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

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

Articles

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.

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

A true biosimilar product has “no clinically meaningful difference” compared with its reference product. Given the structural variance in a biosimilar candidate and its reference product, the regulatory agencies recommend stepwise testing that comprises analytical assessment, animal pharmacology, and clinical pharmacology profiling.

Clinical safety and efficacy testing should not be allowed if there remains a residual uncertainty after the stepwise assessment. Comparative efficacy testing of biosimilars is redundant at best based on the following:

Suppose the molecular structure of biological products were fixed. In that case, no clinical efficacy study would be required, so the emphasis should be on validating structural differences only, using both in vitro and in vivo testing, not clinical efficacy testing that is less sensitive in establishing structural similarity. If a structural element cannot be investigated, the uncertainty applies to both the biosimilar candidate and the reference product.

Regulatory agencies suggest conducting “additional clinical testing” if a residual uncertainty remains in establishing structural similarity; however, “additional clinical testing” does not mean clinical efficacy testing; it could well be an additional clinical pharmacology study. Historically, neither the FDA nor the 

EMA) has identified residual uncertainty in any biosimilar product that will justify conducting comparative efficacy testing.

Comparative efficacy and safety studies require establishing an acceptable difference based on clinical judgment only that varies among agencies. Still, these do not ensure that the biosimilar candidate has sufficient comparable safety and efficacy. The safety and efficacy parameters are entirely arbitrary.

Biosimilar products receive extrapolation of indications, so, if a comparative efficacy study is required to establish biosimilarity, it must be conducted in all indications, not just in a group of indications based on the same mode of action. Such all-inclusive studies are not practical to conduct.

A new biological product is tested for comparative efficacy against a placebo. A statistical model to show a difference in this case is relatively straightforward. To achieve statistical significance in a comparative efficacy trial with biosimilars, many patients are required to demonstrate similarity or noninferiority, possibly more than for the testing of a new biological drug, if done correctly.

It is impractical to test a biosimilar product in a treatment-naïve population, which would increase patient response variability, making such studies complex and difficult to conclude.

Regulatory agencies suggest the use of clinical biomarkers, but there is no correlation among the available markers; one study may obtain results with one marker that may not be replicable using another marker.

Biological products have a broader dose-response relationship, so a product that does not meet the analytical assessment may pass the comparative efficacy testing. Comparative efficacy testing, therefore, risks the approval of unqualified biosimilars.

Patient populations are limited in some indications. In the case of oncology drug testing, this may stretch out the time needed to complete a trial protocol. In many cases, patients are lost to the disease. Given the highly variable patient response, clinical efficacy testing of biosimilar products becomes more demanding than the development of new biologics.

The FDA and European Medicines Agency have approved about 200 biosimilar products; a summary analysis shows no product was rejected based on comparative clinical efficacy testing. Even when there were minor differences, they were accepted. On an intellectual basis, if a test never fails, it means that either the products were similar or the test is not sensitive enough to tell the difference—in both cases, the testing would be redundant and unnecessary.

The FDA may require comparative clinical efficacy for biosimilar approval, but on top of all the other required and available evidence, these trials add little value, Sarfaraz K. Niazi, PhD, states. 

Ten Reasons Why Biosimilar Candidates Should Not Be Tested for Clinical Efficacy

The coronavirus disease 2019 (COVID-19) pandemic has created a rush to develop diagnostic, treatment, and prevention modalities that is unique in the past 100 years. As of the end of August, there were more than 3000 studies underway in 115 countries and in every state in the United States, where there were 685 studies in progress. US federal 

 had gone to 79 studies in 23 countries. There were 108 

 underway. To manage this process effectively, the FDA has developed the

 Coronavirus Treatment Acceleration Program

 (CTAP), and this has reported more than 570 potential COVID-19 treatment development plans. So far, the FDA has reviewed more than 270 trials and authorized emergency use of dexamethasone and remdesivir; no other COVID-19 treatment approvals are imminent (

By far, immunomodulators are the dominant type of drugs 

 as possible treatments for COVID-19 and related conditions.

The diversity of products developed is essential if we are to find a quick solution to controlling the COVID-19 pandemic. The categories of treatment include:

 which keep viruses from multiplying and are used to treat many viral infections (such as HIV, herpes, hepatitis C, and influenza)

 aimed at tamping down the body’s immune reaction to the virus, such as when the patient’s body overreacts and starts attacking its organs

 which may help individuals fight the virus and include manufactured antibodies, animal-sourced antibody therapies, and blood-derived products such as convalescent plasma and hyperimmune globulin, which contain antibodies taken from individuals who have previously had COVID-19

 including cellular immunotherapies; autologous and allogeneic cells, such as stem cells; and related products

 intended to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use. This diversity of products developed is essential if we are to find a quick solution to controlling the COVID-19 pandemic.

The development of vaccines is challenging because they typically require years of research and testing before they reach the clinic. The work to create COVID-19 vaccines began in January 2020 with the deciphering of the SARS-CoV-2 genome. As of this writing, China has approved a Sinovac vaccine for limited use (August 31), and Russia’s Gamaleya has moved to phase 3 testing of a vaccine called Gam-Covid-Vac Lyo, a combination of adenoviruses engineered with a coronavirus gene. The vaccine, dubbed Sputnik V, has conditional approval in Russia pending results of the phase 3 testing. There are no data available to evaluate the safety and efficacy of either of these vaccines.

 on the development of COVID-19 vaccines, requiring that a vaccine protect at least 50% of the recipients.

The guidance mandates testing a new vaccine first on cells and then in animals, such as mice or monkeys, to see if it produces an immune response resulting in the production of virus-specific antibodies. In phase 1 trials, the vaccine is given to a small number of healthy volunteers to test safety and dosage as well as to confirm that it stimulates the immune system. In phase 2, the trial is expanded to hundreds of volunteers split into groups, such as children and the elderly, to see if the vaccine acts differently in them. These trials further test the vaccine’s safety and ability to stimulate the immune system. In phase 3 trials, thousands of volunteers receive the vaccine, and investigators wait to see how many become infected compared with volunteers who receive a placebo. These trials can determine if the vaccine protects against the coronavirus.

On August 30, FDA Commissioner Stephen Hahn, MD, 

 that the FDA would allow review and approval of vaccines based on preliminary phase 3 trials data. The rush to develop by investigators and the desire to approve by the regulatory agencies have brought us to the brink of decision-making that can have serious consequences. At the same time, a new drug approved for a disease or condition demonstrates the risk based on the number of patients exposed. However, with a vaccine that is given to billions of healthy people and, in the case of COVID-19, a majority of the world’s population, a large number of subjects can be adversely affected even if the percentage of events is small; such risk does not apply to therapeutic products developed to treat patients because of the limited use only in patients.

COVID-19 is a challenge that requires novel approaches to manage. One such strategy is using the principles of establishing biosimilarity to assess the safety and efficacy of both treatments and vaccines. Biosimilars are macromolecules that include antibodies, and their safety and efficacy are tested first by comparing the biosimilar candidate with the reference product to ensure that there is no clinically meaningful difference between them. The analytical science has advanced well over the past few decades to enable us to compare the primary, secondary, and tertiary structures of proteins of all sizes with a high degree of accuracy.

I have suggested to the FDA that it require a test comparing the structure of antibodies produced in patients with COVID-19 (serving as an equivalent of a reference product) with the antibodies produced using a vaccine (as the proposed biosimilar product). This test can be conducted within a few days of administering the first dose of the vaccine. This testing can also be a preamble to full-blown testing to further reduce the risk to study subjects. For comparison, there is no need to conduct all tests required to establish biosimilarity; only a structural comparison is needed. The testing will also include binding or functionality tests and any other novel testing methods that the developers can propose to assure that the antibodies produced by a vaccine are highly similar to the antibodies produced in patients. Another test for structural similarity can be a pharmacokinetic study in animal species such as monkeys, where 3 to 4 animals can be administered the 2 antibodies to determine if there are any differences in their disposition kinetics profile. There is no need for animal toxicology studies, particularly not in any species that does not have receptors to interact with antibodies, such as rodents.

The biosimilarity approach detailed above can also serve as an effective tool to a developer of mRNA vaccines wherein testing in animals can provide extensive information on potential efficacy and safety of the antibodies produced.

The antibodies produced in response to a vaccine can be different to some extent than the antibodies produced from a live virus infection and yet still be useful in providing immunity; and significant structural differences will point to unforeseen safety issues.

The biosimilarity approach presented above and detailed to the FDA will enable the FDA to make an early decision on the safety of clinical trials and significantly speed up the development of COVID-19 vaccines.

The development of treatments is more likely to be successful if, instead of repurposing drugs, as hundreds of trials are trying to prove is possible, we can produce the same antibody that is found in patients infected by live COVID-19. Additionally, there are other opportunities in the scaffold antibodies or smaller proteins that simulate antibody function and are synthesized.

I am confident that although we have suffered through this pandemic, science will come out as a savior, and we will have many more novel opportunities to control diseases in the future.

Sarfaraz K. Niazi, PhD

Opinion: A Short History of Biosimilars

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

Ten Reasons Why Biosimilar Candidates Should Not Be Tested for Clinical Efficacy

Biosimilarity: A Novel Approach to Develop Therapies and Vaccines for COVID-19