DRUG REGULATORY AFFAIRS AND BIOTECHNOLOGY  
     
   

(see also the attached presentation <Biotech+DRA.pdf> (1,2 MB) by Dr Axel F Wenzel, P.SS.T)

Biological technologies are of utmost importance in the development and manufacturing of new drugs, not only from the scientific and technical but also from economical viewpoint. Germany e.g. holds worldwide one of the leading positions within the "biotech" nations: more than 300 small and medium sized companies provide more than 8000 jobs directly related to biotech. Additionally, some 300.000 jobs are depending from biotech know how.
Already in 1999 scientists and companies in Germany filed 176 patents related to biotech medicinal products and held with that the number 2 on the list after the US.
As also other drug substances, biotech derived medicinal products must be approved by the authorities before they can be marketed. In the European Union, the development of medical products for human and veterinary use is governed by a variety of laws, legislations, directives and guidelines.
Some of the above mentioned regulations and guidelines were very specifically developed for drugs manufactured by means of biotechnology since there are some major differences to the "normal" New Chemical entities (NCE) produced by chemical synthesis: Biotechnology Drugs are highly complex macromolecules, 2-3 orders of magnitude bigger than NCEs with complex pattern of post-translational modifications, highly specific 3-D folded structure and complex pattern of impurities (product and process related and contaminants ).

The regulatory frame work

Within the EU all biotech drugs must be approved using the so-called centralised procedure (CP; Reg. 2309/93/EEC and new: Dir 2001-83 EEC).
A definition what the EU Commission considers as a "biotech drug" is given in Council Regulation (EEC) Nr. 2309/93 and its Annex Part A: .......biotechnological processes are:

  • Recombinant DNA technology
  • Controlled expression of genes coding for biotechnologically active proteins in procaryotes and eucaryotes including transformed mammalian cells.
  • Monoclonal antibody methodologyFor drugs manufactured by a.m. procedures, the CP is mandatory.

For others listed in Annex Part B it is optional:
medicinal products:

  • developed by other biotechnological processes, which constitute a significant innovation
  • new delivery systems, which constitute a significant innovation ...
  • new indication, which is of significant therapeutic interest
  • Radio-isotopes, ...of significant therapeutic interest ...
  • Processes with significant technical advance
  • derived from human blood or human plasma

Central responsibility lies within the Committee for Proprietary Medicinal Products (CPMP; consisting of representatives from all national authorities) and its working parties e.g. Biotechnology Quality Working Party, BWP); Safety Working Party (SWP) and others which are developing specific guidelines.
It is of importance for all developers – and also the scientist- to know about all these guidelines – and to have always also a regulatory view on the scientific research matters. Even guidelines are not legally binding, they are considered by the authorities as "expert opinions of the agency in advance": Thus, only when there are sound reasons and arguments, the applicant can deviate from such guideline.

Relevant guidelines are publicly reported and available in Volume 3A of the "Rules governing Medicinal Products in the European Union" (EUDRALEX, see http://pharmacos.eudra.org/F2/eudralex/vol-3/home.htm). This referenced internet page is the home of the Pharmaceuticals Unit of the Enterprise DG of the European Commission.

Additional information can be found at

Of special importance are those guidances developed by the BWP.
Experience of the last 20 years has shown, that, because of the nature of biotech products (originating from humans or animals) there are clear differences in the behaviour when applied into the human body. In the mean, clear criteria were developed to establish the risk / benefit ratio of such drugs when filed for a marketing authorisation.
According to the worldwide-standardised requirements for all medicinal products, experts in the authorities review the following 3 aspects of a new medicine:

  • its efficacy in the claimed indication / medical condition
  • its safety in humans
  • its pharmaceutical quality

Especially for biotech derived products, it is not always easy to differentiate these 3 areas.


The development process of biotech products

How do biotech derived medicinal products differ from conventional drugs? In a few words: The focus is in general the validation of the manufacturing process and specially

  • the potential contamination with viruses
  • the impurities occuring during the production process
  • the identity of the structural formula and the 3 dimensional structure of the molecule
  • the reproducibility of the biological activity
  • the immunogenicity

Due to the strict requirements concerning the purity of recombinant durg substances guidelines and regulations can only be a certain help how to approach a problem and give a an idea about limits. The final responsibility lies always with the pharmaceutical entrepreneur.

This situation leads to a certain focus in pre- and clinical development: the emphasis is on safety relevant issues. Thus, it is very important to reveal the pharmacodynamic, pharmacokinetic and toxikological qualities of the impurities and contaminations. Sometimes, the results from these studies may lead to a change of the production process during development. In effect, it happens often, that important parts of the manufacturing process or the formulations of a recombinant medicinal product is changed from pre- to clinical phase.
This is why essentially the following issues must be cleared during pre- and clinical development:

  • Biological activity of the drug substance and its pharmacodynamics
  • reasons for the choice of animals species and experimental models
  • reasons dor the chaice of no and sex of experimental animals
  • reasons for posology
  • Immunogenicity

Additionally, studies for safety pharmacology should focus on:

  • pharmacokinetics and toxikokinetics
  • reasons for the choice of analyticals methodology
  • metabolism
  • single and multiple dose toxicity
  • immuno-toxicological studies
  • reproduction toxicology
  • gene toxicological studies
  • cancerogenicity
  • local tolerance

Such a variety of requirements cannot be covered by the existing guidances. Especially for newer technologies like

  • Gene therapy
  • Plant-made pharmaceuticals (PMPs)
  • "molecular targeted therapies" in cancer

there is still a big lag of guidances. Pharmaceutical companies, in most cases start-up companies, Spin-of entreprices from universities and SMEs are left alone with their problems in finding the right development strategies.

As an example, here the situation for "molecular targeted therapies" in cancer: Over the past few years a variety of new drugs were developed in oncology targeting critical pathways in cancerogenesis. Surprisingly, most failed to meet the conventional endpoint of improved survival in phase III trials (i.e. Iressa TM in non-small cell lung cancer, Avastin TM, MarimastatTM in metastatic breast cancer). With the rapid growth in the discovery of new cancerogenic pathways it becomes evident that multiple critical steps may contribute to malignant cell transformation and that a single agent interfering with a single pathway may not suffice to eradicate cancer.
With large effort and cost, biopharmaceutical companies strive to identify a magnitude of modifiers interfering with important pathways in order to combat cancer. The recent failures to bring drugs to market raised huge uncertainties within medical and biopharmaceutical communities in regard to the most conclusive clinical development of such novel compounds. Conventional endpoints in clinical drug development accepted by regulatory authorities are until now response rates in phase II trials and survival rates in phase III trials. Meanwhile, there is no doubt, that the clinical development of novel "molecular targeted therapies" requires a different, more comprehensive approach with refined concepts in terms of endpoints, quantification of response and/or patient benefit, appropriate patient selection and strategies to combine molecular effectors early on.


The EU Life Science Health Priority Program and SIGRA

One of the objectives of Life Scihealth Priority is to foster the competitiveness of EuropeÕs biotechnology industry by exploiting the wealth of biological data produced by genomics and advances in biotechnology.

The SIGRA Novel BioPharm working group will provide a discussion forum among scientist from academia and industry on the one side and regulatory agencies and legislators on the other side.
It is particularly important that these later ones are well informed about emerging new technologies that may help to develop better products and processes. New technologies can also increase the reliability of safety and quality controls. To speed the development of new and safe biotech products it is necessary that these new tools are included in the testing protocols and accepted by the regulatory bodies. The development of regulatory testing paradigms needs a multidisciplinary approach that due to the size and complexity of the problem is more successfully addressed at an European level and moreover it has to be addressed at European level as biotech products have to be authorized under the centralized procedure.

Vice versa, the scientists need such discussions with regulators to learn thinking in Regulatory levels to acknowledge the importance of such regulations. And also to incorporate regulatory thinking in their day-to-day development strategies.

Both actions will lead to a focused development, to safer medicines which are early on the market.

Our project will, as a first step, address and attempt to solve the current controversies and open regulatory questions in the clinical development of "molecular targeted therapies" in cancer. It is the objective to design European guidelines that emphasize on alternative endpoints, quantification of response and/or patient benefit, appropriate patient selection and strategies to combine molecular effectors early on. These guidelines will serve as a formal basis between the medical and biopharmaceutical communities to discuss unique findings and necessary actions with regulatory authorities. Therefore, the design of such guidelines can be considered a specific support action.

Further issues as mentioned above will be follwed consequently by our SIGRA.

Thus, the SIGRA Novel BioPharm group will contribute to solving both a society problem by benefiting the population health and quality of life through new and safer drugs and an economical problem by reinforcing the competitiveness of the European Pharmaceutical and Biotechnology Industry.

Considering the huge economical impact of the shape of the regulatory framework around these products it is essential to assure scientific driven guidances and interpretation, so all the interested parties should be represented in the working group i.e. academia members and scientists from pharma companies either big or small and either innovator or generic manufacturing companies, and also professional specialist in drug development. Its an objective to also include national medicine board representatives.

Scientific driven and harmonized guidelines are essential tool to assure a more economical use of human, animal and material resources, the elimination of unnecessary delay in the global development and availability of new medicines whilst assuring quality, safety and efficacy, and thus protection of public health.

Again as an example, the impact of guidances for the clinical development of "molecular targeted therapies" in cancer. Such an highly needed discussion between scientists and regulators will serve several purposes:

  • provide conclusive answers for the medical community as well as for biopharmaceutical companies in many areas that need refined assessment (see 4. and 5.)
  • contribute to effective cost and time saving development of novel anti-cancer drugs that require approaches different from traditional chemotherapeutics
  • serve as a position paper and facilitate interactions and discussions with all regulatory bodies
  • set a European standard in terms of dealing with novel "molecular targeted therapies" and facilitate international collaborations

The final goal of the SIGRA working group is to provide to the European regulatory authorities an objective opinion representing a consensus among all biotech stakeholders. The idea is to link scientific principles with practical implementation of guidances and to facilitate the generation of guidance documents harmonized from their beginning.

References:
1. Biotech. Heading for Notice to Applicants
2. CPMP Guideline on Production and Quality control of medicinal products derived by recombinant DNA technology
3. CPMP Guideline on Production and Quality Control of Cytokine products derived by biotechnological process (Guide, addendum)
4. CPMP/ICH Guideline Q5C on Stability testing of biotechnological-biological products.
5. CPMP/ICH Guideline Q6B on Specifications, tests and procedures for Biotechnological/Biological products.
6. CPMP Guideline on Production and Quality Control of monoclonal antibodies