Sarfaraz K. Niazi, PhD, is an adjunct professor of biopharmaceutical sciences at the University of Illinois and the University of Houston, and founder of biosimilars companies Karyo Biologics and Adello Biologics. He also founded the biosimilar advisory company PharmSci.
Sarfaraz K. Niazi, PhD, a member of The Center for Biosimilars® Advisory Board, recounts a debate with a young clinician over the reliability of biosimilarity testing.
After a big pharma biosimilars event with more than 500 clinicians, I conducted a digital poll to evaluate their trust in biosimilars and the FDA. I was surprised that more than half did not trust the FDA. More than two-thirds did not believe in the safety and efficacy of biosimilars. After the meeting, I got a chance to sit down with a young clinician for a dialog. I will call him Dr Young and me, Old Prof.
Old Prof: Do you think our session about biosimilars was helpful to you?
Dr. Young: I came back with more confusion than where I started; but yes, it was informative.
Old Prof: So, tell me, what is a biosimilar product?
Dr Young: It is a cheaper alternative to a potent biological drug.
Old Prof: Cheaper, meaning low-cost alternative?
Dr Young: That, too, but it is a lower-quality product.
Old Prof: Yes, that is what I learned from the survey. Did you indicate that you do not trust biosimilars?
Dr Young: Yes, I do not trust the quality of biosimilars.
Old Prof: Tell me, what is quality?
Dr Young: It should be effective and safe.
Old Prof: But when a biosimilar is approved, it comes with a “good housekeeping seal” from the FDA to certify that it has “no clinically meaningful difference.”
Dr Young: Yes, but if the FDA does not require extensive testing in patients, how can I be sure of its safety and efficacy?
Old Prof: So, I take it that you do not trust the FDA?
Dr Young: I am not saying I do not trust. I am saying that the FDA may not be able to judge.
Old Prof: So, in your understanding, unless a product is tested extensively in patients, its safety and efficacy cannot be established?
Dr Young: Yes.
Old Prof: But you also prescribe generic chemical drugs that are not tested in patients?
Dr Young: Yes. We know that it is the same molecule, and I am told that a biological drug does not have a fixed molecular structure.
Old Prof: That is right that the molecular structure is variable, but by design and not by a fault. Do you know how the FDA assures the safety and efficacy of biosimilars?
Dr Young: Yes, there are many tests done in the lab and some in animals and some in healthy volunteers.
Old Prof: So, in your mind, despite all of these tests, it must be tested in patients?
Dr Young: Absolutely. That is the only way to show safety and efficacy.
Old Prof: Do you know what a phase 3 trial is?
Dr Young: Yes, it is the testing of drugs in patients.
Old Prof: Right, but this is a trial where the efficacy is measured against a placebo and a decision is made whether the efficacy benefits outweigh the risks of adverse events. But in the case of biosimilars, a comparative efficacy study is done side-by-side with the brand biological and is more complex than the tests for new drugs.
Dr Young: Why is that more complex?
Old Prof: To establish equivalence, we first have to decide what is the maximum difference we will accept to declare equality, and this difference is always made arbitrarily. It is based mainly on a clinical judgment that can vary among clinicians.
Dr Young: You mean a biosimilar can't have a higher efficacy than the reference product?
Old Prof: Efficacy and toxicity go hand in hand.
Dr Young: So why wouldn’t the FDA require biosimilar products to be tested like the new drugs?
Old Prof: First, a robust statistical model would require enrolling a very large population because we are trying to find a minor difference; second, a single trial may not be sufficient if the drug has several indications; and finally, it is difficult to find a naive patient population to test. Also, we must ensure that effectiveness does not exceed the margins set for the reference product. Additionally, if we are to rely on comparative efficacy testing, then it must be done in every indication, and that is not practical.
Dr Young: So, the patients are put at risk because it is more expensive and takes longer to test?
Old Prof: No. Testing in patients is more likely to show that a product is biosimilar because of the lack of sensitivity of clinical efficacy testing models. But the FDA assures the safety and efficacy by a stepwise approach to establish biosimilarity.
Dr Young: What is a stepwise approach?
Old Prof: The active drug molecule in a biosimilar product must have the same primary, secondary, and tertiary structure; the same biological activity as judged by in vitro methods; the same animal pharmacology; and finally, the same human pharmacology. Unless a product meets all these tests, it does not qualify as a biosimilar.
Dr Young: But how do these tests assure safety and efficacy in patients?
Old Prof: First, I would like you to agree with me that science has progressed to a point where it is not difficult to tell one molecule from another. Come on. We have robotic explorers searching for evidence of life on Mars; how could we not be able to tell what is in 2 test tubes? There is significant clinical testing of biosimilars in healthy subjects and often in patients, but only to compare clinical pharmacology, which shows us how the molecules see the body and how the body treats the molecule. These are the finest of the tests of structural similarity. With these, you can establish that the biosimilars have the same molecular structure, just as with chemical drugs.
Dr Young: You mentioned that the clinical efficacy testing may not be a sensitive tool, but how sensitive are these other tools?
Old Prof: The decision of safety and efficacy is not based on 1 test; there are often dozens of tests to examine the same physical or chemical attribute, an approach that is not possible when conducting clinical efficacy testing.
Dr Young: But the issue with biosimilars is their immunogenicity, right?
Old Prof: Yes, but what is the concern?
Dr. Young: A biosimilar can be more immunogenic, causing anaphylaxis and other reactions, including autoimmune disorders.
Old Prof: Immunogenicity of protein drugs is not a negative attribute. It is in the nature of proteins to be immunogenic; the fact is that so many things around us are immunogenic. For example, 5% of the American population is allergic to peanuts, and that is far higher than the immunogenicity of many biological drugs. The testing focuses closely on immunogenicity in side-by-side comparisons to assure that the biosimilar product is just as safe as the originator.
Dr Young: But we hear so much about immunogenicity risks, and you make it sound like nothing extraordinary.
Old Prof: Yes, I do, because it is nothing extraordinary; the only time a difference in immunogenicity becomes important is when this alters the drug's pharmacokinetics. For example, the FDA recently stopped requiring immunogenicity testing of insulin if all other attributes are met because any variability in insulin immunogenicity does not alter clinical pharmacology profile, and therefore, clinical efficacy does not change either.
Dr Young: But isn’t the process of making insulin important in reducing immunogenicity risk, as developed by the branded products?
Old Prof: Yes, the process is important, but the results are more important. A brand product uses as its process “a” process, not “the” process, and it is possible to deploy many different methods to arrive at the same product.
Dr Young: So, if I believe you, I can switch over my patients who are getting a brand product to a biosimilar product?
Old Prof: You are talking about interchangeability, which is a legal issue with biosimilars. There is certainly no issue with starting a naive patient on a biosimilar, but switching a patient from a brand to a biosimilar and vice versa can only be done by you as the prescribing clinician and not by the dispensing pharmacy. I am a diabetic who has switched the insulin brands I am repeatedly getting, depending on what the insurance allows. But insulin is a different molecule. The answer to your question is, yes. You can switch a patient to a biosimilar if you consider it appropriate.
Dr Young: I receive a lot of literature from big companies stating that biosimilars are a risky choice, and if I must use them, I should prefer the biosimilars marketed by companies that also have branded biological products because they know the art and science better? What is your reaction?
Old Prof: Unfortunately, the misconceptions about biosimilars are so widespread; but this is nothing new. Back in the 1980s, when chemical generics entered the markets, we heard the same stories, and these misconceptions would die over time. You should listen only to the FDA.
Dr Young: But I see publications in prestigious journals about biosimilars, with detailed clinical trials. Should those trials be a factor in my decision to use a biosimilar A vs biosimilar B that has not been tested in patients or that has no studies reported in journals?
Old Prof: First, all publications of this nature are scientific advertising, and you are the target. The only data of value are a company's biologics license submission to the FDA and whether the FDA accepts or rejects the biosimilar. Again, you should trust only the FDA.
Dr Young: But how can I trust the FDA if every year I hear the FDA issuing warning letters to companies that they are not making safe drugs or failing them in their audits? Don't these events suggest that the FDA is not upholding quality standards?
Old Prof: This is not the fault but the efficiency of the FDA. There will always be culprits in the business world, and catching them is a job of the FDA. They do not get everyone, but that applies to big pharma just as much as it applies to smaller companies.
Dr Young: You seem to convince me that lower cost does not mean cheap; thank you for enlightening me. I will indeed support biosimilars, but I am not sure if I can convince my colleagues.
Old Prof: So, tell me, how should we educate clinicians?
Dr Young: We do not get time to browse through the internet or visit the FDA website, but we do get journals, and we do attend continuing education events; I think it is only the FDA that can help change our mindset, perhaps by sending us concise updates about the approved biosimilars but without expecting us to go on the FDA website and dig out the literature. There is a lot that we need to learn.