Читать книгу Biologics, Biosimilars, and Biobetters - Группа авторов - Страница 102

Biological products are typically derived from living cells and include a wide range of product types including vaccines, blood and blood components, gene therapy, and monoclonal antibodies (mAbs). They can be made of sugars, proteins, nucleic acids, or may be composed of living cells or tissues.⁸ Unlike many small molecule drugs that have known chemical structures that can be synthesized and analyzed fully, most biologics are complex and not easily characterized. Most biologics are made using recombinant DNA (rDNA) technology in which living cells are genetically engineered so that they produce the desired proteins.⁹

Biologics are generally more complex to manufacture than small molecule drugs as they are more sensitive to the environment and small variations in production can alter their function. The human body is designed to detect foreign substances, and biopharmaceuticals are no exception. Large biologic products need to be made and administered in such a way that they will not be rejected or neutralized by the body's immune system. The potential for a person's immune system to reject a life‐saving drug underscores the importance of safe, reliable, and consistent manufacturing. Some of these challenges are described in Table 3.2, which compares the characteristics of small and large molecule drugs.

The complexity of biologic drugs leads not only to unique challenges with producing novel drugs, but it also makes creating similar versions (biosimilars) more difficult. Unlike small molecules that can typically be well defined and re‐created in a laboratory, biologics may have unknown composition, and their synthesis may require thousands of complex steps. In some cases, the exact quantitative components of the finished biologic may be unknown.

Paradoxically, it is the molecular size and relative ambiguity of the large molecule drugs that can make them harder to protect with patents. Their composition is not as easily defined and as such, competitors can develop similar but different drugs. For this reason, both the drug and manufacture/production processes are patented with biologics.⁹ In the United States, the FDA requires a biologic licensing application (BLA) and approval for a biologic to be marketed. Supporting the importance for manufacturing patents, the FDA notes the following requirements for a BLA: “Issuance of a biologics license is a determination that the product, the manufacturing process, and the manufacturing facilities meet applicable requirements to ensure the continued safety, purity and potency of the product.”¹⁰

Table 3.2 Characteristics of small molecule pharmaceuticals vs. biologics.

Source: Adapted from https://www.fraserinstitute.org/sites/default/files/biologics‐revolution‐in‐the‐production‐of‐drugs.pdf.⁹

	Small molecule pharmaceuticals	Biologics
Method of synthesis	Chemical synthesis	Genetically engineered living organisms or cells
Molecular size	Small	Large
Structure	Usually fully known	Complex, frequently partially unknown
Susceptibility to contamination during manufacturing	Low	High
Molecular structure	Relatively simple spatial structures, determined through analytical techniques	Exhibit complex spatial structures, difficult to determine or characterize
Complexity	Relatively pure ingredients	Complex ingredients (impurities, leachables, excipients, by‐products)
Sensitivity to physical factors (heat, light)	Low	High
Clinical behavior	Well understood mode(s) of action	Complicated mode(s) of action, not always well understood
Manufacturing process	Straightforward, relatively simple	Highly complex
Species	Interdependent	Specific
Immunogenicity	Nonantigenic (generally)	Antigenic (frequently)

There are additional elements that protect the innovation of innovator firms from generic or biosimilar competitors. In many countries, data exclusivity rights also exist. These data exclusivity rights are granted to innovator firms to ensure that preclinical and clinical trial data, such as safety and efficacy data, are protected from competitors for a defined time period. The data exclusivity period protects clinical trial data for several years after an innovator product reaches the market, during which time competitors cannot use preclinical or clinical trial data in submissions for biosimilar versions. This can prevent a drug from losing patent exclusivity very close to the time it is marketed, but it could also reduce competition.⁹ Periods of data exclusivity vary by country as can be seen in Table 3.3.

Table 3.3 Preclinical and clinical trial data exclusivity by nation.

Source: Adapted from https://www.fraserinstitute.org/sites/default/files/biologics‐revolution‐in‐the‐production‐of‐drugs.pdf.⁹

Nation	Small molecule (yr)	Large molecule (yr)
Canada	8	8
European Union	10	10
United States	5	12