The FDA Biosimilar Action Plan: Making Biologics More Accessible

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.

December 07, 2018

The Biologics Price Competition and Innovation Act of 2009 (BPCIA) created a new category of biological products, biosimilars, which have similar safety and efficacy profiles as US-licensed reference products. The BPCIA was approved as part of the Affordable Healthcare Act.

Now, a decade later, the FDA has approved only 15 biosimilar products, most of which are not yet launched for legal reasons, and the FDA has yet to approve its first interchangeable biologic product. This pace of market entry is much slower than what the FDA had anticipated. The reasons for the slow entry of biosimilars are many, and I was able to analyze, summarize, and publish my findings recently (in the European Pharmaceutical ReviewGaBI Journal, and BioProcess International) based on my firsthand experience in developing biosimilars.

I sent these publications to the FDA, and a few months later, I filed a citizen petition wherein I provided a detailed scientific thesis on why the existing guidance is impeding the development of biosimilars.

Rationalizing FDA Guidance on Biosimilars

The slow entrance and acceptance of biosimilars in the US is the result of high costs and long development times – nearly US$250 million and almost eight years [7] – as well as a gross misunderstanding of the safety of biosimilars among prescribers and the public, principally due to ideas put forward by the products’ originator companies. While FDA has recently launched a campaign to educate stakeholders regarding the safety of biosimilars [8], much work remains to be done in order to simplify and expedite licensing of biosimilars, as emphasized by the author in several publications and a recent citizen petition to FDA


 This review focuses on actions FDA, biosimilar developers and other stakeholders can take, within the boundaries of the statute, to make biosimilars more accessible. In order to first understand what is feasible for FDA and how the relevant guidelines are constructed, a review of the BPCI Act is necessary 

 Generics and Biosimilars Initiative Journal (GaBI Journal). 2018;7(2):84-91. DOI: 10.5639/gabij.2018.0702.018 

Published in: Volume 7 / Year 2018 / Issue 2 

Why Shouldn't Men Wear Shalwar-Kameez [archived]

Why Shouldn't Men Wear Shalwar-Kameez [archived]

Middle age is defined as the time in life when you stop growing at both ends and begin growing in the middle. If you have ever tried to slip into jeans 2-inch too small in waist, you know what relief it is wearing our traditional shalwar-kameez, a de facto national symbol of the Pakistani male. However, this comfort has a price tag. And time has now come to evaluate if we really need this cross between the traditional pajama (a discovery of the Indian subcontinent now popular throughout the world) and the attire of the sultan's harem girls, the Turkish pants, long outlawed in Turkey.

The first problem with shalwar-kameez is that it resembles too much of what we often wear at home or during night; slipping into clothes different from our dreaming suits is needed to change our professional mind-set. This attire is also dangerous when working with moving machinery and you can easily trip. Wearing shalwar-kameez also keeps you oblivious from the ever-growing bulge in the middle. You can always loosen the shalwar a bit and the long fall of kameez keeps it all hidden, well tucked in. You would never know when you ballooned from waist of 30 to 44. Also, since it hides body curves, it neither lets you lament nor gloat about how you look—a motivation to maintaining good health.

A phenomenon unique to the shalwar-kameez users is the ease and consistency with which they reach for their crotch. This best pastime of the Pakistani male is vividly displayed at bus stops and offices. Embarrassing to the core, the habit can be damaging to the prostate gland.

Finally, men should not wear shalwar-kameez because it resembles a woman's dress. What is the alternate then? Why not adopt the practical modern Western attire? And before you slap the national identity crap on this opinion, remember that the entire West wears pajamas, straight out of our inventory. I think time has come for us to find our identity in better things than in this outdated, physically hazardous, sleepwear that promotes poor attitudes and bad health habits.

[17 March 1995 The Daily Dawn]

On Leaving the Company I founded, Adello Biologics


More than a decade ago, I founded Therapeutic Proteins Inc (now Adello Biologics) with a vision of making affordable biosimilars in USA. Today, Adello has products under approval by the FDA, and uniquely that first therapeutic protein manufactured using a single-use technology that I invented. I wish to thank the angel investors, who gave me a head start, Jim Berens who placed his trust in my passion to help me build clean rooms, Steve Einhorn for providing the first large funding, and Chirag, Chintu and Tushar Patel, who helped me complete a fully integrated GMP facility in Chicago. It was a challenging ride, but we came through.  Now Adello is in good hands with Peter and Mike and it is about time that the baton is transferred to new hands, who are much better at handling supply chain issue than I could. I leave the company I founded with an experience of a lifetime and an immense sense of humility.

Novel Approaches of Demonstrating Bioequivalence

Sarfaraz K. Niazi, Ph.D., SI, FRAS, FPAMS, FACB, Professor of Biopharmaceutical Sciences, Adj, University of Illinois College of Pharmacy, Chicago, Illinois. Founder Adello Biologics, LLC.;; +1-312-297-0000

A Public Meeting was held by FDA on 17 July 2017 on Administering the Hatch-Waxman Amendments[1]: Ensuring a Balance Between Innovation and Access. The comments below were submitted as Comments on this Public Meeting Reference 1k1-8yz7-ttos

The Drug Price Competition and Patent Term Restoration Act (Public Law 98-417) of 1984 has made drugs more accessible. One of the key elements of the Act is the demonstration of bioequivalence of generic products containing drugs that are not eligible for bioequivalence waiver.

Bioequivalence testing originated in the early 1970s with the ±20 rule. According to a separate study, “the shortcomings of this approach were immediately evident, since such a criterion would theoretically allow the parameters of generic product A to differ from the reference (innovator) product by +20%, while allowing the parameters of generic product B to differ from the reference product by -20%. The net difference between the generic products A and B would then be as much as 40% and, therefore, beyond the limits of therapeutic equivalence as originally conceived.”[2] In response, the FDA adopted a powered approach in the early 1980s. However, both approaches were discontinued by the FDA in 1986 because of public concern about bioequivalence and were subsequently replaced by the 90% CI approach in 1992, which remains the current criteria for bioequivalence decisions.[3] How closely the FDA sticks to this guidance is seen in the current bioequivalence testing guidance that states[4] that “We recommend that applicants not round off CI values; therefore, to pass a CI limit of 80 to 125 percent, the value should be at least 80.00 percent and not more than 125.00 percent.” [The upper limit of 125.00 percent comes from the strict 20.00% limit on each end (100/125=0.80)]. Why is there a need to follow this limit so strictly? According to the FDA[5], this range is based on a clinical judgment that a test product with bioavailability that falls outside this range should be denied market access. A 90% CI is used, since a 5% statistical error is allowed at both the upper and the lower limits. Therefore, the total error is 10%, generating the 90% CI. Understanding a predefined range is much more intuitive and easier to grasp than the reality of multiple PK parameters having to fit within a narrow CI.

Now that the FDA has initiated its efforts to bring innovation to the Act, I would like to suggest that we re-examine the current the guidance on how to meet the BA and BE requirements set forth in 21 CFR part 320 as they apply to dosage forms intended for oral administration or non-orally administered drug products when reliance on systemic exposure measures is suitable to document BA and BE (e.g., transdermal delivery systems and certain rectal and nasal drug products). A suggestion for this change comes in The Patient Protection and Affordable Care Act (Affordable Care Act), signed into law by President Obama on March 23, 2010, that amends the Public Health Service Act (PHS Act) to create an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with a FDA-licensed biological product. This pathway is provided in the part of the law known as the Biologics Price Competition and Innovation Act (BPCI Act)[6]. Under the BPCI Act, a biosimilar product is a biological product that is approved based on a showing that it is highly similar to a FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product.

What I am proposing is that we add the consideration of “clinically meaningful” to the bioequivalence testing of generic products, instead of using a fixed range of bioequivalence, to make this test more relevant. An FDA analysis shows that for the submissions between 1996 to 2001 for highly variable drugs, the mean AUC varied by 10%,[7] while the range allowed was 20%. Such statements can be misleading since they do not represent the granularity of data where even 10% variability can be too much and the situations where a 30% variability will still yield a clinically equivalent product. The FDA has recently begun discussion of narrow therapeutic index (NTI) drug bioequivalence[8]. Four new draft guidances are posted online recommending replicate design studies for NTI drugs including tacrolimus, phenytoin tablet, levothyroxine, and carbamazepine. The movement from “one size fits all” to product-specific standards is a sign of the maturation of the generic drug program. However, the emphasis in these recent approaches has been on the statistical design and not the margin that remains an iron-clad acceptance criterion. Replicate design helps reduce the size of the study, yet it does not add a clinically meaningful component to the study.

I am recommending that the FDA allow developers to justify margin that they can demonstrate to provide a clinically meaningful comparison that may include novel in vitro testing methods or any other approaches that have not been explored mainly because of the fixation of complying with the equivalence margins as currently mandated. The roots of this recommendation come from the 21 CFR Part 320[9] wherein: “(e) Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.” Since the site of drug action as cited here is in most case not known and rarely sampled, blood level PK studies were suggested as a surrogate, not a primary test, to demonstrate bioequivalence. In fact, given that blood level studies add substantially more variability in the assessment of bioequivalence, better means of establishing bioequivalence are the in vitro means wherein a generic product is more likely to show a discernible difference. One such means is demonstration of thermodynamic equivalence for which a Citizens Petition is already filed and open for comments ( .

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, may be able to discern the differences not picked up by current dissolution testing. The TE provides a better estimate of the equivalence of the generic and the reference product at the site of administration, a more important attribute since the rest of the complexity and variability stays common with both the generic and reference product. The test of TE can be extended to provide a continuous monitor of bioequivalence of the generic drug over the lifecycle of the reference product, an attribute that is currently not required for testing.

The Public Law 98-417 has served the US citizens well; now it is time that we examine its components utilizing the novel approaches to improving upon its utility, and it requires abandoning the arbitrary equivalence criteria and a redundant blood level study that was a surrogate in the first place, and need not be retained unless proven to bring a greater understanding of any clinically meaningful difference between a generic and a reference product.


[2] Henderson JD, Esham RH. Generic substitution: issues for problematic drugs. South Med J. 2001 Jan;94(1):16-21.



[5] Buehler G. History of bioequivalence for critical dose drugs. FDA.…/UCM209319.pdf. Published April 13, 2010. Accessed June 6, 2016.





FDA Accepts Our Filgrastim Biosimilar Application

It has been a long journey; I founded the company and grew it into a fully integrated, pure-play, US-based company biosimilars company. Our 351(k) application was accepted by FDA for review (Adello Biologics); several more products are underway, now that we have a great team in place. There is no substitute to learning it the hard way. Over next few weeks, I am giving several talks to share my experience and also plans on how to expedite development of biosimilars. and

Fingerprint-like Non-inferiority Similarity Demonstration--A New Invention

The FDA, now now EMA, emphasize analytical similarity as the pivotal step to minimize residual uncertainty, but creating a plan to demonstrate fingerprint-like similarity has been difficult because of improper use of testing methods, testing protocol, statistical modeling and the knowledge of the variability within and between lots. I have addressed this issue in my several books including the Biosimilars and Interchangeable Biologics: Tactical Issues ( but now I have invented a new method that makes fingerprint-like similarity testing possible. This should help bringing biosimilars faster to market by assuring least residual uncertainty in the early phases of development. What will make biosimilars accessible (available and affordable) is a mindset that supports FDA thinking on scientific approaches that the Agency has demonstrated repeatedly; the ball is in the court of developers to give FDA reasons to approve biosimilars without lengthy, expensive clinical trials. I will be happy to provide more information and details to anyone wishing to examine their approach. 

While the concept of non-inferiority testing has been applied to clinical trials, this concept is yet to be applied to analytical similarity testing; the testing protocols as shared by FDA in reviewing three biosimilars, filgrastim, insulin glargine and bevacizumab show a more conventional approach to demonstrate similarity, not non-inferiority. The CQAs for the latter are different than those used of demonstrating similarity. 

My inventions include methods to demonstrate difference through a process of thermodynamic extrapolation. I have shared the novelty aspect as well as the non-inferiority trial designs with regulatory agencies and they have all encouraged this approach. I will soon be filing a CP to enforce these new technology and the proposed approach. Being able to demonstrate non-inferiority is a double-edge sword; biosimilar developers can use it to show fingerprint-like similarity but the LBP companies can use these methods to show lack of similarity as well, whether it is clinically meaningful or not.

I am strong that urging the scientific community in the biologics arena to come up with better tests to allow FDA to approve products without requiring phase 3 studies in those cases where these studies can take long time to complete and add to the cost of biosimilar development.

Making Alcoholic Beverages Unique and Affordable--New Patent Issued 29 August 2017.

The alcoholic beverage industry is bigger than the pharmaceutical industry, over $1.5 Trillion worldwide, yet the technology for aging alcohol, letting it sit in a barrel, dates back thousands of years. While I have developed many technologies with dozens of patents to make biological drugs more affordable, and these technologies are used to reduce the COGs of biosimilars, now I am reporting my new invention for continuous aging of alcoholic beverages, eliminating wood barrels and forcing the natural process by thousands of times by manipulating the thermodynamics of the Fick's law of diffusion. Now for the first time, we can introduce proprietary tastes using several types of wood simultaneously and produce the desire product at a much lower cost. It is about time that we become more creative with what is perhaps the largest product in the world. Yes, we should make drugs affordable, then why not the beverage that makes billions happy ever day. This patent is one of about a dozen patents on fast aging of alcoholic beverages including wines, whiskies and others, allow storage in multiple-use bottles without affecting the quality of content and many more inventions to change a technology that has seen little change over 7000 years.

A Biosimilar Delayed is a Biosimilar Denied

After decades of experience in taking biosimilars from cell line to market and after facing both success and failures, I feel qualified to talk about what not to do when it comes to making biosimilars accessible (available and affordable). I am inviting all of my friends (and I have many) to join me at this conference where I provide a step-by-step approach to succeeding in securing FDA approval of biosimilars. This is an experience based on a first-hand working knowledge of how the FDA lays out its expectations. I have been instrumental in contributing to FDA guidelines and detailed treatises on the science and technology of biosimilar approvals under 351k and 505b2 provisions.