Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Regulatory background in the development of medicinal products for human use produced by transgenic animals - current situation in the EU and USA ***

Dr. Elmar Hermann Schmitt (Abschlußjahr: 2004)

The purpose of this document is to provide guidance on the principles on the development of medicinal products produced by transgenic animals that can enable more effective development, both by regulators and industry. This thesis also provides and summarizes the existing quality practices, requirements, standards, and guidelines regarding the new technology, scientifically based considerations and the regulatory framework for the clinical development and the approval for marketing authorization in the two main ICH areas European Union and the United States of America.

Human proteins for therapeutic use have so far been produced by extraction from tissues and plasma and by recombinant technology from mammalian and microbial cells. Cost effectiveness large scale production of pure, native and stable proteins represents a challenge. Transgenic is the production of animals whose genetic make-up has been changed in some way. As transgenic technology makes considerable progress, so called "animal factories" have drawn much attention to this technology for the production of human proteins in a large and economically feasible scale. A gene from humans or another species is inserted into the animal's DNA. Before starting the transgenic engineering the facility and the genetic transfection process and the use of these animals for TMP production have to be approved by the competent authorities in both the EU and the US.

Typically the expression vector is microinjected into fertilized eggs that are transferred into a recipient female. Offsprings are tested for the transgene. Transgenic animals mate and then the crude bulk material has to be harvested and to be tested on the expression of the active substance. In the farms for transgenic animal creation and TMP production GAP (Good Agriculture Practice) and GMP (Good Manufacturing Practice) is the prerequisite for a safe and high quality product.

There are several concerns in transgenic technology. One of the main concerns about genetic engineering is inefficiency in the production of transgenic animals. Gene transfer studies have revealed that fewer animals were born with the specific gene. Animal welfare problems should be considered because of the unpredictable nature in producing transgenic animals. Any "mistake" that happens usually has disastrous consequences for the animals involved. It is not known what the long-term effects of inserting a foreign gene will be on an animal's health. The welfare of transgenic animals may be further undermined if any defects occur undiscovered. Unrecognized, such defects may cause severe pain and distress to that animal. Other concerns occur regarding the environment and ecosystem. There is a chance that genetically engineered animals can be released into the environment, either deliberately or by accident. As transgenic animals can pass their new genes on to their offspring, it would be difficult to predict what their effect will be on the natural ecology of that area.

Before proceeding into human clinical trials, manufacturers of biological therapeutics are required by regulatory agencies worldwide to show that their products are free from adventitious agents. Regulatory authorities require a multi-tiered approach to thoroughly demonstrate product biosafety. There are a number of regulatory and guidance documents, which provide guidance to assuring that appropriate biosafety testing is performed for a variety of products, which could be reflected to TMPs (for details see 3.2 and 2.5). Regulatory authorities are assessing each biotech-product on a "case by case" basis. Potential biosafety issues of the product would be one of the critical points, which would be assessed in detail by the authorities. Biosafety issues of TMPs represent a great disadvantage as compared to cell culture-based produced biotechnological products. Once appropriate quality and controls are in place, the purification process developed and the biochemical characterization well under way, then, as for any product, non-clinical studies are necessary. The non-clinical plan is based on the product and its intended use, not the transgenic origin of the product. Route of administration, dose, frequency and duration are traditional parameters that need to be defined. To assess product safety and efficacy, both in vitro and in vivo animal models should be considered. At this stage of development the understanding of the mechanism of action, the pharmacodynamic and pharmacokinetic in animals and the toxicology of the recombinant product is the main focus. If the initial non-clincal studies are conducted and favorable, then development proceeds along the traditional path with clinical trials initiated at the different stages.

During that period in both US and EU a close contact to the agencies would be strongly recommended. This will be one of the main success factors in the development of transgenic drugs. In the US the IND process realizes this contact and in EU similar formal community scientific advices and national advices could be initiated.

Additionally, due to the wide range of applications for this new technology, there is a lack of uniformity of standards within the industry and uncertainty as to exactly what the regulatory agencies will require. Approval of the first product from this new technology is greatly awaited as a proof of principle for transgenic recombinant product production. Currently BTC Therapeutics submitted an MAA to the EMEA and the product, a recombinant form of human antithrombin ATryn® produced by transgenic rabbits, is under the evaluation for marketed authorization in Europe (cf. 6.86). The next step will be the revision of the specific guidance documents in the US and EU to support the clinical development and the market launch of TMPs. In the EU the specific guideline revision is pending for two years on the workplan of the EMEA.

However, what is clear, as evidenced by the number of companies with regulatory and clinical milestone achievements, is that moving a transgenic product through both the FDA and European approval process is possible. Medicinal products containing biological active substances manufactured using transgenic animals are clearly covered under the term "biotechnological" as defined in the Annex to Council Regulation (EC) 726/2004. TMPs are therefore subject to the centralised procedure described in this Regulation. Most of the TMPs were developed as alternative methods for protein or biological production. Therefore these products will be new biological entities (NBE) or claimed as "biogenerics". As "biogenerics" they can not be filled as traditional "well established use" products according the Art 10(1)a(iii) of Directive 2003/63/EC amending Directive 2001/83/EC. The new term "similar biological medicinal products" should be used for TMPs and according to that an appropriate non-clinical and clinical program should be provided for the MAA ((Directive 2003/63/EC part 2 number 4). As in the case of an innovator product the applicant is forced to conduct a clinical trial development program. So far, not a single "biogeneric" has been submitted for approval in the EU but the industry expects it for the near future (cf. 6.60). In the US the FDA prepared currently a guidance document for "follow-on" (biogenerics) biologicals under the FD&C Act Section 505 (cf. 6.67). These indicated that both great ICH areas are preparing the field for "biogenerics" in the future. Indirectly TMPs are included, if there were produced as alternative to marketed products (cf. 6.59).The number of transgenic drugs in the pipelines is increasing and thereafter, one can potentially expect to see a number of TMPs approved through the centralized procedure in the EU and/or approved by the FDA for the market launch in the upcoming years. In addition the growing experience of the agencies will also help to clarify the regulatory framework and increasing confidence in the new technology will make future supportive financial investment more probably.

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