Safety is a priority for the development of all medicines, but biologics raise safety considerations above and beyond those of chemical drugs. This is because biologics are more structurally complex medicines than chemical drugs, and even slight changes in their manufacture can cause undetected changes in the biological composition of the product. These changes can in turn affect the safety and effectiveness of the product in patients.
Chemical drugs are typically made by mixing together well-defined chemicals in controllable "recipes" following the formulas and the predictable rules of organic chemistry. The same final product can sometimes be obtained through a very different process, and the product can be analyzed in a laboratory to confirm that it is exactly what it is supposed to be. It is a relatively straightforward exercise to show that a generic chemical product is the same as a branded product. Evidence from clinical trials is not necessary, and cannot be submitted in an application for a generic product.
Biologics are made by genetically engineering living cells to become miniature factories producing the desired molecules (proteins). These living cells are inherently variable and susceptible to slight changes in their environment that can significantly alter the proteins they are engineered to produce. Because no two living cell lines are identical, no two biologics manufacturing processes have identical starting materials or proceed in the same way. A follow-on biologic manufacturer that uses different starting materials and a different process will produce a product that is different from the innovative product. In addition, the complexity of biologics currently makes it impossible to show in the laboratory that one biological product will work the same as another in patients. The effects of the differences between a follow-on and its respective innovator product can only be determined by subjecting the follow-on biologic to substantial clinical testing in patients to prove that it is safe and effective. Therefore it is not possible to have a "generic" of a branded biologic.
Immunogenicity is an important concern regarding the safety of biologics. This occurs when our bodies treat a protein as if it is a foreign substance and try to attack the protein with antibodies. Unlike chemical drugs, all biologics have the potential to stimulate antibody production in patients and such responses are highly unpredictable. Sometimes the antibodies produced in response to a biologic have no effect. Other times they bind and inactivate the biologic, causing disease progression. In still other cases, they can bind to and inactivate a patient's naturally occurring protein, which means that the patient may be left with no options other than regular blood transfusions.
One example of immunogenicity occurred a few years ago when, at the request of the European Health Authorities, Johnson & Johnson made a change in the manufacturing process for its EPREX product - a product that had been marketed for a decade with no evidence of immunogenicity problems. The change caused a serious adverse reaction in a small number of patients. These patients lost their ability to make red blood cells because they produced an antibody (triggered by the EPREX) that inactivated both the administered protein (EPREX) and the body's natural protein that is essential for red blood cell production. Johnson & Johnson eventually was able to determine the cause of this adverse reaction and correct it, but only after a very lengthy and expensive investigation.
The EPREX case shows that one protein can be different from another in ways that cannot be detected in the laboratory, but are seen only by the body's exquisitely sensitive immune system. If one change to a well-established complex manufacturing process, made by the manufacturer who has intimate knowledge of the process, can cause a problem with immunogenicity, surely the risk is even greater with an entirely new manufacturer and process - as will be the case with follow-on biologics.
The EPREX example also underscores two other critical points. First, careful post-market monitoring of the safety of a biologic, whether innovative or follow-on, is extremely important. Second, this example provides a further rationale for not considering a follow-on product to be interchangeable with an innovative product. FDA has stated that it has not determined how interchangeability can be established for complex proteins.