Drug Development Consultant & Regulatory Consultant » clinical

FDA published guidance on clinical considerations for therapeutic cancer vaccines

damienbove — Fri, 16 Dec 2011 08:43:46 +0000

The guidance covers critical clinical considerations for investigational studies in phase 1 and two clinical trials and phase 3 clinical trials. The guidance makes recommendations for the design of clinical trials conducted under an IND to spot subsequent biological license applications. This is finalisation draft guidance was published in September 2009.

the product discussed in this guidance are therapeutic cancer vaccines intended to result in specific responses to tumour antigens and are intended to treat patients with an existing cancer. These products are traditionally regulated by the Centre for Biological Evaluation Research (CBER) and are referred to as cancer vaccines throughout this document.

EMA Announce Meeting on Excellence in Pharmacovigilance in Clinical Trials and Post Marketing

admin — Thu, 08 Sep 2011 11:17:55 +0000

EMA Announce Meeting on Excellence in Pharmacovigilance in Clinical Trials and Post Marketing

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This course is designed to provide a firm grounding in key aspects of global clinical pre- and post-marketing safety.

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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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EMA SME Workshop, Scientific and Regulatory Advice

admin — Thu, 12 May 2011 08:32:07 +0000

EMA SME Workshop, Scientific and Regulatory Advice

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26/05/2011 - 26/05/2011

The workshop presents the support available to SMEs during early drug development and highlight recent experience in quality, non-clinical and clinical scientific advice. In addition, the workshop covers regulatory support available prior to submission of an application for marketing authorisation.

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FDA Publish Guidance on Electronic Source Documentation in Clinical Investigations

admin — Tue, 25 Jan 2011 11:03:22 +0000

FDA Publish Guidance on Electronic Source Documentation in Clinical Investigations

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This document provides guidance to sponsors, contract research organizations (CROs), data management centers, and clinical investigators on capturing, using, and archiving electronic data in FDA-regulated clinical investigations. This guidance is intended to ensure the reliability, quality, integrity, and traceability of electronic source data and source records maintained at the site for FDA inspection.

This guidance is intended to promote the capture of source data in electronic form, which will help to:
• eliminate unnecessary duplication of data,
• reduce the opportunity for transcription errors,
• promote the real-time entry of electronic source data during subject visits, and
• ensure the accuracy and completeness of data (e.g., through the use of electronic prompts for missing or inconsistent data).

This guidance is intended to be used together with the guidances for industry 2 entitled:
• Computerized Systems Used in Clinical Investigations
• Part 11, Electronic Records; Electronic Signatures – Scope and Application
• General Principles of Software Validation; Final Guidance for Industry and FDA Staff.

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FDA Guidance, Cellular Therapy for Cardiac Disease

admin — Sat, 13 Nov 2010 09:51:00 +0000

FDA Guidance, Cellular Therapy for Cardiac Disease.

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The FDA, are issuing this guidance to provide you, sponsors who are developing cellular therapies for the treatment of cardiac disease, with recommendations on the design of preclinical and clinical studies, and on the chemistry, manufacturing, and controls (CMC) information to include in an Investigational New Drug application (IND) for cellular theracardiac disease. This guidance also provides recommendations regarding the information thyou should submit on the product’s delivery system. Sponsors should consult with FDA concerning the regulatory pathway for the use of cell selection devices.

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FDA Publishes Summary of Safety and Effectivenss Data (SSED) Clinical Section Checklist, office of device evaluation

admin — Fri, 10 Sep 2010 15:05:43 +0000

FDA Publishes Summary of Safety and Effectiveness Data (SSED) Clinical Section Checklist, office of device evaluation.

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The Summary of Safety and Effectiveness (SSED) is a document mandated by the Food, Drug and Cosmetic Act subparagraph 520(h)(1)(A) to be publicly available upon issuance of an approval order of a premarket approval application (PMA). The SSED is applicable for all original PMAs and panel-track supplements.
It is an FDA document intended to present a reasoned, objective, and balanced summary of the scientific evidence, both positive and negative, that served as the basis of the decision to approve or deny the PMA.
There can be no claims in the SSED that are unsubstantiated by the clinical results of the PMA clinical study(ies). The SSED is not a marketing document, and should not contain marketing/advertising language.
NOTE: This checklist contains the essential elements that should, at minimum, be included in the clinical section of the SSED. Additional instructions or examples of what should be included under each topic heading are indicated by italicized text. This document is intended to provide general recommendations for writing the clinical portion of the SSED. However, there will be exceptions, as well as devices that will require additional sections.

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FDA, The USA Drug Regulators Publish Guidance for Industry and Researchers, The Radioactive Drug Research Committee: Human Research Without An Investigational New Drug Application

admin — Wed, 18 Aug 2010 13:58:32 +0000

FDA, The USA Drug Regulators Publish Guidance for Industry and Researchers, The Radioactive Drug Research Committee: Human Research Without An Investigational New Drug Application

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This guidance is intended to provide information for those using radioactive drugs for certain research purposes to help determine whether research studies can be conducted under 21 CFR 361.1, Prescription Drugs for Human Use Generally Recognized as Safe and Effective and Not Misbranded: Drugs Used in Research, or whether research studies must be conducted under 21 CFR part 312, Investigational New Drug Application (IND).

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EMA, the European Drug Regulators, Publish Draft Guidance on Non-Clinical and Clinical Aspects of Medical Products Containing Geneticaly Modified Cells

admin — Sun, 25 Jul 2010 09:04:39 +0000

EMA, the European Drug Regulators, Publish Draft Guidance on Non-Clinical and Clinical Aspects of Medical Products Containing Genetically Modified Cells.

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This guideline defines scientific principles and provides guidance for the development and evaluation of medicinal products containing genetically modified cells intended for use in humans. Its focus is on the quality, safety and efficacy requirements of genetically modified cells developed as medicinal products.

genetically modified cells for treatment of monogeneic inherited disease;

genetically modified dendritic cells and cytotoxic lymphocytes for cancer immunotherapy;

genetically modified autologous chondrocytes for cartilage repair; genetically modified progenitor cells for cardio-vascular disease treatment or for in vivo marking studies, particularly for in vivo biodistribution or in vivo differentiation analysis;
−
genetically modified osteogenic cells for bone fractures repair; genetically modified cells for 66 infectious disease treatment.
This guideline defines scientific principles and provides guidance to applicants developing medicinal products containing genetically modified cells. It is recognised that this is an area under constant development and guidance should be applied to any novel procedures as appropriate.

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EMA, the European Drug Regulator Publishes Reflection paper on Quality, Non-Clinical and Clinical Issues related to the Development of Recombinant Adeno-Associated Viral Vectors

admin — Mon, 19 Jul 2010 08:22:00 +0000

EMA, the European Drug Regulator Publishes Reflection paper on Quality, Non-Clinical and Clinical Issues related to the Development of Recombinant Adeno-Associated Viral Vectors

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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.
Infection with wild-type AAV is not associated with any pathogenic disease, and in the absence of a helper virus co-infection, the virus may integrate into the host cell genome or remain as an extrachromosomal form (Schnepp, 2005). In both situations the virus appears to remain latent. In-vitro studies suggest that wild-type viral DNA integration can occur occasionally in a site specific manner (19q13.3) (Kotin, 1990 and 1991 and 1992), but only at very high multiplicities of infection (Hüser, 2002), and this was originally considered to be a safety feature of vectors derived from this virus. However, it has been subsequently shown that site specific integration is dependent on the presence of both the inverted terminal repeats (ITR) and the Rep gene products (Weitzman, 1994; Linden, 1996), the latter of which is not present in rAAV; as such the site specific integration feature of these vectors is lost. The level of integration of DNA into the cellular chromosome in in-vivo models, however remains contentious. Nonetheless, long term protein expression (in-vivo) from the gene of interest inserted into rAAV vectors has been observed (Flotte, 1993; Kaplitt, 1994; Conrad, 1996; Monahan, 1998; Donahue, 1999; Stieger, 2006), even in the absence of identifiable genetic integration (Miller, 2004; Song, 2004; Flotte, 1994). This persistence is thought to be derived from stable concatemerized duplex genome forms (circular or linear molecules) that are transcriptionally active (Duan, 1998; Yang, 1999; Fisher, 1997).
Examples of diseases studied include haemophilia B (Manno, 2006 and 2003), cystic fibrosis (Flotte, 2003), Parkinson’s disease (Kaplitt, 2007), rheumatoid arthritis (www.targen.com [tgAAC94]), Leber’s congenital amaurosis (Bainbridge, 2008; Maguire, 2008; Jacobson, 2006), infantile neuronal ceroid lipofuscinosis (Worgall, 2008) and muscular dystrophy (Xiao, 2000). Furthermore non-clinical studies indicate rAAV expressing heterologous antigenic sequences (HPV16 – Kuck, 2006; HIV – Xin, 2001 and 2002; SIV – Johnson, 2005; malaria – Logan, 2007) can illicit both humoral and cellular immune responses, and modest immunogenicity has been reported in a phase I/II study using rAAV2 encoding HIV antigens (Mehendal, 2008). However, it has been suggested that cellular responses to the transgene products of rAAV vectors may be impaired (Lin, 2007), as such the utility of these vectors when used for prophylactic purposes needs further investigation.
There are currently 6 confirmed serotypes of adeno-associated virus (AAV-1 to -6) and 2 tentative species (AAV-7 and (source: International Committee on Taxonomy of Viruses [ICTV]). However there are a number of publications describing additional serotypes (i.e. 9 and 10) which are currently not recognized by the ICTV. It is likely therefore, that there are significantly more serotypes circulating that have currently not been formally identified or recognized (Pacak, 2006; Limberis, 2006; Gao, 2004). Nonetheless, the majority of the 67 clinical trials undertaken to date using rAAV for gene delivery have used serotype 2 (Gene Therapy Clinical Trials Worldwide. J. Gene Med. March 2009 Update, http://www.wiley.co.uk/genmed/clinical ).
Evidence is accumulating which suggests that different AAV serotypes may have different tissue tropisms, for example AAV-8 is suggested to have a preferred tropism to the liver (Davidoff, 2005), while for AAV-1, -6 and -7 the preferred tropism is to skeletal muscle (Duan, 2001; Chao, 2000), AAV-4 is highly specific to the retinal pigmented epithelial cells in several animal species (Weber, 2003) and the ependymal cells (Zabner, 2000) and AAV-9 is described as being tropic to cardiacmuscle (Pacak, 2006), thought it also tranduces liver (Van den Driessche, 2007) and brain (Foust, 2009). Vectors based on these serotypes, in-vitro selected AAV with altered tropisms and hybrid vectors (i.e. ITR and Rep from AAV-2, Cap (protein coat) from another serotype i.e. are being investigated (in-vitro and in animal models) to evaluate further the utility of the preferred tropisms and their potential for avoiding pre-existing immunity to AAV-2.
A new development in the field of AAV vectors is the use of self complementary (sc) AAV. Conventional rAAV vectors require 2nd strand synthesis before genes can be expressed, and it is theorized that scAAV bypass this step by delivering a duplex genome. This is achieved by deleting the nicking site of one ITR so that it no longer serves as a replication origin but still forms an AAV hairpin structure. The result is a single stranded, dimeric inverted repeat genome with the altered ITR sequence situated in the middle of the molecule and a wild-type ITR at each end. Following infection and uncoating, the DNA is folded to form a double stranded molecule. A closed hairpin end is formed from the altered ITR, and an open end formed from the two wild-type ITR’s, thus mimicking the structure of a single stranded rAAV after 2nd strand synthesis (McCarty, 2003). It is anticipated that such vectors will improve transduction efficiency and improve the level of protein expression from the transgene. The coding capacity of these vectors, however, is reduced by a factor of two.
Given the basic biology of the ‘parent’ virus as described above, 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 and these are discussed further below, however the basic functional requirements for manufacture are:
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The AAV ITR’s flanking the ‘gene of interest’ (this construct contains the cis elements necessary for packaging and replication of its single stranded DNA genome).
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Genetic sequences (Rep and Cap) necessary for AAV replication and viral capsid proteins (generally provided in trans within a plasmid or in a packaging cell line).
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Helper virus functions: either co-infection of the helper virus or co-transfection/infection of a plasmid/chimeric virus encoding the helper genes (adenovirus: E1a/1b, E2a, E4orf6, VA1 RNA; herpes simplex virus: UL5, UL8, UL52 and UL29).
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A cell line capable of supporting helper virus and AAV replication.
The aim of this paper is to discuss quality, non-clinical and clinical issues that should be considered during the development of medicinal products derived from AAV, and to indicate requirements that might be expected the time of a market authorisation application (MAA). The issues raised are specific only to the development of rAAV vectors as medicinal products; general requirements for MAA are not within the scope of this paper. It is recommended that this paper is read in conjunction with the guidance documents referenced in section 4.2.

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EMA, the European Drug Regulator publishes, Draft Guideline on Quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells.

admin — Mon, 12 Jul 2010 10:55:09 +0000

EMA, the European Drug Regulator publishes, Draft Guideline on Quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells.

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Genetically modified cells may be developed either for therapeutic use (gene therapy medicinal products) or to use the genetic modification in the manufacturing process of a cell therapy / tissue engineering product.
The following are some examples of medicinal products containing genetically modified cells (GMC) that have been used in clinical trials:
− genetically modified cells for treatment of monogeneic inherited disease;
− genetically modified dendritic cells and cytotoxic lymphocytes for cancer immunotherapy;
− genetically modified autologous chondrocytes for cartilage repair; genetically modified progenitor cells for cardio-vascular disease treatment or for in vivo marking studies, particularly for in vivo biodistribution or in vivo differentiation analysis;
− genetically modified osteogenic cells for bone fractures repair; genetically modified cells for infectious disease treatment.
This guideline defines scientific principles and provides guidance to applicants developing medicinal products containing genetically modified cells. It is recognised that this is an area under constant development and guidance should be applied to any novel procedures as appropriate.

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