Biosimilars are essential healthcare equalizers, but their regulation is overly complicated due to lobbying by makers of branded biologics looking to maintain blockbuster revenue.
On Dec. 26, 2008, after former President Barack Obama was elected but before he took office, I wrote him an email. Two days later, we met briefly in his interim office in Chicago. I elaborated on my plight: I and others had developed lifesaving biosimilars that could significantly reduce the cost of expensive biologics drugs. However, there was no regulatory pathway to bring them to market.
Several bills had been introduced to Congress to provide this pathway, but none had passed, in part due to lobbying against biosimilars from Big Pharma. When I met with Obama, the latest variation of the legislation remained in limbo.
The president-elect listened attentively and at the end of our meeting he said, “It will be done.” I wasn’t quite sure what he meant by that, but soon after, buried in the 11,000 pages of the Affordable Healthcare Act (ACA) was a revised version of the legislation dubbed the Biologics Price Competition and Innovation Act (BPCIA). A host of FDA guidances for biosimilars followed.
Unfortunately, the BPCIA contained many compromises—strict requirements that essentially treated biosimilars as new biological drugs. These included extensive analytical, animal toxicology and clinical efficacy testing, most redundant and blown out of proportion. Ultimately, these requirements pushed the costs of developing a biosimilar to $100–300 million, with approval timelines of six to nine years. Indeed, the first biosimilar approved in the U.S.—Sandoz’s Zarxio, a biosimilar of Amgen’s Neupogen used to stimulate white blood cell production in cancer patients—didn’t hit the market until 2015, six years after the BPCIA paved the way.
The FDA had no experience approving a product where even the reference product varies from batch to batch—and had no reason to take a risk. Still today, there is a lack of regulatory motivation.
Moreover, many misconceptions swirled about the safety and efficacy of biosimilars—many broadly fanned by Big Pharma —just as when generic drugs were introduced.
Making biosimilars affordable is more than a scientific challenge. Today, only 66 biological molecules are approved as biosimilars despite more than 300 approved biologics.
But progress has been made. In 2024, the FDA made important and beneficial changes to its interchangeability guidelines. And I’m hopeful that the only remaining hurdle to affordable biosimilars, a clinical efficacy testing requirement that adds almost 70–80% of the development cost, will be resolved in 2025.
My life’s mission has been to break down healthcare barriers to ensure global access to biological drugs. Big Pharma’s long opposition to the emergence of biosimilars has always been a stumbling block. Now, I believe I’m on the cusp of seeing my life’s work pay off. Besides Obama, I have met with numerous politicians, testified in front of Congress, authored dozens of books and scores of journal articles and filed multiple Citizen Petitions to push the FDA in the right direction. I will soon file a class action lawsuit against the U.S. Patent Office, on my own, since the biosimilar agencies such as Biosimilar Council have not shown any interest in my proposal to do so.
I am determined to see this through. Not only do these issues remain a professional challenge for me as CTO of the biosimilars company ABYOLO, but more importantly, the world needs better regulatory requirements for biosimilars to incentivize their development. If made widely available, these generic versions of biologic drugs can make a massive difference in the global population’s health.
Interchangeability: A Pointless Distinction
Among the changes I helped initiate to the regulatory process for biosimilars is the recent removal of testing requirements for interchangeability. In 2022, I published a paper suggesting to Congress and the FDA that there should not be two classes of biosimilars—the so-called interchangeable ones, which are permitted to be given in place of the reference product without prescriber intervention and are provided with one year of market exclusivity, and the rest, which do require a doctor to sign off and are given no market protections. I also filed a Citizen Petition on this issue, and the FDA held an open meeting to discuss it in September 2023.
Everyone at the meeting seemed to agree with my arguments that the two classes of biosimilars are illogical. However, soon after the meeting came —predictably—a deluge of opposition from Big Pharma. One example was Amgen’s Leah Christl, a former top FDA regulator of biosimilars, who, in an Endpoints News article, voiced her company’s opposition to the push to do away with interchangeability. At the time, Amgen sought the interchangeability designation for a biosimilar to Humira called Amjevita.
I filed another Citizen Petition with the FDA, emphasizing that the agency can determine if repeated testing is necessary to award interchangeable status. In June 2024, the FDA updated its interchangeability status policy, allowing this status without conducting additional testing. This FDA guideline essentially removed an interchangeability distinction yet maintained its status and complications, such as determining exclusivity. I had the privilege of assisting the U.S. Senate in writing this bill, and while there is less pressure now, I anticipate this will come soon.
These and other changes in the FDA biosimilar guidelines have substantially reduced the development cost. However, we still have one last step.
Evening the Biosimilar-Generic Playing Field
So far, the FDA and other agencies have waived clinical efficacy testing if these molecules demonstrate pharmacodynamic markers that can be compared within the comparative pharmacokinetic studies in healthy subjects. Regulators have not yet allowed for drugmakers to skip comparative clinical efficacy testing, however—a step that is unnecessary and adds almost 70% to the development cost of biosimilars.
Recently, the U.K. Medicines and Healthcare Products Regulatory Agency (MHRA) suggested in its biosimilars development guidelines that clinical efficacy testing may not be necessary, and the European Medicines Agency (EMA) is working on a concept paper for a similar recommendation. I have repeatedly advised the FDA in my publications to make such testing open for consideration—and sometimes not required. The FDA is planning a similar change but has yet to act.
The change will come in the form of FDA guidance, such as recent documents from the agency on biosimilar interchangeability. The FDA has suggested that drug developers will have to request a waiver to secure interchangeable biosimilar status without conducting additional testing.
Another significant cost saving will come if the FDA accepts my proposal to let the U.S. Pharmacopeia (USP) create product release specifications by characterizing branded reference products. These product release specifications could then be used by developers of biosimilars to qualify their drugs without the need to test multiple lots of the branded reference product. In 2018, the FDA blocked the USP from creating classical descriptions, or “monographs,” of pharmaceutical products that are based on standard formulations instead of branded products, saying that due to the variability in structure that is unique to biologics, such monographs would not be acceptable comparisons for biosimilar developers. My proposal overcomes this by having USP create specifications by testing commercial products.
The FDA has responded to me asking for more time to evaluate my request. Should I succeed, the combination of this change and the removal of clinical efficacy testing will bring the total development cost of biosimilars to no more than the development of chemical generic drugs.
Even then, there will still be one more constraint to be removed: the unethical double-patenting laws in the U.S. that can significantly delay the entry of biosimilars. The U.S. Patent and Tradmark Office (USPTO) recognized this and presented a bill to Congress to remove it; however, just when it was ready to go to vote, the USPTO withdrew it. As a patent law practitioner, I published a detailed paper showing why this change is tantamount to a conflict of interest. I also asked the Biosimilar Council to take this issue to court. Still, seeing no move, I have decided to file a class action lawsuit against the USPTO. I am inviting other stakeholders to join without any financial obligation as I fund this lawsuit.
Once the cost of biosimilar development drops, as I anticipate it will, dozens of generic companies will enter the field. More than 100 molecules awaiting entry will arrive as biosimilars, and the world’s patients will benefit from these remarkable lifesaving treatments.
