Need for Regulatory Evaluation in Biotech Investments

As it is stated in the last report published by AseBio, biotechnological companies continue to be amongst the first five to invest the most in I+D department, in comparison to their production level. The year 2023 closed with a 228 million euros inversion in the biotechnological sector, being this the biggest number to date.

Now, we must take into consideration that the concept of Biotechnology, and therefore, the corresponding sector, is extraordinarily vast, as we consider to be Biotechnology whatever technological application that uses biological systems or living organisms -or their derivates- to create or modify processes or products for specific uses, being these uses mainly sanitary, agriculture and livestock, environmental and industrial manufacturing.

Just in Spain, there are 4.447 companies that declare to perform biotechnological activities, being these using Biotechnology as a tool, a secondary activity, or the main activity of the company (Biotech company); the principal area in which these companies thrive is the human health field (>50%).

Getting into the medication field, we understand to be a medicine “whatever substance or combination of substances that has the power or the required properties to treat or prevent illnesses in humans, or that can be used or administrated to human beings so to restore, correct or modify physiological functions, exercising a pharmacological, immunological or metabolic action, or to establish a medical diagnosis.”. The classification of these substances is broad and complex, since we can find categorizations based on their therapeutic indications, their way of administration, their family, their physical state or even their origin (chemical synthesis, biological, radiopharmacs…). This last classification is the most relevant for Biotech companies, and the one that can directly influence the financial milestones of a project and the development cost.

Due to the strategies to access the market, the financing strategy of the potential final commercial product, the periods and costs of regulatory evaluations, the competent regulatory entities, the non-clinical testing for security and toxicology, the type of clinical trial needed, the evaluation taxes and even the players all being different in terms of cost and time, we find an increment or a reduction in the inversion cost, depending on the regulatory the applicable regulatory frame.

According to the Directive 2001/83, a biological medicine is “every product in which the active ingredient is of biological origin, being a biological active substance that that is produced or extracted from a biological source which needs, for its characterization and determination of quality, a combination of physiochemical and biological trials alongside the production and control process.”. Hence, vaccines, allergens, antigens, hormones, cytokines, enzymes, derivates of human blood, serums, immunoglobins, antibodies and fermentation products are all considered biological medicines. However, products derived from the intestinal microbiota, secretomes, and other associated products (RNA, plasmids, vectors, restrictive enzymes…) are also included in this category.

The complexity of the regulatory umbrella is rooted in this last type of product, since according to the therapeutic objective and the obtention/manufacturing process we can find ourselves in midst of the regulatory frame regarding Advanced Therapy Medicine (ATMPs), biological medicine or even chemically synthesize ones.

In regards to ATMPs, the 1394/2007 (CE) Regulations and the Royal Treaty 1/2015 of the 24^th of July are what constitute their regulatory frame. Through these norms, a communal code for medicine for human use is established. ATMPs are defined to be biological medicines for human use, which cane be based in genes (gene therapy), cells (cell therapy), tissues (tissue engineering), or a combination of them (combined advanced therapy medicine), which includes products of autologous, allogeneic, or exologous origin.

As is defined, in cell therapy drugs, the therapeutic product contains or consists of cells or tissues that have undergone a substantial manipulation; or cells or tissues that are not expected to perform the same essential function in the recipient and donor. On the other hand, products created with tissue engineering contain or consist of engineered cells or tissues and are expected to perform a regenerative, restorative or replacement function of a human tissue; often these cells are accompanied by biomaterials.  Finally, gene therapy drugs are those in which the active ingredient is a recombinant nucleic acid, which is used in humans to regulate, repair, replace, add, or eliminate a gene sequence. It should be noted that vaccines against infectious agents are not included in gene therapy and would therefore be considered biological drugs.

For example, if we analyse products based on nucleic acids, we may be presented with situations in which they are considered chemically synthesized drugs, biological drugs and even gene therapy drugs.

If the nucleic acid is synthesized through a process in which the oligonucleotides are modified with chemical synthesis reactions, we shall not consider the drug to be a biological medicinal product since it would not fall under the definition contained in Directive 2001/83. Hence, we would not be able to consider it a gene therapy medicinal product either, since, by definition, ATMPs are characterized as a biological medicinal product.  Therefore, all the regulations for chemically synthesized medicinal products would apply.

On the contrary, we could find ourselves in front of a product that, if it was constituted by a recombinant nucleic acid, would be considered a biological drug, but it could not be considered a gene therapy drug, due to the mechanism of action declared by the Biotech company. This case could occur since the definition of gene therapy drugs calls for them to be characterized by being a biological drug that complies with the following two characteristics: