BioRationality: A Dr Sarfaraz Niazi Column—Misconceptions in the Adoption of Biosimilars

The efforts of stakeholders promoting the adoption of biosimilars should be directed toward pivotal issues and not common beliefs. Biosimilars should be presented, not promoted, as a lower-cost solution to expensive biologic drugs. Advertising their safety and efficacy works against the goal, diluting the FDA declaration of "no clinically meaningful difference. Only 2 factors can hold back wider distribution: their price and the hurdles in distribution.

Analysis of IQVIA’s data on the EU and US adoption and discounts offered by biosimilars shows many surprising results. First, there is no correlation between the discount offered and market share (given here as a percentage of units), even in the countries offering socialized medicine.

For example, in the United States, filgrastim biosimilars gained a much larger market share than pegfilgrastim biosimilars, which offered a higher discount and many competitors. A significant finding is that Amgen, the most prominent innovator and biosimilar products company, offered the highest price reduction at 57% among all infliximab biosimilars against Johnson & Johnson's reference product, indicating a price war that had long been anticipated. How much the price can be reduced can be assessed by comparing the cost of goods of biologic drugs.

For example, the cost of antibodies per gram is projected at $95 to $200 per gram by the World Health Organization, or even lower.[1], [2] As listed by CMS, the reported costs per gram of antibodies range from $24.4 million per gram for inotuzumab ozogam, $2.6 million for ranibizumab, to the lowest $3,500 per gram for infliximab and rituximab.[3] These costs are higher for non-CMS distribution. The cost of currently marketed antibodies in the United States range from $10,000-12,000 per gram for the reference products. The cost of filgrastim, as charged by Neupogen, is $650,000 per gram, and Neulasta (reference pegfilgrastim) is twice as much in the United States. The cost of production of cytokines like the filgrastim ranges between $1,000 to $3,300 per gram, based on the upstream yields of 30 mg to 100 mg per liter.[4]

This observation suggests that the price of biosimilars can be reduced significantly if their development cost is reduced from the current cost ranging from $100 to $ 300 million. Reducing the development cost will bring more competition, as smaller companies will be able to enter the market.

Since the enactment of the Biologics Price Competition and Innovation Act (BPCIA), the FDA and the US government have taken several measures to expedite the development of biosimilars:

Reference product selection. While the FDA still requires bridging study, this is a legal issue as the BPCIA states, "US-licensed product." Efforts are ongoing to remove this term with "or its equivalent."[5] Still, developers can secure the concurrence of the European Medicines Agency and FDA before commencing the development to avoid redundant studies.

Removing animal toxicology testing. The BPCIA was amended to remove "animal" and "toxicology."[6] This major change should reduce the time to market significantly and remove the risk of using animal toxicology testing to justify differences in analytical comparison.

Remove interchangeability. A bill is in the Senate to remove the interchangeable class of biosimilars and is expected to be approved soon. I do not recommend biosimilar developers seek out interchangeability status since it applies only to drugs dispensed at the pharmacy level for self-administration.[7]

Removing comparative clinical efficacy testing. This is the costliest part of development while it is of little value.[8] The FDA's Division of Applied Regulatory Science program suggested using in silico models instead, reducing the development cost by 70%.[9] The FDA has coined a new term, "clinical efficacy testing in healthy subjects" when pharmacodynamic parameters are used to establish clinical similarity. The developers are encouraged to challenge the waiver of efficacy testing in patients based on scientific arguments. Until then, any product that has definite pharmacodynamic parameters would be a good candidate for such waivers.

Harmonization of guidelines. Efforts are underway to harmonize the guidelines under International Conference for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), now an independent entity.

CMS Price Reduction. To remove monopoly for more than 12 years, the CMS can reduce the price of biological drugs by 35% until a biosimilar product is licensed or anticipated within 2 years. Once a biosimilar is licensed, all price reductions go away. This change will reduce the legal challenges to the entry of biosimilars and the time to approval.[10]

Modern Science. Cost reductions can also be made by adopting newer technologies and strategies, such as obviating scaling-up cost by using a smaller clinical batch size and later scaling up under the ICH Q5E guidelines, using higher-yielding cell lines, transforming to continuous manufacturing, applying the new artificial intelligence tools for structure validation, and reducing the approval timeline by avoiding repeated FDA audits.

While the inflection points for biosimilars are connected to their price, an equally significant constraint is the distribution system responsible for holding back market adoption despite price drops of biosimilars. It applies to all countries, but more in the United States, where the distribution system is convoluted, wherein the pharmacy benefit managers (PBMs) and other middle entities complicating the cost optimization. The practices of the PBMs are now under investigation, and new legislation will stop their influence.

Despite all odds, industry associations and other stakeholders have an essential role in bringing more cost-effective biological drugs to patients.This will require working with regulatory agencies to bring more clarity and rationality to approval guidelines, while working with the US Congress to assist in creating legislation to reduce the constraints in the distribution of biological drugs in the United States. There is no need to waste resources on educating prescribers and patients; the FDA is doing that job very well. Instead, millions of dollars spent on promotional advertising should be spent on improving the science, creating collaborative projects, streamlining the partnership, and removing the hurdles in the distribution of biological drugs.

The inflection points for biosimilars are imminent, and a significant shift will occur soon as the prices drop and the markets are allowed to expand.

[1]WHO. July 23, 2021. Accessed February 13, 2023. https://www.who.int/news-room/articles-detail/call-for-consultant-on-monoclonal-antibodies-for-infectious-diseases

[2]Amasawa E, Kuroda H, Okamura K, Badr S, Sugiyama H. Cost–Benefit Analysis of Monoclonal Antibody Cultivation Scenarios in Terms of Life Cycle Environmental Impact and Operating Cost. ACS Sustainable Chem Eng. 2021;9(42):14012-14021. doi:10.1021/acssuschemeng.1c01435

[3]CMS. Updated December 14, 2022. Accessed February 13, 2023. https://www.cms.gov/medicare/medicare-part-b-drug-average-sales-price/2023-asp-drug-pricing-files

[4]Babaeipour V, Khanchezara S, Mofid MR, Abbas MPH. Efficient process development of recombinant human granulocyte colony-stimulating factor (rh-GCSF) production in Escherichia coli. Iran Biomed J. 2015;19(2):102-10. doi:10.6091/ibj.1338.2015

[5]Niazi SK. Biosimilars: harmonizing the approval guidelines. Biologics. 2022; 2(3):171-195. doi:10.3390/biologics2030014

[6]Niazi SK. End animal testing for biosimilar approval. Science. 2022;377(6602):162-163. doi:10.1126/science.add4664

[7]Niazi SK. No two classes of biosimilars: urgent advice to the US Congress and the FDA. J Clin Pharm Ther. 2022;47(9):1352-1361. doi:10.1111/jcpt.13743

[8]Niazi S. Scientific rationale for waiving clinical efficacy testing of biosimilars. Drug Des Devel Ther. 2022;16:2803-2815. doi:10.2147/DDDT.S378813

[9]Chiu K, Racz R, Burkhart K, et al. New science, drug regulation, and emergent public health issues: the work of FDA’s division of applied regulatory science. FrontMed. Published online January 19, 2023. Accessed February 13, 2023. doi:10.3389/fmed.2022.1109541

[10]Niazi SK. The Inflation Reduction Act: A boon for the generic and biosimilar industry. J Clin Pharm Ther. 2022;47(11):1738-1751. doi:10.1111/jcpt.13783