Insulin is not a complex drug, but churning it out in massive quantities at high levels of purity is one of the main hurdles inhibiting biosimilar competition, panelists said.
It’s not easy to break into the insulin market, and for that reason the public should not expect a flood of insulin biosimilars producers, said a panel of experts on biologics manufacturing at the Festival of Biologics USA.
Insulin is a biologic that is very difficult to consistently produce at high purity in large volumes that would be necessary for distribution, and very few manufacturers have the resources to perfect this process and convince regulators that they can get it right, the panelists said.
Further, the United States is an intensely litigious country for biologics producers, and would-be biosimilar contenders may encounter a barrage of legal opposition from entrenched producers, they said. In the United States, Eli Lilly, Novo Nordisk, and Sanofi produce and distribute an estimated 90% of the insulin.
This relative monopoly has given rise to extraordinary inflation in the cost of insulin products. A report from Mayo Clinic in 2020 observed an “inexplicable” 1000% increase in the cost of a vial of Humalog (insulin lispro, Eli Lilly) between 1999 and 2019 ($21 vs $332, respectively).
Clearing the Logjam
The United States has attempted to clear a pathway for the introduction of insulin biosimilars. In 2020, the 351(k) Biologics License Application process under the Public Health Service Act became available for insulins and growth hormones, allowing these products to be approved as biosimilars.
There are no biosimilar insulins so far, although in mid-2020, Biocon and Mylan succeeded in getting an insulin glargine (Semglee) approved under the generic 505(b)(2) New Drug Application pathway and are seeking to have it designated a biosimilar. The panel discussion at Festival of Biologics USA included the participation of Sundar Ramanan, PhD, MBA, vice president and head of Global Regulatory Affairs for Biocon.
Many companies have attempted to bring rival insulin products through the review process in Europe and have failed because the pharmacokinetics of these products are extremely difficult to match precisely with originator products, Ramanan said. “That’s barrier number 1. Barrier number 2 is we need to have economies of scale, and that requires a large capital investment, and not many companies have that to combine with the science. This limits the number of players that are coming in beyond the ones that are truly committed.”
Biocon is one of the success stories, having insulin products approved in more than 60 countries. “It took us a very long time, but now we have that institutional knowledge,” Ramanan said.
Eva Rahman Kabir, PhD, an expert on pharmaceutical marketing who serves as a professor and chair of Brac University in Dhaka, Bangladesh, agreed that manufacturers have difficulty meeting the regulatory expectations for quality. “Regulators are encouraging companies to invest in continuous processing, so that would mean they have the technical mastery over the process. This is easier to say than to do,” she said.
Process validation is another source of regulatory rejections of insulin product applications, she said. Process validation refers to efforts to confirm that drug product of a standard quality can reliably be produced consistently over time.
A Problem of Scale
Insulins are not complex drugs and, in fact, involve a simple amino acid sequence, Ramanan noted. “However, it is not easy to produce insulins of high purity at extremely large scale. That is what scientific capabilities require.” This makes producing insulin biosimilars a challenge, and it’s another reason why the market is not flooded with competitor products, Ramanan said.
“It’s a production manufacturing challenge at scale. The world consumes many times more insulin than monoclonal antibodies,” which are the standard form of biosimilars commonly available in the United States, said Steve Lehrer, MBA, BSE, panel moderator and managing director of SBLehrer, an expert on biosimilar commercialization.
The insulin producer competition in the United States remains scanty, and for this reason, prices are unlikely to come down anytime soon, Ramanan said. Another structural problem in the marketplace is the heavy patenting that originator companies do to protect themselves against competition. “It prevents competition and it keeps the price higher for decades,” Kabir said. Multiple versions of insulin products are needed to really tamp down the price curve, she said.
“Due to the litigious nature of the US market, even before a company finishes a clinical study, there is litigation already ongoing,” said panelist Kaushik Dave, RPh, PhD, MBA, vice president of Global Regulatory Affairs for Gan & Lee Pharmaceuticals USA. Therefore, a company needs significant resources to endure these battles and finally get its product to market.
Despite the expansion of the 351(k) licensing pathway, US regulatory efforts to enlarge the insulin product pipeline have been “lagging,” Dave said. “The decision-making right now is really in the hands of the pharmacy benefit managers in the United States.”
Taking all structural conditions into account, Dave said he anticipates that only a “limited” number of companies will develop insulin biosimilars.
Even if the problem of too few competitors can be solved, there isn’t much hope for price reduction. The benefit for patients and health care systems from having insulin biosimilars will not be as dramatic as has occurred for generic drugs, where deep discounts have been achieved, Dave said.
Biosimilars involve costly biologics manufacturing, and biosimilar developers will not be willing to enter market at deep discounts to the originator products. Combining the scarcity of players in the market and the unwillingness to discount products, the problems of low competition and high prices are very likely to persist, he said.
For an article about legislation introduced to grant automatic interchangeability for insulins, click here.