Abstract

Pharmaceutical products are not limited to therapeutic drugs and biologics. These pharmaceutical products are regulated by different branches of medicinal product’s regulatory agency. In the US, the center for drugs evaluation and research (CDER) reviews and regulates drugs (brand and generic) while the center for biologics evaluation and research (CBER) reviews and regulates biologics, biogenetics, biosimilar, etc. (vaccines, protein-based products, etc.) (NG, 2009). Under each regulatory umbrella, the regulatory oversight and status are different, but in all cases, the main objective is ensuring adequate safety and efficacy evaluation of investigational products intended for a clinical trial or marketing purposes. The evaluation of generic, or biologic or biosimilar product by a regulatory agency follow set standards either for a pre-clinical trial in animals or clinical trial in humans. Some of these standards are not limited to safety, efficacy, patent’s rights, biological and chemical characterization of the product. These criteria are satisfactory measures to be considered for product’s market approval or denial.

 Generics, Biologics, and Biosimilars

Each class of pharmaceutical products (generic, biologic and biosimilar) has different properties from one another. A generic medicinal product is primarily a specified chemical compound/entity that is similar in chemical and physical properties as an off-patent brand product (inventor/pioneer’s product) (NG, 2004). In other words, a generic product could be a synthetic or natural purified chemical entity or compound with the same dosage and active pharmaceutical ingredients (APIs) as the brand product. On the other hand, a generic product may have different excipients’ formulation. However, the safety and efficacy properties of a generic product should be similar to the inventor’s product for the intended therapeutic use. Efuviride, Pegvisomant and Aprepitant are generic names for Fuzeon, Somavert and Emend respectively. Overall, the cost of production and introduction of a generic product in the market is undoubtedly cheaper than the costs associated with the production and introduction of any pioneer/brand products in the market.

In contrast, biologic products are not limited to RNAi, SiRNA, enzymes, hormones, protein, virus (vaccines) or serum based products, etc. (Whitmore, 2004). Unlike a generic product, a biologic product comprises of a mixture of compounds or molecules. Biologic molecules are usually derived or produced from a living cell via biotechnology/bioengineering techniques. In most cases, a bioreactor incubators are used for large scale production of biologic compounds for marketing purposes. Biologic production process is a very complicated, sensitive and cost intensive process, and requires an in-depth knowledge of the biochemical pathways due to the mixture-complexity of the end-product. The product must be purified and validated before it is packaged and released in the market. One of processes employed for the purification of a protein-based product is chromatographic techniques (ND, 2009). Amevive, Crosseal and Xolair are few examples of recent biologic products.

On the other hand, a biosimilar product refers to a resemblance version of a patent biologic pharmaceutical product. By definition, biosimilar and biologic (inventor biologic) products are resemblance in terms of therapeutic use or function. However, biosimilars are not identical generic equivalents of biologic due to differences in protein sources, and extraction, purification and manufacturing processes. Perhaps, biologic similarity is difficult to characterize precisely because biosimilar and biogeneric tests for similarity are not well defined in the case of proteins as it is for a chemical medicinal products (NG, 2009). Therefore, several biologic products such as interferon beta 1-a, interferon beta1-b and Erythropoietin are facing biogeneric challenges.

The approval process for any new investigational medicinal product for marketing purposes requires safety and efficacy testing in clinical studies. However, a generic product approval process does not require any clinical study, but the generic manufacturer must show or prove bioequivalent of a generic product to its off-patent brand product in question. Hence, under the generic application process there is no requirement for an investigational new drug (IND) application since no pre-clinical or clinical trial is required. On the other hand, the regulatory agency requires an abbreviated new drug application (ANDA) for a generic product’s review and approval process. In other words, the generic’s ANDA review is based on a bioequivalence analysis and manufacturing control information (NG, 2009). The generic sponsor is obligated to prove bioequivalence based on chemistry, dosage, bioavailability, pharmacokinetics, pharmacodynamics and toxicity characteristic profiles, etc.

Most importantly, the generic company does not require a patent application for a generic product (not a novel product) for production or marketing purposes. However, a generic company is legally authorized to manufacture a generic product for marketing purpose only when the inventor’s 20 years patent or extended patent expires unless if any special legal provision exists that prohibits generic entry in the market for the product, in question. In contrast, there may be a situation where the government can override patent right and authorize urgent production of the generic product for the well-being of public health especially during epidemic or pandemic situations. Furthermore, in the US, a generic product application, does not require the pioneer to pay the PDUFA fee for data review, but the regulatory agency has strict oversight on generic companies. Generic companies are subject to current good manufacturing practices (cGMPs) and routine inspection to ensure that they are in compliance with the GMP, ICH and regulatory guidelines (Whitmore, 2004). The average approval process for generic products is within few months from the time an ANDA submission is received by the regulatory agency.

An investigational biologic’s marketing process requires an investigational new product application (IND) and biologic license application (BLA). In the US, biologic application requires the pioneer to pay the regulatory agency a PDUFA fee for review process. The US regulatory branch involve in the approval process for a biologic product is the CBER. A biologic products’ manufacturing process involve different cell process including exclusion, destruction, and inactivation of inherent/endogenous pathogens within the host organism, organs or tissues that may be present or have potential harmful effects if not treated or processed properly (Whitmore, 2004). With a biologic product, extensive laboratory research and development is needed to establish a basis for preclinical and clinical trials. By the end of the phase 3 clinical trial, the pharmaceutical company may file a BLA if the trial is promising and satisfactory. The biologic manufacturer is subject to inspection at any time by the regulatory agency within the jurisdiction to assess the risk-based approach to the cGMP compliance. On average, it takes 18.2 months to approve or deny a BLA application. The approval time starts once the IND is filled (Whitmore, 2004).

Due to the complexity of characterizing biologic product’s profiles, there is no statutory provision for allowing any generic biologics or biogenerics in the US, yet, although several biogenerics have beenapproved in Europe. Furthermore, biosimilar tests are not yet well defined scientifically as in the case with other chemical medicinal products. However, scientists are still challenging the idea of similarity and the notion that differences in process may have significant influence on a biologic structure (NG, 2009). Nevertheless, regulatory agencies and scientists recognized that biosimilar products are not similar to a typical generic drug’s property either in terms physical or chemical property. Therefore, it is necessary to ensure a stringent testing process and oversight before a biosimilar or biogeneric entry in the market.

References

NG, R. (2009). Drugs: From discovery to approval (2nd ed.). Hoboken, NJ: Wiley-Blackwell.

Whitmore, E. (2004). Development of FDA-regulated medical products: Prescription drugs, biologics, and medical devices. Milwaukee, WI: ASQ Quality Press.