Earlier this month, the U.S. Food and Drug Administration announced a new initiative, the Biosimilars Action Plan: Balancing Innovation and Competition in furtherance of its efforts "to ensure that this balance between innovation and competition exists across the spectrum of pharmaceutical products." The hoped-for outcome of the BAP: that "[a]fter patents or other exclusivities expire on these novel products, prices can fall dramatically once follow-on products are available, potentially lowering costs for patients and payors and expanding access to these innovations."
The Introduction states that:
The agency is taking steps to more efficiently manage our review and licensure pathways to facilitate biosimilar competition. We are modernizing our policies that govern the development of biosimilar to make it more efficient. We are also educating clinicians, payors and patients about biosimilar products and the rigorous evaluation they must go through. And, we are modernizing regulatory policies to accommodate new scientific tools that can better enable comparison between biosimilars and reference products that may reduce the need for clinical studies.
Some of the bureaucratic measures the agency intends to implement in furtherance of these efforts include:
1. Introducing new FDA tools to improve efficiency of FDA review (e.g., templates "tailored to marketing applications for biosimilar and interchangeable products")
2. Creating information resources and development tools for biosimilar applicants (in silico models and simulations for correlating PK/PD responses to clinical outcomes)
3. Enhancing the Purple Book
4. Looking into data sharing agreements with foreign regulators
5. Establishing a new Office of Therapeutic Biologics and Biosimilars to improve coordination under the BsURA program
6. Providing critical education to health care professionals
7. Finalizing Guidance on labeling
8. Providing finalized Guidance on interchangeable biosimilars
9. Improving analytical approaches for structure/function for demonstrating biosimilarity including statistical methods
10. Implementing standards for manufacturing quality control
11. Improving public dialog with hearings and requests for public input on FDA actions to evaluate and promote biosimilars
Why now? The FDA contends that "[t]his is a crucial time in the emergence of the marketplace of biosimilar and interchangeable products." The agency expects continued expansion in the number of approved biosimilar and interchangeable products in the coming years. The announcement of this new initiative recognizes "barriers to marketing a biosimilar or interchangeable product that are outside of the FDA's purview," but assert that it is part of the agency's mandate to "advance[e] policies to facilitate the efficient development and approval of these products." Hence, the enunciation of the BAP.
There are four "key elements" of the BAP:
1. Improving the efficiency of the biosimilar and interchangeable product development and approval process
How?
• Providing application review templates, formatted for 351(k) BLA requirements
• Transitioning to a Therapeutic Biologics and Biosimilars Staff (TBBS) from the Office of New Drugs under Center for Drug Evaluation and Research (CDER) to the Office of Therapeutic Biologics and Biosimilars (OTBB), intended to "improve coordination and support" of activities under the Biosimilar User Fee Act (BsUFA), increase agency response times, and improve efficiencies in policy development and response to applicants
• Improve coordination with CDER
• Develop information resources for biosimilar applicants, such as an "index of critical quality attributes" for comparing reference products to biosimilars, and comparison metrics that will reduce the size of clinical studies
2. Maximizing scientific and regulatory clarity for the biosimilar product development community
How?
The FDA has issued six final (see "Nonproprietary Naming of Biological Products"; "Considerations in Demonstrating Interchangeability with a Reference Product"; "Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product"; "Scientific Considerations in Demonstrating Biosimilarity to a Reference Product"; "Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product"; and "Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009") and four draft (see "Scientific Considerations in Demonstrating Biosimilarity to a Reference Product"; "Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product"; "Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009," as discussed in "FDA Publishes Draft Guidelines for Biosimilar Product Development" and "More on FDA Draft Guidelines for "Follow-on" Biologic Drug Approval Pathway") Guidance documents relating to biosimilars. The FDA expects additional Guidances to be forthcoming that will involve public hearings, prioritizing the following issues:
• Final or Revised Draft Guidance: Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act
• Final or Revised Draft Guidance: Implementation of the "Deemed to be a License" Provision of the Biologics Price Competition and Innovation Act of 2009
• Final or Revised Draft Guidance: Considerations in Demonstrating Interchangeability with a Reference Product
• Final or Revised Draft Guidance: Statistical Approaches to Evaluate Analytical Similarity
• Draft Guidance: Processes and further considerations related to post-approval manufacturing changes for biosimilar biological products
The agency is also developing guidance for biosimilar applicants who will seek approval for fewer than all conditions for which the reference product is licensed, and developing a formal rule for interpreting the definition of "biological product" under the BPCIA, to provide additional "clarity." FDA is evaluating regulations regarding aBLA submission, and working on an enhanced Purple Book (which will contain "information about newly approved or withdrawn BLAs and about reference product exclusivity determination").
Finally, under this part of the BAP, the agency will be "[s]trengthening its partnerships with regulatory authorities in Europe, Japan and Canada" by "harmonizing requirements for their development as well as sharing regulatory experience across national boundaries," including data sharing agreements to increase the use of non-U.S.-licensed comparator products to support biosimilar application.
3. Developing effective communications to improve understanding of biosimilars among patients, clinicians, and payors
How?
This portion of the Plan is aimed at increased educational efforts according to the Biosimilar Education and Outreach Campaign released in October 2017; continuing efforts including videos, webinars, information on the webpage, and providing educational materials for patients, pharmacists, and other stakeholders.
4. Supporting market competition by reducing gaming of FDA requirements or other attempts to unfairly delay competition
How?
In many ways the most provocative part of the Plan, the announcement states that:
The FDA will clarify our position on issues affecting reference product exclusivity to better effectuate balance between innovation and competition. We will also take action, whenever necessary, to reduce gaming of current FDA requirements, and coordinate with the Federal Trade Commission to address anti-competitive behavior. Additionally, we will work with legislators, as needed to close any loopholes that may effectively delay biosimilar competition beyond the exclusivity periods envisioned by Congress.
The FDA intends to take steps for biosimilars analogous to the Drug Competition Action Plan (DCAP) the agency has implemented for generic drugs, where it was "a priority to address practices that delay or block competition from entering the market." For generic drugs, these efforts were aimed at preventing branded drug makers from activities such as "refusal to sell the samples necessary for developing generic drugs [a practice we've seen with products under limited distribution, whether the drug maker limits distribution voluntarily or does so in connection with a Risk Evaluation and Mitigation Strategy (REMS) program]." Insofar as such practices are being used by reference product sponsors (and the announcement does not provide any examples of such behavior, the agency states that "[w]e will apply the same principles used in DCAP to our BAP to address circumstances in which drug makers refuse to sell samples, or use any other anticompetitive strategies, to delay the entry of biosimilar or interchangeable development and competition."
In conclusion, the FDA says it expects development of biosimilar and interchangeable drugs to "continue to evolve" and thus implementation of the BAP to be "dynamic." And:
The FDA is committed to transparent, science-based regulation of biosimilar and interchangeable products that maintains the dynamic balance between innovation and timely access, as Congress intended. Appropriate market exclusivities allow innovators to recoup their investments, and compensate them for the time, risk and uncertainty that make the cost of capital to undertake these endeavors high. These rewards provide incentives for research and development of new treatment options, as well as help advance medical innovation and improve outcomes.
While a good deal of this announcement is conventional bureaucratic promotion, there are a few nuggets that suggest that the FDA under this Administration may be more confrontational and aggressive towards perceived "bad behavior" by certain of its shareholders. It is certainly the case that the price of drugs, particularly biologic drugs, is high and poses a significant cost burden on the health care system as a whole (both public and private). The BAP appropriately addresses these concerns and recognizes that they must be addressed. But it is also good to try to understand the economic realities that have created the situation (without excessive and unproductive finger-pointing). It is a truism that everything has increased in price (and many things even adjusted for inflation); after all, it isn't just the elderly that are confronted with prices that seem ridiculously excessive. But for drugs it also must be recognized, by policy makers as well as the public, that the low-hanging fruit of small molecule drugs and those with (relatively) simple etiologies have been discovered in the first flowering of the modern pharmaceutical intervention in human disease (see, e.g., Epstein, 2006, Overdose: How Excessive Government Regulation Stifles Pharmaceutical Innovation; and Rosen, 2017, Miracle Cure: The Creation of Antibiotics and the Birth of Modern Medicine). And federal regulation, particularly by the FDA, is more extensive and costly than it was prior to the thalidomide tragedy in 1962. While it is convenient and politically expedient to castigate the pharmaceutical industry for high prices, it is foolhardy not to recognize these and other factors in producing the current price situation.
The context of the comments in the FDA's BAP also comprises statements by Commissioner Gottleib regarding the possibility of changing U.S. drug importation regulations (but with disclaimers regarding exclusivities and prompted by "supply chain disruptions" to soften the political effects of implied threat) to permit "temporarily" importation of drugs from foreign sources. The FDA has also created a task force to address drug shortages, either due to supply chain difficulties or source monopolization of unpatented drugs without remaining regulatory exclusivity due to sole sourcing.
But there is another aspect that is typically overlooked. For many biologic drugs, the diseases they address are ones that a generation ago resulted in significant morbidity and mortality; indeed, some diseases were invariably fatal (many cancers, HIV) or severely debilitating (kidney disease, hepatitis). Some of these were diseases of the elderly, and the wisdom of expending vast sums to extend few lives for short times is a topic for another day. But for the overwhelming number of cases where individuals in the prime of life are cured or their diseases managed, these drugs provide significant advantages, both for the afflicted individuals and society as a whole. In the most hard-hearted, dollars-and-cents analysis, what pundits who bemoan high drug costs appear to forget is that these individuals are returned to the workforce as productive participants, who hold down jobs and pay taxes and participate in the U.S. consumer economy. Society, whether in the form of local or nationwide businesses or federal, state, and local tax collectors, reaps the benefit of those who have returned to the workforce due to the effects of biologic drugs that did not exist twenty, ten, five, or even one year ago.
And that doesn't take into account the human benefits, which now routinely permit individuals (and their spouses, sons, daughters and grandchildren) to enjoy the benefits of longer life and participation in weddings, births, and other lifetime milestones. Undue focus on the goal -- obtaining biologic drugs at reduced prices -- raises a risk of not having these drugs, or their benefits, because private investment is frustrated and the government is a generally a poor source of innovation. It would be well for policymakers, particularly at FDA, to keep such considerations in mind to temper their fiscal zeal.
