Critical Reflection and Global Regulatory Alignment of Complex Drugs Needed

The cost of developing copy versions of complex drugs—biosimilars and follow-ons for biologics and copies of nonbiological complex drugs (NBCDs) such as nanomedicines, including drug-carrying liposomes—can be decreased. Furthermore, access to these high-quality drugs can be improved for the global community if steps are taken to improve regulatory alignment processes undertaken by the FDA, the European Medicines Agency (EMA), and the World Health Organization (WHO), according to the conclusions of a conference on worldwide regulatory frameworks for the approval of complex drug products and their follow-on versions, held last autumn at the New York Academy of Sciences.

All stakeholders at the meeting, including scientists from innovator and generic companies, academia, and regulatory bodies from around the world, agreed that complex drugs and their follow-ons should be evaluated with great care, and that it is an absolute necessity to define their critical attributes in order to ensure the safety and efficacy of these products. With ever-increasing numbers of biosimilars under development, this discussion is critically important if overall expenditures in healthcare are to be reduced through the use of high-quality, safe, and effective biosimilars.

In an associated white paper published in the Annals of the New York Academy of Sciences on April 26, 2017, Leonie Hussaarts, PhD, program manager at Lygature, Netherlands, and colleagues wrote of the development and regulatory challenges for biosimilars and follow-on versions of complex biologics, as well as the challenges of bringing these products to patients. They note that, although the stakeholders attending the meeting often had different and even conflicting interests, they agreed that the most important stakeholder is the patient.

Outstanding challenges that stakeholders believe must be addressed include the following:

• Critical attributes for assessment of therapeutic equivalence of complex drug follow-on versions. What are the critical attributes responsible for clinical performance of biologics and nonbiological complex drugs (NBCDs)? Are clinical trials required if the critical attributes are unknown? Is it feasible to draft the same guidance documents throughout the world, with the WHO in the “driver’s seat”?
• Provision of a scientific base for assessing critical attributes. It is crucial to strengthen the overall knowledge base. Scientists in academia, industry, and regulatory bodies should be encouraged to perform research on outstanding questions and to publish their findings in the public domain.
• Problems with nomenclature and labeling. Differences in terminology exist and continue to grow, even with respect to the way that the term “biologic” is used by different organizations. “There is no worldwide consensus regarding the labeling of biologics and biosimilars,” the paper notes. The meanings of the terms “interchangeability,” “substitution,” and “switching” depend on jurisdiction and must be clarified.
• Substandard follow-on products. The number of products that have been identified as substandard but that are approved as follow-on complex drug products is growing; stakeholders asked if literature reports of substandard complex drug products should be investigated as part of regulatory agency and sponsor pharmacovigilance.

“It is in our hands to bring high-quality, safe, effective, and affordable medicines to patients in a timely and efficient matter,” the white paper concludes. “A critical assessment of how we currently work within the existing frameworks and whether these provide us with the highest chances of bringing those medicines to patients, requires this community to critically reflect on its activities.” Science-based discussions, joint definition of the next steps, and reflection on activities will tell stakeholders whether they are moving in the right direction and whether regulatory frameworks reflect the best science, are fit for purpose, and are ready for the future.