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.

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

The bubonic plague (1347-1351) originated in rats and spread through fleas to wipe out half of Europe’s human population; smallpox has killed 56 million since 1520 and devastated Native American populations; the Spanish flu (1918-1919) killed 40 million to 50 million; and the coronavirus disease 2019 (COVID-19) has, so far, killed over half a million and is still going strong.

In terms of mortality, COVID-19 will compare to Spanish flu if left to spread. The actual numbers will be significantly higher, given that today a virus can travel across the globe within hours. But like every other pandemic, COVID-19 will taper off; we still have people dying of yellow fever, Ebola, and SARS coronavirus. Although COVID-19 will take a heavy toll, it will leave us with a few bright spots as well, mostly relating to the new drugs and treatment modalities that we will see arising shortly.

First, I am confident, after reviewing the current status of vaccine development, that the FDA will approve its first mRNA vaccine. As of today, there is only 1 vaccine approved, Ad5, from the Chinese company CanSino. Based on unique need, this has jumped from phase 2 trials to regulatory acceptance. Such an approval is not likely to happen elsewhere; however, it is almost sure that several of the over 150 vaccines under development will be approved. However, there are 15 vaccines in phase 1, 11 in phase 2, and 4 in phase 3 as of July 16, 2020.  

It is highly likely that the FDA will approve the first mRNA vaccine, which will open the door to many new opportunities for treating infectious diseases. This in turn will create opportunities for smaller companies to jump into the business of vaccines that are synthetic and do not require a large investment. We will certainly be able to handle the next pandemic (and I can assure you it will happen) much better by developing a vaccine faster than we have ever been able to do.

Second, the therapeutic management of COVID-19 has introduced repurposing or purported repurposing of a variety of drugs, including the antimalarial hydroxychloroquine; steroid dexamethasone; remdesivir; a chemical drug developed to treat Ebola, without success, and currently not approved for any indication; antibodies, including itolizumab, sarilumab, bevacizumab; and other repurposed drugs, such as lopinavir, ritonavir, nafamostat, camostat, famotidine, umifenovir, ivermectin, nitazoxanide, and fluvoxamine. Only remdesivir, dexamethose, and enoxaparin have shown a definitive role in therapy. There are many anecdotal treatments and nutrition supports suggested as well. It is doubtful that the FDA will approve any of these treatments, over and above the temporary emergency use allowance. Still, the science of repurposing the drugs will create a race that brings approved drugs for new indications.

Third, we will have a renewed awareness of the importance of our immune system and new knowledge about how the body responds to antigens. More particularly, the cytokine rush will trigger discoveries that may not have been in the pipeline. The perennial search for universal multidomain antibodies will be reinvigorated to produce antibodies that may function by having a flexible structure to bind to specific receptors, yet having sufficient structural control to not bind to other receptors. I foresee a giant leap in the science of antibody design and manufacturing, all of which will lead to a larger portfolio of biological drugs and many new biosimilar alternatives.

Fourth, a better understanding of the nature of viruses will develop from our growing knowledge of the unique nature of COVID-9, which is less infective to children, has fewer mutations, penetrates deeply into vital organs besides the lungs, and passes from person to person efficiently.  

Fifth, investigation leading to DNA/RNA vaccines will create new technology of synthesizing DNA, and it will not be a surprise if we become able to synthesize human genes that will replicate and can be inserted into animal species to produce human organs—even, new species&mdash;while  potentially opening a Pandora’s box.

Sixth, we would have learned the hard way the importance of speedy development of new drugs. If this learning leads to changes in the pace of new drug discovery, we will have acquired a high-value advance in our technological and medical capability.

Although we are still struggling with getting out of this pandemic, I am confident, as an optimist, that we will come out with more tools to improve health care, a better understanding of infectious diseases, and perhaps a revolutionary technology that was lurking beneath the spiked protein of an enveloped virus.

Although devastating in its toll on human life, the coronavirus disease 2019 will likely bring new understanding and technology and leave us better prepared to manage the next health threat of this scope.

Biological Drugs in the Aftermath of the Pandemic

 28 biosimilar products, 19 monoclonal antibodies, 6 cytokines, and 1 fusion protein since the first biosimilar was approved in 2015 (

). A detailed analysis of the regulatory submissions that led to the approval of these products shows high diversity, frequent unnecessary testing, and reliance on studies that may not assure the safety and efficacy of biosimilars. The paradigm of stepwise development and evaluation suggested by the FDA has not worked either, and now we have sufficient data to indicate that a significant change in the biosimilars approval guidance is required to eliminate redundant testing and reduce the risk of approval of unsafe biosimilars.

The FDA got its charter to approve biosimilars in 2009.

 The FDA has issued 10 regulatory guidance documents

, and it redrafted 1 pivotal guidance on analytical testing

 after the author pointed out inconsistencies in the original.

 However, this fresh guidance still leaves out several key elements that are suggested in this column.

First, I will provide a broad summary of the scope and redundancies in the regulatory submissions from 8 companies among the 28 approvals. Not including the most recent applications for the pegfilgrastim biosimilar Nyvepria and adalumumab biosimilar Hulio (for which the FDA has not yet posted the Biologics License Application [BLA] details) there were over 1100 analytical similarity, 96 animal pharmacology, 42 in-vitro/ex-vitro pharmacology, 52 clinical pharmacology, and 32 clinical efficacy studies conducted. Here are the highlights of the compiled data:

There was no consistency in the number of studies submitted for the same molecule: 5 adalimumab biosimilar applications included 31 to 105 studies; 5 trastuzumab biosimilar applications, 48 to 111 studies; and 4 infliximab biosimilar applications, 48 to 80 studies.

Twenty-seven animal pharmacology studies were not reviewed by the FDA, which labeled them as them unnecessary or unwarranted.

No animal pharmacology or in-vitro/ex-vitro studies failed.

A few clinical pharmacology studies had to be repeated to meet acceptance criteria due to inappropriate choice of the study population. None failed.

No clinical efficacy studies failed. There were no instances where the primary end points were not met. Additionally, post hoc analyses revealed no justification for invalidating the studies, nor were there additional scientific justifications for nulling these studies. In 2 cases, higher immunogenicity was overcome by making minor changes to the manufacturing process. No product was rejected based on a failed efficacy study.

In summary, all analytical similarity testing met the acceptance criteria, the animal pharmacology studies added little to the knowledge, all clinical pharmacology studies met the criteria, and even when there were differences in clinical efficacy studies, these were overcome by a discussion of data and marketing authorization was granted.

The FDA has long emphasized a stepwise approach to the development of biosimilars, and the stereotypical pyramid showing the importance of various studies has been circulated ad infinitum. The analytical similarity testing is the largest component and clinical efficacy, the smallest piece of the pyramid. However, the developers, all of them being large pharmaceutical companies with 1 exception, decided to conduct extensive, costly clinical efficacy testing; Coherus BioSciences, the exception, received approval without submitting a clinical efficacy study.

There are several fundamental arguments against the use of clinical efficacy testing to establish biosimilarity. First, no product is allowed to move forward to the clinical efficacy stage unless it meets analytical similarity and animal toxicology criteria. The FDA states that if there remains any “residual uncertainty,” additional testing may be required. Does this mean that the clinical efficacy testing is needed for the FDA to resolve any residual uncertainty? I could not find any such indication in any of the Biologics License Application documents that are in the public domain. Were the clinical efficacy studies conducted to support marketing plans or to support biosimilarity? None of the efficacy studies resulted in any rejection, which suggests that if a product meets the requirements up to the clinical pharmacology stage, it is not likely to fail in clinical efficacy testing.

There are additional reasons why clinical efficacy studies are less meaningful in establishing biosimilarity. Every study conducted as a noninferiority study needs an acceptance criterion before the study is initiated, a parameter that is strictly arbitrary and supposed to be drawn from clinical judgment. Given that there are few data on the long-term use of biosimilars, such conclusions can be only arbitrary, at best.

Second, because biosimilars receive extrapolation of indications, does a single study suffice to remove all residual uncertainty for all indications? The correct answer can only be no. The dependence on clinical efficacy testing has the risk that other elements of dissimilarity, such as may emerge from analytical or clinical pharmacology, will be ignored, leading to the possibility that relying on efficacy studies may result in the approval of biosimilars that are not safe and effective.

Third, since none of the clinical efficacy testing failed, it means that either all products were clinically similar or the protocols were not sensitive enough to differentiate the products. In both cases, the utility of clinical efficacy testing can be questioned. A greater concern arises where a limited clinical efficacy study is conducted to overcome any residual uncertainty in analytical, animal, and clinical pharmacology studies, where the product may be approved in multiple indications with greater risk for safety and efficacy.

In the case of monoclonal antibodies, the mechanism of action is generally known, allowing use of in-vitro/ex-vitro methods to compare efficacy. These tests can be more robust and reliable than the study of clinical responses in patients, particularly in the case of anticancer drugs, where it is almost impossible to secure a treatment-naïve patient population or even a sufficiently large number of patients and there is high variability of response. Do these studies bring added confidence to the safety and efficacy of the biosimilar product?

The issue of immunogenicity testing also needs to be reevaluated for 2 reasons: First, if a product is highly immunogenic, testing it in naïve subjects raises ethical issues; second, if immunogenicity does not alter the pharmacokinetic (PK) profile, then it should not be a major concern, in line with the position taken by the FDA in allowing the waiver of clinical immunogenicity testing of insulins.

The animal pharmacology studies were another area of much confusion and abuse by the biosimilar developers; the FDA had refused to consider multiple safety studies in the evaluation of a product when the FDA rejected one-third of studies as redundant. Typical examples were testing antibodies in species that do not have a receptor to demonstrate toxicity, evaluating immunogenicity in animal species, and dosing animals based on human doses or multiples of human doses. To the best of my knowledge, no study on the testing of biosimilars has ever failed in animal testing because it cannot. The best use of animal testing is in comparative PK profiling, as an extension of analytical similarity testing, where a biological system views the structure and responds to its variability. In India, dozens of monoclonal antibodies are approved by testing in rats because mammalian species, such as the monkey, are not allowed to be tested.

Although the analytical assessment forms the basis for establishing biosimilarity, these studies are unnecessarily complicated due to lack of simple understanding that if the FDA agrees with the release specification of the final product, the tested attributes need not be made part of analytical similarity testing; if it is good enough for the patient, it should be good enough for the FDA! This scientific thesis should limit analytical similarity testing to primary, secondary, and tertiary structure testing and other safety-related attributes.

In conclusion, I believe now is the time for the FDA to lead again in revising the guidance, eliminating all animal toxicology studies, and replacing them with larger-species PK studies, allowing the conduct of human PK studies using novel clinical protocols to combine the PK/pharmacodynamic/immunogenicity testing in a single study, and, where possible, avoid these studies if an in-silico approach can provide the confidence of pharmacologic similarity.

The majority of biosimilar products are monoclonal antibodies where highly relevant receptor binding studies can be conducted to demonstrate safety and efficacy. An excellent example supporting this suggestion comes in the evolution of anticancer treatments, where it is impossible to secure a treatment-naïve population, resulting in high variability in response and in many cases inability to complete the studies. The clinical efficacy testing should not be allowed to overcome any residual uncertainty, and all such products should be rejected as biosimilars under the 351(k) approval pathway and switched over to 351(a) if the developers so desire to continue with the development. The FDA has been forthcoming in taking bold steps that are scientifically based, such as removing clinical immunogenicity testing of insulins, because differences in immunogenicity do not affect the pharmacokinetic profile

FDA. Title VII—Improving Access to Innovative Medical Therapies: Subtitle A&mdash;Biologics Price Competition and Innovation. https://www.fda.gov/media/78946/download

FDA. Biosimilars Guidances. Updated June 21, 2019. Accessed July 10, 2020. https://www.fda.gov/vaccines-blood-biologics/general-biologics-guidances/biosimilars-guidances

Keown A. FDA Withdraws Draft Guidance on Biosimilar Development. 

. July 3, 2018. Accessed July 10, 2020. https://www.biospace.com/article/fda-withdraws-draft-guidance-on-biosimilar-development/

Niazi SK. A critical analysis of the FDA draft guidance on development of therapeutic protein biosimilar: comparative analytical assessment and other quality-related concerns. 

. Published June 4, 2019. Accessed July 10, 2020. https://www.centerforbiosimilars.com/contributor/sarfaraz-niazi/2019/06/a-critical-analysis-of-the-fda-draft-guidance-on-development-of-therapeutic-protein-biosimilars-comparative-analytical-assessment-and-other-qualityrelated-considerations

BioSpace. FDA allows waiver of clinical trials for insulin biosimilars as recommended in Niazi citizen petition. 

. Published December 3, 2019. Accessed July 10, 2019. https://www.biospace.com/article/releases/fda-allows-waiver-of-clinical-trials-for-insulin-biosimilars-as-recommended-in-niazi-citizen-petition/

FDA. Zarxio (filgrastim-sndz). Published April 20, 2015. Accessed July 10, 2020.  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125553Orig1s000TOC.cfm

FDA. Inflectra (infliximab-dyyb) for injection. Updated July 6, 2016. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125544Orig1s000TOC.cfm

FDA. Drug approval package: Erelzi (etanercept-szzs). Published October 25, 2016. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761042Orig1_toc.cfm

FDA. Drug approval package: Amjevita (adalimumab-atto). Published November 9, 2016. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761024_toc.cfm

FDA. Drug approval package: Renflexis (infliximab-abda). Published December 10, 2018. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761054Orig1s000TOC.cfm

FDA. Drug approval package: Cyltezo (adalimumab-adbm). Published September 27, 2018. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761058Orig1s000TOC.cfm

FDA. Drug Approval Package: Mvasi (bevacizumab-awwb). Published October 10, 2018. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761028Orig1s000TOC.cfm

FDA. Drug Approval Package: Ogivri (trastuzumab-dkst). Published November 29, 2018. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761074Orig1s000TOC.cfm

FDA. Drug approval package: Ixifi (infliximab-qbtx). Published November 29, 2018. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761072Orig1s000TOC.cfm

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FDA. Drug approval package: Fulphila. Published October 26, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761075Orig1s000TOC.cfm

FDA. Drug approval package: Nivestym (filgrastim-aafi). Published February 21, 2019. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761080Orig1s000TOC.cfm

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FDA. Drug approval package: Udenyca. Published March 5, 2019. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761039Orig1s000TOC.cfm

FDA. Drug approval package: Herzuma. Published February 7, 2019. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761091Orig1s000TOC.cfm

FDA. Drug approval package: Ontruzant (trastuzumab-dttb). Published March 5, 2019. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761100Orig1s000TOC.cfm

FDA. Drug approval package: Trazimera (trastuzumab-qyyp). Published May 17, 2019. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761081Orig1s000TOC.cfm

FDA. Drug approval package: Eticovo. Published June 18, 2019. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761066Orig1s000TOC.cfm

FDA. Drug approval package: Kanjinti. Published July 18, 2019. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761073Orig1s000TOC.cfm

FDA. Drug approval package: Zirabev. August 14, 2019. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761099Orig1s000TOC.cfm

FDA. Drug approval package: Ruxience. August 9, 2019. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761103Orig1s000TOC.cfm

FDA. Drug approval package: Hadlima. Published September 5, 2019. Accessed July 10, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761059Orig1s000TOC.cfm

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Now is the time for the FDA to lead again in revising the biosimilar development guidance by eliminating all animal toxicology studies, and replacing them with larger-species pharmacokinetic (PK) studies, allowing the conduct of human PK studies using novel clinical protocols to combine the PK/pharmacodynamic/immunogenicity testing in a single study, and, where possible, avoid these studies if an in-silico approach can provide the confidence of pharmacologic similarity.

Analysis of FDA-Licensed Biosimilars: Time for a Paradigm Shift

The European Medicines Agency (EMA) became the first regulatory agency to issue biosimilar guidance in 2005; the FDA and the World Health Organization (WHO) followed in 2009. Most of the developed country guidelines draw from the FDA and EMA guidance, while the rest of the world relies on the WHO guidance to assure the safety and efficacy of biosimilars. A comparison of the global guidelines shows that the WHO guidance that has impacted the largest patient population is replete with scientific misconceptions, leading to lack of trust in the safety and efficacy of biosimilars developed under this guidance.

This brief review points out a few questionable elements of the WHO guidance and the dire need for it to be aligned with acceptable scientific grounds.

First, the WHO suggests that before a biosimilar product can be approved, reference products should have been marketed for a “suitable duration” of time in “a jurisdiction with a well-established regulatory framework and principals.” This creates doubts about the safety of an approved product. The guidance does not indicate how long this waiting period should be. However, there should be no doubt about the safety and efficacy of a product if a credible regulatory agency approves it. The WHO also fails to identify the jurisdiction of the approving agency. The standard should be the first approved biological product based on a complete dossier.

Second, the WHO recommends that regulators use their prior knowledge, based on the evaluation of the manufacturing process of similar products, to judge the safety and efficacy of new biosimilar products. Besides the ethical considerations, such comparisons are scientifically flawed, because it is not possible to draw a parallel between products manufactured using different processes.

Third, the weakest area of the WHO guidance is in the most critical part of the evaluation of biosimilars: their analytical similarity. The WHO allows the use of production lots from different manufacturing sites to establish analytical and biological similarity with the reference product, an allowance that violates the basic principles of similarity testing, even if each of the manufacturing sources is good-manufacturing-process compliant. No other regulatory agency allows this practice.

On a more specific scientific consideration, the WHO states that “It may not be possible to set a definite number of lots to be analyzed in the comprehensive comparability exercise.” Nothing is farther from the truth. The number of lots tested is well-defined in the standard equivalence testing models, where at least 6 to 10 lots must be analyzed to establish an acceptable statistical basis. The WHO considers that statistical models are not yet ready to apply to analytical similarity assessment, contrary to the well-established utility of statistical modeling by all developed agencies.

In another significant scientific mistake, the WHO considers comparative stress testing of the biosimilar and the reference product unnecessary. However, this is one of the most sensitive methods to test structural similarity, and all developed country agencies require it. The WHO states that these studies only help establish appropriate conditions for shipping and storage. The fact is that the biosimilar must have the same storage condition as the reference product, and there is no need to justify a new storage condition. The shipping stress testing is conducted under a different protocol based on the prevalent practices of shipping.

Fourth, one of the most divisive suggestions by the WHO is that toxicology studies in monkeys should be avoided. This has led to the approval of a large number of biosimilars across the globe based on valueless testing in rats, which do not have receptors to show toxicity to monoclonal antibodies. The WHO suggestion to study pharmacodynamics and immunogenicity in animal species does not take into account that certain animals do not replicate human responses.

The WHO’s animal testing protocols based on multiples of human dose are also flawed because this dosing is not in the linear toxicity range to detect any difference between a biosimilar and a reference product.

Finally, the WHO suggests using a noninferiority testing model for clinical efficacy, allowing acceptance of higher efficacy, without realizing that higher efficacy may also lead to higher adverse events. The correct protocol for efficacy testing is the equivalence model. Further, the WHO does not recommend evaluation of the most frequent adverse effect of local reactions at the injection site that are caused by the agent’s formulation and not by the active molecules. Because biosimilars are allowed to have a different formulation composition, evaluation of local reactions is pivotal in assuring the safety of the products.

The WHO guidance is widely adopted in many countries that have added their own arbitrary and unjustified changes. For example, in China, India, and Russia, local clinical trials are required, but not a suitable a statistical protocol. Iran, Peru, Nigeria, and Venezuela have removed all clinical testing requirements. And none of the Indian biosimilar antibodies were tested for safety in monkeys, the only suitable model, because of religious constraints. 

I strongly urge the WHO to revise its guidelines, bringing it into compliance with the current scientific and logical thinking to assure the safety and efficacy of biosimilars used by the majority of the world population. Not doing so will continue to risk the lives of patients.

The World Health Organization’s guidance for the development and approval of biosimilars is based on faulty science and reasoning, and it represents a hazard to the safety of patients that must be corrected, according to Sarfaraz K. Niazi, PhD.
 

WHO Biosimilar Guidance Is Based on Weak Science

 on demonstrating interchangeability of a biosimilar with its reference product to assist sponsors in showing that a proposed therapeutic protein product is interchangeable with a reference product for submitting a marketing application or supplement under section 351(k) of the Public Health Service Act (PHS Act) (42 U.S.C. 262[k]). In formulating the final guidance, the FDA had considered the comments provided in response to the invitation by the FDA when it posted draft 

There were 53 comments posted by the deadline of March 20, 2017, and these came from diversified sources, 

 a private consumer who suggested that the Affordable Care Act not be repealed to a 

 suggesting the use of suffix to biosimilars, to 

 like Coalition of State Rheumatology Organizations, which suggested that a case-by-case approach is not satisfactory and that no extrapolation should be allowed unless a product is tested in patients for all conditions. The Parenteral Drug Association 

 the role of human factor studies and need for new regulations to provide comparison; Johnson & Johnson 

 extrapolation and recommended that testing be done in each condition, and that the labeling of biosimilar products declare when they are not interchangeable. Apotex 

 clarification on the meaning of immunogenicity and if a product is given at 2 doses; would it mean 2 separate studies? The Biosimilars Council 

 whether studies will be required in conditions that are not claimed or how extrapolation will be allowed; AbbVie and other reference product companies 

 with almost everything in the draft guidance and suggested that the FDA does not have the authority to go around the Biologics Price Competition and Innovation Act (BPCIA) requirements.

In addition to the above comments from stakeholders, there were several 

 that pointed out the shortcomings of the FDA guidance in establishing biosimilarity and interchangeability. There were 2 

 that questioned the FDA guidelines on biosimilars.

The final guidance on interchangeability took into account several recommendations that were made by me, including using biodistribution in pharmacokinetic (PK) and pharmacodynamic studies (PK) studies, de-emphasizing clinical efficacy studies, and allowing sponsors to propose novel approaches to licensing of biosimilars and interchangeable biologics. 

It is important to reiterate that the FDA guidelines are not binding, and for the same reason, they do not preclude a sponsor from making an alternate proposal to the FDA, even though most sponsors would hesitate to do so. In this paper, I am suggesting that sponsors exercise their privilege to question the guidance and fully exploit the opening provided by the FDA for alternate proposals.

Section 351(k)(4) of the PHS Act provides that an interchangeable product must be “biosimilar to the reference product” and additionally, it “can be expected to produce the same clinical result as the reference product in any given patient.” For a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.

A sponsor may choose to file a new application for approval as a biosimilar or an interchangeable biosimilar; there is no requirement that the product must be first approved as a biosimilar.

To demonstrate biosimilarity, the sponsor can refer to previously submitted data, but only after consultation with the FDA, since the FDA now requires that, in addition to the data required for demonstration of biosimilarity, developers should also include analyses of any differences in the expected PK and biodistribution, toxicities of the product, immunogenicity risk of the product, and any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which the reference product is licensed. 

The final guidance on interchangeability resolves some issues, creates many new issues and inquiries, and offers a path&mdash;albeit not a clear one&mdash;that is filled with scientific and clinical challenges.