Thermodynamic Equivalence to Demonstrate Bioequivalence

The 1980s saw emergence of generic drugs in the US that has saved hundreds of billions of dollars to patients and improved accessibility to drugs. The statute that created this abbreviated pathway for approval of generic drugs stated that therapeutic equivalence means same concentration of active drug at the site of action, an evaluation that was neither possible nor practical. So, the FDA recommended using blood level studies as a surrogate test demonstrating bioequivalence. Later, FDA agreed to remove this requirement, the biowaiver, for drugs that are highly soluble. I am now introducing a new concept--thermodynamic equivalence, in lieu of bioequivalence testing. 

Thermodynamic equivalence (TE) is by another name, the “basis” for biowaivers, in place for years. For a highly soluble drug, the barrier Delta G is small, overcoming any differences between two products. I am expanding this concept to drugs subject to blood level studies. Why would a drug product fail in BE, when it has the same chemical entity? It is inevitably the release profile at the site of delivery, since this point forward, all factors apply equally. Dissolution rate testing is the best example of measuring chemical potential and while it works well for products with small DG, it fails for drugs that are not released instantly. Creating a matrix of dissolution profiles, independent of any physiologic conditions, such as a 3x3 matrix, may be able to discern the differences not picked up by current dissolution testing. This is not a theoretical suggestion, it  is already in practice, such as in the comparison of biologics, where a different approach to matching CQAs allows FDA to approve them without requiring phase 3 studies. The industry should attempt now to use this concept to request biowaivers, particularly for highly complex product designs to reduce cost and time to market.

It was after years of similar discussion that the FDA agreed to look into the concept of TE that can be continually used to assure life-cycle therapeutic equivalence. The FDA has now opened up this discussion agreeing that the concept needs to be explored further.

From writing the suggestions for the first guidance for bioequivalence to biosimilarity testing, I have been engaged with FDA and I am now confident that we are entering a phase of scientific reality that can bring another phase of reduced burden on development of drugs.


Why do we exist?

About 80,000 years ago, a variant of the Homo genus, the Sapiens, came out of East Africa and spread across the globe, annihilating other Homo genus title holders, many large animal species and now finally devouring the environment that supports his existence. The renewal of species is a common occurrence in the mega plan of evolution and tomorrow’s Homo genus species will be very different from us, but today, we are not able to predict, how? The span of 80,000 years is not enough to produce any significant changes in our genetic code, one of which made us curious and inquisitive—perhaps as a means of protecting us against the unknown—the survival of our species depended on it. Some day when we will not fear walking in a dark room, we would have overcome this genetic coding, not now. Our curiosity and inquisition were endless 80,000 years ago, and it remains so today, except we have a better vocabulary to frame our questions.

The first question that came to the mind of the foraging Sapiens was: “How do we survive?” We had not yet domesticated crops or bred animals for food and lived off whatever came in our path as we moved around, mostly in groups of less than 100, for anything bigger than that caused a split and rise of another group that was not likely to be friendly to us. While our toolmaking skills were superior to Neanderthal and Erectus species, we excelled in organizing our groups. We realized early in our foraging times that some of us better at doing one task over others and that gave rise to what we call today, professions. Now, as tasks were assigned, it became difficult for us to leave the group as we became dependent on others in the group for our survival, and thus grew societies and kingdoms. Those who were good at ruling, found this to be a great profession, and thus came dictators, pharaohs, prophets, kings, and bigots to rise. You can now appreciate, how one question asked resulted in a creation of civilization.

Another issue that came way after we had assured our survival was “Where are we?” We could see the stars around us and had wanted to know our place in the arena of whatever was visible to us. Our condescending nature led us to believe that we are the focus of the Universe. Historically, the center of the Universe had been thought to be several locations. Many mythological and religious cosmologies included an Axis Mundi, the central axis of a flat Earth that connects the Earth, heavens, and other realms together. In the 4th century BCE Greece, the geocentric model was developed based on astronomical observation, proposing that the center of the Universe lies at the center of a spherical, stationary Earth, around which the sun, moon, planets, and stars rotate. With the development of the heliocentric model by Nicolaus Copernicus in the 16th century, the sun was believed to be the center of the Universe, with the planets (including Earth) and stars orbiting it. In the early 20th century, the discovery of other galaxies and the development of the Big Bang theory led to the development of cosmological models of a homogeneous, isotropic Universe (which lacks a central point) that is expanding at all points. The reason why we resisted accepting that we are not the center of the Universe comes from realizing how small and insignificant we are? Narcissism bred into our genes has not yet left our construction.

The question, “Who are we?” created great tumult in human society because of its amorphous nature. The early foraging Sapiens are desiring to grow their community as produced con artists who sold gods and what better way to connect than by assuring that we are indeed the chosen people. The story caught on well, and every religion claims that they are the righteous ones, or else why would anyone believe in it? Today, most of us believe we are a creation of God, of one type or another kind of God. Moreover, despite the indisputable theory of evolution as proposed by Mr. Darwin in the mid-19th century. Evolution is a change in the heritable characteristics of biological populations over successive generations. Evolutionary processes give rise to biodiversity at every level of biological organization, including the levels of species, individual organisms, and molecules. All life on Earth shares a common ancestor known as the last universal common ancestor (LUCA), which lived approximately 4.1 billion years ago. Repeated formation of new species, change within species, and loss of species or extinction throughout the evolutionary history of life on Earth are demonstrated by shared sets of morphological and biochemical traits, including shared DNA sequences. [We still carry a few genetic sequences of the Neanderthals}. More than 99 percent of all species that ever lived on Earth are estimated to be extinct, and estimates of Earth's current species range from 10 to 14 million. Primates diverged from other mammals about 85 million years ago, and the Hominini tribe (humans, Australopithecines and another extinct biped genre, and chimpanzees) parted from the Gorillini tribe (gorillas) some 8-9 million years ago, and a couple of million years later, we further separated into more refined humans and biped ancestors.

The creation–evolution controversy is an ongoing, recurring cultural, political, and theological dispute about the origins of the Earth, of humanity, and of other life. Within the Christian world (not the fundamentalists) evolution by natural selection has been established as an empirical scientific fact stating that “evolution requires the creation of beings that evolve." Ironically, the rules of genetic evolutionary inheritance were first discovered by a Catholic priest, the Augustinian monk Gregor Mendel, who is known today as the founder of modern genetics. Most other religions totally deny evolution, as it threatens their very foundation. While the question, “who are we?” remains disputed, it has lost much of its stigma and no longer a thorny issue.

There remains just one question, “When did we begin?” Early shamans resolved this issue by relegating the responsibility to gods, and we were relatively satisfied with this resolution that it happened whenever we think it did. Aristotle taught that the universe had existed forever to avoid invoking divine intervention to create the universe as those who believed the universe had a beginning, used it as an argument for the existence of God as the first cause. To Aristotle, this was disturbing because that would raise the question of who created God, the omnipotent. An interesting philosophic argument goes as follows: “Can God create another God stronger than Him?”  If the answer is yes, our God is not omnipotent, and if the answer is no, then our God is not omnipotent.  According to the Book of Genesis talks about the creation of the world at 9 in the morning on October the 27th, 4,004 BC. 

In 1915, Einstein introduced a General Theory of Relativity, according to which, space and time were no longer absolute, no longer a solid background to events. Since time began with the beginning of the universe, the question what existed before that moment becomes redundant. It is like asking, what is north of the North Pole? The equations of General Relativity would break down at the singularity. What we do know today is that the universe is expanding, so if the galaxies are moving away from each other, they must have been close to each other at one time, taking us back to God, inevitably. Scientists proposed a theory of Steady State wherein as galaxies moved apart; new galaxies form from matter continually created throughout space. This way, the universe would have existed forever looking the same always. It could not be proven. Another attempt to avoid the universe having a beginning was the suggestion that there was a previous contracting phase, but because of rotation and local irregularities, the matter would not all fall to the same point. Observational evidence to confirm the idea that the universe had a very dense beginning came in October 1965 with the discovery of a faint background of microwaves throughout space. These microwaves are the same as those in your microwave oven, but very much less powerful. 

The Einstein's theory cannot predict how the universe will begin, but only how it will evolve once it has begun; the theory breaks down in the adamant gravitational fields in the early universe. However, if we combine this theory with quantum theory. We can get rid of the problem of time having a beginning. Suppose the start of the universe was like the North Pole of the earth, with degrees of latitude playing the role of time. The universe would start as a point at the North Pole. As one moves south, the circles of constant latitude, representing the size of the universe, would expand. To ask what happened before the beginning of the universe would become a meaningless question because there is nothing north of the North Pole. 

Moreover, now comes the final question, “Why do we exist,” a matter that is readily answered if we assume the divine power. It was God’s desire. So, if science says, it was 15 Billion years ago, so be it. However, we cannot ask why 15 Billion; what happened that moment to make God decide to say, “Let there be light.” If there was an event, regardless of how disputed it may be, our existence must have a reason to be, if it is not God’s will. Quantum mechanics may even go as far as telling us that do not actually exist, it is all in our imagination, and while such arguments go above the boggle line of most, it nevertheless offers a proposition that too is subject to the “why” question. Both existence and lack of existence need an explanation why this duality was necessary? For thousands of years, we have tried answering the question in vain. However, all we needed to do was to re-examine our curiosity and inquisition instincts as the new species. Our understanding of where, how and when continues to go through major transformations as we develop new capabilities, if not the abilities to deconstruct our observations. We may be able to fully understand that quantum mechanics proves that there is no need for anything to exist without a beginning, but the fact that it exists keeps the question, “why” open. As science grows, our boggle line, a limit above which we do not understand, keeps getting lower. Where this line sits depends on our ability, not capability to understand. To most, the General Theory of Relativity is clearly above the boggle line, to some, why it takes 8 minutes for the sunshine to reach earth remains above the boggle line. Imagine being a frog in a well, looking outside from within. Can you see what is outside of the well? The answer is no. Try asking a bat, “what do you see,” and bat responding, “you mean what I hear?” These are called the dividing lines, not the boggle lines. We are an integral part of the universe in a matter and energy maze and therefore unable to go around this maze to see where we are. 

In quantum mechanics, the uncertainty principle, also known as Heisenberg's gives us an opportunity to answer the “why” question. According to the principle, if there are two physical properties, such as position and momentum of a particle, then you can only know only one property accurately, not both at the same time. The more precisely the position of some particle is determined, the less precisely its momentum can be known, and vice versa. A bullet shot out of a rifle can be accurately recorded for its position in the air or its momentum (mass times velocity) but not both at the same time because if you need to hold the bullet at a point to know its position that will change its velocity and thus the momentum. However, the Heisenberg principle goes beyond that and works on a probability function that includes the wavelike function as well. If you find this confusing, think of this: by looking at the moon, you change the course of the moon! Now you get it? 

Many other examples defy human imagination. Think of present and past. We see things because the light reflected from them reaches the back of our eyes. Given that light travels at a speed of 186,000 miles per second, nevertheless, every quantum of light reaching our eyes take a finite time, and therefore, what we see is always a past event, for there is no present event that can be seen. If you divide any number by zero, the answer is infinity. Now no matter how large a number you label this to be, any definition would always be less than infinity. In other words, if you can find define infinity, it is not infinity. If you divide the circumference of a circle by its diameter, you end up with “pi” that has been calculated to several trillion decimal figures and never ends in its accuracy. Surprised? Moreover, if you want to appreciate the limitations of human mind, think of the famous paradoxes of philosophy.

Can you define what infinity is? For if you can, then it is not infinity.

Suppose someone tells you “I am lying.” If what she tells you is true, then she is lying, in which case what she tells you is false. On the other hand, if what she tells you is false, then she is not lying, in which case what she tells you is true. In short: if “I am lying” is true then it is false, and if it is false then it is true. 

Suppose that there is motion. Assume that Achilles and a tortoise are moving around a track in a footrace, in which the tortoise has been given a modest lead. Naturally, Achilles is running faster than the tortoise. If Achilles is at point A and the tortoise at point B, then to catch the tortoise Achilles will have to traverse the interval AB. However, at the time, it takes Achilles to arrive at point B; the tortoise will have moved on (however slowly) to point C. Then to catch the tortoise, Achilles will have to traverse the interval BC. However, at the time, it takes him to arrive at point C, the tortoise will have moved on to point D, and so on for an infinite number of intervals. It follows that Achilles can never catch the tortoise, which is absurd.

The riddles, paradoxes, and undefined realities surround us because of one reason: Our vocabulary. If we did not have a vocabulary, we will never the talking to ourselves and asking these questions, “Why are we here?” There canbe no dialog. Stephen Hawking said aptly,” What was God doing before He made the world? Was He preparing Hell for people who asked such questions?” So, we come to a crossroad where we must question whether our minds have evolved enough to frame a question correctly. Is the question, “Why are we here,” a question or a statement? No answer can satisfy every curious mind. Those unable to question their ability to question inevitably fall to accepting a Creator and close the issue, those who have evolved enough not to have at least some basic wisdom would say: this is not a frame-able question.

Amorphous Scalia And The New USA

The death of Justice Antonin Scalia in 2016 reminded me of his vote in 1986 for the Louisiana law that forbade public schools to teach evolution without also instructing students also on “creative science.” Then the Chief Justice William Rehnquist joined Scalia, who was heavily criticized by the academicians, as Jay Gould of Harvard said, “I regret to say that Justice Scalia does not understand the subject matter of evolutionary biology.” Scalia was open about the reasons for his decision. He said, “what we can really know for sure?”, criticizing his colleagues’ decision for treating the evidence for evolution as “conclusive.” To Scalia, ‘creative science’ was indeed a science as well. It was a constitutional issue of church and state to other justices, but to Scalia, it was a matter of belief, not necessarily in creation but the proof against creation science. In the 17th century, Galileo was ordered to turn himself into the Holy Office to begin trial for holding the belief that the Earth revolves around the Sun, which was deemed heretical by the Catholic Church. In 1616, exactly 300 years ago, the Inquisition found heliocentrism to be formally heretical, and heliocentric books were banned, and Galileo was ordered to refrain from holding, teaching or defending heliocentric ideas. More than 350 years after the Roman Catholic Church condemned Galileo, Pope John Paul II rectified this Church's most infamous wrongs. Three centuries from today, we will look back and find a member of the Supreme Court just as primitive as was the Church six hundred years ago. But with a caveat.

The judiciary faces judging cases based on merit and beyond a reasonable doubt. This task becomes onerous when the judgment involves amorphous considerations. There is no sharp line in judging when a decision resides on values, morality, and more particularly on the complexity of the issue that is beyond the capability the of a judge to understand. Scalia admitted, he does not get the science and has moral issues with his beliefs regarding Creation. What folks three hundred years from now will find is that there was a drastic change in the US values as the judges rendered a plurality of decisions that on amorphous grounds that changed our society for all time to come. It was too late.



On Being an Inventor

With around 100 inventions, I can talk about the experience of being an inventor. The simile of light bulb for an idea is not far fetched. Owning patents in a variety of fields, some farthest away from my professional field, is the fun part of inventing. An invention is:

  1. A "process" is defined as a process, act, or method, of doing or making something, and primarily includes industrial or technical processes.
  2. A "machine" would be anything that would commonly be considered such, from a clockwork to a tractor to a computer.
  3. The term "manufacture" refers to articles which are made and includes all manufactured articles.
  4. A "composition of matter" is a chemical composition, and may include mixtures of ingredients as well as new chemical compounds.

There are three tests to know if a flash of an idea (what lawyers call the subject matter) can become an invention: 

  • Is it patentable? Some inventions like the laws of nature, physical phenomena, and abstract ideas are not patentable subject matter. It includes a discovery, scientific theory or mathematical method, an aesthetic creation, a scheme, rule or method for performing a mental act, playing a game or doing business, or a computer program, a presentation of information, a procedure for surgical or therapeutic treatment, or diagnosis, to be practiced on humans or animals. A new mineral discovered in the earth or a new plant found in the wild is not patentable subject matter. Likewise, Einstein could not patent his celebrated E=mc2; nor could Newton have patented the law of gravity. Such discoveries are manifestations of nature, free to all people and reserved exclusively to none. The Atomic Energy Act of 1954 excludes the patenting of inventions useful solely in the utilization of special nuclear material or atomic energy for atomic weapons. In the case of mixtures of ingredients, such as medicines, a patent is not granted unless the mixture is more than the effect of its components. It is of interest to note that so-called “patent medicines” are not patented; the phrase “patent medicine” in this connection does not mean that the medicine has a patent.
  • Is it novel? Has anyone mentioned the invention anywhere? Novelty means other patents, anything on the Internet and a thesis hiding in a dusty library thousands of miles away. I get amazed when I check out a new idea on the Internet and find that I am the last one to think of it. It is humbling. Crafting a question on the Internet requires a little bit of practice but not very difficult to practice. 90% of ideas fall on this requirement. 
  • Is it non-obvious? Would someone hold an ordinary qualification in the field of the invention has thought of it? Obviousness is the hardest hurdle to overcome. In today’s advanced science, one with ordinary qualification has a Ph.D. and years of experience, so how would you know if he or she is not capable of thinking what you are thinking. Most patents are denied on this ground once they are determined to be novel. The obviousness determination goes farther to inherence, which means that even though the specific applications of an idea may not have been spelled out but if the function is present in something already reported, you have no invention. 
  • Is it useful? “Useful” refers to the condition that the subject matter has a useful purpose and that also includes functionality, i.e., a machine which does not operate to perform the intended purpose would not be called useful, and therefore would not be granted patent protection. One can find a use for just about anything under the sun, so this remains the least of the hurdles.

Once put to above tests, it becomes evident why an invention is a fleeting dream. Being an inventor does not mean that you are a genius or that you understand the science better—it only tells that you were the first ones to put the nuts and bolts together for a useful idea (subject matter). Socratic method, also known as a method of elenchus, elenctic method, or Socratic debate, is named after the classical Greek philosopher Socrates. It is a form of inquiry and discussion between individuals, based on asking and answering questions to stimulate critical thinking and to illuminate ideas. When you are in the inventing mode, the conversation takes place with yourself. You keep asking questions until you hit a wall. It is this point when you come up with an alternative proposition.

Let me share with you a few examples of my personal experience. Bioreactors or fermenters are used to brew beer, making recombinant drugs and grow organs. We are using them for thousands of years, but the first US patent for a bioreactor was issued on 1 April 1842 to C. C. Edday (US Patent 2,535), titled Fermenting Vat. Today, 170 years later, we still use an upright vat, a stirring propeller, a sugar solution, a biological entity to produce all products, from wine, beer, drugs to organs. At a commercial level, these vats are tall, sometimes two and three stories tall, but in most cases, require a tall ceiling to operate. When I started my company to manufacture recombinant drugs using bacteria and mammalian cells, I ran into a wall when I found that the manufacturing facility that was made available to me, thanks to a kind investor, had an 8-ft ceiling height. The choice was constraining enough to prevent big investors to help me out. After a few weeks of pondering, I came up with an idea of laying the vat horizontally, instead of vertically. There is no limitation on the size of the bioreactor because of its height when it lays horizontally. Combining this idea with a single-use bioreactor, a replacement of stirring mechanism and many other variations that were not possible in an upright vat, I could secure dozens of patents. It turned out that the new configuration of a bioreactor was also much cheaper to construct and operate, making this technology accessible to more users, opening the possibility of faster drug development and making them more affordable. A list of my patents is available by clicking here. What I learned from this experience is that we need to look for alternates when there is already a well-established technology, and it is the simplicity that makes things more useful

My other patents in the field of new drug applications, devices and methods, all came from the same approach of visualizing a simpler path to the utility of a process, machine, manufacture of a composition. 

It has been fun because I became used to being humbled.

On the Death of Moore’s Law





