Hubris

Originally the intentional use of violence to humiliate or degrade others, Hubris has evolved--an overweening presumption that leads a person to disregard the divinely fixed limits on human action in an ordered cosmos.

The most famous example of hubris in ancient Greece was the case of Meidias. In 348 BCE struck the orator Demosthenes in the face when the latter was dressed in ceremonial robes and performing an official function. This sense of hubris could also characterize rape. Hubris was a crime at least from the time of Solon (6th century BCE), and any citizen could bring charges against another party, as was the case also for treason or impiety. (In contrast, only a member of the victim’s family could bring murder charges.)

The most important discussion of hubris in antiquity is by Aristotle in his Rhetoric:

Hubris consists in doing and saying things that cause shame to the victim…simply for the pleasure of it. Retaliation is not hubris, but revenge.…Young men and the rich are hubristic because they think they are better than other people.

Hubris fit into the shame culture of archaic and Classical Greece, in which people’s actions were guided by avoiding shame and seeking honor. However, it did not fit into the culture of internalized guilt, which became crucial in later antiquity and characterizes the modern West.

Today, hubris is everywhere, but now we also know why. This is part of the genetic evolution to claim peace of mind and soul. Animals have no issue--fight or flight--only humans think about a third choice. It always leads to downfall, not just of individuals but societies and nations, from a Pharaohs onward.

Letter to Kamala Harris--Time to make life-saving drugs affordable--the INSULIN pathway

RE: H.R.5623 - The Insulin Cost Reduction Act

 Dear Madam Kamala Harris:

 Thank you for your words of kindness in accepting my dedication to you for my book, The Future of Pharmaceuticals--A Nonlinear View.

 As the House approved the H.R.5623 - The Insulin Cost Reduction Act to cap patients' out-of-pocket costs at $35 a month for their insulin, it has to go through the Senate. To educate the senators, know that monthly supplies of insulin currently average around $375-1,000 to two million Americans. In addition, insulin is presently sold at 31 cents per unit[1], while the production cost is less than a penny. Therefore, the House Bill fixing a ceiling price of $35 per month is well justified[2] and practical[3]. How can any senator not vote for it; I have educated all senators individually also.

 We should revisit our previous discussion to bring a legislative change to allow the CMS to negotiate prices. Medicare could have saved more than $16.7 billion from 2011 to 2017 on insulin purchases had it been allowed to negotiate the pricing. Moreover, these savings should extend to all biological drugs; the cost of producing every monoclonal antibody is less than $100 per gram[4] , and these sell at thousands to hundreds of thousand dollars per gram. I have met with the CMS and submitted a bill draft to provide CMS with more authority.

 Thank you for your leadership and understanding that access to life-saving drugs is a right, not a privilege.Thank you for your leadership and understanding that access to life-saving drugs is a right, not a privilege.

 Sincerely yours,

 Sarfaraz K. Niazi, Ph.D.

Adjunct Professor of Pharmaceutical Sciences

College of Pharmacy, University of Illinois, Chicago, IL

[1] https://www.goodrx.com/healthcare-access/research/how-much-does-insulin-cost-compare-brands

[2] https://crsreports.congress.gov/product/pdf/IF/IF11026

[3] www.civicarx.org

[4] https://www.researchgate.net/publication/284086808_Cost_evaluation_of_antibody_production_processes_in_different_operation_modes

Understanding Beauty: Santayana and I Debate

George Santayana [1863 – 1952] was a philosopher, essayist, poet, and novelist. He is popularly known for aphorisms, such as “Those who cannot remember the past are condemned to repeat it,” “Only the dead have seen the end of the war” (often misattributed to Plato). The definition of beauty as “pleasure objectified.” Santayana was profoundly influenced by Spinoza's life and thought of a devoted Spinozist. He wrote books and essays on a wide range of subjects, including philosophy of a less technical sort, literary criticism, the history of ideas, politics, human nature, morals, religion's influence on culture and social psychology, all with considerable wit and humor. 

He held racial superiority and eugenic views. He believed superior races should be discouraged from “intermarriage with inferior stock.”

Although he declined to become an American citizen, Santayana is usually considered an American writer, resided in Fascist Italy for decades, and said that he was most comfortable, intellectually and aesthetically, at Oxford University. Santayana described himself as an “aesthetic Catholic.”

Santayana's primary philosophical work consists of The Sense of Beauty (1896), his first book-length monograph and perhaps the first major work on aesthetics written in the United States; The Life of Reason five volumes, 1905–6 is his first extended treatment of pragmatism. The high point of his Harvard career; Skepticism and Animal Faith (1923); and The Realms of Being (4 vols., 1927–40). Santayana's one novel, The Last Puritan, is a bildungsroman, centering on the personal growth of its protagonist, Oliver Alden. His Persons and Places is an autobiography. 

Like many classical pragmatists, and because he was well-versed in evolutionary theory, Santayana was committed to metaphysical naturalism. He believed that human cognition, cultural practices, and social institutions have evolved to harmonize with the conditions present in their environment. Their value may then be adjudged by the extent to which they facilitate human happiness. Santayana was an early adherent of epiphenomenalism, but also admired the classical materialism of Democritus and Lucretius. 

In large part, Santayana is remembered for his aphorisms, many of which have been so frequently used as to have become clichéd. His philosophy has not fared quite as well. Santayana's passing is referenced in the lyrics to singer-songwriter Billy Joel's 1989 music single, “We Didn't Start the Fire.”

The Sense of Beauty was published in 1896 and divided into four parts: “The Nature of Beauty,” “The Materials of Beauty,” “Form,” and “Expression.” Beauty, as defined by Santayana, is an “objectified pleasure.” It does not originate from divine inspiration, commonly described by philosophers, but from naturalistic psychology. Santayana objects to God's role in aesthetics in the metaphysical sense but accepts God's use as a metaphor. His argument that beauty is a human experience based on the senses is influential in aesthetics.

According to Santayana, beauty is linked to pleasure and is fundamental to human purpose and experience. Beauty does not originate from pleasurable experiences, by itself, or from the objects that bring pleasure. It is when the experience and emotion of pleasure intertwine with the object's qualities that beauty arises. Beauty is a “manifestation of perfection,” and as Santayana writes, “the sense of beauty has a more important place in life than aesthetic theory has ever taken in philosophy.” He describes sight as “perception par excellence” and form as usually visual experience to be almost a synonym of beauty.

 Santayana claims that pleasures derived from all human functions may become objectified. Hence, the beauty material is most easily done in vision, hearing, memory, and imagination.  Form, however, which needs constructive imagination, is preceded by the effects of color in vision. The example of sound serves as an example of the delicate balance between simplicity and variety that leads to the experience of beauty: Discrimination of tones from the chaos of sound is pleasurable, but the pure tone of a tuning-fork is dull. Santayana states that touch, taste, and smell are less likely to lead to “objectified” pleasure because they ″remain normally in the background of consciousness.” 

Santayana further distinguishes vital (bodily) from social functions with sexual instinct as an intermediate form. The latter is acknowledged to profoundly influence humans' emotional lives, generating a passion that overflows to other topics if not directed towards another human. However, because of their abstract nature, Santayana regards social objects, such as success or money, as less likely to attract aesthetic pleasure because they are too abstract to be directly imaginable.

Santayana notes that sensuous material a) is necessary for finding or creating beauty (how else could one perceive the poem, building, etc. in question?), and b) can add to the experience of beauty as the sensuous material itself may elicit pleasure.

He identifies symmetry and a balance between uniformity and diversity as eliciting such a pleasing perceptual experience; as an example, he uses the beauty one finds in the stars. Santayana points out that memories and other predispositions (″mental habits″) contribute to the perception of an object and hence of its value - that may ultimately be beauty. Here, another distinction is made between ″value of a form″ and ″value of the type as such″; in the latter sense, an object also has a value in how well it is an example of its class.

″Everything is beautiful because everything is capable of some degree of excitement and charming our attention. Still, things differ immensely in this capacity to please us in contemplating them, and therefore they vary immensely in beauty. ″

In contrast to Plato and Socrates, Santayana does not necessarily see a relation between beauty and utility. 

The qualities that an object acquires indirectly using associations (such as with other concepts and memories), he calls “expression.”. The pleasures elicited by such an association are said to yield pleasure just as immediately as the perception of the object itself. However, an expression - which is merely a thought or meaning - cannot elicit beauty in and by itself; it needs an object that gives it a sensual representation. The aesthetic value may thus have two sources: 1) in the process of perceiving an object itself, called sensuous and formal beauty, and 2) value derived from the formation of other ideas, called beauty of expression.

What happens if an object's expression is negative? Santayana answers that the object itself may nonetheless be beautiful. Thus, even if evil is portrayed, e.g., in a play or novel, we can experience beauty despite evil suggestions. 

To Santayana, an object's price per se cannot add to its aesthetic value; only if the observer re-interprets the price as the human work and craft invested in that object can add to the object's value. The utility of an object, in more general terms, is said to enrich or diminish the beauty of an object. If it fits its purpose well, this may add to the object's beauty, but knowledge about unfitness for the given purpose may also spoil the experience of beauty.

″The intoxicatingly beautiful″ is said to take pleasure in contemplation, to sink into the object, the pure perfection of the sublime dissolves the object altogether. 

Santayana says that beauty cannot be described in words, except as ″the harmony between our nature and our experience″. Under the premise that perfection is ″the ultimate justification of being″, Santayana ends with the statement: ″ Beauty is a pledge of the possible conformity between the soul and nature, and consequently a ground of faith in the supremacy of the good.″

While I am also a Spinozist and a pragmatist like Santayana, I have a different view of beauty.  I agree with Santayana that utility is not essential for beauty, or else a hammer and a pair of pliers would be labeled as the most beautiful objects. However, I disagree with his assertion that beauty is a “manifestation of perfection.” Perfection is in the eye of the beholder as he agrees that the sight is the perception par excellence. No different than any other physical attribute, perfection is subjective and not universal. “Perfect” anatomy in one culture will be considered unacceptable in another.

According to Santayana, beauty is linked to pleasure. It is fundamental to human purpose and experience, and it does not originate from pleasurable experiences, by itself, or from the objects that bring pleasure. Here Santayana could have gone a step farther in defining what constitutes pleasure? Pleasure is a pure chemical reaction that was now well-described when he wrote his book; a chemical reaction release chemical of joy in the body is a physical experience or a pleasure of a beautiful thought. Santayana would not have been satisfied with this description because it raises the question, “why is it so?” We both agree that there is no hand of God in anything. Could this be a genetic coding to motivate us towards an object? And why would there be no universal definition of beauty? While a useful definition can be set aside, it cannot be ignored. Let us talk about the most widely used term, a “beautiful woman.” All physical attributes that help nurture the offspring are considered beautiful in most, but not all cultures. Men's physical characteristics, physical strength, and ability to support family remain attractive, though they are not labeled as beautiful. It is all chemically driven, and it would not be improper to state that just like the human race has varied genes, they have varied stimuli for pleasure. There is nothing universal about it. It is only one of the thousands of mental responses.

In women's case, beauty is also an element of genetic strengthening; being attracted to men who have better genes, the offspring come out better; this roulette is played widely every day without us realizing it. Santayana failed to address the basic emotional response—a lust that is most attributed to male species. You hear much about “dirty old men” but rarely “dirty old women” because men remain sexually active longer than their counterparts. The human species is not a monogamous species like any other animal; women must remain monogamous since they need to raise a child with support from the father. Further support for polygamy comes from the expected loss of attraction between couples due mainly to the monotony that is a diversifying factor leading to polygamy.

A comparison that may not go well with many is that men are antigens and women, its antibodies. Think.

Further complicating the resolution of being beautiful is the aesthetic suggestion that comes from perceiving an object itself, called sensuous and formal beauty. The value derived from the formation of other ideas is called the beauty of expression. I am not sure if we are qualified to determine a global standard of aesthetics. Being sensuous is so highly variable, so is the formation of an idea. A poet looking at clouds may see a divine message, a commoner looking to hide from the rain. 

What is beautiful is a question that cannot be answered equivocally, just like the question, why do we exist? Beauty, if it brings joy, is a remarkable tool of pharmacology; if it helps create a behavior conducive to species survival, it is noble; but if it draws usurping others' rights, it can be just as devastating as the worst human instincts.

Letter to VP-elect Senator Kamala Harris

07 November 2020

 Senator Kamala Harris
112 Hart Building, 
Washington, DC 20510

Dear Senator Harris:

Congratulations on breaking so many barriers today. As a woman, you bear the torch to the suffrage movement. As a black person, you the have the burden of muting the racial discrimination. As an Asian gene holder, you assert that every American, except the American Indians, we are a land of immigrants. These are significant responsibilities, but with your passion and youth, I am confident you will serve as a role model, and you have the best wishes of millions behind you. 

I am writing to you at the behest of Vice President Joe Biden, who, a few weeks ago, asked me to continue my advisory to President Barack Obama. I was able to educate President Obama about the biosimilars, and he engineered these into the AHCA. Now the AHCA is under attack, and my advisory is now focusing on making medicines affordable, particularly the essential lifesaving medicines like insulin. This was also the subject of my communications that we exchanged when you were a presidential candidate. My communications with President Obama are now present in President Obama's library. And all my advisory submissions to the US FDA are cataloged by the US FDA in www.regulations.gov –all aimed at taking a creative approach to healthcare.

Once you have established your transition office, I will be honored to meet with you and your team to share a possible strategy for making medicines affordable, particularly the lifesaving medicines like insulin, to all. However, this should not be a disincentive to the US pharmaceutical industry that has introduced almost all medicines used today. The cost of medicines is unaffordable to many—that is what we need to address it, and it is possible, as I will demonstrate in my thesis. 

I was invited by the CMS early this year to suggest how to reduce the CMS budget and concluded that this require a legislative change; this is one of my advice I will submit to you.

 Again, congratulations, and I look forward to meeting you soon.

Sarfaraz K. Niazi, Ph.D., SI, FRSB, FPAMS, FACB.
Adj Professor of Pharmaceutical Sciences, College of Pharmacy, University of Illinois
833 S. Wood Street, Chicago| Illinois | 60607 | USA
Phone: +1-312-297-0000; Fax: +1-312-297-1100; 
sniazi3@uic.edu; www.niazi.com

A Meaningful Dialog with a Young Pastor

A Meaningful Dialog with a Young Pastor

 The most joyful moments of my life come when I meet another human who is passionate about whatever there is to be passionate about! When I am spending time in Wisconsin, I run into a young pastor at Starbucks. The pastor owns the Lakewood Baptist Church. He is in his early thirties, an extremely handsome man with a great sense of respect for other human beings; he has adopted four infants of color in his early marriage [he does not have any children of his own, yet; yes, he is white] and extremely articulate in expressing his beliefs. Invariably, I never engage in any discussion on politics or religion, but he tempted me with his great smile. So, we decided to have a written dialog; here is an unedited exchange between a young pastor and an old man [me].

 PASTOR:

 As you know, we all view the world through our lenses; such is our worldview. From my understanding, yours is a rationalistic-scientific lens, which cannot itself be proven to be an accurate lens for all of life’s questions. In other words, one cannot prove the axiom, “everything that we believe must be verified by the scientific method,” because the scientific method itself cannot be used to prove the axiom in question. Science, as you know, has limitations; namely, it is limited to what is observable and repeatable. And so, when it comes to questioning, “how we came into existence,” science is actually the wrong tool because the event(s) of our origination is neither observable nor repeatable. Of course, this is no slight towards science, for the method can answer a great many important questions, just not this one. So, when you say, “To make a scientific discussion…we need a clean slate, to begin with,” I challenge the presupposition that any scientific discussion can have truly begun with a “clean slate.” To invoke a worldview that demands that all claims be verified by the scientific method is not really a clean slate at all, because it rests upon the unproven presupposition that all truth need to verify by a scientific authority (when, again, science itself cannot be used to prove that it is the required intellectual authority). I’m belaboring this point, however… 

 ME:

 One assertion that was made clear is that whether there is anything to know; I agree that once we decide that there is a first cause, then it must have an existence raising the question of what and who. The reason we dwell on a first cause because our brain seeks out the first cause to everything and this is the pivotal reason why we need to invent god or a first cause; what I am saying is that even the desire to know the first cause is based on the faulty brain network that forces us into requiring an answer to our existence. A clean slate means to remove this desire as well, and then establish the need for creating god. It has little to do with science and deals with rationality. Now one can say being rational too is a presumption and again it is this dilemma that makes us vulnerable to accepting a divine existence. Our current stage of evolution is not advanced enough to provide us wisdom to assert that there has to be a starting point to everything. We should always leave science out of the discussion because it is indeed limited by the accuracy and precision of our observation and that is surely not either. So again, a clean slate would mean taking out the human thought to have a starting point—if you say otherwise then you are basing it on a scientific viewpoint that we both agree can only be as perfect as our observations.

Your statement that not being knowable is a characteristic of god presupposes that there is an existence of an unknowable entity, a circular argument.
PASTOR:

 My dear Sarf, further, when you state that “we cannot know, ‘what’ or ‘who’ is this first cause,” you imply the positive assertion that the first cause is unknowable. Ironically, unknowability, then, is an attribute or quality of this first cause — the same first cause that you have already labeled as unknowable. Philosophically, this is a self-contradictory belief — that one can attribute certain qualities to that which is unknowable, without acknowledging that we must know something about that which we speak. Again, your discussion plate is not clean, because your unprovable presupposition is that the first cause is unknowable. 

            My foundational presuppositions are mainly these: (a) God exists, and (b) God has revealed Himself to His creation in a comprehensible manner. These presuppositions have led me to the meaningful evaluation and comparison of religious texts — not to sweeping out-of-hand dismissals that lack nuance, but sadly characterize much religious discussion in our world today. For example, I will not judge the merits of Islam based upon the horrific actions of radical jihadists, nor will I judge the merits of Catholicism based upon the crimes of the Crusaders or the modern priest molestation scandals. I actually reject them both on other bases altogether. 

 ME:

 See the doctrines of belief to determine our behavior; it is intended to distinguish the believers for the same reason the foragers huddled together but broke the ranks when the size of the group increased to about 50-70; religion brought a possibility to expand this group by handing over the authority to an unquestionable ruler; later came empires to do the same and now we live in a “civilized” societies called nations. The motives of the human mind remain the same, and it could not change much in a 100,000 year, to control others—nothing does better than religion. It is a doctrine of politics that sells very well because our thinking comes to a halt once we begin questioning our existence and our future.
ME:

ADDITIONAL COMMENT:

 As a scientist, I am used to taking a structured, step-wise approach to resolving a query, the most fundamental being, “how did we come into existence,” I did not form the question, “who created us,” that would make the question is biased. Over 5 out of 7 billion people living today think (I am not saying belief) that there is a greater power, an omnipotent God out there managing and manipulating the Universe, including our day to day fate and who condescended to reveal Himself in the Bible, as Christians would, in the Quran, as the Muslims would say and in Torah, as Jews would say. Each one making it omniscient to their belief. Now, to make a scientific discussion (not argument), we need to have a clean slate to begin. 

 Because we exist (physically), there must be a precedence to our existence, for we believe that something cannot happen from anything—that is our genetically coded though response. Until about the middle of the last century, this hard connection was stable, but with quantum physics, we have learned that electrons, photons, and muons, and many other fundamental particles do not really exist until they strike another. So, perhaps our hard-wired belief that there must be a precedent is now questioned—but let us leave that discussion on the side, for now. Let us start with a clean slate again. We know we exist, so there must be a first cause. And we cannot know, “what” or “who” is this first cause. Every religion making a claim to a god or God addresses it as if it were a human; in Quran, there are 99 names for Allah, each one of them representing a human trait—and that worked nicely with over a billion people believing in Allah that is God of Muslims, not Christians, not Jews, nor anyone who does not believe in Qur’an. So, if one believes that Qur’an, Bible, or Torah are the books of divinity, indisputable and unquestionably true, then there can be no further discussion of any kind because we do not have our discussion plate clean. 

 I have absolutely no druthers about listening to proof that God needed to create books to communicate with humans. At the same time, I would expect those believing in their faith to be open to hearing an alternate presentation. So here is that presentation. Humans are differentiated from other species by our ability to use a language that creates beliefs; you need a medium to talk to yourself. And when we fail to resolve an observation, like “how we came into existence,” because our brains are not yet evolved to deconstruct this question, we become prey to religion because every religion closes this uncertainty. Religion came into existence and remind an exercise in the political control of fellow human beings. And I have no issue with that until I conclude that much of the hatred across the globe is because of, not despite religion. Indeed, accepting for a moment that “He” is omnipotent, and then examining His impotence leads to contradictions, as Mother Teresa says in her book. Christians talk a lot about "faith." At points in her life, Mother Teresa could no longer believe in God. Does that mean she didn't have faith? Well, she was an ordained sister in the Catholic Church, and she devoted her life to following the teachings of Jesus. Objectively, she was a Christian, no matter what she subjectively believed. She practiced "the faith of the body" as opposed to the "faith of the mind," a concept captured by the proverb "Act as though ye had faith, and faith shall be given to you.”

Biosimilars in the aftermath of COVID-19;

How to establish safety of vaccines using the principles of biosimilarity

An Open Letter to Hon. Justice Amy C. Barrett

September 26, 2020

Hon. Judge Amy C. Barrett
Robert K. Rodibaugh United States Court House
401 S. Michigan Street
South Bend, IN 46601-230
Dear Judge Barrett:

Congratulations on your nomination to the Supreme Court. Consider yourself the luckiest person; you will soon have an opportunity to serve the country you love and the Constitution you adore, as you said in your acceptance speech.

You have repeatedly stated that your personal beliefs do not enter your judgment making, and I believe it because you are a person of faith, a firm believer in whatever is your belief. You have a character. However, it is difficult to walk a delicate path when it comes to interpreting the law. You are first an English major and then a lawyer. Everything is written can be reinterpreted if it had been establishing a while ago; the intents do not change; their practice to apply changes frequently. An excellent example that you had offered is how sex discrimination will have to be interpreted today in trans-genders’ age. Laws may become obsolete with time. While this is the legislators’ job to keep the legislation updated, it does not happen as efficiently as it should, leaving the interpretation in the hands of the courts. If the Bible says, “Thou shall not…” there is never an interpretation required, but in the seat you will occupy, you will find that “shall” and “will” can be interpreted differently, as it happened in the Sandoz Inc v. Amgen Inc. case [No. 15–1039. Argued April 26, 2017—Decided June 12, 2017].

More problematic is decision-making that can have an enormous impact on the life of Americans. The Affordable Healthcare Act was voted in by the House, the Senate, and signed by the President. Did the three entities act following the Constitutional limits? The lawmakers, whoever they were, decided so. Now the ACA is coming to the Supreme Court for a challenge. I need not tell you how it will decimate the lives of millions of Americans. Even with the ACA, one of the worst countries to support its citizens for their ultimate healthcare needs. Taking down the ACA will have many more impacts, such as removing the BPCIA. This act created generic forms of biological drugs that save several trillion dollars and make expensive medicines accessible to all. So, when the ACA comes up for a judgment, it is not just an interpretation of the Constitution, capable of doing. Still, the Constitution does not teach you how to interpret its nuances—and it must be a nuance; otherwise, the lawmakers would not have voted it in. The filing to remove the ACA does not offer an alternative that must be required to consider repealing the ACA. A lot will depend on how you show that you love America for decades; you have the ultimate destiny for any human being—to able to serve. Now begins the hard part. Assure me that you will not politicize your opinions just as you have promised not to let your religious beliefs affect your decision. Good luck!

Most sincerely,

Sarfaraz K. Niazi, Ph.D., SI, FRSB, FPAMS, FACB
Adjunct Professor of Pharmaceutical Sciences
College of Pharmacy, University of Illinois
833 S. Wood Street. Chicago, IL 60612. USA
Ph: +1-312-297-1100; Email: sniazi3@uic.edu
www.niazi.com

RESPONSE FROM THE FDA ON MY LETTER TO DR STEPHEN HAHN ON COVID-19 ISSUE

RESPONSE FROM THE FDA ON MY LETTER TO DR STEPHEN HAHN

RECEIVED 23 SEPTEMBER 2020 

 CBER OCOD Consumer Account <cberocod@fda.hhs.gov>

2:21 PM (6 hours ago)

to sniazi3@uic.edu

Dear Dr. Sarfaraz:

Thank you for your recent email to Dr. Stephen Hahn, Commissioner of Food and Drugs, concerning the development of vaccines to prevent coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2. We appreciate your interest in this important topic.

 The FDA recognizes the urgent need to develop vaccines to prevent COVID-19, and we are working collaboratively with industry, federal, domestic, and international partners to accelerate this work. We are committed to working with these partners to efficiently advance the development of safe and effective vaccines intended to prevent COVID-19. The nature of a particular candidate vaccine and its intended use may impact the specific data required to advance the development and licensure of that vaccine. Please note that the goal of these development programs is to demonstrate safety and effectiveness of a vaccine for the prevention of COVID-19. We are committed to working with these partners to efficiently advance the development of safe and effective vaccines for COVID-19. We also recognize that transparency around the FDA’s review, evaluation and decision-making with respect to COVID-19 vaccines is likely to impact public confidence in these vaccines and we are committed to being as transparent as possible throughout the process.

When making decisions about Emergency Use Authorization (EUA) or licensure of COVID-19 vaccines, we will apply the relevant statutory and regulatory requirements in the Federal Food, Drug, and Cosmetic Act and the Public Health Service (PHS) Act. FDA staff involved in the evaluation of vaccines are highly qualified scientists and physicians who are knowledgeable about the complexity of vaccine development. The same FDA scientists and physicians who routinely advise sponsors on vaccine development programs, manufacturing considerations, and assessment of safety and effectiveness of all vaccines are the experts who are focused on the work related to COVID-19 vaccine development.

As with all vaccines, the FDA requires that vaccine developers provide sufficient data to the FDA to evaluate the safety and effectiveness of the vaccine for its intended use and population. The FDA is working with vaccine developers to help ensure that ongoing and planned clinical trials will provide sufficient data to support approval of safe and effective COVID-19 vaccines in the United States.

We understand that there may be a perception that typical vaccine development steps are being skipped, but please know that FDA scientists will not allow corners to be cut in the fundamental steps required for vaccine development. In addition, the FDA will thoroughly evaluate the data submitted in support of a vaccine candidate’s safety and effectiveness and will only authorize or approve a vaccine for the prevention of SARS-CoV-2 infection and/or COVID-19 if the vaccine meets the Agency’s statutory and regulatory standards.

 After issuance of an EUA or approval of a BLA for a COVID-19 vaccine by the FDA, FDA will continue to closely monitor the safety of COVID-19 vaccines various existing surveillance systems and, when appropriate, require the manufacturer to conduct post-marketing studies to further assess known or potential serious risks.

 The FDA’s guidance entitled, Development and Licensure of Vaccines to Prevent COVID-19, addresses considerations regarding EUA of an investigational vaccine – and makes clear that an assessment regarding using any potential EUA for a COVID-19 vaccine would be made on a case-by-case basis considering the target population and the totality of the relevant, available scientific evidence, including preclinical and human clinical study data of the product.

 The guidance reflects the recommendations and advice the FDA has been providing over the past months to companies, researchers and others, and describes the Agency’s current recommendations regarding the data needed to facilitate the manufacturing, nonclinical and clinical development, and approval of COVID-19 vaccines.

 Additionally, the guidance provides an overview of key considerations to help manufacturers satisfy requirements for chemistry, manufacturing and controls, and nonclinical and clinical data needed for development and licensure and for post-licensure safety evaluation of vaccines. The guidance explains that, given our current understanding of SARS-CoV-2 immunology, the goal of development programs at this time should be to support traditional FDA approval by conducting studies to directly evaluate the ability of the vaccine to protect humans from SARS-CoV-2 infection and/or disease.

 The guidance document provides transparency about the FDA’s current thinking about the scientific data needed to support approval of safe and effective COVID-19 vaccines. As part of these efforts to communicate about our expectations, we recently updated our guidance agenda to include an upcoming guidance on EUAs for vaccines to prevent COVID-19.  The new guidance will expand on our June guidance, and is intended to provide sponsors of requests for EUAs with recommendations regarding the scientific data and information necessary to support issuance of an EUA.

 Also, on October 22, 2020, the FDA will convene its Vaccines and Related Biological Products Advisory Committee (VRBPAC), a panel of outside, independent, technical experts from various scientific and public health disciplines that provide input on scientific data and its public health significance in a public forum. The VRBPAC will meet in open session, to discuss, in general, the development, authorization and/or licensure of vaccines to prevent COVID-19. No specific application will be discussed at this meeting.  This advisory committee for the FDA is the appropriate advisory committee to obtain input on scientific issues related to the development of vaccines to prevent SARS-CoV-2 infection and/or COVID-19. Given the widespread potential use of these vaccines, transparent discussion at VRBPAC will help ensure clear public understanding of the evidence supporting vaccine safety and effectiveness. While the October 22nd meeting is not intended to discuss any particular vaccine candidates, the agency is also prepared to schedule additional meetings of the Committee promptly following submission of a request for an EUA or BLA for a COVID-19 vaccine to further ensure transparency.

 Further details on this meeting are available on the FDA’s website at https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-october-22-2020-meeting-announcement.

 We will continue to explore additional mechanisms to be as transparent as possible about our decision-making and general thinking regarding vaccines to prevent SARS-CoV-2 infection and/or COVID-19 disease.

 We sincerely appreciate your concerns and interest in this topic, as well as the opportunity to provide this information to you.

 Sincerely,

  Hope Anderson

Health Communications Specialist

Center for Biologics Evaluation and Research

Office of Communication, Outreach and Development

U.S. Food and Drug Administration

Tel: 240-402-8010

OCOD@fda.hhs.gov

Biosimilars: No Rationale for Clinical Efficacy Testing

Biosimilars: No Rationale for Clinical Efficacy Testing

Sarfaraz K. Niazi, Ph.D., Adjunct Professor, Pharmaceutical Sciences, the University of Illinois, and the University of Houston.  Patent Law Practitioner, US Patent, and Trademark Office.

niazi@niazi.com; www.niazi.com

The US FDA got its charter to approve biosimilar biologics in 2009,[i] once the patents expire on new biological drugs; the goal of this charter for the FDA is to expedite the entry of biosimilars to increase accessibility: availability and affordability. The FDA has issued ten regulatory guidance documents[ii], and it redrafted[iii] one pivotal guidance on analytical testing after the author pointed out inconsistencies in the original guideline.[iv]

As of July 2020, the FDA has approved 27 biosimilar products, comprising 19 monoclonal antibodies, seven cytokines, and one fusion protein since the first biosimilar was approved in 2005. Data for one cytokine has not been reported by the FDA yet. The regulatory submissions that lead to these approvals provide a keen insight into how the developers are approaching the development and how the FDA is assessing the submitted data.  There are four key studies pivotal to the approval of biosimilars comprising analytical assessment, nonclinical pharmacology, clinical pharmacology, and clinical efficacy. The 26 approved products submitted over 1100 analytical similarity, 96 animal pharmacology, 42 in vitro/ex vitro pharmacology, 52 clinical pharmacology, and 32 clinical efficacy studies.  There was no consistency in the number of studies submitted for the same molecule; five adalimumab biosimilars submitted 31-105 studies; five trastuzumab biosimilars submitted 48-111 studies, and four infliximab biosimilars presented 48-80 studies. Dozens of animal toxicology studies were rejected by the FDA as being irrelevant. However, none of the accepted animal toxicology studies failed. All PK/PD studies also passed, a few requiring repeat testing due to the choice of wrong population acceptance criterion. 

A few clinical pharmacology studies had to be repeated to meet acceptance criteria due to inappropriate choice of the study designs. Finally, no clinical efficacy study failed, and two products were approved without clinical efficacy testing.

Biosimilarity is a judgment made by the regulatory agencies for a product that has a “clinically meaningful difference” with its reference product. There are several fundamental arguments against the use of clinical efficacy testing to establish biosimilarity. The FDA requires stepwise testing wherein the development reaches the clinical efficacy testing only after confirming analytical similarity, animal toxicology, and clinical pharmacology assessment. And even then, the FDA must identify a “residual uncertainty,” before extensive clinical efficacy testing is suggested. Since all except two products conducted clinical efficacy testing, it was not made clear by the FDA what was the “residual uncertainty?” Were these studies conducted voluntarily by the developers to support their marketing program, or they were required by the FDA remains uncertain. However, if we can establish that these studies are not necessary, then conducting these studies will be considered unethical for a variety of reasons.

One strong argument against conducting clinical efficacy testing comes from the experimental design that is mostly a noninferiority testing requiring that the developer establish a range of differences between the biosimilar and the reference product as clinically acceptable. While the proponents of clinical efficacy argue that this acceptance criterion can be established on clinical judgment, the choice, nevertheless, remains arbitrary. The proof of this arbitrariness comes from the analysis of studies conducted on the same molecule with a highly variably acceptance criterion. The mode of action of biological drugs often leads to a broad dose-response relationship confounding any real difference. The assessment of clinical efficacy is straightforward in the case of a new drug, where a placebo control quickly establishes efficacy vis-à-vis the observed side effects.

Further compounding the lack of utility of clinical efficacy comes from the current practice of testing a product in just one of several indications, leaving doubt, if the efficacy can be extrapolated among the indications. However, the FDA allows extrapolation of all indications, even if the testing is conducted in just one indication. Does this allowance leave much to doubt about the safety and efficacy of a biosimilar? However, requiring testing in all indications will defeat the purpose of the pathway to approve biosimilars leading to cost that may even be higher than developing a new drug.

The validity of clinical efficacy testing can be challenged on a logical ground as well. So far, none of the efficacy testings failed provided the biosimilar product met all other stepwise similarity testings. Was it because all products were biosimilar, or the efficacy testing was not sensitive enough to identify differences? A more pressing concern arises if the FDA accepts the results of efficacy testing to overcome the lack of similarity in analytical, nonclinical, and clinical pharmacology assessment. Given that there will never be data available to judge relative safety and efficacy, the risk of approving products that are not biosimilar gets higher.  One factor that adds significant variability to clinical data is the selection criterion of the study population. In the case of oncology antibody testing, it is almost impossible to find naïve subjects or patients with similar prior treatment; additionally, the clinical markers cannot be established given the peculiarity of the disease for each patient. All of these observations establish a premise that it is not possible to create a testing plan that can be reasonably rational.

In the case of monoclonal antibodies, the mechanism of action is generally known, allowing the 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 naïve patient population or even a sufficiently large number of population and the high variability of response; do these studies bring added confidence to the safety and efficacy of the biosimilar product?

Responsible regulatory guidance should require minimal testing needed to assess the safety and efficacy of a product, and if clinical efficacy testing is not useful, these studies should be discouraged and not just added as supplementary proof. The same holds true for animal toxicology testing that is ruthlessly conducted by developers even when it makes little sense, like testing a monoclonal antibody in a rodent species that does not have receptors and cannot show a toxic response—it is required when a new molecule is developed, but it must be discouraged in the testing of biosimilars. Even when developers use animal toxicology to justify any difference in the analytical assessment, there can never be an assurance of the safety testing in animals because these studies never fail because they are conducted at the higher end of the efficacy-toxicity curve to induce a toxic response. As evidenced by the data submitted by the developers, none of the studies failed. It is almost comical that the antibodies approved in India are tested in rodents only because testing in monkeys (who have the receptors) is against the religious practice. 

Better use of animal testing comes in comparing PK profile (PD may be added if relevant but not likely) to establish structural similarity, as recommended by the FDA, and these studies can be conducted in a small number of animals, not establish any statistical equivalence but an overall profile comparison.

The FDA continues to discourage irrelevant and unnecessary studies, as demonstrated by a recent guideline on the testing of insulin products where immunogenicity testing was removed as a requirement if all other similarity criteria were met. The FDA responded to my petition and made the change that will go a long way in supporting faster approval of insulin products.[v] The justification for this waiver comes from the understanding that differences in immunogenicity do not affect the PK/PD profile.

The basis of removing clinical efficacy testing comes from a robust analytical assessment first. However, this reliance must be strengthened by focusing on testing that is more discriminatory rather than filing hundreds of tests that may not be relevant. A good example is the statistical acceptance criteria of the critical quality attributes that were recently revised by the FDA in response to my petition.[vi] This scientific thesis should limit analytical similarity testing to primary, secondary, and tertiary structure testing and other safety-related attributes and remove the testing of critical quality attributes included in the release specification that determines what is safe and effective for a patient.

Further support for obviating clinical efficacy testing comes from the robustness of PK/PD studies, and as a matter of record, no product was approved by the FDA that did not show high similarity at the PK/PD stage; however, there is a need to analyze data more relevant adding more PK parameters like the distribution volume and rate of its change as an indicator of receptor binding, to make these studies more discriminatory.

We have come a long way over the past 15 years of evaluating the safety of biosimilars in Europe and US; we have better confidence in declaring that a biosimilar product has “no clinically meaningful difference” with the reference product, and now we have to make the approval guidance rational without compromising the safety of the product. 

My proposal for rationalizing the testing of efficacy came in 2019[vii]  , and the majority of the biosimilar industry agreed with me[viii] in a publication a few months after my analysis, while failing to point out the scientific rationale. I this article, I am bridging the gap but describing in clear words how we can make biosimilars more accessible by reducing or eliminating all studies that are not relevant, whether these are analytical similarity, animal pharmacology and toxicology, clinical pharmacology and more particularly the clinical efficacy testing.

The FDA has always promoted science as it was made evident in the Biosimilars Action Plan that was revealed by the FDA after I filed a petition against the FDA to make the guidelines rational.[ix] The FDA and EMA are open to suggestions from the developers but unfortunately, the developers, who have all been the big pharma, have failed to understand that biosimilars are not new biologics and since most of them have been involved in the development of new drugs, their mindset remains fixed to more studies than necessary. I have said it repeatedly that it takes more science to develop a safe biosimilar than it takes to develop a new biological drug. It should also take less investment if we are to see the biosimilars deliver the promise they were supposed to—more available drugs.

[i] https://www.fda.gov/media/78946/download

[ii] https://www.fda.gov/vaccines-blood-biologics/general-biologics-guidances/biosimilars-guidances

[iii] https://www.biospace.com/article/fda-withdraws-draft-guidance-on-biosimilar-development/

[iv] 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

[v] https://www.biosimilardevelopment.com/doc/fda-allows-waiver-of-clinical-trials-for-insulin-biosimilars-niazi-citizen-petition-0001

[vi] 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

[vii] https://www.biosimilardevelopment.com/doc/biosimilars-lessons-learned-from-regulatory-approvals-0001

[viii] https://link.springer.com/article/10.1007/s40259-020-00422-1

[ix] https://www.forbes.com/sites/nicolefisher/2018/07/25/one-mans-mission-to-fix-the-fdas-biosimilar-problem/#1951b1922380

A Critical Analysis of the Final Guidance on Demonstrating Interchangeability of a Biosimilar With Its Reference Product

A Critical Analysis of the Final Guidance on Demonstrating Interchangeability of a Biosimilar With Its Reference Product

Sarfaraz K. Niazi, PhD

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.

May 21, 2019

Introduction

The FDA has issued its final guidance 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 guidance.

There were 53 comments posted by the deadline of March 20, 2017, and these came from diversified sources, including a private consumer who suggested that the Affordable Care Act not be repealed to a physician suggesting the use of suffix to biosimilars, to organizations 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 emphasized the role of human factor studies and need for new regulations to provide comparison; Johnson & Johnson opposed extrapolation and recommended that testing be done in each condition, and that the labeling of biosimilar products declare when they are not interchangeable. Apotex sought clarification on the meaning of immunogenicity and if a product is given at 2 doses; would it mean 2 separate studies? The Biosimilars Council questioned whether studies will be required in conditions that are not claimed or how extrapolation will be allowed; AbbVie and other reference product companies disagreed 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 publications that pointed out the shortcomings of the FDA guidance in establishing biosimilarity and interchangeability. There were 2 citizen petitions and several testimonies 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.

Overarching View

Essential Definition

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 use of “differences in the expected” in the above description creates a dilemma for the sponsors: there is no such expectation, since the sponsor knows that the product is a biosimilar and therefore presents "no clinically meaningful difference" from the reference product in a situation in which the sponsor is filing for a change of status to the interchangeable product.

Even in those situations in which the sponsor is making its first filing and anticipates receiving an interchangeable status, there are no expectations of differences, and none can be scientifically anticipated. A more appropriate language would be "any clinically meaningful observed differences." I am suggesting that the sponsor make this assumption regarding the expectations of the FDA.

It is noteworthy that the FDA has recognized biodistribution in PK studies as a critical parameter; I had provided details of the clinical importance of the distribution volume parameter during a testimony given to the FDA recently. More details on this subject are provided in the section on Advice to the FDA, below.

Statutory Language

The BPCIA states that an interchangeable product “can be expected to produce the same clinical result as the reference product in any given patient,” and this statutory language forms the basis of an allowance made in the final guidance. The statement, which cannot be modified by the FDA, can be construed to state that a biosimilar interchangeable product is “capable of demonstrating the same clinical result as the reference product in any patient”; the description of the test subject as “any patient” may also mean “not necessarily the patient treated for a disease for which the product has been approved.”

As a result, sponsors may use a patient population that is different from that used to support licensure of the reference product, or in healthy subjects, provided the sponsor also gives adequate scientific justification to support the fact that the study population is adequately sensitive to detect the impact of switching (eg, differences in clinical PK and/or PD, common adverse events [AEs], and immunogenicity). The use of healthy subjects may cause a lifetime autoimmune response—a risk to be evaluated and agreed upon by the FDA.

Pathways

The final guidance allows several pathways, and studies associated with each pathway, to secure an interchangeable status for a biological product.

Stepwise Approach

The FDA has long advised sponsors first to secure approval as a biosimilar product and then follow it up with a change of status to interchangeable; the final guidance details how the data submitted for approval as a biosimilar product will be referred to in an interchangeable application, what additional data will be required pertaining to the studies that were required for approval as a biosimilar, and how additional structural similarity testing and safety assessments can be used to support interchangeability.

1-Step Filing

The FDA will allow a sponsor to file its first application as an interchangeable application where a single clinical study may fulfil the primary requirement of biosimilarity and the secondary qualification as an interchangeable product.

Focus on Immunogenicity

Clinical experience with the reference product and comprehensive product risk assessments (eg, regarding immunogenicity) may also affect the data and information needed to support a demonstration of interchangeability. For example, products with a documented history of inducing detrimental immune responses may require more data to support a demonstration of interchangeability than products with an extensively documented history showing that immunogenicity does not impact clinical outcomes.

Totality of Evidence

Less Complex Molecules

Some products have relatively low structural complexity, and their reference products have no history of inducing severe immune responses related to immunogenicity. For biosimilar products that have demonstrated a low incidence of serious AEs related to immunogenicity, similar in nature and frequency to those observed with the reference product as demonstrated in clinical studies, sufficiently extensive comparative analytical data and data derived from an appropriately designed dedicated switching or integrated study will be sufficient to support a demonstration of interchangeability.

More Complex Molecules

For more complex products that may have a history of rare, life-threatening AEs related to immunogenicity, postmarketing data for the product as a licensed biosimilar, in addition to an appropriately designed switching study, may be required to support a demonstration of interchangeability.

Postmarketing safety monitoring for an interchangeable product should also have adequate pharmacovigilance mechanisms in place. Generally, postmarketing data collected from products first licensed and marketed biosimilars, without corresponding data derived from an appropriately designed, prospective, controlled switching study or studies, would not be sufficient to support a demonstration of interchangeability.

However, in certain circumstances, postmarketing data from a licensed biosimilar product may be helpful as a factor when considering what data are necessary to support a demonstration of interchangeability. For example, some sponsors may wish to submit postmarketing data describing the real-world use of the biosimilar product, including certain safety data related to patient experience with some switching scenarios.

Such data may reduce uncertainty about interchangeability and thus the data needed to support a demonstration of interchangeability. The FDA will evaluate proposals to include postmarketing data in applications to support demonstrations of interchangeability on a case-by-case basis. This scenario will apply to a licensed biosimilar product where the sponsor later files for interchangeable status.

Switching Studies

A switching study is supposed to establish whether switching results in differences in immunogenicity and PK and/or PD (if available), as compared to not switching, as the primary end point. An application will otherwise be rejected.

A switching study may also incorporate the evaluation of efficacy end points as a secondary end point or as supportive data, as the FDA concludes that clinical efficacy end points would generally be less sensitive to detect changes in exposure and/or activity that may arise as a result of alternating or switching.

The clinical PK, PD, and immunogenicity assays must be developed and validated early in product development, and must show capability of detecting changes on the selected PK and/or PD end point or end points as a result of alternating or switching between products.

The validation study should demonstrate that the assay performs similarly for both the proposed interchangeable product and for the reference product. There may be situations in which the assays may be suitable for demonstrating biosimilarity but not interchangeability; sponsors are encouraged to seek FDA advice early in the program.

Dedicated Study

A study with a lead-in period of treatment with the reference product, followed by a randomized 2-arm period—with 1 arm incorporating switching between the proposed interchangeable product and the reference product (the switching arm) and the other receiving only the reference product (the nonswitching arm)—may be appropriate when designing a switching study.

The sample size of the switching study should generally be based on PK considerations. Inter-subject variability in AUCtau or Cmax as described for the reference product should be primary considerations, and prior information on product immunogenicity incidence and consequences should also be considered to justify the sample size. Study designers should anticipate the possibility of a considerable dropout rate for reasons unrelated to the study treatment.

The number and duration of switches between the reference product and the proposed interchangeable product should take into consideration the clinical condition to be treated, the therapeutic dosing of the product, and the duration of the exposure period to each product that would be expected to cause the greatest concern in terms of immune response and a resulting impact on safety and efficacy, if any.

To capture the full PK profile, intensive PK sampling should be performed during the final exposure period after at least 3 half-lives have elapsed following the last administration of the reference product in the switching arm.

Trough PK sampling should be conducted at an appropriate time point during each exposure period to ensure that a steady state is attained, when appropriate. The timing of PD and immunogenicity sampling should be appropriately justified.

For intravenous (IV) studies, AUCtau will be considered a primary study endpoint. For subcutaneous (SC) studies, Cmax and AUCtau will be considered as co-primary study endpoints. The statistical modeling follows bioequivalence testing, and for PD parameters, the sponsor will propose margins and statistical analyses.

Integrated Studies

For studies that have an integrated design that proposes to demonstrate biosimilarity and interchangeability at the same time, a 2-part design may be warranted. Following time points for the evaluation of biosimilarity, subjects in the reference arm may be randomized in the second part of the study to a nonswitching arm or a switching arm. Such a study would need to be powered to the appropriate endpoints, including PD and PK.

The population for these studies should be adequately sensitive to detect differences (and should be part of a licensed condition of use), and the patient population may be different from the one used to support licensure of the reference. If using healthy volunteers, sponsors should weigh the benefit and risks of exposing individuals to the product.

General Considerations

Population

The population for switching studies should be adequately sensitive to allow for the detection of differences as a result of switching between the reference product and proposed interchangeable product in terms of PK and/or PD, common AEs, and immunogenicity between the switching and nonswitching arms.

Patients

Sponsors should use patients in switching studies because these studies are designed to assess the impact of switching as it may be observed in clinical practice. For treatments that have a long course of therapy, sponsors should anticipate dropouts in the study and should use a scientifically justifiable method to address the increased possibility of missing data.

Alternate Population

Sponsors may also use a patient population that is different from the one used to support the licensure of the reference product, or in healthy subjects, provided the sponsors should also provide adequate scientific justification to support the fact that the study population is adequately sensitive to detect the impact of switching (eg, differences in clinical PK and/or PD, common AEs, and immunogenicity). The use of healthy subjects may cause a lifetime autoimmune response—a risk to be evaluated and agreed upon by the FDA.

Route of Administration 

A sponsor should select a route of administration that is more likely to challenge the patient's immune response, such as subcutaneous over intravenous, where such choices are available.

Non-US Comparator

A “bridge” between the non–US-licensed comparator and the US-licensed reference product is required, similar to the requirement for biosimilarity testing, with more extensive testing. The comparator product (whether it is a non–US-licensed product or a US-licensed reference product) serves as a control against which the proposed product is evaluated. However, in a switching study, the comparator product plays a different role, as a control in both the active switching arm and the control nonswitching arm.

For example, it is possible that the reference product and the non–US-licensed comparator product have subtle differences in levels of specific structural features (eg, acidic variants or deamidations), process-related impurities, or formulation. However, in the context of switching between the products, multiple exposures to each product may potentially prime the immune system to recognize subtle differences in structural features between products. The overall immune response could be increased under these conditions. This immunologic response is highly dependent on the structural differences between the proposed interchangeable product and the comparator product used in the switching study, in addition to other potential differences between the products, such as impurities or formulation.

The FDA does give sponsors an opportunity to present a scientific argument to allow the use of a non–US-licensed comparator. In most cases, the non–US-licensed comparator may have been registered using essentially the same dossier as the US-licensed product, reducing the requirements of extensive testing; whether animal toxicology or other studies are required, besides analytical similarity, is a point for discussion in early development stages.

End Points

Primary end points will be PK/PD and distribution parameters, and secondary end points will be safety, immunogenicity, and efficacy assessed descriptively.

Regarding safety, it could be reasonable for a sponsor to focus on an evaluation of all serious AEs, immune-related safety events, and AEs of interest (eg, known cardinal adverse events previously described with the use of the reference product).

The immunogenicity assessment should include, but should not necessarily be limited to, an assessment of antidrug antibody (ADA) and neutralizing antibody (NAb) incidence, ADA and NAb titers, and an evaluation of the impact of the development of ADAs and NAbs on PK, PD, safety, and efficacy. Immunogenicity assays should be adequately sensitive to detect ADAs and NAbs in the presence of drug concentrations in study samples. Sponsors should discuss with the FDA their planned evaluation of safety and immunogenicity.

Structural Complexity

The product’s degree of structural and functional complexity may influence the extent of clinical data needed to support a demonstration of interchangeability. For example, clinical data needed to support a demonstration of interchangeability of a product expected to have a single target (eg, a receptor) may be more limited than the clinical data that may be needed for a product acting on multiple targets or on less-defined biological pathways.

In addition, the extent of clinical data needed may be affected by the presence of structural features that specifically impact interchangeability (eg, features that influence patient response to one product after exposure to another product).

Data sets that include highly sensitive analytics and/or sequential analytical methods that can identify molecules with different combinations of attributes (eg, charge variants and glycoforms), as well as a comprehensive assessment of the relationships between attributes, may provide information that reduces the uncertainty about interchangeability.

These approaches could be of greater importance for more complex products because these products would have a larger number of attributes and thus a potential for greater uncertainty regarding interchangeability. Advances in analytics may allow for extended analytical characterization that affects the extent of other data and information needed to support a demonstration of interchangeability, and may in certain circumstances lead to a more selective and targeted approach to clinical studies intended to support a demonstration of interchangeability.

Switching Study Waivers

If a sponsor of a proposed interchangeable product believes that data from a switching study is not necessary, the FDA expects the sponsor to provide a justification for not needing such data as a part of the demonstration. For biological products that are not intended to be administered to an individual more than once, the FDA expects that switching studies would generally not be needed. For products intended to be administered more than once, sponsors are encouraged to meet with the FDA to discuss the planned development approach, including any proposed justification of why data from a switching study is not needed.

Extrapolation of Indications

While a sponsor may seek licensure for a proposed interchangeable product for fewer than all conditions of use for which the reference product is licensed, the FDA recommends that a sponsor seek licensure for all of the reference product’s licensed conditions of use when possible.

This statement should not be misconstrued as the FDA recommending switching studies in all indications, as demanded in several comments provided to the FDA by the reference product suppliers concerning the draft guidance.

A sponsor may conduct a study or studies in 1 or more indications and then create an argument to allow extrapolation of indications—the burden of proving that the extrapolation will not result in “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.” This exercise is no different from the request for extrapolation made in the development of biosimilars.

However, the nature of this submission will likely be different from what is expected when a sponsor requests extrapolation of a biosimilar product:

• A sponsor may obtain licensure only for a condition or conditions of use for which the reference product is licensed.
• A sponsor should choose a condition of use to study that would support subsequent extrapolation of data to other conditions of use.
• A sponsor should use a condition of use that would be adequately sensitive to assess the risk of alternating or switching between the products, in terms of safety or diminished efficacy, in a switching study.
• A sponsor may not choose an indication that was approved under section 506(c) of the Federal Food, Drug, and Cosmetic Act and 21 CFR part 601, subpart E (accelerated approval) if the anticipated clinical benefit in that indication has not yet been verified in postmarketing studies.
• Advanced structural and functional characterization may provide additional support for the justification for extrapolation.

Recommendations to the FDA

Sponsors are well aware that the FDA guidelines are not binding to the FDA, but they often do not fully realize that they, too, are not bound by this guidance; in this final guidance, the FDA has taken a major step in stating that a sponsor may present alternate protocols and studies, provided guidance on staging the development from biosimilar to interchangeable, clarified the status of simpler and safer molecules, and provided an experimental design for a dedicated switching study.

The FDA has also stated that efficacy studies are not a good predictor of interchangeability, and therefore, by extrapolation, of biosimilarity, as stated in the guidance: “Although assessments of efficacy endpoints can be supportive, at therapeutic doses many clinical efficacy endpoints would generally be less sensitive to detect changes in exposure and/or activity that may arise as a result of alternating or switching,” leaving the focus mainly on PK/PD studies, even allowing the use of healthy subjects. Such scientifically sound and practical approaches should allow more sponsors to pursue interchangeable products, either in a series of approvals or as the first approval.

However, there remain several key elements that have not been made clear, and these include:

• A non-US comparator that has been approved using essentially the same dossier as the US-licensed product and that meets all other requirements of BPCIA should be allowed without any additional testing, except for release, using the specification applied to the biosimilar candidate.

• For products administered intravenously, the FDA now states that only the AUC should be used as the comparative parameter, yet continues to require the statistical modeling applied to bioequivalence testing—a scientific glitch, since products given by intravenous routes are, by definition, bioequivalent. The only reason the AUC might vary is because of differences in the elimination rate constant and in the distribution volume. By using the AUC alone, the impact of receptor binding (distribution volume) and elimination rate constant (how the body sees the molecular structure) are heavily confounded. It will be a rare event if these studies ever fail, let alone fail in a situation where subtle differences in the PK parameters are sought. The use of individual parameters has been widely established, and this change will also remove the need for the statistical model for bioequivalence testing. The end result of this change will be a more robust model, with fewer subjects and data that are more clinically meaningful. I presented the concept of distribution volume in 1976, and the concept has been used widely to evaluate the safety and efficacy of drugs, more particularly the drugs that bind to receptors.1-3

• While the FDA has allowed sponsors to discuss the study protocols required for drugs that are not administered as repeated doses, it would have been more appropriate if the FDA were to define the available options. In my opinion, this is a simpler question; since a biosimilar product comes with an assurance that it has "no clinically meaningful difference" from the reference product, simpler side-by-side multiple dose PK studies should suffice to establish interchangeability.

Summary

The final guidance on interchangeability resolves some issues, creates many new issues and inquiries, and offers a path—albeit not a clear one—that is filled with scientific and clinical challenges. While the FDA has opened that path for the sponsors to offer alternate study designs to satisfy the requirements to meet the safety and efficacy standards set forth in the BPCIA, the FDA also opens up many possibilities for the sponsors to realize the complexities and the costs involved in seeking an interchangeable status.

References
1. Niazi S. Volume of distribution as a function of time. J Pharm Sci. 1976;65(3):452-4. doi: 10.1002/jps.2600650339.
2. Niazi S. Volume of distribution and tissue level errors in instantaneous intravenous input assumptions. J Pharm Sci. 1976;65(10):1541-1543. doi: 10.1002/jps.2600651034.
3. Wesolowski CA, Wesolowski MJ, Babyn PS, Wanasundara SN. Time varying apparent volume of distribution and drug half-lives following intravenous bolus injections. PLoS One. 2016;11(7):e058798. doi: 10.1371/journal.pone.0158798.

A Critical Analysis of the FDA Guidance on Clinical Immunogenicity Testing of Insulin

The FDA has now agreed with my suggestion to remove the requirements of clinical testing where it does not definitively add any value.

Sarfaraz K. Niazi, PhD

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.

November 27, 2019

The Section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009 (BPCIA) requires that on March 23, 2020, an approved application for a biological product under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355) will be deemed to be a license for the biological product under section 351 of the PHS Act (42 U.S.C. 262).

In anticipation of the licensing of insulin products under the BPCIA in 2020, the FDA has recently issued draft guidance on the clinical immunogenicity testing as part of the biosimilarity determination for biosimilars. To be licensed as a biosimilar, an application submitted under section 351(k) must contain, among other things, information demonstrating that the biological product is biosimilar to a reference product based upon data derived from analytical studies demonstrating that the proposed biosimilar is highly similar to the reference product, animal studies, and a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics); the FDA has the discretion to determine that an element described in section 351(k)(2)(A)(i)(I) is unnecessary.

The FDA has concluded that, because insulins are relatively smaller-sized biologics that are structurally uncomplicated and have few post-translational modifications, they can be well-characterized analytically to leave little residual uncertainty regarding the risk of clinical impact from immunogenicity.

The FDA further states that there is minimal or no clinical relevance of immunogenicity with insulin product use. The FDA determination comes from:

• Recommendations from the European Medicines Agency, which published a revised guideline in 2015 that no longer recommends a clinical immunogenicity study to support a biosimilar marketing application

• Decades of insulin products’ listings in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”) with little concern for any meaningful clinical impact of immunogenicity on the safety or efficacy of insulin product use

• Decades of clinical experience with approved insulin products, including the lack of a correlation between immunogenicity and safety or effectiveness as reflected in approved product labeling for insulin products, and published literature indicating a poor correlation between immunogenicity in insulin-treated patients and clinical impact on safety and efficacy

• Public comments received by the FDA in response to the May 2019 public meeting, “The Future of Insulin Biosimilars: Increasing Access and Facilitating the Efficient Development of Biosimilar and Interchangeable Insulin Products”

• Better purification methods developed over time that have reduced the concerns about the risk of clinical immunogenicity

Based on the premise presented above, the FDA determined that the current analytical tools used to evaluate quality attributes for insulin products can support a comprehensive analytical comparison that leaves little residual uncertainty regarding immunogenicity and that has minimal or no risk of clinical impact from immunogenicity. In such cases, a comparative clinical immunogenicity study would generally not be necessary to support the licensure of a proposed biosimilar or interchangeable product.

The FDA now recommends that, to secure licensing under the 351(k), the developers will need to provide:

• Adequate chemistry, manufacturing, and control information to fulfill product quality-related requirements described in 21 Code of Federal Regulations 601.2, including a validated manufacturing process, and to support an inspection of the facility that is the subject of the application (ie, a facility in which the proposed biological product is manufactured, processed, packed, or held)

• A comprehensive and robust comparative analytical assessment between the proposed insulin product and the proposed reference product demonstrating that the proposed insulin product is “highly similar” to the reference product

• A comparative clinical pharmacology study between the proposed insulin product and the reference product that provides a time-concentration profile and a time-action profile over the duration of action of each product based on reliable measures of systemic exposure and glucose response (eg, glucose infusion rate), using a euglycemic clamp procedure or another appropriate test

• An immunogenicity assessment justifying why a comparative clinical study to assess immunogenicity is not necessary to support a demonstration of biosimilarity; this justification may reference other data and information in the application, eg, a comparative analytical assessment with very low residual uncertainty. Where differences in certain impurities or novel excipients give rise to questions of residual uncertainty related to immunogenicity, these should be adequately addressed and may not require clinical testing.

Of greatest significance is a clear direction to developers that a comparative clinical immunogenicity and efficacy study is not required if the analytical assessment supports high similarity. Further, the design of clinical pharmacology study need not be complicated if the duration of action is determined based on reliable measures of systemic exposure and glucose response.

The draft guidance on clinical immunogenicity testing for insulin products is indeed a historic event: a bold step by the FDA that shows a determination that there is a need to bring into market lower-cost alternates to the reference products if the clinical studies that contribute to the majority of cost and time are not required.

I anticipate FDA issuing similar assessments of other biological products like the cytokine inhibitors that too fall in a similar category of highly characterizable products, and particularly the products that have little immunogenicity risk, like the filgrastim.

An ending thought remains: Why did it take the FDA 4 years to accept the thesis that is already practiced in European Union? Perhaps it was the inevitable pressure to make insulins more affordable. The fact is that, unless we have this level of clarity, it will be difficult to make biosimilars more accessible.