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

Section 7002 of the Biologics Price Competition and Innovation Act, which details the approval pathway for biosimilar biological products, has come a long way with the issuance of several FDA guidance documents—some revised and 1 withdrawn. Developers and the FDA have collaborated on rewriting recommendations for establishing biosimilarity that will support the Section 7002 mandate to enable faster development of biosimilars, benefiting American patients. This column is abstracted from my citizen petition to the FDA on the same topic.

Although all FDA guidelines include a disclaimer that the guidance provided is suggestive and neither the developer nor the FDA is bound by it, this disclaimer is universally ignored, and the developers try to comply with the listed recommendations. I recommend that the FDA look at the suggestions made here and create a new guideline that will be rational and less demanding on developers without compromising the safety and efficacy of biosimilars.

In submitting my thesis, I am introducing a few new terms. Legacy attributes are the critical quality attributes (CQAs) for which release specifications have been well-established. There is no need to test these attributes side by side with the reference product. Nonlegacy attributes are established based on the testing of the reference product, but not necessarily in a comparative mode. Qualification testing is intended to verify that the active molecule sufficiently matches the reference product, and all of this testing is conducted on a smaller number of batches.

Creating a rational approach requires examining all CQAs based on the relevance and appropriateness of testing. The CQAs are divided into product-related and process-related attributes; the former require comparative testing with the reference product and the latter only if a legacy range of variability cannot be established. This concept is presented in the 

CQAs comprise the properties that can affect the safety and safety of the product. How these attributes are tested should be segregated by product attributes associated with the expression system and process attributes associated with the manufacturing process. The product attributes are the least variable, as they should be, and establish the suitability of the product for further development. These attributes should not be compared with legacy values such as the structure reported in the literature; the comparisons must be made in side-by-side testing with the reference product. Because the product-related attributes have narrow acceptance criteria, only 3 lots of biosimilar candidates and reference products would suffice for testing. Forced degradation studies can be considered as both product and process-related attributes as they tell much about the inter- and intramolecular bindings determined by the primary, secondary, and tertiary structures. Unfortunately, the 

 does not recognize the value of forced degradation or accelerated stability testing in a comparative mode, missing out on a critical method of evaluating molecular structure.

The molecular structure is further confirmed through a biological lens that can comprise in vitro pharmacology, nonclinical pharmacology (pharmacokinetic [PK] studies in animals). Animal PK studies help support structural similarity through the eyes of a biological system to view the molecules, albeit the disposition profiles are different in humans. Although such studies are required for antibody testing in larger species, these should be required for all products.

The most important test is the human PK/pharmacodynamic (PD) study based on how the body sees the molecules and how the molecules see the body. Novel study protocols can combine the PK/PD and immunogenicity testing in a single study that can be made more powerful by narrowing down the inclusion/exclusion criteria, because the purpose of these studies is to compare, not characterize, the profiles. One such type of study can be a 2-periods, parallel, 2-dose study.

Although the expression system determines the product's structure, the rest of the variations result from differences and variabilities in the process, from upstream to downstream to the formulation. These CQAs cannot be 1-time testing and should be included in the release specifications. The CQAs can be classified into 2 categories: 1 where the release limits are well-known and well-established, and the other where the limits must be established based on the ranges obtained from the reference product. This concept of similarity establishment is efficient and based on scientific principles, and it reduces the burden of testing substantially (

Animal toxicology studies are not needed, because the molecule's safety has been established, and any minor differences in the structure or posttranslational modificationprofile will not be detected because the testing is conducted at the higher end of the linear range of toxicity. In most cases, the animals do not have similar receptors, which makes these studies least relevant. This same argument holds for any PD and immunogenicity testing in animals. There is also little correlation with the human dose to make such studies redundant. The European Union and FDA have approved more than 100 products, and none of the products failed in animal toxicology testing because they cannot.

Clinical efficacy and safety studies comprise the most significant time and cost hurdles in the development of biosimilars, even though these studies do not add any assurance to the safety and efficacy evaluation. Hundreds of clinical efficacy and safety studies reported were conducted without the European Union or the FDA establishing that there is any “residual uncertainty” primarily to support the marketing of these products. However, if a biosimilar product fails to meet any of the studies stated above, particularly the clinical pharmacology, the FDA does not allow testing in patients because these studies can never resolve any “residual uncertainty” for the following reasons:

A single study in 1 of the several possible indications does not resolve uncertainty even where the mechanisms of action are cross-validated.

Efficacy studies require an arbitrary selection of differences in efficacy based on a clinical judgment that can vary widely.

A noninferiority study may allow a product with higher efficacy and, therefore, a possible higher safety risk.

Clinical markers are often unreliable and, in some populations like cancer patients, highly variable.

Many studies lose patients in critical care and rarely find naïve patients to reduce the variability and increase test power.

The statistical model of demonstrating that 2 products are not different is more complex than showing the efficacy of a product against a placebo.

None of the biosimilars tested for safety or efficacy failed the test. The clinical safety and efficacy are already subject to 

postmarket drug and biologic safety evaluations

In evaluating biosimilars, the FDA has created precise and scientifically significant vocabulary terms such as “no clinically meaningful difference” and “residual uncertainty” that are relevant and represent a creative approach to ensuring the safety of biosimilars. However, certain practices are needed to enable faster approval of biosimilars.

The following is a summary of my recommendations to the FDA:

Reduce comparative similarity assessment to relevant attributes.

Allow inclusion criteria in clinical pharmacology studies to reduce intersubject variability

Define “residual uncertainty” for every product evaluated and reject those where a resolution cannot be made.

Rely on postmarket evaluation for safety and efficacy instead of limited testing that cannot support removing any residual uncertainty.

Articles

Sarfaraz K. Niazi, PhD, a member of The Center for Biosimilars® Advisory Board, reports on his citizen petition to the FDA to rationalize testing of biosimilars. 

Opinion: A Rational Approach to Establish Biosimilarity

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.

Do you think our session about biosimilars was helpful to you?

I came back with more confusion than where I started; but yes, it was informative.

 So, tell me, what is a biosimilar product?

It is a cheaper alternative to a potent biological drug.

 That, too, but it is a lower-quality product.

 Yes, that is what I learned from the survey. Did you indicate that you do not trust biosimilars?

 Yes, I do not trust the quality of biosimilars.

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.”

 Yes, but if the FDA does not require extensive testing in patients, how can I be sure of its safety and efficacy?

 So, I take it that you do not trust the FDA?

I am not saying I do not trust. I am saying that the FDA may not be able to judge.

 So, in your understanding, unless a product is tested extensively in patients, its safety and efficacy cannot be established?

But you also prescribe generic chemical drugs that are not tested in patients?

 Yes. We know that it is the same molecule, and I am told that a biological drug does not have a fixed molecular structure.

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?

Yes, there are many tests done in the lab and some in animals and some in healthy volunteers.

 So, in your mind, despite all of these tests, it must be tested in patients?

 Absolutely. That is the only way to show safety and efficacy.

 Yes, it is the testing of drugs in patients.

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.

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.

You mean a biosimilar can't have a higher efficacy than the reference product?

 So why wouldn’t the FDA require biosimilar products to be tested like the new drugs?

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.

So, the patients are put at risk because it is more expensive and takes longer to test?

 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.

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.

 But how do these tests assure safety and efficacy in patients?

 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.

You mentioned that the clinical efficacy testing may not be a sensitive tool, but how sensitive are these other tools?

 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.

But the issue with biosimilars is their immunogenicity, right?

 A biosimilar can be more immunogenic, causing anaphylaxis and other reactions, including autoimmune disorders.

 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.

But we hear so much about immunogenicity risks, and you make it sound like nothing extraordinary.

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. 

But isn’t the process of making insulin important in reducing immunogenicity risk, as developed by the branded products?

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.

 So, if I believe you, I can switch over my patients who are getting a brand product to a biosimilar product?

 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.

 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?

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.

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?

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.

 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?

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.

 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.

 So, tell me, how should we educate clinicians?

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.

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. 

Column: A Biosimilars Dialogue With a Young Clinician

The foundations for generics and biosimilars were laid in the enactment of several key pieces of legislation. In 1962, the Kefauver-Harris Amendments required proof of a product’s safety and efficacy, and they mandated that drugs released between 1938 and 1962 be reviewed for safety. In the late 1960s, the FDA developed the abbreviated new drug application for approval of generic drugs. The Drug Price Competition and Patent Term Restoration Act of 1984 (aka Hatch-Waxman) allowed the FDA to approve applications to market generic versions of brand-name drugs that were released after 1962 without repeating efficacy and safety studies; it also gave manufacturers of originator drugs 5 years of exclusivity for new products that contain previously unapproved chemical entities.

Originator drug companies were opposed to the idea of generic drugs and declared that these copycat drugs would cause havoc to health care. The protests were unsuccessful, and many of these manufacturers ultimately made generic drugs as well, although generics were less profitable for them.

Now, 37 years after Hatch-Waxman, despite widespread use of generic drugs, the controversy continues about their safety and efficacy, particularly in prescribers’ minds. In 2010, the Biologics Price Competition and Innovation Act (BPCIA) was signed into law, and we saw history repeating itself as originator companies objected to biologics, as they had once objected to generics. However, this time, they found a sympathetic audience because the stakes were much higher. The most common argument presented was that biological drugs do not have a fixed structure, and manufacturing process controls are pivotal to assuring safety and efficacy. Because only innovator producers are privy to these controls, they contended, it is impossible to create a safe and effective copy of a biological drug.

AbbVie protested to the FDA in a citizen petition that the BPCIA constitutes an unlawful taking of private property under the Fifth Amendment because each biologics license application (BLA) contains trade secrets and confidential commercial or financial information, and the “approval of a biosimilar necessarily relies on and uses the trade secrets that the innovator sponsor submitted in support of the BLA.”1 The petition was denied by the FDA.

Many more petitions demanded that within biosimilar product labeling should be a declaration acknowledging that a biosimilar is different from the reference product. Extended lobbying efforts, as well, were aimed at getting state legislatures to preemptively ban interchangeable biosimilars. When originator companies realized that biosimilars were not going away, however, they got aboard the train, just as they did for the generic drugs. Big-name companies with many original biologics became the largest producers of biosimilars. Of 29 biosimilars so far approved by the FDA, all but a few are owned by the larger pharmaceutical companies. It might be assumed that the distrust sowed against biosimilars’ safety and efficacy by major pharmaceutical manufacturers would have dissipated, but it did not. Patients were reluctant to use these agents. And the same companies that once revolted against biosimilars adopted a new mantra: “Only we know how to make biosimilars because only we know how to make biological drugs.”

Physicians get information about new drugs from medical journals, continuing education meetings, and, most important, from visits by medical reps who are employed by the pharmaceutical industry. Physicians are good at what they do, but they are not scientists. They are well able to understand the results of a published clinical study, but most would be lost in the jungle of protein structure and immunogenicity profiling that is critical for biosimilar approval. Overall, the message received by physicians was simple: “Do not risk your patients.” The FDA did a lot to educate every stakeholder, including the physicians, but that was not enough to fully counter the bias created against biosimilars.

Over my career, I have conducted many advisory board meetings with stakeholders to introduce biosimilars. In 2019, I was hired by an originator company to educate physicians about biosimilars. To one group of about 500 primary care physicians, I presented a high school–level science lecture on biosimilars, with graphics, to reduce the jargon and complexity. Before my talk, I asked them to take a survey that included 2 questions: (1) Do you trust the safety and efficacy of biosimilars? and (2) Do you trust the FDA? Most physicians did not believe that biosimilars are safe, despite the FDA labeling that biosimilars in comparison with originator drugs have “no clinically meaningful difference” In response, I asked why they believed the FDA would not be truthful about biosimilars. The typical response was that, every year, many drugs are recalled and many companies are given citations for lack of current good manufacturing practice compliance. I had difficulty connecting these issues with the biosimilar issue, but the responses helped me understand the provider mindset: The FDA cannot assess the safety of biological drugs because if you do not know what you are looking for, how would you know you are not finding it?

Later, I gave these physicians another survey that asked these questions: (1) Would you prescribe a biosimilar to a patient if the insurance will not pay for the originator product? and (2) Would you trust biosimilars from smaller companies, now that the innovator companies are also making biosimilars? To the first question, the answer was an overwhelming yes. And to the second question, it was overwhelmingly no. I did not get a chance to continue my arguments. Still, in a social gathering over lunch, many physicians agreed that they did not have the time to understand the scientific nuances I presented in my talk. In brief, physicians remain misinformed or ill-informed about the FDA’s role in assuring the safety and efficacy of drugs, and originator companies perpetuate the confusion by asserting it is only a published clinical trial of efficacy that matters.

One physician was very frank. Her hospital has a policy of using biosimilars where available, and prescribers can get approval for an innovator biologic only by filling out a 10-page form. That killed the revolt against biosimilars quickly, she said.

So, where do we go from here to make physicians believe in biosimilars? The first responsibility goes to the FDA. Often, physicians do not scroll the pages of FDA websites or watch FDA YouTube videos. My suggestion to FDA Acting Commissioner Janet Woodcock, MD, is that she send a direct communication to physicians (a paper letter, not an email) to assure them that when the FDA approves a biosimilar, that is a golden seal of “no clinically meaningful difference.”

Second, payers can do their part to increase biosimilar use by establishing reimbursement policies that favor biosimilars, a sure-fire means of getting lower-cost biosimilars into play. I have also met with CMS leaders and suggested a legislative change to enable CMS to create a biologics substitution list that is based on cost with no other differentiation between a biosimilar and a reference product. This has already been tried in Europe; it works and will work in the United States.

Third, biosimilar developers should monitor misleading or anticompetitive public statements made about biosimilars and report these to the FDA and Federal Trade Commission. Innovator companies have been admonished for such actions by regulators before. Merely reaching out to physicians to explain the advantages of biosimilars may not be enough if entities opposed to biosimilars continue to disparage these agents.

With proper, unhindered education about the value of biosimilars, these cost-saving agents can become as significant a force in improving access to health care as generics have before them.

Regulations.gov. Citizen petition from AbbVie, Inc. FDA. Published June 3, 2015. Accessed February 16, 2021. https://www.regulations.gov/document?D=FDA-2015-P-2000-0001

Biosimilars have come a long way, and their path has mirrored that of generics—fraught with obstacles. Still, a stronger embrace is needed from physicians and payers. 

Opinion: A Short History of Biosimilars

Boehringer Ingelheim (BI) is one of the most prestigious biopharmaceutical companies 

 in the United States. BI has 1 monoclonal antibody product (adalimumab, Cyltezo) licensed as a biosimilar and several other products under development.

 asking the FDA to change its interpretation of the term 

 in the Public Health Service Act (PHS) to allow biosimilar developers more flexibility in developing formulations and enable active drug delivery in smaller volumes. The FDA has 

 for review and will likely take a few months to respond.

I have reviewed the BI petition and conclude that BI has overlooked some compelling arguments that could have helped persuade the FDA to make this pivotal change. I am presenting my analysis of this petition along with alternative arguments to support the petition.

The focus of the BI petition is to address the technical and legal issues that biosimilar developers face in meeting the definition of a biosimilar product under the Biologics Price Competition and Innovation Act (BPCIA), which is authorized by the PHS Act and states that the “route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product.”

The BI petition suggests the FDA take the 

Interpret the term strength as it is used in section 351(k) of the PHS Act to mean the “total drug content” in the drug container (eg, single-dose vial, prefilled syringe) regardless of concentration or total volume.

Revise agency guidance documents on biosimilar development, interchangeability, and the BPCIA to be consistent with this interpretation.

Apply this interpretation to pending and approved 351(k) applications, amendments, and supplements, including advice provided during biosimilar biological product development meetings and in review correspondence, such as complete response letters.

The issue of product concentration arises mainly in the formulation of monoclonal antibodies (mAbs) where the dosing is higher. The first generation of mAbs were for intravenous (IV) infusion because the larger injection volume made self-administration impractical. Traditionally, the 

 from 4 to 200 mg/mL. High-concentration products can be injected subcutaneously, increasing patient compliance and reducing hospital patient visits. However, a high protein concentration (≥ 50 mg/mL) creates formulation challenges with regard to colloidal properties and physical and chemical protein stability, and resolving these issues can allow the innovators to secure additional formulation patents that extend their market exclusivity. A good example is the new Humira (adalimumab) 

, which is citrate-free and twice as concentrated as the original product.

Although the definition of the administration route and the dosage form is clear, the strength definition is not. According to section 351(k)(2)(A)(i)(IV) of the PHS Act:

In general, a sponsor of a proposed biosimilar product or proposed interchangeable product with an “injection” dosage form (eg, a solution) can demonstrate that its product has the same strength as the reference product by demonstrating that both products have 

the same total content of drug substance (in mass or units of activity) and the same concentration of drug substance

 (in mass or units of activity per unit volume). In general, for a proposed biosimilar product or proposed interchangeable product that is a dry solid (eg, a lyophilized powder) from which a constituted or reconstituted solution is prepared, a sponsor can claim that the product has the same strength as the reference product by demonstrating that both products have the same total content of drug substance (in mass or units of activity).

Although not a part of demonstrating the same strength, if the proposed biosimilar product or proposed interchangeable product is a dry solid (eg, a lyophilized powder) from which a constituted or reconstituted solution is prepared, the 351(k) application generally should contain information that the concentration of the proposed biosimilar product or proposed interchangeable product, when constituted or reconstituted, is the same as that of the reference product when constituted or reconstituted.

It is noteworthy that these guidelines were moved from final guidance to draft guidance in 2018, a sign that the FDA has not confirmed the definition of strength. BI argued that even though the definition of strength in the revised guidance is moved from final to draft, this has little meaning because the context remains the same. I disagree with this assertion. The FDA will not move a guidance from final to draft without having the intention to accept changes. The FDA is willing to accept arguments relating to the definition of strength.

BI claims that the FDA’s interpretation of strength is unreasonable because it encourages, or at least permits, brand sponsors to use minor concentration changes as an anticompetitive tactic to prevent biosimilar and interchangeable biological products from coming to market, thereby depriving patients of access to more-affordable biological products, contrary to the goals of the BPCIA. I disagree with this conclusion because it is not the FDA's role to consider the “accessibility” issue. The reference product developer must present a sound and rational argument before the FDA will allow the change—it can never be an unjustified proposition. This argument of BI’s reduced the strength of their case for a different interpretation.

BI further misunderstood the issue when they claimed that the FDA should not treat lyophilized products differently when defining the concentration. A lyophilized product is diluted to a similar concentration as the reference product before administration, so it is appropriate if the lyophilized powder quantity's active content is different.

BI’s case is significantly weakened by the following statement in the petition:

Finally, even assuming Boehringer Ingelheim’s other arguments do not compel an interpretation of “strength” to mean only “total drug content,” FDA should still exercise discretion to change its policy because that definition better promotes the goals of the BPCIA, and there are no countervailing regulatory interests that outweigh this important benefit. Accordingly, FDA should reverse this policy and interpret “strength” to mean “total drug content” without regard to concentration.

A regulatory agency does not make decisions based on any consideration other than a scientific justification. Although the purpose of the BPCIA is to introduce more-affordable products, it should not be expected that the FDA reinterpret the legislation based on soft considerations.

Although the FDA may allow a developer to commercialize a generic medicine before the patent expires on the originator product, the FDA will not do this for biosimilar producers, so it is up to the biosimilar developer to create a strategy to go around patents. As a patent law practitioner in this field, I see many opportunities to challenge these patents and, when this is not possible, change a product’s concentration and present it as a scientific argument rather than a strategy to obviate potential infringement of an intellectual property.

I agree with BI that a medicine's strength is the amount of active ingredient (ie, the drug that it contains). It has little to do with the volume of a liquid, so it is appropriate to vary the liquid injectable concentration. 

In general, subcutaneous (SC) injections of mAbs are preferred over IV administrations from patient compliance and ease-of-use perspectives. For mAb-based therapies, typically, high doses in the range of hundreds of milligrams to a gram are needed per dose to achieve the desired therapeutic concentration. To administer such a high dose range in a volume less than 1.5 mL by the subcutaneous route, as required by FDA, these mAb formulations may need to be prepared at a concentration greater than 100 mg/mL. However, such highly concentrated mAb preparations can present challenges in the manufacturing process as well as for stability. 

The solubility of mAbs can be enhanced by adding nonreducing sugars, such as sucrose, and kosmotropic salts, such as sodium chloride, which changes the conformation and provides preferential hydration. In recent years, many mAbs that were first approved as IV infusion solutions have been reformulated into higher concentration 

 versions. Examples of therapeutic proteins that were originally formulated for IV administration and subsequently developed for SC administration include abatacept (Orencia, Bristol Myers Squibb), alemtuzumab (Lemtrada, Sanofi Genzyme), rituximab (MabThera, F. Hoffmann-La Roche), tocilizumab (Actemra, F. Hoffmann-La Roche) and trastuzumab (Herceptin, F. Hoffmann-La Roche). Rituximab (Rituxan) was initially approved for administration in non‐Hodgkin lymphoma at a dose of 375 mg/m

 body surface area as 1.5‐ to 6‐hour IV infusions; the new formulation for SC administration is 12 times more concentrated. 

Although the switch from IV to SC route does have some patient advantages, the more convincing reason for the originator products to switch the route of administration is to preclude biosimilars if the new formulation has patent protection. A patent search for “higher concentration monoclonal antibody” and “subcutaneous” yields more than 

The approach taken by BI to convince the FDA to allow different concentrations in the formulation is most likely aimed at reducing the injection volume, which is always desirable, either in IV or SC administration. The correct argument for seeking a reinterpretation of “concentration” should be based on the BPCIA description that a biosimilar product may have different inactive ingredients. When a formulation is changed for whatever reason, the optimization of the solution's thermodynamic stability may require a different concentration. So, if a different formulation is allowed, it should also be allowed to have a different concentration, higher or lower. This is a scientific suggestion that should strongly support the request for clarification in the guidance. Support of a formulation with a different concentration can be provided from the demonstration of the comparable stability and bioavailability of the biosimilar candidate with the reference product.

I anticipate that the FDA will decide in favor of the BI petition, despite the weak approach taken by BI.

Boehringer Ingelheim's argument hinges on how "strength" of formulation is defined in regulatory language.

Sarfaraz K. Niazi, PhD

Opinion: A Rational Approach to Establish Biosimilarity

Column: A Biosimilars Dialogue With a Young Clinician

Opinion: A Short History of Biosimilars

Opinion: Boehringer Ingelheim May Win Regulatory Language Change Despite Weak Argument