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FDA, Publish Guidance on Animal Studies for Cardiovascular Disease

admin — Sat, 11 Sep 2010 15:13:23 +0000

FDA, Publish Guidance on Animal Studies for Cardiovascular Disease.

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FDA has developed this guidance document to assist industry in designing evaluation strategies for, and reporting the results of, animal studies involving cardiovascular devices, including intra-cardiac devices and devices used in the coronary and peripheral vasculature. The animal studies utilized for the assessment of these devices typically provide initial evidence of device safety, their potential performance when used in a living system, and the biologic response that a living system may mount towards the device. We recommend that members of industry and FDA staff who perform or review evaluations of animal studies for cardiovascular devices use this guidance. In this document, the terms “you” and “your” refer to members of industry, also known as “sponsors” or “applicants”. The terms “we,” “us,” “our,” and “Agency” refer to FDA.
The intent of this guidance is to provide a reference of best practices for the approach, conduct, and presentation of animal study data intended to demonstrate that the device under study is sufficiently safe for early human experience, while accounting for modern animal care and use strategies. The guidance makes multiple references to pre-existing regulatory requirements involving animal care and use. Of note, FDA maintains a memorandum of understanding (MOU) with the U.S. Department of Agriculture (USDA) and the National Institutes of Health (NIH) that addresses common areas of regulatory practice under which animal studies are to be performed.
We recommend that you use this guidance to develop and present animal study protocols, methods, and reports that support the safety and performance of cardiovascular devices. We intend to use this guidance to review animal study protocols, methods, data, and reports provided in regulatory submissions to demonstrate the safety and performance of cardiovascular devices.

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Damien Bové is THE Drug Development and Regulatory Consultant (pharmaceutical or biotechnology), I work with my 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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DA has developed this guidance document to assist industry in designing evaluation strategies for, and reporting the results of, animal studies involving cardiovascular devices, including intra-cardiac devices and devices used in the coronary and peripheral vasculature.

Drug Regulators, FDA, Publishes Guidance on S9 Non-Clinical Evaluation for Anticancer Pharmaceuticals

admin — Fri, 12 Mar 2010 08:31:33 +0000

Drug Regulators, FDA, Publishes Guidance on S9 Non-Clinical Evaluation for Anticancer Pharmaceuticals.

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The purpose of this guidance is to provide information to assist in the design of an appropriate program of nonclinical studies for the development of anticancer pharmaceuticals. The guidance provides recommendations for nonclinical evaluations to support the development of anticancer pharmaceuticals in clinical trials for the treatment of patients with advanced disease and limited therapeutic options.
This guidance aims to facilitate and accelerate the development of anticancer pharmaceuticals and to protect patients from unnecessary adverse effects, while avoiding unnecessary use of animals, in accordance with the 3R principles (reduce/refine/replace), and other resources.
As appropriate, the principles described in other ICH guidances should be considered in the development of anticancer pharmaceuticals. Specific situations where recommendations for nonclinical testing deviate from other guidance are described in this document.

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Drug Regulators, EMEA, Publish ICH S6(R1), Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

admin — Sun, 27 Dec 2009 09:28:48 +0000

Drug Regulators, EMEA, Publish ICH S6(R1), Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.

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Biotechnology-derived pharmaceuticals (biopharmaceuticals) were initially developed in the early 1980s. The first marketing authorisations were granted later in the decade. Several guidelines and points-to-consider documents have been issued by various regulatory agencies regarding safety assessment of these products. Review of such documents, which are available from regulatory authorities, may provide useful background in developing new biopharmaceuticals.
Considerable experience has now been gathered with submission of applications for biopharmaceuticals. Critical review of this experience has been the basis for development of this guidance that is intended to provide general principles for designing scientifically acceptable preclinical safety evaluation programs.

Regulatory standards for biotechnology-derived pharmaceuticals have generally been comparable among the European Union, Japan and United States. All regions have adopted a flexible, case-by-case, science-based approach to preclinical safety evaluation needed to support clinical development and marketing authorisation. In this rapidly evolving scientific area, there is a need for common understanding and continuing dialogue among the regions.
The primary goals of preclinical safety evaluation are: 1) to identify an initial safe dose and subsequent dose escalation schemes in humans; 2) to identify potential target organs for toxicity and for the study of whether such toxicity is reversible; and 3) to identify safety parameters for clinical monitoring. Adherence to the principles presented in this document is intended to improve the quality and consistency of the preclinical safety data supporting the development of biopharmaceuticals.

This guidance is intended primarily to recommend a basic framework for the preclinical safety evaluation of biotechnology-derived pharmaceuticals. It applies to products derived from characterised cells through the use of a variety of expression systems including bacteria, yeast, insect, plant, and mammalian cells. The intended indications may include in vivo diagnostic, therapeutic, or prophylactic uses. The active substances include proteins and peptides, their derivatives and products of which they are components; they could be derived from cell cultures or produced using recombinant DNA technology including production by transgenic plants and animals. Examples include but are not limited to: cytokines, plasminogen activators, recombinant plasma factors, growth factors, fusion proteins, enzymes, receptors, hormones, and monoclonal antibodies.
The principles outlined in this guidance may also be applicable to recombinant DNA protein vaccines, chemically synthesised peptides, plasma derived products, endogenous proteins extracted from human tissue, and oligonucleotide drugs.
This document does not cover antibiotics, allergenic extracts, heparin, vitamins, cellular blood components, conventional bacterial or viral vaccines, DNA vaccines, or cellular and gene therapies.
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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Drug Regulators, EMEA, Publish ICH S9 Guidance, Nonclinical Evaluation for Anticancer Pharmaceuticals

admin — Sat, 26 Dec 2009 09:23:49 +0000

Drug Regulators, EMEA, Publish ICH S9 Guidance, Nonclinical Evaluation for Anticancer Pharmaceuticals

Full Text Here

The purpose of this guidance is to provide information to assist in the design of an appropriate program of nonclinical studies for the development of anticancer pharmaceuticals. The guidance provides recommendations for nonclinical evaluations to support the development of anticancer pharmaceuticals in clinical trials for the treatment of patients with advanced disease and limited therapeutic options.
This guideline aims to facilitate and accelerate the development of anticancer pharmaceuticals and to protect patients from unnecessary adverse effects, while avoiding unnecessary use of animals, in accordance with the 3R principles (reduce/refine/replace), and other resources.
As appropriate, the principles described in other ICH guidelines should be considered in the development of anticancer pharmaceuticals. Specific situations where recommendations for nonclinical testing deviate from other guidance are described in this document.

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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This guideline ap

recombinant vaccines for the prevention and treatment of infectious disease, and provides guidance on quality, non-clinical and clinical aspects.

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Drug Regulators Publish ICH consideration on Virus and Vector Shredding

admin — Fri, 21 Aug 2009 07:02:13 +0000

EMEA Publishes ICH Considerations on the General Principles to Address Virus and Vector shedding

a copy is available here.

Introduction

Drug Regulators Publish ICH consideration on Virus and Vector Shredding Virus / vector shedding should not be confused with biodistribution, e.g., spread within the patient’s body from the site of administration.1 Virus / vector2 includes gene therapy vectors3 and oncolytic viruses.

Assessment of shedding can be utilized to understand the potential risk associated with transmission to third parties and the potential risk to the environment. The scope of this document excludes shedding as it relates to environmental concerns because it is regulated differently in various regions.

The focus of this document is to provide recommendations for designing non-clinical and clinical shedding studies when appropriate. In particular, emphasis will be on the analytical assays used for detection, and considerations for the sampling profiles and schedules in both non-clinical and clinical studies. The interpretation of non-clinical data and its use in designing clinical studies is also within the scope of this paper, as well as the interpretation of clinical data in assessing the need for virus / vector transmission studies.

Biological Properties of the Virus / Vector

Information on the known properties of the wild-type strain from which the virus / vector under consideration was derived is essential in guiding the design of shedding studies.

In practice, most viral / vector products currently under investigation are replication incompetent or conditionally replicative. It is likely that virus / vector shedding in these cases would be of a much shorter duration, and, depending on the route of administration, would display a different shedding profile as compared to shedding following infection with the wild-type counterpart.

Other property of the replication-competent virus / vector that should be considered when designing shedding studies would be whether infection is expected to be short- or long-term.

Analytical Assay Considerations

Having suitably qualified analytic assays in place for shedding studies is very important. Assays should be specific, sensitive and reproducible. Quantitative assays are preferred as these will aid in quantifying the probability of transmission. Assessment of interference from the biological sample matrix is important and it might be appropriate to dilute the sample prior to analysis to avoid extensive interference.

Polymerase chain reaction (PCR) and infectivity are the two assays typically used for the detection of shed virus / vector. Use of a quantitative PCR (qPCR)-based assay to detect viral / vector genetic material is recommended.

To accurately assess the potential for transmission of shed material, the use of an infectivity assay is considered important as this will allow for an accurate assessment of the nature of the shed material (e.g., intact virus / vector vs. fragments of virus / vector).

Non-Clinical Considerations

Non-clinical shedding studies help guide the design of clinical shedding studies. The aim of a nonclinical shedding study is to determine the secretion / excretion profile of the virus / vector.

Animal Species

One of the difficulties of investigating virus / vector products in non-clinical studies is the relevance of the animal species as a large number of virus / vector products under clinical evaluation are derived from parental strains which do not readily infect and rarely replicate in non-human species.

Dose and Route

Wherever possible the dose and route of administration used in non-clinical shedding studies should reflect those intended for use in the clinical setting.

Sampling Frequency and Study Duration

Known biological properties of the wild-type strain can be used to guide the frequency of sampling after virus / vector administration. In general, one might need to take samples more frequently in the first days following administration in order to detect a transient shedding profile.

Sample Collection

The characteristics of the virus / vector, the route of administration, and animal species should be taken into consideration in determining the samples to be collected. Examples of collected samples most commonly include urine and faeces, but could include other sample types such as buccal swabs, nasal swabs, saliva, and bronchial lavage. It is worth considering the samples that should be taken and the volumes that should be collected in order to perform quantitative, suitably qualified analytical assays. For certain secreta or excreta, such as urine, it can be difficult to collect sufficient sample material. Pooling of samples from several animals at the same time point receiving the same dose might be an option so that sufficient sample size or volume can be obtained.

Interpretation of Non-Clinical Data and Transmission Studies

It is important to keep in mind that data from non-clinical shedding studies are useful in guiding the design of clinical shedding studies, particularly as to sample types, sampling frequency, and duration.

Clinical Consideration

The considerations raised above for non-clinical studies are relevant to the design of virus / vector shedding studies in a clinical setting (i.e., route of administration, duration of shedding observed, sample types to be taken and frequency). The known biological properties of the parental virus / vector, the replication competence of the product, dose, route of administration, and patient population will be key factors to consider in the design of clinical shedding studies.

Interpretation of Clinical Shedding Data

There are a number of factors to take into account when assessing the clinical shedding data and the potential risk associated with transmission from shed virus / vector. An important factor to consider is to identify and characterize what is being shed. Specifically, if the assay used does not distinguish intact from degraded or non-infectious virus / vector, then the data might not be informative as to the potential risk associated with transmission.

Determining how virus / vector is shed is an important factor when assessing the potential risk associated with transmission. One should also consider how much is being shed and the duration of shedding.

Third Party Transmission

In some cases, when shedding is observed, the potential for transmission to third parties might need to be investigated. These investigations would involve evaluation of persons that come into close contact with virus / vector recipients (e.g., family members, healthcare workers) for evidence of transmission. The immunological status of the third party should be considered. A high proportion of the population might already have pre-existing immunity to the virus / vector; in this case, clearance should be effective in those individuals. However, the immune status of the third party contacts could be compromised, e.g., in the elderly or very young, and so clearance mechanisms might be inefficient. Thus the consequences of infection might be more significant in these individuals.

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

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Cardiovascular Toxicity (QT prolongation) in Drug Development Overview

admin — Tue, 31 Mar 2009 16:48:21 +0000

Nobody working in drug development can fail to be aware of the issue that is QT prolongation, however some people are finding they need a little more information if they are going to tackle and plan for it within their drug development programmes.

There are three main ways that cardiovascular toxicity can present itself:

Changes to heart rate
Changes to conductivity within the heart
Changes to the repolarization of the heart (QT prolongation)

It is this QT prolongation that is obviously the hottest issue and is a consequence of impacting the repolarization of the cardiomyocytes. The pathway is the hERG channels are blocked, which increased the action potential of the cells in the heart, which in turn causes the QT prolongation.

This problem has been seen in a large number of drugs and has impacted on a great many drug development programmes, from complete removal of a drug from the market, to prescribing restrictions, delays in approval and a huge number of drugs killed at an early stage. It is also worth noting that there is not a pattern to those drugs affected and it appears to affect a large number of different drugs.

But what can be done to manage this risk? Well there are a wide variety of early discovery screens, In-vitro, Ex-vivo, and In-vivo.

The most common In-vitro study is the Patch Clamp – this is actually the gold standard study and involves measuring the current through the hERG channel (Ikr Chanel) to give an IC50 for the drug, this IC50 will give you an indication if you are going to see effects at therapeutic dose levels. Whilst this is the gold standard it is not a test that lends itself well to high throughput screening.

Another test is the hERG binding assay, this is a competitive assay that tests your drug against a radio labeled standard, this is a good test which can be used in high throughput screening, and is well correlated to the Patch Clamp test.

Another is the Rubidium Flux assay, where you load the cells with rubidium add your compound and KCl, this allows you to measure the rubidium excreted from the cell and from this judge hERG channel activity. This once again lends itself to even fast screening but there is some drop off in relation to the gold standard.

The final test is the membrane potential dye test, where cells are loaded with dye and as the hERG channel functions dye is flushed from the cell, this is the fastest test but least accurate.

The tests most commonly used are the hERG binding assay and Rubidium flux tests

In terms of Ex-vivo models the most popular are pukinji fiber tests and isolated heart tests, these whole tissue and whole organ tests are expensive but do provide a lot more information on what is going on and provide a wider insight.

In-vivo tests include dogs, non-human-primates, and pigs, rodents are not a good model for the human heart and should not be used. Again the expense of these models is made up for by the excellent data they provide. The studies are generally conducted in conscious animals which are remotely monitored, single dose cross over study designs are used, time and duration of effect is looked for and compared with systemic drug levels. Heart rate, ECG, Blood Pressure, Body Temperature, and activity levels are all monitored.

One of the most important things to look at is left ventricular pressure as this gives the greatest insight into normal function, Charles Rivers have done a great deal of work to validate this with Atenolo and Pimobedam. With both drugs systolic BP, diastolic BP and heart rate remained the same but changes in left ventricular pressure alluded to issues that needed to be addressed.

There are two guidelines that need to be referred to when planning these studies ICH57A (general safety pharmacology) and ICH57B (Specific QT prolongation regulations).

When assessing the Pre-clinical it is important to take a good look at the data and consider the following; what was actually observed as the assays are not 100% effective, any small flags will impact on clinical trial design, how will the expected PK/PD profiles impact on the results, will you expect patients to get into affected dose levels?

Before commencing human trials there are guidelines that need to be considered ICH E14 which gives instruction on the evaluation of QT prolongation in man, in some regions its now compulsory, but in others you can argue away from it with pre-clinical data. In the clinic QT prolongation is tested in healthy volunteers at therapeutic doses and multiples thereof, metabolic inhibition may be needed to raise drug levels levels high enough, positive controls are also used (moxifloxacin).

Where QT prolongation is seen the following guidelines are provided:

<5 msec – no risk
6-10 msec unlikely risk
>10 msec possible risk

These regulations are the same for cardiovascular drugs as for other therapy areas.

Another important thing to consider is that QT prolongation is not an issue that affects biologicals, as demonstrated by Vergas, Boss et al 2008 (J Pharmacol and Tox Method 58;72-76)

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