The Name Game
Biologics are, according to the Food and Drug Administration (FDA), medical products “made from a variety of natural sources (human, animal or microorganism). Like drugs, some biologics are intended to treat diseases and medical conditions. Other biologics are used to prevent or diagnose diseases.” Top-selling biologics include Humira® (adalimumab) and Remicade® (infliximab), which are both used for treating rheumatoid arthritis, and Rituxan® (rituximab), which is used to treat non-Hodgkin’s lymphoma. These remarkable drugs represent the future of drug research and development.
In the United States, there has been an abbreviated pathway at the FDA to approve generic versions of chemically-based, or small molecule drugs since the passage of the Drug Price Competition and Patent Term Restoration Act of 1984. The law is more popularly known as the “Hatch-Waxman Act,” after the legislation’s authors, Sen. Orrin Hatch (R-Utah) and Rep. Henry Waxman (D-Calif.). Prior to the passage of Hatch-Waxman, only about 35 percent of brand drugs had competition after their patent expired. Now, approximately 84 percent of all drugs dispensed in the United States are generics. According to the Generic Pharmaceutical Association (GPhA), generic drugs have saved the U.S. healthcare system a total of $1.2 trillion over the past decade.
While the FDA continues to approve brand-name biologic drugs, there was no abbreviated licensure pathway to approve the “generic” versions of biologics, more properly called biosimilars, to the marketplace until 2010 when the Biologics Price Competition and Innovation Act (BPCIA) was signed into law as part of the Affordable Care Act (ACA). Four years later, not one biosimilar has been approved. The agency has been slow to issue guidance for biosimilar applications.
This delay has been unfortunate for both taxpayers and patients. The Congressional Budget Office estimated that competition from biosimilars would reduce drug spending by approximately $25 billion over 10 years, resulting in nearly $6 billion in savings for the federal government. The Regulatory Affairs Professional Society reported on July 24, 2014 that “at the time of the passage of the Biologics Price Competition and Innovation Act in 2010, congressional budget forecasters said they believed biosimilar drugs could save consumers and the federal government billions each year by incentivizing market competition. However, given the difficulties of bringing biosimilar drugs to market so far, some analysts have expressed concerns that the true savings to US consumers could be much lower than anticipated.”
One reason for the failure to issue final, clear guidelines for approval of biosimilars is that the FDA is spending too much time trying to decide if a biosimilar should have the same International Nonproprietary Name (INN) as its corresponding brand-name biologic or reference drug. This indecision has created an opportunity for playing the “name game.”
The World Health Organization (WHO) established the INN in 1950 “to identify pharmaceutical substances or active pharmaceutical ingredients. Each INN is a unique name that is globally recognized and is public property. A nonproprietary name is also known as a generic name.” According to WHO, “since its inception, the aim of the INN system has been to provide health professionals with a unique and universally available designated name to identify each pharmaceutical substance. The existence of an international nomenclature for pharmaceutical substances, in the form of INN, is important for the clear identification, safe prescription and dispensing of medicines to patients, and for communication and exchange of information among health professionals and scientists worldwide.” As an example, omeprazole is the INN for the active ingredient in the chemically-based drug Prilosec marketed in the U.S. But in European countries, omeprazole has different branded names such as Antra, Logastric, or Zoltum.
It would seem logical that the naming convention would continue in which the reference biologic drug and corresponding biosimilars would share the same INN. That is what currently happens in the European Union (EU), which has had an approval process for biosimilars since 2006.
Unfortunately, some research-based companies are pressuring the FDA to create unique INNs for each biologic and each biosimilar drug. They argue that different INNs are needed because biosimilars are similar but not the same as their reference biologic drug and that different names are needed for tracking adverse events.
Those opposed to developing different INNs have notified the FDA of their concerns. In a citizen’s petition to the FDA, the GPhA stated, “a major goal of the BPCIA is to create competition in the marketplace for biologics, thereby expanding access to, and increasing the affordability of, these critical medicines. Adoption of unique names for each biosimilar could frustrate this goal as well as jeopardize patient safety, inhibit market competition and innovation, and disrupt the current global naming system. GPhA proposes that the same scientific principles that underlie the 60-year-old policy of INNs, as applied throughout the world to drugs and biologics, also must apply to biosimilars.”
GPhA noted that the “highly similar biologic standard is conceptually the same regulatory standard that FDA currently applies to originator products undergoing manufacturing changes – a showing of similarity between batches of active ingredient before and after the manufacturing change enables FDA to conclude the batches have no clinically meaningful differences.” GPhA also stated, “biosimilars, as highly similar to their RPPs [reference protein product], should share INNs with RPPs just as post-manufacturing change biologics share INNs with their pre-change versions.”
GPhA warned that if the FDA believes that “biosimilars require different INNs than their RPPs, there will be consequences for all biologics because regulatory parity and consistent scientific reasoning dictates that if biosimilars require unique INNs then:
(1) All current products sharing INNs must be reexamined.
(2) In the future FDA must require new INNs for any product, originator or biosimilar, which undergoes a manufacturing change using comparability.”
Novartis, a research-based company, argued in its citizen’s petition to the FDA that “assigning different INNs to products approved as biosimilars would introduce unnecessary confusion into the healthcare system and could unintentionally communicate increased caution, unfounded risk, or other regulatory reservations that are purely hypothetical. Significantly, it would put into question years of FDA’s practice of using the well-established analytical standard of high similarity to approve major manufacturing changes of originator biologic products without a parallel change in the originator INN, despite the fact that the manufacturing changes have altered, sometimes substantially, the originator biologics’ molecular structures.” In addition, Novartis said, “INNs are not, and cannot, be the primary tool relied on for tracking and tracing…INNs are intended to facilitate the identification of pharmaceutical substances or active pharmaceutical ingredients by healthcare professionals worldwide…and are by definition non-proprietary and therefore not designed to identify a specific product; indeed, once an INN is established, it identifies ALL products matching the respective molecular substance.”
In a May 25, 2012 joint comment to the FDA’s draft biosimilar guidance, the American Pharmacists Association, the National Association of Chain Drug Stores, and the National Community Pharmacists Association expressed their opposition to having a different INN for a biosimilar. They said, “The use of different INNs would increase the burden of being able to distinguish which products are biosimilar and interchangeable with which reference drug and may pose difficulties in recognizing the best alternative drug for therapeutic use in a timely manner. Such confusion may lead to medication errors such as therapeutic duplication. Furthermore, unique INNs would be contrary to the World Health Organization (WHO) naming system that is accepted globally, causing confusion within the global marketplace.”
Proponents for separate INNs for the reference biologic and a corresponding biosimilar argue that such a naming system is necessary in order to ensure safety, and to help track and trace adverse events back to the appropriate source. The May 2012 joint letter weighed in on this issue as well, stating, “We acknowledge that the ability to uniquely identify which biological product a patient is taking is important, especially in cases of adverse events and quality issues. However, the use of INNs is not a warranted solution and may interfere with current pharmacy safety alert systems and complicate the collection of global safety information. Using examples of successful biopharmaceuticals marketed under the same INN, such as human growth hormone and insulin, the FDA can apply the same concept for naming the biosimilar products.”
In addition to utilizing the proprietary or trade name, the national drug code, the manufacturer’s name, the batch and lot numbers are also utilized to track and trace products in case of an adverse event. In Europe, where biosimilars have been marketed since 2006 and the reference product and biosimilar share the same INN, there have not been any track and trace problems.
In October 2013, the WHO held the 57th Consultation on International Nonproprietary Names (INNs) for Pharmaceutical Substances in Geneva, Switzerland. At that meeting, interested parties called for the WHO to assign the same INN for biosimilars as their reference biological, while others called for distinct INNs for biosimilars.
At the European Commission’s Pharmaceutical Committee meeting held at the same time in Brussels, it was made known that a “majority of the Member States strongly supported the current EU thinking that biosimilar medicinal products should be closely aligned with their reference medicinal products and that an INN qualifier for biosimilar medicinal products would be contrary to such alignment. Several Member States voiced concern that a distinct INN for biosimilar medicinal products could undermine the trust of healthcare professionals and the public in biosimilar medicinal products. The same INN should be used for both the reference medicinal products and the biosimilar medicinal products.”
With respect to concerns over traceability of biological medicinal products to an adverse reaction and the need for a unique biosimilar INN, the Member States answered “it is not problematic to identify the biological medicinal products which are the subject of adverse reaction reports.”
While following the EU is not always the best practice in other matters, in this case, they are eight years ahead of the FDA in the biosimilar approval and safe utilization process. Their recommendations should be heeded.
Because of the FDA delay in finalizing a biosimilar pathway, state legislators have been lobbied to address biosimilar substitution and interchangeability. As a result, laws have been passed in some states that will stifle the ability of patients to access less expensive biosimilars.
The Council for Citizens Against Government Waste, along with the Competitive Enterprise Institute, FreedomWorks, and Taxpayers for Common Sense, wrote a letter to the FDA urging the agency to use the same INN for an originator biologic product and an equivalent biosimilar. In addition, a coalition of insurance plans, labor groups, pension plans, and pharmacies also wrote a similar letter to the FDA, as did the American Consumer Institute Center for Citizen Research.
In spite of all the delays and name-game gyrations, the first biosimilar application was accepted by the FDA on July 24, 2014 for the drug Neupogen® (filgrastim) by Sandoz (a division of Novartis). It will be interesting to see how the FDA handles the final approval of this biosimilar under BPCIA, especially since additional decisions have to be made by the agency on substitutability, interchangeability, and naming. If the drug is approved by the FDA, it could signal how well the new pathway works and how biosimilar products will be priced.
It appears the name-game pressure has had an effect on WHO. On Friday, August 1, the WHO released a draft proposal for the INN system. It would add a biologic qualifier (BQ) to all biologics and biosimilars and would be separate from the INN system. It would be voluntary and would apply prospectively and retrospectively. The BQ would be used to “complement the INN for a biological substance and it uniquely identifies directly or indirectly the manufacturer and manufacturing site of the active substance in the biological product. Availability of the BQ scheme will avoid proliferation of separate and distinct schemes developed by individual regulatory authorities.”
According to Ed Silverman of the Wall Street Journal, the WHO proposal “appears to be something of a compromise” and that “one source familiar with the issue says the proposal indicates that the WHO is not in favor of changing the current system, but is striving to facilitate a common global approach. In other words, the agency is offering a compromise, of sorts, since the existing approach for declaring names would not change, but the coding would add a distinguishing feature.” The WHO will accept comments on the proposal until September 19, 2014.
Meanwhile, to encourage more firms to take the leap and submit applications for biosimilars, the FDA must complete its mandated role to deliver a clear, regulatory pathway for bringing biosimilar products to the marketplace and provide well-defined guidance on when these new products can be substituted for a branded biologic. And the FDA should, and encourage the WHO as well, to continue to recognize the current naming system whereby products worldwide may share the same INN based on drug substance and not adopt a system that would likely bring more confusion to the entire process.
