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

for similar biotherapeutic products (SBP). A year later, the WHO proposed to 

these guidelines, accepting several suggestions that I and perhaps others had made but leaving many out that were just as important, which I have described below. Nevertheless, I hope that the WHO will reconsider, because its guidelines are followed worldwide. Furthermore, any flaws in guidance can result in significant safety and efficacy issues with biosimilars.

The WHO suggests that national regulatory authorities (NRAs) decide the prescribing information (PI) to go with the SBPs; this is not correct; the PI should be identical to the product information for the reference product. Both the FDA and the European Medicines Agency (EMA) provide guidance on how to write the PI.

The WHO guidelines continue using the term “comparability” as it pertains to a guideline published by the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). This guidance is known as the ICH Q5E, and many NRAs simply adopt this automatically.

With over 100 biosimilars approved, the choice of critical quality attributes should not be left to the developers but to the regulatory agencies. Any selective choice made by the NRAs can create significant safety problems.

The WHO suggests that clinical efficacy testing can be reduced based on results of animal testing, but this is not rational; biological drugs act by receptor binding unique to humans. Their toxicity is an extrapolation of their pharmacologic response. Thus, these types of testing are of little value in deciding biosimilarity. Both the FDA and EMA have agreed to exclude animal testing, and the WHO should follow the same path. Furthermore, the WHO suggestion that animal testing should be designed based on shortcomings in structural variability is also faulty; an animal model cannot tell whether a molecule is different.

One piece of advice from the WHO to NRAs is that, to assure that the reference product is safe, they should wait for a few years before allowing SBPs; this view questions the rigor of the regulatory approvals of new products; it also delays the entry of SBPs into the countries that need them most.

The WHO unnecessarily confuses local or nonlocal reference biotherapeutic products (RBPs) and how to match the two; the RBP must be the first product approved in a developed country using the complete dossier; there is no need to confuse the issue.

While in the past, the WHO had declared that no statistical modeling should be done in analytical similarity testing; now it proposes to use mean+/-x*SDoftheRBPbatchdata as the range, basing the choice of the multiplier (x) on the criticality/importance of the attribute. But the multiplier cannot be arbitrary; the FDA learning this the hard way when it was forced to withdraw earlier 

. The best choice is to use the value of 3, which covers 99% of the range. The WHO further states that if the analytical similarity does not match, then its impact on safety and efficacy should be addressed using functional assays. Unfortunately, the fact is that there is no way to resolve this issue, and the product must be rejected.

The WHO further recommends using in vivo animal studies to resolve relevantdifferences informulation(eg,using excipientsintheSBPnotwidely usedinmedicinalproducts). This is the most irrational suggestion. No animal study can establish the safety of a formulation and its interaction with the active biological entity; a good 

 was the interaction of erythropoietin with surfactants to cause 

. Therefore, an SBP should not contain an excipient that is not used in other products.

The WHO suggests that pharmacokinetic (PK)/toxicokinetic (TK) studies in animals should be interpreted by considering neutralizing antibodies formed; the fact is that animal model antibodies have little correlation with human response, and a PK/TK study in animals adds little to ascertain the safety in humans. The only species that might bring some value, but only in the PK studies, are the lower primates, but primate studies are discouraged by the WHO. The toxicokinetic studies are useless because they require a dose range of nonlinear responses, making it impossible to differentiate between an SBP and RBP.

One suggestion of the WHO is that if the SBP contains impurities that are not present in the RBP (eg, because of the use of a novel expression system), the developer should justify it based on additional safety data or a scientific rationale; this suggestion is flawed because, unlike chemical drugs, the toxicology of biological products is related to their pharmacodynamics, which makes such a determination impossible. For this reason, the FDA and EMA discourage using alternate expression systems, even though they are allowed. In addition, no unmatched impurity should be present unless this has already been reported in the reference product's literature.

The WHO takes a nonscientific view of immunogenicity and suggests more investigations if the immunogenicity difference is large; but proving that these differences are not clinically relevant is almost impossible, short of extensive human testing. 

, differences may be allowed where the immunogenicity does not affect the drug’s disposition, or bodily elimination, profile. Still, if the difference is large in the immunogenicity, the SBP should be rejected, even if there is evidence that immunogenicity does not affect the pharmacokinetics.


The WHO is not a regulatory agency, but its recommendations are widely adopted globally, mainly by developing countries. The new proposal by the WHO to revise its guidelines is a significant step in bringing these guidelines into accord with FDA and EMA recommendations. Still, the WHO guidance continues to miss out on several key concepts of safety and efficacy. For example, the continued insistence by the WHO that animal testing and clinical efficacy studies, both of which are least sensitive, can be used to justify differences in analytical assessment and clinical pharmacology is fallacious. I hope that the WHO will continue to improve its guidelines as they impact most of the world.

Articles

An expert on biotherapeutics recommends more science be applied to World Health Organization (WHO) biosimilar guideline revisions. 

Opinion: One Step Forward, Half a Step Back for WHO Biosimilar Guidance 

The alcoholic beverage industry is bigger than the pharmaceutical industry—over $1.5 trillion worldwide. The technology for aging alcohol (letting it sit in a barrel) dates back thousands of years, and it remains an enigma. While I have developed many technologies with dozens of patents to make biological drugs more affordable, now I am reporting my inventions for aging of alcoholic beverages by eliminating the use of wooden barrels and accelerating the natural process by thousands of times through thermodynamic manipulation under Fick's law of diffusion. 

Now, for the first time, we can create proprietary tastes using several types of woods simultaneously, and all at a fraction of the cost, resulting in “biobetter” whiskey. It is about time that we become more creative with one of the world’s most popular commodities. Yes, we should make drugs affordable, but we should also not deprive humanity of the taste of the best whiskeys (the “reference” products) at the lowest cost to make billions of people happy every day. I am trying to let happiness be affordable.

After decades of effort to make biological drugs affordable as biosimilars, I realized that one conventional paradigm must be shifted—the belief that aged whiskeys should be expensive

Glenfiddich Janet Sheed Roberts Reserve 1955

How many of you would ever have the good fortune of tasting the most expensive whiskeys? And if you did, would you be able to tell which is which? I began to wonder why we give such reverence to aged whiskey. First, I disagreed with the choice of the word “aging”; nothing can age if it is not alive, and to the best of my understanding, molecules do not have a soul. Over time, the only thing that happens in a whiskey barrel is the evaporation of alcohol and the completion of chemical reactions with a high thermodynamic barrier. The label affixed to the bottle trains your mind to anticipate something of ethereal nature. In the end, the secret of whiskey boils down to simple chemical reactions; so, what if I were able to expedite the reaction process? Would I be able to produce a good-tasting 12-year-old whiskey within hours? The answer was yes, absolutely. 

 on the downstream processing (“distilling”), I developed a way to “age” whiskey, or expedite the chemical reactions, more appropriately than commercial manufacturers can do. Before I share the proprietary technology and make you believe that you can taste a $1000 bottle of whiskey without taking another mortgage on your home, I will share the facts about how whiskey got its start.

 is standard in Ireland and the United States, while 

 is used in all other whiskey-producing countries. It is a distilled alcohol made from fermented grain mash; grains are malted to improve fermentation and include barley, corn, rye, and wheat. Whiskey is typically aged in wooden casks, often old sherry casks, or may also be made of charred white oak.

The history of whiskey possibly began 4000 years ago, when the Babylonians in Mesopotamia may have practiced distillation. The aging process was accidentally discovered as the alcohol was transported in wooden barrels. The oak wood was used because these barrels had the most negligible evaporation, the oak being a tight grain wood. As the delivered goods tasted better than when they started the journey (that often took months), the era of aging alcohol began and continues today, also in wooden barrels.

: lignin (18%-35%) and carbohydrate (65%-75%). Both are complex polymeric materials. In addition, minor amounts of extraneous materials, mainly in organic extractives and inorganic minerals (ash), are also present in wood (usually 4%-10%). Overall, wood has an elemental composition of about 50% carbon, 6% hydrogen, 44% oxygen, and trace amounts of several metal ions. Lignin polymers form the structural materials in the support tissues of plants, including cell walls. Over time, lignin breaks down into gallic acid, furfural, vanillic acid, 5-methyl furfural, syringic acid, vanillin, syringaldehyde, scopoletin, salicylaldehyde, coniferaldehyde, sinapaldehyde, maltol, pentanedione, diacetyl, polyhydroxybutyrate, hydroxymethylfurfural. So, in essence, the aging of alcohol is no more than the extraction of lignin, its breakdown over time, and intermolecular reactions that create byproducts changing the beverage's flavor.

So, as I began the journey of making biosimilar whiskey, I analyzed my favorite brands and then a few of the most expensive brands. Testing included discovery of the chemical composition of the components listed above. I found that what I liked had an aroma and a taste that kept changing in the mouth. I concluded that such an impression could only come from the more volatile (producing the smell) and most reactive components (creating the taste). I then plotted the melting point and boiling points of these chemicals; there was a clear trend. I knew which chemicals would give me the first whiff suggestive of flavor and which ones would give a fabulous taste.

Having established that the smell and taste of whiskey depends on chemical composition, I began my prototype biosimilar whiskey by accelerating the extraction of wood elements. Instead of putting the alcohol in a wooden barrel, I put some finely ground barrel wood (100 microns) into alcohol by a process similar to downstream purification of proteins—a chromatography column made up of the wood grains and supported by glass marbles, to keep the column from collapsing. This did the job.

During fermentation and distillation, the acids react with the alcohol, forming esters, and these develop over time during aging, but because I kept the temperature high this process happened much sooner. Esters provide the flavor, and I was successful in maintaining the right temperatures over time.

I raised the temperature of the alcohol to about the boiling point, and what came out was a thick dark liquid that had absorbed 100 to 1000 times more of everything that an aged whiskey would have. I then let it cool down slowly to allow the reactions to take place. Based on the free energy of reactions, the process was efficiently expedited several fold. The figure below shows the extract compared with the best bourbon on the shelf.

The 2 data clusters on the right represent the best-selling and the most expensive bourbons. The rest are my samples prepared under different conditions. The taller columns represent larger quantities of the essential lignin components that give the whiskey its flavor. This means I could dilute my whiskey to reduce alcohol content without as much flavor loss as would occur with the aged whiskeys I tested.

Suddenly, I had a whiskey that tasted just as good as a $1000 bottle but cost me no more than $3. I then mixed various wood grains to produce unique flavors (biobetters), including a “Japanese whiskey” I created using wood brought in from Japan.

While I had access to liquid and gas chromatography, spectroscopy, mass spectrometry, and other test methods, none of these proved of any significant value. What counted was the tasting done by the “sommeliers,” who included knowledgeable whiskey drinkers. I invited several and conducted blind testing. We used quality store-bought whiskeys for the testing, some of them $100 a bottle, and none of them made it to the top, and neither did mine, but it came close.

Convinced that he could circumvent the time-consuming process of aging whiskey, Center for Biosimilars® Advisory Board member Sarfaraz K. Niazi, PhD, used a lab process to create "biosimilar" whiskey. 

Column: CFB Board Member Creates "Biosimilar" Whiskey

There are hundreds of potential biosimilar candidates that can be brought to the market readily to expand into the untapped market of biosimilars without significant patent challenges and producing significant revenue. Not least of the advantages is fulfilling the dire need for affordability. Yet, with over 100 biosimilars approved in the European Union and United States, we can see a trend that all companies are running after the market leaders like adalimumab. There is even a bigger market potential available in the forgotten molecules. Of the 83 biosimilars candidates, whose patents have expired, only 18 molecules are 

 in the European Union and 11 in the United States (

). Antibodies lead the list of over 100 approved biosimilars. It is about time that we find the hidden biosimilar gems and expand the market of diseases treated with biosimilars.

The question arises, why are we hovering over a relatively small number of molecules approved in the European Union and the United States? In this column, I will answer this question and suggest how biosimilar developers can go against the grain. With this column, I have included patent expiration dates for molecules that are available for biosimilar development or will be (

Table. Patent Expirations of Biologic Candidates for Biosimilar Development

A detailed analysis of the 100 approved biosimilars in the European Union and United States reveals that there is no impossible challenge in getting a new biosimilar approved. The regulatory agencies worked with extreme sensitivity as they tried to overcome the shadow of risk cast by the originator companies—“only we know how to make these products” was a slogan that has evaporated now. The science of biosimilars is now better understood, the milestones to reach biosimilarity are evident, and the technology to produce biological drugs has lowered the cost of goods.

Still, the most significant investment in the development of biosimilars remains their testing for safety and efficacy in a clinical setting. This exercise is most demanding for oncology products, where a larger population of patients than for the originator biologic is required to prove similar efficacy and safety because it is impossible to secure a treatment-naive patient population; thus there is a very high degree of variability in their responses due to prior treatments.

So, how should a developer choose a product as a biosimilar candidate?

The development of mammalian products is more expensive and takes a much longer time.

It is also complex to establish analytical similarity for mammalian products because of their innate variability in the fermentation process.

Some categories like hormones and cytokines will have a perpetual market, so it would be fruitful to look for products like follicle-stimulating hormone, where biosimilarity demonstration is relatively more straightforward.

Most cytokines will qualify because clinical efficacy testing will generally not be required because of their pharmacodynamic attributes, which are readily measured.

Develop the products as a group; it is OK to have 2 or more biosimilars for the same indication; developers will not be cannibalizing their sales.

Investing in regulatory planning will reduce the cost burden and time to market, making it possible to select any available products.

The Center for Biosimilars® Advisory Board member Sarfaraz K. Niazi, PhD, explains an “against the grain” approach to tapping unmet need and revenue potential in biosimilars.

Opinion: The “Forgotten Molecules” May Reward Biosimilar Developers

Analytical similarity assessment of biosimilar candidates is the backbone for establishing biosimilarity, a primary requirement for the licensing of biosimilars. After 

 its pivotal final guideline on analytical similarity testing, the FDA issued 

 (Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations), with many apparent and subtle differences, primarily based on my 

 to the FDA. For example, few people noticed that the FDA replaced “testing” with “assessment.” To assess is to test the value of something using various tools. Testing is when something is put through a series of trials to determine its value. Thus, 

 is one of the ways to assess something. In this paper, I will draw attention to both substantive and subtle changes to help reduce the cost and time for the approval of biosimilars.

 Orthogonal testing uses different testing methods to affirm the same attribute, such as the protein content using an ultraviolet (UV) reading and chromatography reading. The need for such testing comes when one method cannot be suitably validated. However, many reported tests have used multiple validated methods to confirm the same finding. As an example, 25 analytical tests were submitted for Pfizer’s adalimumab biosimilar, while the Boehringer-Ingelheim adalimumab biosimilar came with 

. Which company was more brilliant: the one that chose to do just 25 tests or the one that overkilled the testing? The FDA guidance stresses the use of orthogonal testing to "definitively" identify differences in product attributes.

 Expression systems are the genetically modified bacteria or Chinese hamster ovary cells that produce a therapeutic protein as a byproduct. You cannot change this with any process changes; as a result, you need not use a large number of lots to confirm. Primary, secondary, and tertiary structures fall in this category; you can use just 3 lots, but these must be assessed side by side with the reference product because you cannot rely on any legacy values (such as those given in pharmacopeia or scientific literature); most methods of assessment for structure are also not well validated, so side-by-side testing removes the constraints of the validity of the test. This stage of development can use orthogonal testing; for example, the secondary and tertiary structures are challenging to study, and innovations such as changing the temperature, osmolality, pH, or ionic strength of the solutions tested can provide greater confidence of 

. "Use of different expression systems will be evaluated on a case-by-case basis," the guidance states.

 Although the expression system is unchanging, what happens to molecules after they are expressed mainly depends on process conditions such as bioreactor operation parameters and chromatography technologies. These are often termed posttranslational modifications, such as glycosylation or impurities. Instead of justifying the differences, it is better to adjust the process to match the profile with the reference product. Know that more important is the identity of variables and not their ratio vs that of reference product variables. 

 Comparison of a biosimilar candidate and the reference product begins with choosing the properties of the reference product to match or deciding what is critical to match. When biosimilars were introduced, the selection of these attributes was a complicated exercise of weighing risk factors and figuring out how to avoid variability during manufacturing; now we know well what the CQAs are and what should not be a CQA. For example, based on the earlier FDA guidance, Sandoz, which developed the first US biosimilar (Zarxio, filgrastim), tested the protein content as a CQA and kept failing until 

, even though none of the lots were out of release specification, meaning they met standards for acceptance. Such exercises are no longer necessary; if you are able to establish release specification based on either acceptance variation or based on variation in the reference product, there is no need to test these attributes in an elaborate side-by-side comparison exercise.

 The first final guidance on analytical testing was rife with mistakes relating to the statistical modeling of CQAs. Without any rationale, the FDA had created a 3-tier system. The most rigid was Tier 1, where the 90% confidence interval of the biosimilar product had to be within 1.5 of the standard deviation (SD) of the reference product. It turned out that most CQAs assessed failed. The new guidance removes statistical modeling but advises that enough lots should be used in a side-by-side comparison if SD is used to measure variability. Likely, the FDA will allow pooling analytical assessment data as they did to evaluate the Sandoz filing.

 Both FDA and the European Medicines Agency have experience evaluating submissions of dozens of biosimilar products, and the initial emphasis on “more is better” is fading away. Still, the need for a “stepwise approach” to biosimilar development remains. Generally, if fewer lots are used for comparison, there is a higher chance of a biosimilar failing (remember Sandoz did 71 lots to pass the protein content test). Matching with fewer lots should be preferred unless the CQA is highly variable. Most traditional CQAs are not highly variable. Testing more than necessary not only adds to the cost of development but also extends the timeline for submission. The goal is not to cut the corners but to go around the corners where appropriate.

We have come a long way from the early days of superfluous testing of biosimilars; the new FDA guidance should be read carefully between lines; it is a more rational approach to achieving the demonstration of biosimilarity, but the FDA is like any other agency—if you keep offering to assess ad infinitum, they will have no objection to it. Manufacturers must learn the difference between “testing” and “assessment.”

Refinements to the analytical testing of biosimilar candidates to verify similarity were worked into 2019 guidance from the FDA. These changes offer what the author considers a more "rational approach." 

Opinion: FDA Changes to Biosimilar Development Guideline Save Money and Time

In the United States, the use of animals to test human pharmaceuticals dates to 1937, when a liquid formulation of a sulfa antibiotic dissolved in diethylene glycol resulted in the deaths of 107 adults and children. The incident led to the 1938 

, mandating animal toxicity testing. In 1946, language was incorporated into what became the 

designed and based on the results of animal experimentation

 [author’s italics] and a knowledge of the natural history of the disease.” 

The previous statement was written by Andrew Ivy, a strong proponent of animal research. Still, it was 

 such a requirement would improve the safety or efficacy of human drug development. Today, the FDA generally 

 preclinical testing of any new drug or biological therapeutic in animals “for pharmacologic activity and acute toxicity” before human clinical trials begin. However, recently, the FDA indicated it was open to considering 

A weight-of-evidence approach is practiced for biotechnology-derived products when a carcinogenicity assessment is warranted. Genotoxicity [damage to DNA or chromosomes] testing is generally inappropriate for biological products and is not part of the assessment. When sufficient information is available, the need to conduct additional nonclinical studies, regardless of whether the biologic is active and testable in a rodent bioassay, is not warranted. If the assessment does not suggest carcinogenic potential, a rodent bioassay is considered unlikely to add value, and no additional nonclinical testing of biologic products is recommended. Prior knowledge of target-based risks figures prominently in developing a strategy to assess the carcinogenic risk of each new biologic because the nonspecific activity of such molecules is generally considered to be low.

 exploring the use of NAMs to improve regulatory efficiency and potentially expedite drug development. All of these discussions apply to new drugs or biological ones. No animal studies are required for generic chemical drugs because their chemical structures are identical to the reference products’ structures. Biosimilars have presented a dilemma; their molecular structure may be highly similar but not identical to the reference products’ makeup, which actually varies from batch to batch. The 

Biologics Price Competition and Innovation Act

 (BPCIA) states that the data required for FDA approval 

include animal studies (including an assess­ment of toxicity). This requirement of the BPCIA has caused significant confusion and resulted in delays in the approval of biosimilars.

In most cases a correlation between animal toxicology and safe use of biological products in humans cannot be made because of the differences in the receptors between humans and animals. This is well established.

Biosimilar developers, with a mindset of new drug development, took the toxicology studies to a different level, submitting studies that were refused by the FDA. The worst examples were (number rejected/number submitted): 

 (pegfilgrastim; 8/13). For example, for Mvasi (bevacizumab), mice and rat studies were reported to demonstrate that the high mannose variants in the biosimilar candidate were not meaningful—an irrelevant exercise because rodents do not have receptors to bind monoclonal antibodies. 

The same is true about testing trastuzumab in mice (Trazimera and Herzuma), where trastuzumab does not identify the neu receptor. For the etanercept biosimilars Eticovo and Erelzi, studies were conducted in mice and rats that were irrelevant for the same reason. Fifteen animal toxicology studies were reported for an epoetin biosimilar (Retacrit) to justify higher antidrug antibodies than the reference product produced—an irrational approach. It was later determined that the differences were due to formulation and route of administration. 

Testing biosimilars in species that do not present receptors is irrelevant, as the European Medicines Agency and the FDA have repeatedly pointed out. Genotoxicity testing is disallowed because it is irrelevant. However, the difference between how a chemical species interacts with the body vs biological molecules remains included in the approval guidelines. A reference biological product that has undergone extensive multispecies testing has established safety in humans; when it comes to biosimilars, analytical similarity alone is enough to demonstrate that there is no risk of unexpected response.

The most misleading advice comes from the WHO; it states that toxicology studies in monkeys should be avoided, animal toxicology studies should be conducted at several different doses, and immunogenicity testing in animals should be evaluated—all of which are irrational suggestions; unfortunately, many countries follow the WHO guidance, such as India, leading to inappropriate approval of biosimilars. The following points are important to keep in mind:

Unlike chemical drugs, biological drugs do not elicit a pharmacologic response across species and there is no extrapolation to human safety.

The new FDA advice discourages animal testing of new biologicals.

Animal immunogenicity testing is irrelevant; the human immune response has a different infrastructure than for any type of animal species.

No animal testing can be used to justify any differences in analytical similarity; for example, an unidentified and unreported impurity in a biosimilar candidate vs a reference product cannot be proven irrelevant by any animal testing.

Multiple species testing, as reported, is of little value for the same arguments.

Differences in antidrug antibodies in humans can never be resolved with any testing protocol in animals.

In summary, a detailed review of over 100 biosimilars approved in the United States and European Union by the author reveals that none of the animal toxicology studies was pivotal in the approval of the product; essentially, there was sufficient evidence without them for a regulatory decision. Now that the agencies have 2 decades of experience in approving biosimilars, it is about time that clear guidelines against animal toxicology testing are adopted. The advantages of this guidance will include:

Developers will be forced to produce a more analytically similar product because they cannot rely on animal testing to justify any significant differences in the structure.

It could prevent the approval of biosimilars that may not be adequately confirmed to be biosimilar based on irrelevant animal toxicology testing.

There would be a significant reduction in the testing time and cost—both relevant to making biosimilars affordable.

The only justified use of animal studies is in animal pharmacology testing in larger species such as monkeys. The pharmacokinetic profile provides an additional element of analytical similarity—how the body views the molecule, which is the same justification for clinical pharmacology testing in humans.

Animal toxicology studies still get included with biosimilar approval applications, although there are strong arguments that most of these studies are unnecessary. Sarfaraz K. Niazi, PhD, explains the pros and cons. 

Opinion: The Debate Over Animal Toxicology Studies 

My analysis of all biosimilars licensed by the FDA and EMA shows a common trend: Except in a few instances, all products were tested for clinical efficacy and safety; none of the tests failed, and where results were borderline, the FDA allowed adjustment of acceptance criteria to make approval possible. No product was tested in more than 1 indication, despite the allowance of all indications by the FDA and European Medicines Agency (EMA).

If you are one of the big pharma companies dabbling in biosimilars, you would prefer to conduct these studies because you are used to meeting with prescribers with published clinical studies in hand. Other companies, not as well grounded in the value of clinical studies, performed them because they kept thinking of biosimilars as new biologics and had great uncertainty in their abilities. This article is not for those who are fixed in their belief that clinical efficacy testing is needed. Here are a few points of advice for biosimilar developers. First, I continue to 

 that big pharma will soon walk out of the biosimilars field; after my first prediction, I got a lot of wrath from big pharma, although several pulled out within a few months.

One should learn from history: The same things occurred when generic laws came into effect. First, big pharma predicted that use of generics would lead to the demise of millions of patients because only big pharma knows how to make safe products. That campaign was not successful, so they joined the party and began offering generic versions of their products (some still do). But when the bottom fell out with 70% to 90% price reductions, most big pharma companies went back to doing what they best, creating new products. The same will happen to biosimilars, once the price bottom falls.

It may be a surprise to some that clinical efficacy testing for biosimilars is not always a requirement for approval. When I reviewed all licensed products, I inquired why the FDA required these studies; to my surprise, the answer was that the developers offered these studies as part of establishing biosimilarity. If you provide the FDA or EMA with an extensive plan to test clinical efficacy and safety, the agency cannot say no. What if they discouraged these studies and there were safety issues?

The most glaring example of redundant efficacy testing was the approval of Retacrit (epoetin alfa) by Hospira, which conducted efficacy testing in 1000 individuals for its European submission. When Hospira applied for FDA approval using the same EU data, the application was rejected and the FDA required a stepwise approach which involves analytical characterization of the proposed biosimilar, then animal studies, possibly, and then comparative clinical studies. Instead of examining the extensive clinical efficacy proof, the FDA did not require any efficacy testing and accepted the EU study only as an ancillary study. The FDA and EMA are also not requiring clinical efficacy testing for products such as teriparatide, insulins, low-molecular-weight heparins, filgrastim, pegfilgrastim, and other cytokines with pharmacodynamic markers. Some products would not even need safety assessments, such as teriparatide, low-molecular-weight heparin, and insulins.

Here is how biosimilar developers should challenge the FDA if asked to do clinical efficacy testing:

Force the FDA to explain, in writing, where they see any “residual uncertainty,” a prerequisite before the agency will ask for “additional clinical testing.”

If the agency insists, counter that this study need not be in patients, as the Biologics Price Competition and Innovation Act does not require patient testing.

Suppose there are safety issues (such as variability in the posttranslation modifications). Developers could offer to conduct a limited safety study in healthy subjects.

If there is still no concurrence, then it could be argued that conducting efficacy testing in 1 indication (which is currently required and practiced) does not assure efficacy and safety assurance in other indications; therefore, the testing would be limited and wasteful.

A final argument should be to agree to a postmarketing study in an open protocol for a limited time.

In my recent interactions with both the FDA and EMA, there is an openness to receive creative approaches to establishing biosimilarity. We have more than 15 years of experience in seeing the approval of over 100 biosimilar products.

The reason I am insistent on helping biosimilar developers simplify the qualification process is that, so far, the approval of biosimilars has been disappointing; first, markets for biologic drugs are still very much controlled by big pharma; and second, this is keeping smaller companies from entering the field. The reason I am so confident is that I know exactly what it costs to manufacture biological products. Biosimilar antibodies should not cost more than $150/g to manufacture in Western countries. But, not surprisingly, the cost to patients is still about 100-fold; this must come down if the promise of biosimilars will be realized.

Clinical efficacy studies are not always required for biosimilars, and it's possible to resist if the FDA does ask for them. Sarfaraz K. Niazi, PhD, suggests a game plan. 

Opinion: How to Get FDA Clinical Efficacy Testing Waivers for Biosimilars

This year marks 12 years since the appearance of the Biologics Price Competition and Innovation Act of 2009 (BPCIA); and, the FDA has approved 30 biosimilar products comprising 10 molecules. A critical analysis of the licensed biosimilars 

 a dire need to review the BPCIA pathway to find ways to go around it to expedite the entry of more biosimilars. First, let me share with you a few facts about the licensed biosimilars. Except for 2 biosimilar products, clinical efficacy testing was done for all biosimilar products although they met all other requirements of biosimilarity. None of the products that were tested failed. So, a question arises: What would it be like if these applications were filed under 351(a) for standalone biological products instead of under 351(k)? For example, Teva famously filed for FDA approval of its filgrastim product (Granix) as a standalone biologic. Did it make a difference? No. The biggest problem with BPCIA is the 12-year exclusivity of the reference product. Now that we have reached the 12th anniversary of the BPCIA, let us examine how we can go around the hurdles inherent in the BPCIA.

Using 351(a) for Copies of Approved Drugs

Although the 351(a) pathway is intended for new molecules, it is also available for copies of approved molecules and to add new indications (uses); in a way, it resembles the 505(b)(2), which is a streamlined product approval filing for new chemical generic drugs. The FDA has stated clearly in its guidance for COVID-19 product candidates that, under 351(a), the studies required for product approval may be reduced if a similar product has been approved, essentially inviting the developers to challenge the concessions available for biosimilars. Although there is no reference product required for the development of a copy biologic under 351(a), a dataset that is created comparing the product candidate with a reference product will be accepted as proof of comparable safety and efficacy.

We could unofficially call such imitator products “biosimilars.” There would be no 12-year exclusivity to worry about because originator products would not be involved; there would be no marginal failures in similarity testing and no discussions of minor differences in posttranslational modifications. There would be no patent dance and necessary litigation because the onus of proving intellectual property infringement would lie with the claimant. Manufacturers would have to choose just 1 indication for the purposes of efficacy testing—the same way it is done for biosimilars now. For example, manufacturers could select psoriasis for an adalimumab (Humira) imitation product, and this would be a much cheaper study to conduct. Once approved, prescribers and payers would be able to use the product off-label and compete with Humira for all of its approved indications. I am not recommending breaking any laws; I am presenting facts. For example, bevacizumab (Avastin) is used for age-related macular degeneration as an intravitreal injection, but no bevacizumab products are specifically approved for this use. Does it make a difference if one uses bevacizumab or biologically equivalent products for this purpose? Notwithstanding any special formulation factors, it should be OK.

The cost and time for developing products in this new pathway I am suggesting—a modified 351(a)—would not be higher than for a 351(k) application, but with benefits of getting around the 12-year exclusivity automatically granted to originator products when the filing is made under 351(k)—a big game-changer. Incidentally, when the BPCIA was drafted, I had the privilege of explaining to then–president-elect Barack Obama all about biosimilars. He was opposed to the 12-year exclusivity for originator products, and preferred 8 years at most, although he yielded under opposition from big pharma. This issue becomes more acute if we talk about the creation of biosimilar mRNA vaccines; 12 years is too long a period of exclusivity for the originator products because the vaccine will likely change during that time. 

In this column, I am using the term “biosimilar,” and this needs explanation. Biosimilar means a biologically similar product, not a similar product that is biologic. So, we can use the term “biosimilar” to characterize a product approved under 351(a). It need not be essentially associated with BPCIA. However, if you get approval for a standalone product, it will not be eligible for interchangeable status, as was recently awarded to Semglee (insulin glargine). This alternative approval should not be considered as a path opening for interchangeability.

To help my understanding of these issues, I communicated with the FDA about its guidance for COVID-19 products, which reads as follows:

COVID-19 vaccine development may be accelerated based on knowledge gained from similar products manufactured with the same well-characterized platform technology, to the extent legally and scientifically permissible. Similarly, with appropriate justification, some aspects of manufacture and control may be based on the vaccine platform, and in some instances, reduce the need for product-specific data. Therefore, FDA recommends that vaccine manufacturers engage in early communications with [Office of Vaccines Research and Review] to discuss the type and extent of chemistry, manufacturing, and control information needed for development and licensure of their COVID-19 vaccine.

My question to the FDA was, would this advice also apply to other biologics? The answer was, “File a formal meeting request Type B.” This is the FDA asking us to challenge them. I am confident that we can convince the FDA not to require many studies, such as toxicology testing, if we can demonstrate analytical similarity. The pharmacokinetic/pharmacodynamic (PK/PD) studies will be inevitable. We can present the data collected in a comparative study as standalone data to calculate the dose, which we already know, and then demonstrate the PK/PD behavior as additional proof of similarity. A PD response mainly for cytokines where PD parameters are available can be used in lieu of any efficacy testing. Choosing the most straightforward protocol will do; it will not be an equivalence study, nor would it be a noninferiority study, but it can be conducted side-by-side as a monitor arm. The statistical model is relatively simple but requires a bit of creativity. The fact that you would not be able to get interchangeable status is not an issue.

The most significant advantage with the modified pathway I suggest under 351(a) is that you could get into the market at least 5 to 8 years earlier than if you were to enter via the 351(k) pathway; for some products, the 351(k) official biosimilars pathway would be futile if the reference product has changed—a tactic widely adopted by the innovators. You will be able to meet with the FDA in a Type B meeting that is free, and there will be no commitment to paying the yearly BPCIA fee to begin talking to the FDA. The high burden of conducting similarity studies, many of which make no sense, will be reduced. As an example, the biosimilar product may meet all release requirements such as content and potency. However, the product may still fail in comparative testing if the innovator product has lesser variability—which is inconsequential anyway. In short, your biosimilar candidate may be good enough for the patients, but not the FDA.

To recap, I suggest biosimilar developers consider using a modified 351(a) approach for products when establishing biosimilarity is difficult and where there is a need to avoid getting bound by the 12-year exclusivity. The fact that an efficacy and safety study was done for every biosimilar that has been licensed by the FDA (with a couple exceptions) makes the advantages of filing a biologics license application under 351(k) less attractive.

Use of the 351(k) biosimilar approval pathway entails legal challenges, high costs, and potentially higher clinical evidence standards. Sarfaraz K. Niazi, PhD, suggests that using the 351(a) pathway for standalone drugs and copy products may be faster and better. This is part 3 of a series.

Opinion: A Modified 351(a) Licensing Pathway for Biosimilars

, I created a new term, “biosimilar mRNA vaccine,” to suggest that chemically synthesized messenger RNA (mRNA) vaccines can be approved as biosimilars under the 351(k) provision by the Center for Drug Evaluation and Research (CDER) rather than as standalone or “novel” 351(a) drugs under the Center for Biologics Evaluation and Research (CBER).

However, there are pros and cons to both pathways to approval. In the biosimilar pathway, a 12-year exclusivity protection will apply if the reference vaccine is revised to address new mutations. This would require biosimilar developers to file a new biologics license application (BLA).

The analytical similarity testing can also be challenging depending on which is considered the active ingredient: the mRNA or the translated protein. In a standalone approval, complete testing will take a longer time and cost. However, given the recent guideline on COVID-19–related products, the FDA is willing to consider standalone filing with the same concessions as are allowed in the filing of biosimilar products. It remains to be seen how the first product filing will be treated.

Today, the world needs about 8 billion doses to create herd immunity worldwide; the WHO and other global agencies are urging that vaccines be supplied to countries that could not afford the cost of the first wave of COVID-19 vaccines. Although there is a surplus of vaccines in the United States, 75% of the world’s population is still waiting for shots. To meet this challenge, we will have to develop a novel pathway to secure faster entry into the market for the COVID-19 mRNA vaccine.

In this article, I present a path that manufacturers could follow for quick access to the market 

. To make the best use of the available technology, a creative and well-organized approach is required:

The chemical synthesis of mRNA is much simpler than manufacturing antibodies and other biological products. Therefore, the production facility setup is a lower-cost step. Additionally, since the vaccine dose is small (micrograms), we need to manufacture smaller quantities (eg, 30 kg to make 1 billion Pfizer vaccine doses). Therefore, an adequate, 6000-square-foot facility can quickly be installed using modular systems within 3 months.

The only biological step in the production is the creation of DNA from a genetically modified 

; thus, this step is not rigorous. A 30 L bioreactor can easily produce 250 million doses per year. Comparing this with production of an antibody such as bevacizumab, a similar number of doses would require 250,000 kg of drug substance. If this antibody process produces 5 g/L of culture media, it would take a 100,000 L bioreactor to produce 5 kg of vaccine, and it would take 5000 batches to produce the required quantity.

Whereas a certain minimum number of reference product samples are required for testing, there are some ethical constraints in using a commercial vaccine in short supply for research purposes; however, enough sample material for testing could be obtained by pooling vaccine from used vials.

With a vaccine design that duplicates the reference vaccine, a contract research organization could be employed to manufacture an initial product sample.

The mRNA vaccine manufacturing process, as with other biological drugs, is heavily 

. The onus of proving infringement lies with the claimant. Most significantly, Moderna owns several mRNA-vaccine patents and has 

 without claiming infringement. So, a copy of the Moderna vaccine should not be subject to any intellectual property (IP) infringement, notwithstanding any IP Moderna is using under a license.

By now, this would be the third month of planning, and the facility would be outfitted. After that, the manufacturer would be scheduling the first meeting with the FDA to discuss the regulatory review plan, including analytical, in vitro, and animal model testing for antibody production.

The sooner a manufacturer decides on the scale of production, the sooner cost estimates can be prepared. For example, producing 1 billion doses of a COVID-19 vaccine will require about 31 kg of mRNA, and the cost will be about $0.68 per dose in a bulk form and about $1 in finished form. About 68% of the cost is associated with the chemicals required to make mRNA, and the rest is packaging. These costs will be lower if the vaccine is manufactured outside the United States where the labor costs are lower. At this point, roughly 6 months would have passed, and it would be time to file the BLA if the intention is to secure FDA approval; otherwise, the unpackaged vaccine will be ready for export. FDA approval is not needed to export in bulk if the vaccine is not in package form for administration.

Distributing and selling the COVID-19 vaccine requires collaboration with global health agencies, like the WHO. Many countries will prefer to receive the vaccine in bulk to package it, to save cost. Although FDA approval is not required for bulk export, Good Manufacturing Practice compliance is required. In my opinion, everything will go faster if a manufacturer seeks FDA approval. There are many global concerns interested in developing mRNA vaccines that are now providing many funding resources, making this a lucrative 

Biosimilar mRNA vaccines, approved under 351(k) or a modified 351(a), can fulfill the present and future needs of accessible life-saving vaccines across the globe. The original developers are not able to offer these products at an affordable cost for many reasons, including their capital investment and their need to show a robust profit because they are publicly traded companies. Since the dose of the vaccine is minimal, the production costs are also low. If the cost of an amount provided as bulk is about $0.68 and sold at $3 per dose, it can generate an income of billions of dollars. Still, the reference vaccine producer will not enter these markets, or else they will lose their most profitable business, supplying to richer countries at almost 10 times the price they would get from developing country patients.

Biosimilar mRNA vaccines, approved under 351(k) or a modified 351(a), can fulfill the present and future needs of accessible life-saving vaccines across the globe. 

 will need to wait another 2 years before being vaccinated against COVID-19. Around 11 billion doses are required to fully vaccinate 70% of the world’s population against COVID-19. However, the most effective mRNA vaccines are not going to be available to developing countries. Pfizer has 

 its investors that the rewards of producing a vaccine for low-income and mid-income countries will be nonexistent to very low. The position taken by Pfizer is in 

 to Moderna, which has allowed the use of its pending intellectual property (patents). However, with intervention from the US government and the World Trade Organization, Pfizer will allow the use of the IPs if the intent is to distribute these vaccines to the developing countries.

Therefore, I am encouraging companies to consider this remarkable opportunity to help in ending this pandemic and saving millions of lives.

The road to production of biosimilar messenger RNA (mRNA) vaccines could be very swift compared with the experience for other biologics. With fewer intellectual property restrictions, small manufacturers could step right in, according to Sarfaraz K. Niazi, PhD. 

Biosimilar mRNA Vaccines, Part 2: Fast-to-Market Approach!

The COVID-19 pandemic has brought a remarkable shift in how we will prevent infections and autoimmune disorders in the future. The nucleic acid vaccines, including messenger RNA (mRNA) and DNA vaccines, have been under development for decades, but there was no opportunity to test their safety and efficacy; vaccines may take years and decades to provide sufficient proof of safety and efficacy. Then came COVID-19, caused by the SARS-CoV-2 virus. Fast data collection became possible because the virus was so widespread. Even with small infection numbers (n = 150) among study populations that averaged about 30,000 to 40,000, it was clear that mRNA vaccine efficacy was surprisingly high: 95% or better. The FDA would have approved the use of the mRNA vaccine at even at 50% efficacy.

The safety of the mRNA vaccines was confirmed clearly in multiple studies across the globe. However, not all COVID-19 vaccines fared well. The 

, by CureVac, failed because its developers chose not to follow the teachings of the common wisdom. mRNA vaccines work by introducing a harmless piece of the virus into the body and triggering an immune response that conditions the body to recognize and attack the true virus. Moderna and Pfizer–BioNTech vaccines use modified RNA (pseudouridine); CureVac chose not to modify the RNA, and its vaccine uses normal uridine. It produced lower levels of antibodies than the Moderna and Pfizer-BioNTech vaccines and was just 

 at preventing COVID-19 infection. Incidentally, the name Moderna comes from “modified RNA.”

, a traditional inactivated virus vaccine, also failed. This failure brought great misery because the Chinese government had used this vaccine as a diplomacy tool, supplying billions of doses to developing countries. As of today, none of the non-mRNA COVID-19 vaccines have come close to the efficacy of the mRNA vaccines.

We have 2 mRNA vaccines approved under Emergency Use Authorization (BNT162b2, mRNA-1273/NAID), and I anticipate their full approval soon. Pfizer has filed for the modification of storage temperature, and Moderna has filed for the reduction of dose; the Pfizer dose is 30 mcg, and the Moderna dose, 100 mcg. There are now newer lipid nanoparticle (LNP) formulations that can provide better temperature stability allowing only refrigeration storage.

mRNA vaccines have been under development for decades, so much of the base technology is already in the public domain. Both 

 have shared their clinical protocol, and that is a rare event, as these protocols cost millions to produce and billions to execute. 

 the use of its patented LNP technologies to any company. Although the challenges to overcome IP issues remain, the humanitarian considerations make these challenges manageable. The US government has proposed to 

 relating to the COVID-19 vaccines. This action will require EU cooperation that is yet to come. However, as a patent law practitioner, I am confident that we can make COVID-19 vaccines without any patent infringement that remains in our way. mRNA vaccines have been under development for decades, so much of the base technology is already in the public domain. Both 

 have shared their clinical protocol, and that is a rare event, as these protocols cost millions to produce and billions to execute. No other vaccine developer has shared these protocols in public. The mRNA vaccine developers now have a clear understanding of the regulatory process required to approve new mRNA vaccines.

At the time of the enactment of the Biologics Price Competition and Innovation Act (BPCIA, 2010), there was no indication that the introduction of mRNA vaccines would create a dilemma for the FDA in deciding an appropriate regulatory pathway.

The FDA’s Center for Biologics Evaluation and Research (CBER) jurisdiction includes biological products such as prophylactic and therapeutic vaccines, whole blood and blood products, cellular products and exosomal preparations, gene therapies, tissue products, and live biotherapeutic agents. CBER also regulates selected drugs and devices used to test and manufacture our biological products. In keeping with that mission, 

 filed with CBER include 351(a) filings, which are for “standalone” or original products, rather than biosimilars (21 Code of Federal Regulations [CFR] 601.2). The biologics license application (BLA) is regulated under 21 CFR 600 – 680.

 the Center for Drug Evaluation and Research (CDER), including biosimilar and interchangeable biologics. For example, in March 2020, insulin, glucagon, and human growth hormone regulated as drugs under the Food, Drug, and Cosmetic Act came into the CDER BLA program.

mRNA vaccines have a unique feature: They are manufactured chemically, not biologically, as are many other vaccines. As a result, the vaccine structure is completely known, unlike the therapeutic proteins. The variations in the secondary and tertiary structures and post-expression modifications require intensive evaluation of similarity to allow them a biosimilar status. A proposed biosimilar mRNA vaccine can provide a 100% match for a reference product sequence. Thus, mRNA vaccines are closer to generic chemical products than biological therapeutic proteins.

In my opinion, the traditional vaccines can stay within the jurisdiction of CBER, and the chemically synthesized vaccines be approved under BLA by CDER under the 351(k) filing where suitable.

 (February 2021) on the development of products for the treatment and prevention of COVID-19, which states:

“COVID-19 vaccine development may be accelerated based on knowledge gained from similar products manufactured with the same well-characterized platform technology, to the extent legally and scientifically permissible. Similarly, with appropriate justification, some aspects of manufacture and control may be based on the vaccine platform, and in some instances, reduce the need for product-specific data. Therefore, FDA recommends that vaccine manufacturers engage in early communications with [Office of Vaccines Research and Review] to discuss the type and extent of chemistry, manufacturing, and control information needed for development and licensure of their COVID-19 vaccine.”

This statement can be construed as pointing to the possibility of a biosimilar application filing for a licensed (BLA) product to meet all requirements of the BPCIA. If the sequence of a biosimilar mRNA vaccine matches a reference product sequence, then the need for extensive toxicology and efficacy testing can be reduced, on a case-by-case basis, depending on other factors of variation. In my earlier conversation with the FDA, I appreciated the broad encouragement I received to discuss the development plan in a Type B meeting first, where the possibilities of a modified 351(a) filing or a 351(k) filing for a biosimilar mRNA vaccine can be discussed; the 351(a) modified approach will be analogous to a 505(b)(2) new drug application under the FDC Act. I will keep my readers informed of any new indications from the FDA.

mRNA vaccines are now at the forefront of hundreds of possibilities, including preventing infections to preventing autoimmune disorders. Since the antigens focused on the design of mRNA vaccines cannot be 

, a biosimilar vaccine product may likely produce the product without any infringement issue. The testing proposal presented above will help expedite the approval of biosimilars without risking the safety and efficacy of biosimilar products.

For the first time, we have a scientific challenge to meet: how to classify mRNA vaccines as chemical drugs or as biosimilars rather than standalone biologics?

To promote the idea of creating a new category of products, biosimilar vaccines, I have filed a citizen petition to the FDA advising the agency on creating new guidance for this new class of biosimilar products.

In contrast to chemically synthesized small molecular weight drugs, which have a well-defined structure and can be thoroughly characterized, biological products generally derived from living material (humans, animals, or microorganisms) are complex in structure and, thus, are usually not fully characterized. However, this last consideration does not apply to mRNA vaccines.

To promote the idea of creating a new category of products, biosimilar vaccines, I have filed a citizen petition to the FDA advising the agency on creating new guidance for this new class of biosimilar products. In my opinion, the agency will agree to many of my suggestions because the issue of structural similarity with a reference product is no longer an issue. Preclinical toxicology studies can be waived based on in vitro and situ studies, requiring only comparable antibody production in animal species. The immunogenicity—stimulation of immune response—is not a significant issue because vaccines are supposed to be antigenic. A limited trial in animal species capable of showing antibody response that is comparable to findings with the reference mRNA vaccine will suffice to establish equivalent safety with the reference product.

I have also developed several mRNA vaccines, including COVID-19, flu, HPV, HIV, and tuberculosis, that are under advanced stages of development across the globe, including one with a biosimilar status. Today, the world needs about 8 billion doses of COVID-19 vaccines that work. I have concluded that we can make 1 billion doses using 30 L bioreactors in 6 months with our cost of goods not exceeding $0.50 per dose in bulk and $0.90 in final packaging if the vaccine is manufactured in the United States; the costs can be lower if manufactured in developing countries. For example, the cost of Moderna single dose is $32 to $37, and Pfizer’s, $22 in final packaging. I can confirm these costs of manufacturing that make the commercial manufacturing of COVID-19 vaccines a highly profitable project.

While there is an excess of COVID-19 vaccine in the United States, the rest of the world is still starving for it. The WHO has also told me that the world needs 8 billion doses of COVID-19 vaccines and that they will be very proactive if anyone can supply the mRNA vaccines; the trust in all other vaccines has declined. This is a remarkable business opportunity for many companies since the capital expenditures (CAPEX) and operating expenditures (OPEX) are very small. In my next article on the topic, I will provide details of strategies to take the mRNA vaccines to market fast and reduce CAPEX and OPEX significantly. I want to enable newcomers to appreciate that mRNA technology will revolutionize health care, and there are many opportunities to join this revolution.

mRNA vaccines are chemically derived and have fixed chemical structures; it is possible to fully replicate a reference product sequence, reducing the burden of proving biosimilarity required for therapeutic proteins. The FDA has already suggested a new pathway for mRNA vaccines, but this path will only come into being when enough companies join in taking steps toward this strategy.

Watch for the second article in this series: Biosimilar mRNA Vaccines—Fast-to-Market Strategies.

Sarfaraz K. Niazi, PhD, discusses the regulatory approval of future messenger RNA (mRNA) vaccines, which will likely face fewer patent issues and are easy to replicate. 


Biosimilar mRNA Vaccines, Part 1: Regulatory Revolution!

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

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

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

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

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

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

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

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

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