarthritis therapies, these are medications that affect the symptoms and/or modify structures within the disease. The nomenclature currently proposed recognises 3 types of drugs acting on osteoarthritis: fast acting drugs that induce symptomatic relief, slow acting drugs that induce symptomatic relief and disease modifying drugs.

Due to the pathophysiological differences of osteoarthritis in different body parts the EMEA treats different body parts sa different indications for the purposes of results interpretation and product registration.

The paper also goes on to describe the primary and secondary efficacy endpoints for the different types of drug: symptom modifying drugs, largely rely on pain and function as primary endpoints. Structure modifying drugs rely on long-term outcomes such as necessity for joint replacement time to need surgery and long-term clinical performance (pain and disability).

The paper also includes guidance on clinical trial design for dose finding and therapeutic comparative trials: study population is given particular attention, as is concomitant interventions. The use of placebo and the choice of comparators is also addressed in the document as are safety considerations.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug  development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

ida consultants freestrategyconsultation 515x64 EMEA republish points to consider on clinical investigation of medicinal products used in the treatment of osteoarthritis

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EMEA re-post Draft Guidance on the Clinical Evaluation of Anti-virals intended for HepC

Posted on May 27, 2009 by admin| 1 Comment

The EMEA has reposted draft guidance on the “Clinical Evaluation of Direct Acting Antivial Agents Intended for the Treatment of Chronic Hepatitis C”. the guidance was originaly posted in April 2008, but the EMEA has re-posted it.  the contents don’t appear to have altered and in summary:

  • The guidlines are focused on testing new therapies as add-on to current gold standard (Pegalated-interferon alpha 2a and 2b).
  • A special concers is the high mutation rate of HepC with the attendant risk of selection of drug resistant variants.
  • Initial studies should enrol subjects naive to Standard of Care who do not have advanced fibrosis or HIV co-infection.
  • The next study coudl enrole patients with genotype 1 infections who have had a sub-optimal response to standard of care or relapsed.
  • Once effect of the add-on therapy have been described later studies can look at specific groups such astumour types, HIV infected patients and mornull  responders to standard treatments

There is also discussion of epidemiology of infection  quoting around 3% of the worlds population has been infected and around 200 million people at risk of developing serious liver morbidity. The natural course of infection is also discussed around 60 to 80% of infected individuals becoming chronic carriers.and after about 20 years 20 to 30% of them have progressed cirrhosis, the five-year risk of hepatic decompensation is around 15 to 20% and that of hepatocellular carcinoma around 10%.

Guidance is provided on the design of exploratory and confirmatory clinical studies considered to be of relevance for the evaluation of direct acting anti-hepatitis C compounds as add on to standard of care in different populations. Guidance is given on subjects characteristics and selection of subjects, guidance is also provided on genotyping, primary endpoints the recommendation in this case sustained virological response defined as undetectable virus RNA six months after completion of therapy. Secondary endpoints are also described, end of treatment response and time to confirmed undetectable viral load, rapid viral response and early viral response, liver histology guidance is also provided.

Guidance goes on to describe the pharmacokinetic studies that are required the pharmacodynamic studies that are required, the guidance then goes on to describe appropriate for one studies in special populations; transplant patients and  studies in children.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug  development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

ida consultants freestrategyconsultation 515x64 EMEA re post Draft Guidance on the Clinical Evaluation of Anti virals intended for HepC

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EU announces 246 million Euros of medical research funding and tells us what they are looking for in the next round

Posted on May 20, 2009 by admin| Leave a comment

The European Commission and the EFPIA announced on Monday that 15 research projects were selected to receive a total of 246 million Euros (US$333 million) in research funding made available through the Innovative Medicines Initiative (IMI). The selected projects will address the main causes of bottlenecks in the pharmaceutical R&D process.

the 15 projects will focus on the health issues such as diabetes, psychiatric disorders, severe asthma and pain. The Pharmaceutical industry provides 136 million Euros (US$184million) through provision of their resources, facilities, materials and staff, and the remaining 110 million Euros goes to other participants such as small businesses, patient groups and academic groups.

The next call for proposals, is in the autumn and they will be seeking products in Oncology, Chronic Inflammatory disease, among others.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug  development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

ida consultants freestrategyconsultation 515x64 EU announces 246 million Euros of medical research funding and tells us what they are looking for in the next round

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EMEA puts out a new concept paper – developing a guidline for the use of Pharmcogenomic Methodologies in the Pharmacokinetic Evaluation of Medicinal Products

Posted on May 15, 2009 by admin| Leave a comment

EMEA put out a concept paper on “The development of a guidline on the use of pharmacogenomic methodologies in the pharmacokinetic evaluation of medicinal products”

Background

In recent years there has been a rapid development regarding our understanding of the genetics behind interindividual differences in drug response, pharmacogenomics forms a major part of this research area, where interindividual variability in genes encoding drug transporters, and drug metabolising enzymes affects the systemic and target organ exposure of pharmacologically active substances, thereby affecting the efficacy obtained of drug treatment as well as the occurrence of adverse drug reactions. The highest abundance of genetic polymorphism is registered at the level of drug metabolism where approximately 40 % of phase I metabolism of clinically used drugs is catalysed by enzymes with polymorphisms known to have a marked impact on their function in vivo.

In light of the evolution and broad acceptance of genotyping methods, as well as increased experience in the use of such pharmacogenomic methodologies during drug development, the EMEA considered it appropriate to update and align this progress in a Guideline on this topic.

What the guideline hopes to achieve

The fundamental issues to be discussed in a proposed CHMP Guideline is how to implement pharmacogenetics affecting PK in drug development, how the pharmacokinetic variability arising from pharmacogenetic differences may best be determined, how to assess clinical relevance of the pharmacokinetic differences and recommendations on how to reflect these data in the labelling.

So if you have any interest in the topic you need to be getting in touch with the EMEA and register your interest.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug  development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

ida consultants freestrategyconsultation 515x64 EMEA puts out a new concept paper developing a guidline for the use of Pharmcogenomic Methodologies in the Pharmacokinetic Evaluation of Medicinal Products

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EMEA publishes a reflection paper – Recombinant Adeno-Associated Viral Vectors

Posted on May 3, 2009 by admin| 8 Comments

The EMEA today released a reflection paper regarding Quality, non-clinical and clinical issues relating specifically to recombinant adeno-associated viral vectors. It is still open for comment until September 2009.

Recombinant adeno-associated viral (rAAV) vectors are derived from the single stranded DNA virus adeno-associated virus which belongs to the genus dependovirus within the Parvoviridae family. As the name suggests the wild type virus is incapable of independent replication and relies on co-infection of a helper virus to enable a lytic replication cycle (Gonclaves, 2005). Adenovirus (Ad), herpes simplex virus (HSV), pseudorabies virus (PrV) and human papilloma virus (HPV) are known to support wild type AAV replication.

Given the basic biology of the ‘parent’ virus, the methods for manufacture and quality control of product are complicated, and the long-term fate of the administered vector is at present unknown. There are a number of manufacturing strategies that can be used to produce rAAV vectors.

The aim of this reflection paper is to discuss quality, non-clinical and clinical issues that are specific only to the development of rAAV vectors as medicinal products. The paper goes on to discuss in some details the different manufacturing methodologies that can be used to generate rAAV including:

  • Virus containing production systems (helper virus & hybrid vectors)
  • Virus-Free production systems (tri-plasmid transfection & packaging cell lines)
  • Self-complementary adeno-associated virus

There are a number of quality considerations that are specific to these systems, from the standard issues of cell banking, seed stock and qualified cell lines, virus origine and stock control/testing. There are also a number of specific issues to be considered:

Virus Containing Production Systems: The main disadvantage of this system is the potential for contamination of the product with the helper/hybrid virus,and strategies for dealing with this are described. “It is recommended that a quality specification for the helper/hybrid virus is set, and the testing strategy detailed in the Ph. Eur. (Monograph 5.14 Gene Transfer Medicinal Products for Human use) can be used for guidance in defining an appropriate testing program. In particular, if the helper/hybrid virus is considered to be replication incompetent, the specification should include a test for replication-competent virus contamination.”

Virus Free Production Systems: Limitations of a manufacturing approach that relies solely on plasmid transfection lie in the difficulties of process scale up and the consistency of manufacture due to the inherent variability of the transfection process itself. However, the advantage of such an approach is that the quality of the final product is improved as there will be no contamination of the product with a helper/hybrid virus. It is recommended that the transfection conditions are thoroughly evaluated and optimized at each scale of manufacture to assure consistency in product quality and yield. Following each manufacturing change product characterization should be undertaken to assure that the introduced changes do not impact on product quality. Furthermore, the purification process should be sufficiently robust to assure removal of excess plasmid from the final product. Quality issues specific to packaging cell lines are identical for those used to manufacture recombinant proteins in that the genetic stability of construct should be shown, at or beyond the expected number of population doublings required for manufacture.

Issues of Non-Clinical Evaluation

Choice of Animal Model – AAV is a species specific virus, therefore it is possible that the biodistribution of a human serotype derived vector in a mouse or rat may not correlate to that when administered to man as cellular/organ uptake may be different as a result of differences in, or differential expression of, the receptor used for entry. A number of animal species have been used in non-clinical evaluation of rAAV vectors (rats, mice, rhesus monkey, non-human primates, dogs, cats and pigs); however it is not clear which is the most appropriate model to use, and it may be necessary for more than one species to be used to complete a full non-clinical development program. Given these difficulties there may be scientific justification for using in pivotal non-clinical studies, a serotype of virus that is specific to the animal model of choice, rather than the human serotype that will be used in clinical studies. Such studies may provide more useful information in relation to biodistribution and the impact of pre-existing immunity to the vector to it.

Vector Persistance – The safety of rAAV in terms of insertional mutagenesis is still under debate following a recent publication where an increased rate of hepatocellular carcinoma was observed in neonatal mice treated with a rAAV (Donsante, 2007). While this study is not definitive in confirming the oncogenic potential of these vectors (Kay, 2007), the implications of the study can not be ignored, and the level of integration of the vector under investigation should be evaluated. Non-clinical studies should be considered which are designed to investigate how long-term gene expression is expected to be achieved i.e. episomal or integration.

Tissue Tropism – Different serotypes of AAV have been associated with specific tissue tropisms, for example AAV 1, 6 and 7 are effective at transducing muscle cells; serotype 9 preferentially transducing the myocardium and AAV 5 is suggested to be more tropic to the airway epithelium and the central nervous system (at least in the mouse model). This preferential transduction activity does not mean however, that the vector is not distributed to other organs. It is possible therefore, that tissue tropism defined non-clinically may not be observed following administration to humans, and it is recommended that a cautious approach is taken when translating non-clinical data to humans.

Reactivation of Productive Infection – When developing rAAV vectors as medicinal products the consequence of long-term episomal maintenance and the potential for re-activation of virus if the subject is infected with both wild-type AAV and a helper virus should be considered. Where possible or relevant, this should be investigated in non-clinical studies such as those described by Afione et al (Afione, 1996). Associated treatment during clinical studies i.e. chemotherapy, immuno-suppression, anti-inflammatory medicines, may also impact on virus biodistribution and maybe even the likelihood of viral reactivation, particularly if immuno-suppression is being given. Where possible these additional treatments should be addressed during non-clinical evaluation of the product.

Germ-line transmission – Biodistribution studies have shown in the mouse and the rat that rAAV DNA can be detected in gonadal DNA (Arruda, 2001) for a variable duration. Furthermore following hepatic artery delivery of a rAAV for the treatment of hemophilia B, transient dissemination to the semen in 1 patient was observed (Schuettrumpt, 2006). The potential for germ-line transmission can not therefore be entirely ruled out (Honaramooz, 2008), as such it is recommended that germ-line transmission studies are undertaken prior to first in man studies.

Environmental risk Considerations

There is a substantial amount of literature available suggesting that shedding of rAAV is dependent on the dose and route of administration, and that vector DNA can be detected for a number of weeks in serum, and early times i.e. day 1 post administration, in saliva, serum, urine and semen (Favre, 2001; Manno, 2006; Provost, 2005). Ideally, if positive DNA signals are observed, the samples should be followed up for infectious virus quantification. The data derived from non-clinical shedding studies and from early phase clinical studies can then be used to assess the likelihood of transmission and to justify the extent of viral shedding evaluation in subsequent trials.

Clinical Considerations

Biodistribution and shedding studies – The extrapolation of biodistribution data from animal models to humans is not straight forward. It is recommended that wherever possible an investigation into the biodistribution of the vector, by screening for DNA sequences in the first instance, should be included within a clinical trial protocol is included.

Immunogenicity – Equally the extrapolation of immunogenicity data for therapeutic applications of AAV vectors from animal models to humans is not simple, and the route of administration may also impact on the immunogenic profile of the product. It is recommended therefore that consideration is given to the potential of subjects having pre-existing antibodies to the serotype of AAV under investigation, and that evaluation of the immunogenicity of both the vector and the transgene is assessed in terms of neutralizing and non-neutralizing antibody formation during clinical trials

Germ-line transmission – The question of germ-line transmission in humans has not been fully resolved and short term DNA persistence has been observed in semen (serotype 2), therefore it is recommended that germline transmission is investigated during clinical studies and that the use of barrier contraception for individuals enrolled in clinical trials is included in study protocols.

Long-term follow up – Non-clinical studies may indicate long-term persistence of the vector, be it due to viral DNA integration or episomal maintenance, in which case long-term follow-up of the patients treated with a rAAV product could be necessary, not only in terms of safety evaluation but also efficacy. It should also be considered that where these vectors are being investigated for preventive vaccination uses, long term expression of the antigenic proteins may be a safety risk rather than a desired outcome.

The paper goes into greater detail on these issues and requires detailed consideration for those working in this field.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug  development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

ida consultants freestrategyconsultation 515x64 EMEA publishes a reflection paper Recombinant Adeno Associated Viral Vectors


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New EMEA Draft Concept Paper – Immunogenicity Assessment of Manoclonal Antibodies for In-vivo clinical use

Posted on May 3, 2009 by admin| 1 Comment

The EMEA release for review a draft concept paper today (24th March) on immunogenicity assessment of monoclonal antibodies for in-vivo clinical use. the consultation period lasts until June 2009.

Backgound to the concept paper

Unwanted immunogenicity is a significant problem with therapeutic biologicals. The clinical problems associated with unwanted immunogenicity vary in nature and incidence. The importance of the unwanted immunogenicity problem has led to the preparation and adoption of the ‘Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins’ by the CHMP (adopted April 2008).
Monoclonal Antibodies (mAbs) comprise a large important class of therapeutic biologicals. Different mAb products share some properties, but may differ in other aspects. Many mAb products are known to be associated with unwanted immunogenicity. Some issues pertaining to unwanted immunogenicity of mAbs differ in important aspects from those generally associated with therapeutic biologicals.

The Main problem being addressed

The incidence of immunogenicity associated with mAbs differs greatly between products, patients and even in different studies with the same product and patient type. The complexity of structure of mAbs possibly explains at least some of this variation. In some cases, especially with humanised or human sequence mAbs the immune response is predominantly anti-idiotypic, which clearly can compromise clinical responses to the mAb. In some cases the induced antibodies reduce clinical responses to the mAb to such an extent that further therapy has to be terminated.
The very large number of mAbs in clinical development and undergoing regulatory scrutiny emphasises the critical need for provision of appropriate guidance on the unwanted immunogenicity of this large class of biologicals. Questions on immunogenicity are often asked during assessments of marketing authorizations for mAbs. The development of biosimilar mAbs is prevalent in various parts of the world, which again stresses the importance of having good guidance available, as unwanted immunogenicity is well known to also be a concern with biosimilars.

The main recommendation from this concept paper are, the drafting of a guideline on immunogenicity assessments of monoclonal antibodies intended for in vivo clinical use. The EMEA are looking for expert input and opinion into this subject from the pharmaceutical industry.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug  development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

ida consultants freestrategyconsultation 515x64 New EMEA Draft Concept Paper Immunogenicity Assessment of Manoclonal Antibodies for In vivo clinical use

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Bioequivalence of Therapeutic Proteins

Posted on March 25, 2009 by admin| 1 Comment

As the first major generation of therapeutic proteins come of age and their patents expire the possibility of “generic versions” has raised. However the regulatory pathway for such “generic” drugs does not fit the complexities of therapeutic proteins. However the EMEA released guidelines on so called biosimilars (follow-on biological product in the USA), and a number of products have made it to market, we ask what are the key learning’s.

The issues to overcome:

  • Large complex molecules and standard analytical methods do not allow their full physical characterisation
  • Heterogenicity due to natural processes in the host cells needed for their production
  • Modification introduced during production, purification, formulation and storage
  • Impurities introduced during production and purification
  • Production processes are dynamic and undergo continuous improvement
  • Changes are accepted if similarity can be established, their is no need to be identical
  • In house methods and standards are not in the public domain

The Regulations

The EMEA is the only regulator to introduce regulations, these regulations make it clear that biosimilars are not the same and are not regulated in the same was as generic drugs. The regulations hinges on clinical data, and needs to go through the centralised procedure. The regulations provide clear guidance on data requirements and quality standards that need to be established to gain market approval, the requirements include:

  • Same extensive data on quality and safety as an innovative protein drug
  • Supplement showing similarity in quality, safety and efficacy between biosimilar and the same reference product
  • Extensive comparability exercise is required to demonstrate that the similar biological medicinal product in terms of quality, safety and efficacy to the reference medical product
  • Assessment of biological properties.
  • Results of biological assays
  • Non-clinical and clinical focusing on Pharmacokinetic (PK), Pharmacodynamic (PD), efficacy and safety with a focus on immunogenicity

Practicle Experience

A recent product approved as a bio-similar, Retacrit has provided a number of insights into the process and how data is evaluated through the publication of its European Public Assessment Report (EPAR), the issues considered in detail included:

  • Structural comparability
  • Purity comparisons
  • Biological activity
  • PK profiles
  • Clinical effect and side effects (over 600 patients were used in the studies)

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a development target, define a development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch

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