Recently, we conducted a Web-based interview with someone who has been exceedingly important to the advancement of the biosimilar industry, Sarfaraz Niazi, PhD. Dr. Niazi, Adjunct Professor of Pharmaceutical Sciences at the University of Illinois and the University of Houston, founded the first US biosimilar company, Therapeutic Proteins (later Adello and Kashiv), and is the founder of Novel351k; as well as a biosimilar advisory company PharmSci. In part 1 of this two-part interview, we talked with Dr. Niazi about numerous topics critical to streamlining biosimilar regulation and speeding products to the market, including the cost of clinical trials, elimination of late-stage clinical trials and animal toxicology testing, and global regulatory harmonization.
Biosimilars Review & Report: Tell us a little bit about your background in biosimilars, and how you became involved with biosimilar regulation and development.
Sarfaraz K. Niazi, PhD: I was able to set up the first US company to make biosimilars and also wrote the first book on the subject. My company, of which I am no longer a part, having gotten diluted heavily, got three products approved. But I realized that the cost of getting to the finish line is just enormous and matches what was cited in the current McKinsey report: It costs between $100 million to $300 million to obtain US product approval. Though the numbers can be flexible depending on the nature of the product, at that price range, you will deter entry of real competitors, smaller companies.
At the time I was developing biosimilars, I found many problems with the regulatory guidelines. The first one had to do with analytical assessment; the FDA used to call it analytical similarity testing; now the FDA calls it analytical assessment. I believed the guidelines on this were wrong, and I filed a petition with the FDA; the guideline was withdrawn, a rare happening and replaced with another guidance that removed the objections I had raised. Since then, I’ve been working very closely with the three agencies: European Medicines Agency, the UK’s Medicines and Healthcare Products Regulatory Agency, and the US FDA. Most of my interaction with the FDA is reported by the FDA on the website regulations.gov. Most recently, I filed for a regulatory harmonized guideline with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use or ICH.
If a molecule looks the same as another, analytically such that we cannot tell the difference, then neither can the body. I found that fear of safety of biosimilars inculcated by the extensive efforts of the big pharma had begun to take root; though it was totally untrue.
I started writing papers that questioned the existing guidelines regulating biosimilar development and testing. For example, I had always believed that there is no role for any animal toxicology testing in biosimilar development. Very simply, there is no receptor binding in an animal; to an animal, the medicine is just extra food. I published an article in Science and got in touch with Senator Ben Ray Luján (D-NM), who was writing a legislation to modify the BPCIA to remove this testing; I shared my paper and my thesis with all Senators and Representatives and I am not sure how much this impacted, but the Senate passed the FDA Modernization Act 2.0 based on removing animal toxicology testing.
Today, I’m working on a bill with Senator Michael Lee (R-NC), on removing the interchangeability designation from the BPCIA. Again, this must be done legislatively, because it is part of the original Act.
I’m doing my best to make the guidelines more rational. I’m having some success, but there’s still a long way to go.
International Harmonization of Regulatory Guidelines
BR&R: You’ve mentioned several areas, and I want to discuss each in a bit more detail. Let’s talk about regulatory harmonization first. Why is global harmonization of biosimilar regulatory guidelines so important for the future of the industry?
Dr. Niazi: If one set of regulatory guidelines is accepted globally, then a company that obtains approval in one jurisdiction can then distribute their product to many more countries. Efforts to achieve this in the past have not been successful. The ICH was an institution run by the US, Europe, and Japan. Recently, the ICH was reincorporated as a separate, totally independent entity. So, the new ICH is not the old ICH.
If we have an accepted ICH regulatory guideline, it will help make all products uniformly safe and effective across the globe. If I’m investing something like $100 million to develop my biosimilar product, I would like to be able to sell it across the globe without further regulatory costs.
BR&R: What percentage of the total development costs are associated with clinical testing?
Dr. Niazi: That’s probably the hottest thing to talk about. The FDA has now begun using a new terminology—“clinical efficacy in healthy subjects,” which is pharmacokinetic and pharmacodynamics testing.
Generally, when you are talking about clinical efficacy in healthy subjects, the cost can range from $1 million to $3 million. In contrast, efficacy testing in patients could bump costs up to $30 to $50 million. In my opinion, those clinical tests account for most of the costs of development.
This also depends on disease state. For instance, if you are developing an oncology drug, it becomes far more expensive because of the difficulty in finding study patients. It requires a multicenter, global study, which might cost $50 million to $70 million.
BR&R: At the Festival of Biologics meeting we attended in March, we heard Dr. Gillian Woollett of Samsung Bioepis state that “unnecessary human testing is unethical,” and that we have learned nothing from late-stage clinical testing in biosimilars that we didn’t already know from analytical evaluations. Are we in a position today to reduce or eliminate the need for human clinical testing for biosimilar candidates?
Dr. Niazi: Let’s specify testing in healthy subjects versus testing in patients. There is a huge difference. When speaking about testing in patients, I totally agree. I have written several papers on this. The ethical statement is a universal rule, but I have additional reasons, which are different from anybody else’s.
In my papers, I took a statistical modeling approach to the issue. Remember, with biosimilars, we are, for the first time, attempting to compare two products that are already proven to be similar through analytical means. Basic statistical knowledge will tell you that when the two things are known to be similar, a great many subjects will have to be enrolled in a study to yield a statistically significant difference. Consider that if it took 300 patients to demonstrate a difference in efficacy between the reference product and placebo, it may take 100,000 enrolled patients to demonstrate a difference when comparing the biosimilar and the reference product.
To resolve this problem, the FDA allows a specific predefined level of variability, based only on clinical judgment. It’s completely arbitrary. But the argument that has been more convincing is the scenario where the comparison study fails to show equivalence between the biosimilar and reference product. Any time a study fails, statistical calculations will always show that this conclusion is incorrect, as I published my work based on Bayes theorem. It is easy to understand that if a drug study fails, the chance of a false-negative result is zero percent.
Then I evaluated the approximately 180 studies conducted testing biosimilars and reference products in patients. Can you guess how many failed? None. My argument is very simple. It is not based on the reason to reduce the cost of development. So, I agree with Dr. Woollett. We should eliminate these biosimilar clinical studies in patients.
Do We Really Need Animal Testing for Biosimilars?
BR&R: You also mentioned the lack of information we obtain from the animal toxicology studies. Can you elaborate?
Dr. Niazi: Yes. The language of the BPCIA includes a statement about “animal toxicology testing.” Biosimilar developers interpret the statement to mean that animal testing is mandated. Hundreds of animal toxicology testing data were submitted, showing that none of these studies failed—using rats, monkeys, rabbits, whatever. Animals don’t have the receptors that humans have; monkeys may have some receptors, but the receptor response would not be the same. There’s no way an animal model can demonstrate toxic effects of these medications. You will not obtain any useful toxicology information from this type of testing.
I confronted one very large company that conducted 17 animal toxicology studies and submitted them to the FDA. Of course, none of them failed, so I asked them, “What do you have against animals?” The FDA didn’t even review their studies.
So, we wanted to remove those two words—animal toxicology—from the BPCIA, and as of January 2023, they are now replaced with “non-clinical.” Of course, non-clinical testing may include animal testing, if necessary, but we have so many tests available that are much more sensitive and give you an orthogonal comparison; I do not foresee biosimilars tested in animals going forward, but I am afraid that the change in mindset may take a while.
BR&R: Excellent. If we’re talking about phase III or IIb testing in patients being unnecessary, the FDA has a great deal of latitude in terms of requesting or mandating certain tests for certain products. Does this decision have to be made by anyone else? Or does language have to change in the BPCIA to stop requiring their use?
Dr. Niazi: The guidelines state that the HHS Secretary has the option. So, the FDA has the last word. This is right, but it also gives the developer an opportunity to challenge. For example, the FDA has approved an interchangeable ranibizumab product (Coherus’ Cimerli®) without requiring a switching and alternating study. My biosimilar products were approved with no testing, as I asked the FDA this question: “Do you see any residual uncertainty after completing the PK/PD studies? but before you answer, is there any study that will remove it?” I hope everybody will ask this of FDA.
So, yes, FDA has the authority to waive any requirement for biosimilar approval, but the developers must stand up and ask the question.
In part 2 and the conclusion of our interview, we discuss with Dr. Niazi the role of artificial intelligence in biosimilar development and how he believes the Inflation Reduction Act will benefit biosimilar manufacturers.
