Others have taken note of Dr. Niazi’s extensive work, and through published articles and awarded accolades, celebrated his accomplishments. Find below examples of the kind words that have been shared on Dr. Niazi’s feats and endeavors. And also, the talks Dr. Niazi has given.
Views of Professor Niazi
https://bioprocessintl.com/2019/january-february-2019/january-february-bioprocess-insider/
Biosimilar developers are targeting blockbuster “Big Pharma” biologic originator companies. Roche and AbbVie, two companies most susceptible to biosimilar erosion, have vocalized a need for stringent regulatory frameworks — calling for appropriate data, individualized labels, and unique identification for all biotherapeutics — while attempting to rebuff competition by reformulating their products and beefing up both their pipelines and intellectual property (IP). Meanwhile, several other Big Pharma companies are dominating European and US biosimilar markets: namely, Novartis, Pfizer, and Amgen, which claim some of the largest biosimilar pipelines in the industry.
Through its Sandoz division, Novartis has been marketing biosimilars in Europe for over a decade. It was first to launch a US biosimilar when its version of Neupogen (filgrastim), received approval in 2015. Pfizer has had four US approvals, including the first biosimilar version of J&J’s Remicade (infliximab). The company expanded its biosimilar pipeline in 2015 through a $17 billion ( €14.9 billion) acquisition of Hospira. And despite suffering revenue loss from an influx of first-wave biosimilars while trying to defend against versions of bestselling biologic Enbrel (etanercept), Amgen has 10 biosimilars in a portfolio that includes US-approved versions of AbbVie’s Humira (adalimumab) and Roche’s Avastin (bevacizumab).
History Repeating: Even so, Big Pharma’s interest in biosimilars may be soon to end, according to Sarfaraz Niazi, a pharmaceutical sciences and biotechnology expert with over 30 years of industry experience who founded biosimilar developer Karyo Biologics earlier this year. In his 2014 book Handbook of Biogeneric Therapeutic Proteins, he predicted that exit would occur once specialized biosimilar developers have appeared on the scene.
“This is history repeating from the generics era,” he said. “There are so many ways to cut the cost of development and manufacture, but because of their mindset and design, Big Pharma cannot do this. They can change both, but that requires a monumental shift.”
Niazi told BioProcess Insider that back in the 1980s, many large pharmaceutical companies planned to enter the generics market. “However, as the prices tanked, they all pulled out.” So far, the big companies are seeing much bigger profits from biosimilars than are sustainable, Niazi argued. “Once prices fall to below 60% of the current prices, it will no longer be feasible for the Amgens and Pfizers to stay in this market for long.”
He says their exit will accelerate when other companies from overseas bring forth products at substantially lowered costs. “Every MAb, regardless of its use, costs about $150–200/g. This price will drop by another 50% once the Indian and Chinese companies start getting approvals; at this stage, prescribers will become redundant and payers will take over.”
Biosimilar Exit? When asked for examples, Niazi cited Merck KGaA’s 2017 divestiture of its biosimilars business to Fresenius for an upfront payment of €170 million ($195 million). Last month “the other Merck” — Merck & Co. (known as MSD outside North America — dropped its Lantus (insulin glargine) biosimilar program after assessing its pricing and costs of production. And recently Sandoz, after a US Food and Drug Administration (FDA) complete response letter (CRL) demanding more data, has pulled the plug on its US rituximab program.
“It will take at least five and perhaps 10 years before the real impact of dropping prices is felt,” Niazi warned, “given that the approval of biosimilars is not fast enough, but it is coming.” He predicts that specialized biosimilar companies such as Samsung Bioepis and Coherus, both of which are already competing in the space, will take over as Big Pharma backs out. A joint venture between Biogen and Samsung BioLogics, Bioepis has a Remicade (infliximab) biosimilar competing in the United States and several other such products in Europe. And Coherus recently won US approval for its version of Amgen’s Neulasta (pegfilgrastim).
Meanwhile, the traditional generic drug companies also are lining up to take their place: Teva, which has seen success with first-wave biosimilars in Europe, is poised to enter the US market with a Celltrion-developed Rituxan (rituximab) biosimilar. Mylan already has a Neulasta biosimilar approved in the United States and boasts another 20 biosimilars and insulin analogs in its portfolio.
Economy of scale at Sandoz
Big Pharma Responds: When Merck & Co. pulled its insulin glargine product, it told BioProcess Insider that it remained committed to biosimilars. Sandoz, Pfizer, and Amgen also have dismissed the idea of any looming exit from the space.
“Pfizer is committed to biosimilars as an important treatment option for patients,” spokesperson Thomas Biegi said. “We are working hard on bringing our biosimilars to market and will continue our efforts to ensure that patients around the world have access.”
Amgen’s Kelley Davenport added: “While we can’t comment on our strategy, with 10 biosimilars in our portfolio, Amgen remains committed to its biosimilars program.”
Sandoz spokesperson Chris Lewis said his company is a “global pioneer and leader” in biosimilars and remains committed to the sector. However, he acknowledged that this is a challenging space in which “only a handful of players will succeed globally in the mid to long term.”
Nicole Fisher Contributor
And is currently listed as the largest solo holder of bioprocessing patents in the world.
In an extraordinary move, the FDA has withdrawn the draft guidance, "Statistical Approaches to Evaluate Analytical Similarity,” after receiving public comments and one citizen petition (FDA-2018-P-1876). The goal of the guidance was to provide an action plan for evaluation of similarity between proposed biosimilars and the original products. FDA Commissioner Dr. Scott Gottlieb, ordering the withdrawal of the guidance, expressed disappointment with the current pace of biosimilar development. “As the cost to develop a single biosimilar product can reach hundreds of millions of dollars, it's important that we advance policies that help make the development of biosimilar products more efficient, and patient and provider acceptance more certain," he said.
But what makes the FDA about-face on biosimilar evaluation so monumental, is that it was the direct result of the citizen petition. Filed by one man: Dr. Sarfaraz Niazi, Adjunct Professor at the University of Illinois at Chicago and CEO of Pharmaceutical Scientist, Inc. When asked about his success in influencing the FDA, the man I once wrote about as the most interesting man revolutionizing the health world, commented, “The idea of making biosimilars accessible has not worked out well to date primarily because of the complexity and redundancy in the regulatory pathway. After I pointed out the complexities and errors in the regulatory guidance and offered alternative approaches, the FDA Commissioner became motivated to make changes. This is the first time that the FDA has simply withdrawn one of its guidance.”
So, what makes the opinions of Dr. Niazi so influential? In 2003, he established Therapeutic Proteins Inc., later named Adello Biologics, with the goal of manufacturing biological drugs and supply them, “at any cost affordable by anyone across the globe.” He then went on to write the largest number of books on biosimilars and worked with the White House in developing the details of the Affordable Care Act that included the Biologics Price Competition and Innovation Act (BPCIA). And is currently listed as the largest solo holder of bioprocessing patents in the world.
Challenging Biosimilar Development Plans
Although there have been barriers to biosimilar uptake in the U.S. that range from lack of provider education to therapeutic interchangeability, the FDA and non-big pharma supporters have high hopes for the future of biosimilars. So, when Dr. Niazi contacted the FDA and told them there was a dire need to re-evaluate the scientific rationale behind the current methods of testing biosimilarity – with aim to reduce barriers including redundant analytical testing and testing in humans without compromising the quality to save significant amounts of time and money – they listened.
His basic premise is built around the FDA’s commitment to engaging scientific methods that reduce testing; in line with US 21 CFR 320.25(a), which codifies the universal belief that, “No unnecessary human testing should be performed.” In the case of biosimilars, testing in healthy subjects is unethical because of their potential of making the study subjects immunoreactive for the rest of their lives. The second premise proposed by Dr. Niazi is to invoke new technologies to establish similarity between biosimilars and reference products to remove any “residual uncertainty,” to allow faster approval of biosimilars. Dr. Niazi argues the use of “thermodynamic equivalence,” a process he created that he claims removes the need for blood-level studies to determine differences between products, can do this.
Other ideas presented included eliminating bridge testing when a non-U.S. reference is used in certain conditions (reducing the number of reference product batches required), creating a mechanism to make reference samples freely available (allowing more ethical in-vitro immunogenicity testing), minimizing non-inferiority testing in patients because of their lack of utility, and changing the pharmacokinetic testing to disposition-related parameters and allowing testing in more homogenous populations. Dr. Niazi also suggested that the FDA promote substitution of biosimilars for new patients through educational programs.
What’s Next?
Within days of the FDA withdrawing the guidance on biosimilars, Dr. Janet Woodcock, Director of Center for Drug Evaluation and Research (CDER) and the FDA Commissioner issued a July 1, 2018 Biosimilar Action Plan that considers most of the recommendations made by Dr. Niazi.
In the 1980s, the Hatch-Waxman Act created a new class of drugs – generic – that has saved American patients over a trillion dollars. If successful, biosimilars, like generics, can save a lot more by making biological drugs more affordable. The FDA has demonstrated that it listens to scientific and creative suggestions. And Dr. Niazi may finally be able to reach his dream of making healthcare more affordable. “Now that FDA is open to scientific approaches to proving biosimilarity, the burden lies on developers to design their plan more creatively. I anticipate a wave of approvals by FDA that will bring price drop of more than 50% – a threshold required to disrupt the markets by taking the decision-making from the hands of prescribers to payers. Eventually I see biosimilars becoming biogenerics, which I had predicted in my first book on the subject," he said.
The H.R. 3590 Sec. 7002, the Biologics Price Competition and Innovation Act of 2009 (BPCIA) created a new category of biological products, biosimilars, having a similar safety and efficacy profile as a US-licensed reference product. The BPCIA was approved as part of the Affordable Healthcare Act, after years of politicking in the US Congress without any resolution as big pharma kept pushing its approval. In 2008, when Barack Obama was elected President, I wrote a personal letter to him that is now in the Obama Library in Chicago, where I found the privilege of advising him on the need for this legislation and apprised him on the critical elements of the bill that needed to be kept intact. President Obama was convinced that a seven-year exclusivity period for new biologics should suffice, as I had recommended; but then the political pressure came into play, and he reluctantly agreed to a 12-year exclusivity. The frenzy that preceded the passage of the Affordable Healthcare Act, wherein the BPCIA was a minor add-on, perhaps escaped the scrutiny of many vested interests, yet, some elements that should not have been in the bill, could not be deleted—most prominently, the dual classification of biosimilars, as biosimilars and interchangeable biosimilars, the latter requiring testing that would prove to be irrelevant and scientifically irrational.
I have continued to write about the slow entry of biosimilars to the US markets and continue to hope that someday we will be able to find a rational approach to make biosimilars affordable.
This letter is in the Obama Libraray in Chicago. .
Biosimilar Regulatory Roundup: March 2019
March 2019 kicked off with a surprise, when FDA Commissioner Scott Gottlieb, MD, announced he was leaving the administration. In addition, the FDA released updated draft guidance on the naming of biologics, biosimilars, and interchangeable biosimilars; approved a Pfizer biosimilar; and more.
Allison Inserro
March 29, 2019
The man many in the biosimilar world credit with being proactive about government efforts to educate and develop the industry in the United States gave his 1-month notice early in March 2019, and that was just the start of a flurry of regulatory news this past month.
FDA Commissioner Scott Gottlieb, MD, is leaving his post, with his last day set to be April 5, just 2 days after he testifies about the FDA’s budget request to Congress. He will be replaced by Ned Sharpless, MD, who has a track record with the biotechnology industry and oncology and is said to have a friendly relationship with Gottlieb.
Still, all of the major biosimilar organizations expressed surprise and regret about Gottlieb’s decision; most observers credit him with a sea change at the FDA.
However, days later biosimilar developers were even less pleased about the FDA’s updated draft guidance on the naming of biologics, biosimilars, and interchangeable biosimilars. According to industry, the FDA’s decision to require 4-letter, nonmeaningful suffixes for biosimilars, interchangeable biosimilars, and new biologics—but not already approved biologics—could seriously hinder biosimilar uptake.
In addition, the International Generic and Biosimilar Medicines Association, a global umbrella group, called the US policy a “notable outlier” that diverges from global consensus on biosimilar naming. The draft guidance also drew the attention of an adjunct professor and founder of biosimilar companies, who filed a citizen petition with the FDA seeking that the guidance be withdrawn.
Sarfaraz K. Niazi, PhD, adjunct professor of biopharmaceutical sciences at the University of Illinois and the University of Houston, is asking that the agency modify its position to state that no suffixes are required for any biologic products and instead state that brand names can be used along with National Drug Codes (NDCs).
In other FDA news, it approved Pfizer’s trastuzumab-qyyp (Trazimera), a biosimilar referencing Herceptin. Trazimera earned EU authorization in July 2018.
The FDA also issued a Form 483 to Biocon after a February 2019 inspection of its Bangalore, India, facility. One issue documented by the FDA says that procedures designed to prevent microbiological contamination are not established or followed and points out a lack of appropriate procedures to prevent contamination on the drug product fill line. The second issue states that written records of investigations into unexplained discrepancies sometimes lacked adequate conclusions or follow-up.
Biocon acknowledged the Form 483, saying that it was related to a preapproval inspection of a new injectable manufacturing line. A representative from Biocon said that the company has already addressed the observations and made a response to the FDA.
In European regulatory news, the European Commission approved Roche’s innovator rituximab, sold in Europe as MabThera, for the treatment of pemphigus vulgaris (PV), a rare autoimmune disorder. The approval marks the first biologic approval for PV in the European Union and the first major new therapeutic option in 60 years.
In Japan, Lupin and YL Biologics received approval to manufacture and sell YLB113, a biosimilar etanercept product. The product will be Lupin’s first biosimilar to come to the Japanese market.
Back in the US capitol, 2 senators launched a bipartisan effort to address the issue of patent thickets. Senator Susan Collins, R-Maine, and Senator Tim Kaine, D-Virginia, introduced the Biologic Patent Transparency Act, which would require companies to publicly disclose the patents that protect their originator biologics, thus making it easier for competitors to evaluate and plan for the development of biosimilars.
The House Committee on Energy and Commerce held a Health Subcommittee legislative hearing on lowering the cost of prescription drugs. The 7 bills that were the subject of the hearing include several items of legislation that have long waited for congressional action as well as new proposals to address the need for increased competition. They include the Creating and Restoring Equal Access to Equivalent Samples (CREATES) Act, which would allow a biosimilar or generic developer to bring a civil action against an innovator drug company if the latter refuses to make available enough samples of a product for testing.
It also includes the Fair Access for Safe and Timely Generics (FAST Generics) Act. This proposed legislation would amend the Federal Food, Drug, and Cosmetics Act to prohibit license holders of FDA-approved drugs or biologics from restricting availability of their products for testing by competitors who seek to develop generics or biosimilars. It would also stipulate that Risk Evaluation and Mitigation Strategies cannot restrict the supply of samples to generic or biosimilar developers.
The Most Interesting Man Revolutionizing The Health World
Nicole Fisher Contributor
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He wrote his first world-renowned book at the age of 26. On weekends he recites love poems (ghazals) on Voice of America. He casually – and humbly – references his more than 70 patents that range from aging wine to chewing gum to bioreactors to air scrubbing systems at his infamous Chicago wine parties. And his mustache rules his twitter feed. In 2013 he was awarded the Star of Distinction, the highest civil award by the Government of Pakistan, for his inventions that are making significant impact in developing countries. He has written over 50 books, well over 100 research papers, and hundreds more articles in the field of science, philosophy, rhetoric, poetry and religion, drawing thousands of hits per day on his blog. Dr. Sarfaraz Niazi might just be the most interesting man in the world, but he is certainly the most interesting man pursuing biosimilars in the United States.
Throughout his career his driving principle has been to make things simpler. He did this while at Abbott Labs, as a former tenured professor at the University of Illinois at Chicago (UIC), in developing countries, and presently in his independent career at Therapeutic Proteins International, LLC (TPI) where he is working on biosimilars – or “copies” of current biologic pharmaceuticals that are about to lose their patents. Although only 17 biosimilars have been approved to date worldwide, though none in US, Dr. Niazi and TPI have nine in the pipeline to transform the entire market. According to photographer Steve Huff, Dr. Niazi is, “An amazing man, in fact the most interesting man in the world!”
Flexibility Is Key To Innovation
When asked his advice to other inventors in a recent interview, Dr. Niazi explained his philosophy that, “You should never get enamored by your thoughts. If the idea does not solve a problem or move the quality of life farther, there are many more things to be invented.” With that mentality, he is filing two products this year alone, similar to Amgen Inc.’s $6 billion molecule white blood count product, due to its expiring patent in the cancer market. Next year, the two molecules he plans to take to market are similar to AbbVie’s expiring $12 billion product Humira.
With movement like that, it’s no wonder Dr. Niazi claims that the U.S. Food and Drug Administration (FDA) is his “friend.” Nevertheless, he notes extreme complications with the rolling submission model, which can cost up to $4 million per submission in fees alone. Additionally, the four levels of the FDA’s “analytical similarity” benchmarking can be troublesome if one has a new biologic entity. This benchmarking, however, allows scientists and the FDA to work together in a predictable, step-wise fashion to move products to market quickly that have fingerprint-like similarity to existing US-licensed biologic products.
Dr. Niazi’s strategy is to create an analytical and clinical equivalent to biologics with expiring patents, which is preferred even over a Phase 3 clinical trial. By doing this, the cost of production is reduced drastically and the speed of development increases by 2-3 times. Dr. Niazi estimates an overall reduction in production costs for his biosimilars of up to 50% or higher compared to market competitors.
With movement like that, it’s no wonder Dr. Niazi claims that the U.S. Food and Drug Administration (FDA) is his “friend.” Nevertheless, he notes extreme complications with the rolling submission model, which can cost up to $4 million per submission in fees alone. Additionally, the four levels of the FDA’s “analytical similarity” benchmarking can be troublesome if one has a new biologic entity. This benchmarking, however, allows scientists and the FDA to work together in a predictable, step-wise fashion to move products to market quickly that have fingerprint-like similarity to existing US-licensed biologic products.
Dr. Niazi’s strategy is to create an analytical and clinical equivalent to biologics with expiring patents, which is preferred even over a Phase 3 clinical trial. By doing this, the cost of production is reduced drastically and the speed of development increases by 2-3 times. Dr. Niazi estimates an overall reduction in production costs for his biosimilars of up to 50% or higher compared to market competitors.
In 2003, the TPI founder committed that his work and company would stay in Chicago. He believed that from creation to manufacturing and testing to going to market, that TPI would excel in the Midwest due to Chicago’s health care ecosystem, experts and manufacturers.
Through a focus on creating “generic equivalents,” Dr. Niazi is proving that TPI can be wildly successful in the Midwest, and further, that in the same way generics revolutionized how people access pharmaceuticals, biosimilars can revolutionize the way those around the world access lifesaving treatments.
As his biosimilars enter the market with FDA approval, the ability of Dr. Niazi to impact the entire health sector grows because his biosimilars can be substituted for its reference product without provider or patient intervention. However, the FDA has not yet finalized these guidelines, and only 17 biosimilars have been approved internationally to date, of which none are by the FDA.
Ultimately, with numerous billion-dollar biologics coming off patent over the next six years, and the exorbitant cost for specialty drugs, the nine biosimilars TPI has in the pipeline stand to make a huge impact in the health sector. While Dr. Niazi could be doing many interesting things these days as an international man of mystery, he has devoted his research, time and energy to bringing high quality, cost-effective treatments to the US, and beyond. So long as he maintains his wine parties and poetry readings, its certain no one will complain.
Impact of proposed changes to FDA approach to biosimilars Posted 08/03/2019
In the Opinion article, Professor Sarfarez Niazi urges the US Food and Drug Administration (FDA) to make adjustments to its guidance on biosimilar development [1]. Niazi’s proposals are consistent with the anti-regulatory political rhetoric and administrative actions that are becoming increasingly widespread in the US. In this article, Professor Pekka Kurki comments on some of Niazi’s proposals from a global perspective [2].
Bridging studies. Most regulatory agencies require ‘bridging studies’ to demonstrate that a foreign sourced reference product and the corresponding domestic product are highly similar. Niazi proposes that bridging studies should not be required if the two products have the same composition and have been licenced based on the same documentation. Kurki agrees that some bridging studies may not be needed for products sourced from ‘highly regulated’ regions, as these have had regulatory surveillance for over 10 years and should therefore be very similar and safe. He notes that collaboration and data sharing between key regulatory agencies would facilitate the acceptance of a global reference product, and that FDA should promote this.
Clinical trials. Single-dose comparative pharmacokinetic (PK) studies are recommended by regulators where the product can be safely administered to healthy volunteers. Niazi makes several proposals to reduce the requirements of PK evaluation, and proposes PK studies in monkeys. He promotes the use of in vitro and in vivo non-clinical testing of immunogenicity in place of clinical immunogenicity studies. Kurki argues that PK studies in monkeys would be problematic from scientific, ethical and global development perspectives. He notes clinical immunogenicity studies aim to look for harmful immunogenicity and the ability of in vitro tests to entirely mimic the human immune system is inadequately documented for regulatory purposes.
Interchangeability. Fundamental to the economic benefits of biosimilars is the ability and willingness to switch between originator products and their biosimilars. Profession Kurki believes that the differing policies of leading regulatory authorities regarding interchangeability creates uncertainty among stakeholders worldwide. He argues the global market would benefit if FDA would clearly separate interchangeability without (automatic) substitution from interchangeability associated with substitution at the pharmacy level, and that this would allow prescribers and local regulatory authorities to develop safe methods for switching. He believes the requirement of specific switching studies using the local reference product discourages global development of biosimilars.
Education. Niazi believes that FDA needs to provide more information on the safety of biosimilars. By contrast, Kurki argues that the problem is not the availability of information on biosimilars, but rather that the information is likely to only reach prescribers who have a specific interest in the data. The recent consultation on FDA draft guidance on interchangeability clearly established that the views of physician societies closely follow the opinions of the innovator sector of the industry. Kurki therefore encourages FDA to engage in discussion with medical societies who publish position papers on biosimilars.
Balancing innovation with competition. Niazi criticizes FDA’s approach to manufacturing, analytical comparisons and clinical development of biosimilars. FDA has recently published a plan to revise its approach to biosimilars, the Biosimilar Action Plan (BAP) with the aim of streamlining biosimilar guidance and restoring the balance between protection of innovation, and competition and access to biologicals [3]. Many of the points raised by Niazi and Kurki will be considered as part of this plan.
Obstacles to success for biosimilars in the US market
Since 2007, the EMA has approved 31 biosimilar products1 and refused or withdrawn around five. The FDA, however, since the enactment of the Biologics Price Competition and Innovation Act (BPCIA) in 2009,2 has licensed six products under PHS 351(k) of the Public Health Service (PHS) Act; approved one product under 505 (b)(2) of the Federal Food, Drug, and Cosmetic (FD&C) Act; and sent out four Complete Response Letters (CRLs) to 351(k) Biologics License Applications (BLAs),3 including two applications each for pegfilgrastim and erythropoietin alfa (Table 1).
This commentary is based on my hands-on experience of developing biosimilars in the US and taking them to the 351(k) filing. More specifically, I will share a novel model for developing biosimilars that appears promising in overcoming many obstacles identified herein.
1. Obstacle 1: understanding the guidance
FDA writes the guidance to comply with two distinct requirements: statutory and scientific. Statutory requirements include analytical similarity, PK/PD, immunogenicity and animal toxicology, which the BPCIA mandates must be met based on scientific requirements that remain flexible and negotiable. I suggest that developers read the BPCIA carefully before reading the guide. One might be surprised to note that the FDA does not mention ‘phase 1’ or ‘phase 3’ in its guidance because human studies for biosimilars are intended to provide a comparative profile, not a measure of efficacy. This distinction is important, yet difficult to embed in the minds of scientists who are used to traditional phase 1-3 studies. Concessions such as using a development lot for a phase 1 study are not available for PK/PD studies for biosimilars, as these must be at-scale GMP lots.
The FDA uses the terms, ‘no residual uncertainty’ and ‘step-by-step’ approach, carefully and in a structured format. If you have resources that allow you to jump the steps, you should find that you are awarded a CRL; never make the mistake of doing what should not be done, such as unnecessary studies in patients.
Table 1: FDA approved biosimilars
2. Obstacle 2: not knowing your molecule
Biosimilar development requires a deeper understanding of the molecule of choice to replicate all limitations and all ‘imperfections’ of the reference product. With a new molecule, you take whatever you have and prove its safety and efficacy; in the case of biosimilars, you need to replicate, even if a feature is not clinically relevant, using a technology that may be protected by hundreds of patents designed to prevent you producing the same molecule. These scientific constraints are better addressed when the development work is outsourced to qualified teams that may not be possible to gather in-house. I strongly urge developers to explore the power of partnering with CDRMOs.
3. Obstacle 3: ignoring importance of freedom to operate
As of today, every product approved by the FDA is under litigation.4 An extensive freedom to operate analysis will teach that developers should concentrate on a wide choice of potential candidates with a market of over $120bn that have a lesser risk of litigation. Teaching science to the legal team and law to the scientists does not work well; however, there are several expert teams available to conduct these determinations. I recommend outsourcing this work, rather than doing it internally and getting constrained by the available expertise.
4. Obstacle 4: reliance on patient studies
The reason that the FDA does not mandate a patient study for the approval of biosimilars has its roots in the statutory declaration in CRF 320.25 (a) that, “no unnecessary human research should be done”. When this statute was established for the bioequivalence testing of chemical drugs, the prospect of highly potent biosimilar antibodies was not envisioned; today, the declaration applies more to biosimilars as we develop highly potent and immunogenic products whose testing in humans is riskier. In addition, we now face a new conundrum5 where it has become more difficult to find patient populations on whom to test drugs, causing delays and escalating costs in the development of biosimilars. Developers should aim to avoid all studies in patients, and that requires a different approach to designing other similarity testing studies. A fingerprint-like molecule is least likely to invoke any need for studies in patients.
5. Obstacle 5: underestimating interchangeability plan
The FDA allows two types of approvals for biosimilars and one of these grants permission to interchange without consultation with the prescriber – an interchangeability designation that requires, by statute, a patient study to demonstrate switching and alternating, demonstrating no less efficacy and no more safety issues. Given the dearth of patients, particularly for anticancer drugs, developers face difficulties in managing patient studies and, as a result, I see fewer applications for the interchangeable status coming to the FDA. My advice: stay away from interchangeable filings if you want a fast-to-market entry. My Citizens Petition to the FDA questions the scientific rationale of approval once the FDA determines that there is ‘no clinically meaningful difference’.
6. Obstacle 6: not understanding side-by-side testing
Safety and efficacy are tested side by side, with highly complex statistical modelling to prove similarity. How does one determine that there remains no ‘residual uncertainty’? How does one design studies that are sensitive to demonstrating differences rather than similarity? For example, the choice of dosing level in animal toxicology studies, whether for rodents or other mammals, should be within the escalating range of the sigmoid curve. The three statistical tiers in analytical similarity testing are not intended to make one test more important than the other. The tier 1 and tier 2 tests remain fraught with mathematical difficulties that the FDA still needs to fix. A tier 1 test where the reference product has very small standard deviation will always fail, and a tier 2 test will fail if the biosimilar products have fewer degradants or aggregates. The FDA does not allow non-inferiority testing in analytical similarity. Still, the developer needs strong statistical expertise to develop analytical similarity testing protocols. Similarly, clinical studies cannot be overpowered to obviate deficiencies in the design or testing of drugs or antibody levels. The FDA is still improving its guidance on statistical testing; the developer is advised to read the reports that the FDA has made public while approving biosimilar products.
7. Obstacle 7: GMP compliance
Unlike in the development of a new product, the FDA expects all testing to be done using at-scale lots in a GMP environment and in a CFR Part 11 compliant laboratory. This requirement comes because there is no mandatory patient trial anticipated to establish safety and efficacy of the product. The FDA guidance on GMP for investigational drugs6 is interpreted differently for biosimilars, and the FDA can audit the facility for full GMP compliance in response to an Investigational New Drug (IND) filing – an aspect that many new developers fail to realise. It is for this reason that biosimilar development works better when development work is outsourced, rather than creating a fully integrated traditional facility. Outsourcing also allows developers to bring in creative technologies7 to obtain lower cost of goods sold. In my calculations, it is more efficient and less costly to work with CDRMOs than doing the work internally.
8. Obstacle 8: FDA meetings
Formal meetings with the FDA are designed to address the issues of ‘residual uncertainty’, rather than function as teaching lessons for developers. A well-informed developer should be able to write meeting requests that result in the definite closure of issues rather than seek general advice. The FDA has made public its evaluation of the first biosimilars approved, and this information should be sufficient to write appropriate protocols, establish analytical similarity testing, select an animal toxicology model, etc. The goal of Type 2 meetings is to come out ready for the Type 3 meeting without going back to another Type 2, as most developers have done recently. Another piece of information for small companies is that while the FDA may waive the filing fee for your first application, the fee for meetings cannot be waived according to the 2017 revision of the Biosimilar User Fee Act (BsUFA). Generally, consultants hired to write and manage FDA applications have little experience and mistake this exercise for a validation of plans – the goal is to negotiate terms, not just shake hands.
9. References
1. www.ema.europa.eu
2. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ucm216146.pdf
3. www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm
4. www.healthlawpolicymatters.com/wp-content/uploads/sites/8/2016/08/Status-of-Biosimilar-A pplications-August-2016.pdf
5. www.nytimes.com/2017/08/12/health/cancer-drug-trials-encounter-aproblem- too-few-patients.html?_r=0
6. www.fda.gov/downloads/drugs/guidances/ucm070273.pdf
7. www.niazi.com/bioprocessing
10. Biography
SARFARAZ K NIAZI, PhD, SI, FRSB, FPAMS, FACB, is the Founding Executive Chairman and CSO of Karyo Biologics, LLC, the Founder of Adello Biologics, LLC, a fully integrated US biosimilar company, and Adjunct Professor of Biopharmaceutical Sciences, University of Illinois, Chicago. He has over two decades of hands-on experience in taking biosimilars to market globally. He has authored dozens of major books about biosimilars, bioprocessing, pharmaceutical formulations and regulatory
Sarfaraz K. Niazi, Founder at Karyo Biologics, Adello Biologics and Pharmaceutical Scientist, LLC
https://biotechpharmasummit.com/index.php/speaker/sarfaraz-k-niazi/
Sarfaraz K. Niazi (1), Adjunct Professor of Biopharmaceutical Sciences, University of Illinois College of Pharmacy, University of Houston and several other academic institutions, is the founder of Karyo Biologics (www.karyobio.com), Adello Biologics (www.adellobio.com) and Pharmaceutical Scientist, LLC (www.pharmsci.com). Sarfaraz is globally recognized as a pioneer of biosimilars having developed novel technology and regulatory plans to take dozens of biosimilars to the market over a period of over 30 years.
In 2014, the Forbes Magazine’s recognized him as “The Most Interesting Man Revolutionizing The Health World” (2), for his lifetime efforts in making high cost essential drugs, biosimilars and complex generics, accessible across the globe.
In 2018, the Forbes magazine reported him as “Scientist Invented A New Pathway To Approve Biosimilars, And The FDA Is Listening” (3), for his efforts to convince the US FDA to adopt a more rational approach to approve biosimilars reduce the cost of development. He is now advising the US FDA in defining the structure of their new Biosimilars Action Plan (BAP) (4) that was issued by the US FDA after Sarfaraz filed a citizen petition against the FDA (5) (FDA-2018-P-1876). The FDA has also shared the progress made in collaboration with Sarfaraz on the US government portal (6, 7). Sarfaraz’s efforts in changing the FDA approval process are widely acclaimed to be the most pivotal move to make biological drugs affordable (8-24).
To promote faster adoption of biosimilars, Sarfaraz has written dozens of major books (25), including the first book on biosimilars and coined the phrase “biosimilar” in his first biosimilars guidance advise to FDA. Other major books of Sarfaraz include the first book on single-use bioprocessing, a textbook on bioprocessing, a two-volume book on biosimilars, a six-volume set of cGMP manufacturing encyclopedia, the largest book on bioequivalence testing and the first book on preformulation of biologics and botanical drugs. He has also authored 100+ research papers and hundreds of blogs. His most recent book, Biosimilarity: The FDA Perspective, published July 2018 is dedicated to Dr. Janet Woodcock, Director, CDER at the FDA. His other books have been dedicated to Dr. James Watson, Nobel Laureate, who discovered DNA structure and President Barack Obama with White House approval, among other notable personalities.
Sarfaraz has also authored a large number of internationally published blogs on topics ranging from contemporary scientific ideas to philosophy, poetry and ironies of life.
Sarfaraz has been a keynote speaker on the topic of biosimilars including presenting the FDA viewpoints before the industry audience (26). He is a fellow of several learned societies and a widely sought-after speaker with over 500 talks across the globe. In his capacity as an academician, Sarfaraz has trained 50+ graduate students and scores of FDA inspectors.
A few notable contributions of Sarfaraz include:
Contributed to BPCIA as advisor to the US Congress and President Obama.
Received first waiver of in-patient testing of a biosimilar candidate under 351(k).
Developed a fourth-dimension analytical similarity testing to achieve fingerprint-like similarity for biosimilars.
Developed an ISO 9 bioreactor used to file the first BLA of a biosimilar.
First book authored by Sarfaraz and FDA on the topic of biosimilarity (27) and dedicated to Dr. Janet Woodcock, Head, CDER, FDA.
Published advise to the US FDA and the industry to identify and obviate the impediments to slow entry of biosimilars in the US markets (28,29).
Filed citizen petition on the subject of changing evaluation of biosimilars by the FDA (30).
Trained FDA inspectors on cGMP compliance.
Coordinated dozens of FDA audits of generic and biological manufacturers, particularly managing consent decrees.
Consultants to investment bankers, VC groups and private investors on value proposition analysis in the field of pharmaceutical and biopharmaceuticals.
Served as expert witness in IP and pharmaceutical cases.
Trained scientists on behalf of the USP.
Translated love poems of famous Asian and Persian poets into English.
Taught thousands of primary and secondary care physicians in the US on the regulatory pathways and safety features of biosimilars.
Sarfaraz is the largest solo inventor of bioprocessing inventions with over 100 inventions (31), additionally including new drugs, new dosage forms, bioequivalence testing methods and a large number of other patient-related inventions that are widely used across the globe. His patented invention of demonstrating analytical similarity methods (32) was accepted by the FDA to allow waiver of patient trials of biosimilar products.
Sarfaraz is also a licensed practitioner of the patent law at the United States Patent Office, an expertise he has used to create the FTO boundaries for biosimilars to avoid litigation under the BPCIA (33, 34). Sarfaraz provides this service free of charge to the Third World scientists and has secured over 400 patents for his clients.
The President of Pakistan conferred the high civil award, Start of Distinction (35), upon him in the field of engineering sciences, as his 100+ inventions are helping a large population around the world with more affordable drugs, clear water, new drugs, new devices, and novel disease management systems.
Sarfaraz is working with global biosimilar companies to help them secure faster approval of biosimilars as well as working with the US Congress, the FDA and the media to avoid impediments to adoption of biosimilars; recently, Sarfaraz and Pfizer have joined and advised the FDA to adopt the policies that will prevent companies like Amgen to differentiate biosimilars (36). Sarfaraz is also teaching physicians in the US on behalf of the largest biosimilar companies on the safety and regulatory paths to approvals.
Sarfaraz was born in Lucknow, India. He received as MS degree in pharmacy from the Washington State University, and a PhD in pharmaceutical sciences from the University of Illinois, where he began his academic career and continues as Adjunct Professor of Biopharmaceutical Sciences at the University of Illinois College of Pharmacy and additionally at the University of Houston and several other academic institutions around the world. Sarfaraz became a tenured professor at the age of 28, a position he left to join Abbott Laboratories International, where he was tenured as Volwiler Fellow. He left Abbott to develop biosimilars to make them accessible globally.
Sarfaraz is an avid photographer, a musician, a poet, a radio broadcaster (Voice of America, US State Department) with audience of over a billion, on literary and philosophic topics. He is also a translator of Asian love poems into English; he resides in Deerfield, Illinois.
References
http://www.fdalawblog.net/2018/05/biosimilar-approval-better-stronger-faster/
https://www.regulations.gov/document?D=FDA-2018-P-1876-0003
https://www.regulations.gov/document?D=FDA-2018-P-1876-0004
https://www.biospace.com/article/fda-withdraws-draft-guidance-on-biosimilar-development
https://seekingalpha.com/news/3367537-fda-withdraws-draft-guidance-related-biosimilar-development
http://www.fdalawblog.net/2018/05/biosimilar-approval-better-stronger-faster/
https://www.europeanpharmaceuticalreview.com/article/70987/obstacles-success-biosimilars-us-market/
https://www.jdsupra.com/legalnews/fda-to-hold-public-hearing-on-67759/
https://exlevents.com/fda-12. withdraws-biosimilar-draft-guidance-after-public-outcry/
https://www.epmmagazine.com/news/fda-is-asking-for-public-comments-on-bioequivalence-testing-/
https://www.rdmag.com/article/2014/10/biosimilars-market
https://www.niazi.com/scholar/
https://karyobio.com/news/2017/11/6/dr-niazi-invited-as-keynote-speaker-at-the-fdacms-conference
https://www.barnesandnoble.com/w/biosimilarity-sarfaraz-k-niazi/1125939292
https://www.europeanpharmaceuticalreview.com/article/70987/obstacles-success-biosimilars-us-market/
http://www.fdalawblog.net/2018/05/biosimilar-approval-better-stronger-faster/
https://sarfaraz-niazi.squarespace.com/s/biomolecule-patent.pdf
https://patents.google.com/patent/US20180024137A1/en?oq=US20180024137A1
https://www.law.cornell.edu/uscode/text/42/262
https://en.wikipedia.org/wiki/Category:Recipients_of_Sitara-i-Imtiaz
Scientist Invented A New Pathway To Approve Biosimilars, And The FDA Is Listening
Nicole Fisher Contributor
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And is currently listed as the largest solo holder of bioprocessing patents in the world.
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In an extraordinary move, the FDA has withdrawn the draft guidance, "Statistical Approaches to Evaluate Analytical Similarity,” after receiving public comments and one citizen petition (FDA-2018-P-1876). The goal of the guidance was to provide an action plan for evaluation of similarity between proposed biosimilars and the original products. FDA Commissioner Dr. Scott Gottlieb, ordering the withdrawal of the guidance, expressed disappointment with the current pace of biosimilar development. “As the cost to develop a single biosimilar product can reach hundreds of millions of dollars, it's important that we advance policies that help make the development of biosimilar products more efficient, and patient and provider acceptance more certain," he said.
But what makes the FDA about-face on biosimilar evaluation so monumental, is that it was the direct result of the citizen petition. Filed by one man: Dr. Sarfaraz Niazi, Adjunct Professor at the University of Illinois at Chicago and CEO of Pharmaceutical Scientist, Inc. When asked about his success in influencing the FDA, the man I once wrote about as the most interesting man revolutionizing the health world, commented, “The idea of making biosimilars accessible has not worked out well to date primarily because of the complexity and redundancy in the regulatory pathway. After I pointed out the complexities and errors in the regulatory guidance and offered alternative approaches, the FDA Commissioner became motivated to make changes. This is the first time that the FDA has simply withdrawn one of its guidance.”
So, what makes the opinions of Dr. Niazi so influential? In 2003, he established Therapeutic Proteins Inc., later named Adello Biologics, with the goal of manufacturing biological drugs and supply them, “at any cost affordable by anyone across the globe.” He then went on to write the largest number of books on biosimilars and worked with the White House in developing the details of the Affordable Care Act that included the Biologics Price Competition and Innovation Act (BPCIA). And is currently listed as the largest solo holder of bioprocessing patents in the world.
Challenging Biosimilar Development Plans
Although there have been barriers to biosimilar uptake in the U.S. that range from lack of provider education to therapeutic interchangeability, the FDA and non-big pharma supporters have high hopes for the future of biosimilars. So, when Dr. Niazi contacted the FDA and told them there was a dire need to re-evaluate the scientific rationale behind the current methods of testing biosimilarity – with aim to reduce barriers including redundant analytical testing and testing in humans without compromising the quality to save significant amounts of time and money – they listened.
His basic premise is built around the FDA’s commitment to engaging scientific methods that reduce testing; in line with US 21 CFR 320.25(a), which codifies the universal belief that, “No unnecessary human testing should be performed.” In the case of biosimilars, testing in healthy subjects is unethical because of their potential of making the study subjects immunoreactive for the rest of their lives. The second premise proposed by Dr. Niazi is to invoke new technologies to establish similarity between biosimilars and reference products to remove any “residual uncertainty,” to allow faster approval of biosimilars. Dr. Niazi argues the use of “thermodynamic equivalence,” a process he created that he claims removes the need for blood-level studies to determine differences between products, can do this.
Dr. Sarfaraz K. Niazi
Niazi.com
Other ideas presented included eliminating bridge testing when a non-U.S. reference is used in certain conditions (reducing the number of reference product batches required), creating a mechanism to make reference samples freely available (allowing more ethical in-vitro immunogenicity testing), minimizing non-inferiority testing in patients because of their lack of utility, and changing the pharmacokinetic testing to disposition-related parameters and allowing testing in more homogenous populations. Dr. Niazi also suggested that the FDA promote substitution of biosimilars for new patients through educational programs.
What’s Next?
Within days of the FDA withdrawing the guidance on biosimilars, Dr. Janet Woodcock, Director of Center for Drug Evaluation and Research (CDER) and the FDA Commissioner issued a July 1, 2018 Biosimilar Action Plan that considers most of the recommendations made by Dr. Niazi.
In the 1980s, the Hatch-Waxman Act created a new class of drugs – generic – that has saved American patients over a trillion dollars. If successful, biosimilars, like generics, can save a lot more by making biological drugs more affordable. The FDA has demonstrated that it listens to scientific and creative suggestions. And Dr. Niazi may finally be able to reach his dream of making healthcare more affordable. “Now that FDA is open to scientific approaches to proving biosimilarity, the burden lies on developers to design their plan more creatively. I anticipate a wave of approvals by FDA that will bring price drop of more than 50% – a threshold required to disrupt the markets by taking the decision-making from the hands of prescribers to payers. Eventually I see biosimilars becoming biogenerics, which I had predicted in my first book on the subject," he said.
222,767 viewsAug 30, 2014, 08:31am
https://biosimilars.annualcongress.com/ocm/2019/sarfaraz-niazi-karyo-biologics-and-adello-biologics-usa
13th International Conference on
Biosimilars and Biologics
March 18-19, 2019 Holiday Inn Amsterdam - Arena Towers
Theme: European Biosimilars: Present Scenario & Future Prospects
https://www.prnewswire.com/news-releases/fda-withdraws-its-pivotal-biosimilar-products-testing-guideline-after-sarfaraz-niazi-founder-of-pharmaceutical-scientist-files-the-first-citizen-petition-challenging-its-clinical-relevance-300675168.html
FDA Withdraws its Pivotal Biosimilar Products Testing Guideline After Sarfaraz Niazi, founder of Pharmaceutical Scientist, Files the First Citizen Petition Challenging its Clinical Relevance
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Jul 02, 2018, 12:00 ET
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CHICAGO, July 2, 2018 /PRNewswire/ -- In an unprecedented move on 21 June 2018, the FDA withdrew the draft guidance, "Statistical Approaches to Evaluate Analytical Similarity," issued in September 2017, after receiving public comments and the only citizen petition (FDA-2018-P-1876) filed by Sarfaraz K. Niazi, Adj. Professor, the University of Illinois and the founder of Pharmaceutical Scientist, Inc, on 14 May 2018, in his individual capacity.
The FDA Commissioner Scott Gottlieb, MD, ordering the withdrawal of the guidance expressed disappointment with the current pace of biosimilar development. He said, "as the cost to develop a single biosimilar product can reach hundreds of millions of dollars, it's important that we advance policies that help make the development of biosimilar products more efficient, and patient and provider acceptance more certain."
The Niazi petition suggests waiving the bridging studies for qualified non-US comparators and encouraging payers to reimburse only for biosimilars when prescribed for new patients; the FDA Commissioner agrees. Further, Niazi pointed out several errors in the analytical similarity testing protocols and offered alternative approaches that limit the testing to non-release quality attributes to reduce the number of reference product batches required, a major issue; creating a mechanism to make reference samples available freely, allowing more ethical in vitro immunogenicity testing, where justified; minimizing non-inferiority testing in patients because of their lack of utility; allowing the use of surrogates and markers to prove clinical efficacy; and changing the pharmacokinetic testing to disposition-related parameters and allowing testing in more homogenous populations. In a communication to Niazi on 26 June 2018, Dr. Janet Woodcock, the Head of the CDER at the FDA, acknowledged taking into considerations the recommendations made by Niazi to promote a more competitive and efficient pathway for the development of biosimilars.
"This quick action by the FDA is a historic step providing a remarkable opportunity to develop biosimilar at reduced time and cost by invoking creative, clinically relevant, approaches," said Niazi, who has written the largest number of books and papers to make biosimilars more accessible. Niazi also assists biosimilar developers in expediting their programs.
Pharmaceutical Scientist, Inc., is a consulting company using a novel fast-to-market model, as recently used by Karyo Biologics, to bring insulin glargine and bevacizumab biosimilars to the clinical stage and licensing out within 12 months.
Contact: niazi@pharmsci.com.com; +1-312-297-0000; www.karyobio.com; www.niazi.com; www.pharmsci.com
Citizen Petition: https://www.regulations.gov/document?D=FDA-2018-P-1876-0001
Papers: https://karyobio.com/news/
https://exlevents.com/speakers/sarfaraz-niazi/
Bye Bye biosimilars: Big Pharma’s imminent exit in sight, says expert
by Dan Stanton Wednesday, November 7, 2018 4:38 am
As prices drop, Big Pharma will exit the biosimilar space over the next five to 10 years, says industry expert Sarfaraz Niazi. Amgen, Novartis and Pfizer refute the claim, saying they are in the sector for the long-term.
Blockbuster biologic originator companies are, by definition, Big Pharma firms and the target of biosimilar developers. Roche and AbbVie, two of the firms most susceptible to biosimilar erosion, have vocalized the need for a stringent regulatory framework – including calls for appropriate data, individualized labels, and unique identification for all biotherapeutics – while attempting to bat off competition by reformulating products and beefing up both their pipelines and IP.
But at the other end of the Big Pharma spectrum, there are several firms that dominate the biosimilar European and US markets, namely Novartis, Pfizer and Amgen, which all claim to have some of the largest biosimilar pipelines in the industry.
Big Pharma will exit biosimilars over the next ten years, an industry expert predicts. Image: iStock/kanvag
Novartis – through its Sandoz division – has been marketing biosimilars for over a decade in Europe, and was the first to launch a biosimilar in the US after Zarxio, its version of Neupogen (filgrastim), received approval in 2015.
Pfizer, which was the first to launch a version of J&J’s Remicade (infliximab) in the US, has four US approvals. The firm expanded its biosimilar pipeline through the $17 billion ( €14.9 billion) acquisition of Hospira in 2015.
Amgen, despite suffering revenue loss from an influx of first-wave biosimilars and trying to defend against versions of its bestselling biologic Enbrel (etanercept), has 10 biosimilars in its portfolio that includes US approved versions of AbbVie’s Humira and Roche’s Avastin.
1. Just a little bit of history repeating
But Big Pharma’s interest in biosimilars is soon to end, according to Sarfaraz Niazi, a pharmaceutical sciences and biotechnology expert with over 30 years of industry experience.
In 2014, Niazi wrote the Handbook of Biogeneric Therapeutic Proteins, a book that predicted Big Pharma will exit the biosimilars space once specialized developers appear on the scene.
“This is history repeating from the generics era,” he said. “There are so many ways to cut the cost of development and cost of manufacture but because of their mindset and design, Big Pharma cannot do this. They can certainly change both but that requires a monumental shift.”
Niazi, who founded biosimilar developer Karyo Biologics earlier this year, told BioProcess Insider that back in the 1980s many large pharma planned to enter the generic market. “However, as the prices tanked, they all pulled out.”
So far, the big companies are seeing much bigger profits in biosimilars than sustainable, Niazi argued. “I have projected that once the prices fall to below 60% of the current prices, it will no longer be feasible for the Amgens and Pfizers to stay in this market for long.”
And this will be accelerated when companies from India and perhaps China bring in products with substantially lowered cost, he continued. “Every monoclonal antibody regardless of its use costs about $150-200 per gram. This price will drop by another 50% once the Indian and Chinese companies start getting approvals; at this stage, the prescribers will become redundant and payers will take over.”
2. Biosimilar exit?
There are already signs of Big Pharma exiting the space, he continued, citing Merck KGaA’s exit from the space in 2017 when it divested its biosimilars business to Fresenius for an upfront payment of €170 million ($195 million).
And last month the other Merck – Merck & Co. (known as MSD outside North America – dropped its Lantus (insulin glargine) biosimilar program after assessing the anticipated pricing and cost of production of the product.
Meanwhile in the past few days, Sandoz, on the back of a US Food and Drug Administration (FDA) complete response letter (CRL) demanding more data, has pulled the plug on its rituximab program in the US.
“It will take at least five and perhaps 10 years before the real impact of dropping prices is felt, given that the approval of biosimilars is not fast enough, but it is coming,” Niazi warned.
The market therefore will be taken over by specialized biosimilar firms such as Samsung Bioepis and Coherus, both of which are already competing in the space. Samsung Bioepis, joint venture between Biogen and Samsung BioLogics has a Remicade (infliximab) biosimilar competing in the US and several others in Europe, while Coherus this week saw its version of Amgen’s Neulasta (pegfilgrastim) approved in the US.
And the traditional generic pharma firms are also lining up to make their mark. Teva, which has seen success with first wave biosimilars in Europe, is poised to enter the US market with the Celltrion developed Rituxan (rituximab) biosimilar CT-P10. Mylan, meanwhile, already has a Neulasta biosimilar approved in the US and claims to have 20 biosimilars and insulin analogs in its portfolio.
3. Big Pharma Responds
When Merck & Co. pulled its insulin glargine product it told this publication that it remained committed to biosimilars. Similarly, Sandoz, Pfizer and Amgen dismissed the idea of any looming exit from the space when contacted by BioProcess Insider.
“Pfizer is committed to biosimilars as an important treatment option for patients,” spokesperson Thomas Biegi said. “We are working hard on bringing our biosimilars to market and will continue our efforts to ensure patients around the world have access.”
Amgen’s Kelley Davenport added: “While we can’t comment on our strategy, with 10 biosimilars in our portfolio, Amgen remains committed to its biosimilars program.”
And Sandoz spokesperson Chris Lewis said his firm is both a “global pioneer and leader” in biosimilars and remains committed to the sector. However, he acknowledged that this is a challenging space and “only a handful of players will succeed globally in the mid to long term.”
January-February From the Editor
https://bioprocessintl.com/2018/january-february-2018/january-february-editor/
by S. Anne Montgomery Friday, February 16, 2018 1:42 pm
Happy New Year! This is our first combined January–February issue, but it should give you plenty of reading material to compensate for the absence of a January issue. There are some new approaches at work for us this year that bring new opportunities for both end-user and supplier authors, as well as offering us additional options for more timely publication of high-priority information.
As you look at our table of contents, the most obvious change is the change to sponsored “Supplier Side” articles. Because our audited, controlled-publication model imposes strict ratios of editorial to advertising pages, we’ve been able to publish only one such paper per issue (two at most). But these articles often are timed to coincide with an event or product launch. The editorial part of the process(es) for supplier-written papers has not changed very much, but allowing for sponsorship gives us pages for more of them. This introduces a more collaborative (editorial + marketing) process that can help you get the word out about your company’s solutions to myriad production, processing, and formulation challenges.
We editors are especially excited about bringing you more information in the form of full articles, eBooks, and inserts (Featured Reports) derived from conference presentations. You will see more content derived from presentations given at Biotech Week Boston in the fall, BPI West in San Francisco this March, and other KNect365 events that we’ve not covered as much in the past. We might arrange for permission to record a presentation and work with a transcript; we might interview a presenter after the fact to expand on his or her talk. Cheryl Scott’s featured report in this issue includes a technical overview from the Fill–Finish sessions at BWB Boston this past fall. Sarfaraz Niazi’s biosimilars eBook in January was submitted as a manuscript and prepared for him to share at KNect365’s FDA/CMS Summit in December — where he discussed his suggestions with regulators. The big-data eBook in January is based on Lisa Graham’s BWB presentation.
We’ll clarify these connections where they apply, and we hope that BPI magazine’s relationships with our KNect365 events helps to provides a broader audience for both authors and presenters. Our normal submission and review processes otherwise remain unchanged but enhanced by these new options. BPI plans to publish 33 eBooks this year — with a digital process that’s more streamlined than print publication allows. Find out all that is on our plates for 2018 online and see if you’d like to participate. If you’ve written for us before but not spoken at one of our events, let us know how we get you in touch with our conference colleagues. Or if you’ve presented but not written, then let me know how I can work with you to bring your work to the attention of our global biopharmaceutical/biotherapeutics audience.
The world is bringing challenges to our industry from all sides with changes in political, economic, social, scientific, environmental, and ethical institutions and interest groups. All of us who care deeply about the future of healthcare and access to innovative, life-saving therapeutics share a responsibility to keep industry needs at the forefront of related discussions. BPI editors and our event organizer colleagues together remain committed to conveying your insights to as broad — and influential — an audience as we can.
https://www.omicsonline.org/speaker/sarfaraz-k-niazi-theraproteins-usa-536232203/\
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Sarfaraz K. Niazi
TheraProteins, USA
Title: Succeeding in the Biosimilars Market: A Pure Play Perspective
Biography
Sarfaraz K. Niazi, Ph.D., a leading authority on today’s biologic drug industry. Founder and Chairman of TheraProteins (TPI), a pure play biosimilar company located in Chicago, he is leveraging his diverse background and experiences to revolutionize the way biologics are made with the goal of enabling greater access to high quality, life-changing biosimilars. Niazi began his career in pharma at the University of Illinois, College of Pharmacy where he was a tenured professor before entering industry at Abbott Laboratories as Director of Technical Affairs in its international Division. Throughout his experiences, he witnessed a global disparity that fueled his passion for making high quality biologics affordable and accessible to people in need. He departed Abbott as a Volwiler Fellow to pursue that goal, first through consulting and soon thereafter through the founding of TPI.
Abstract
Competition in the small molecule market is clearly divided into two categories, brand and generic companies. Of course, some brand companies have generic businesses and some traditional generic companies such as Teva have launched their own brand products. But for the most part, the small molecule market is comprised of brand and generic players. With the biosimilars market, we’re seeing a competitive landscape that goes beyond the traditional brand/generic paradigm. Traditional brand companies such as Pfizer, Amgen and Merck are developing biosimilars, as are major generic companies such as Sandoz, Hospira and Apotex. But all these companies have business in areas outside their biosimilars unit as well, be it in novel drug development or in generic manufacturing. Pure Play biosimilar companies have a sole focus: developing biosimilars. Since these companies did not exist prior to the creation of the biosimilars market, they face many challenges and opportunities that other established competitors are without, ranging from financing to commercialization. This presentation will explore both the risk and benefit associated with competition in the biosimilars market as a pure play company, and provide insight into how these risks and benefits differ from those of an established generic or brand company.
https://markets.businessinsider.com/news/stocks/fda-issues-new-biosimilar-action-plan-bap-accepting-recommendations-made-by-sarfaraz-niazi-ceo-of-pharmaceutical-scientist-to-modernize-regulatory-approval-process-of-biosimilars-1027383309
FDA Issues New Biosimilar Action Plan (BAP) Accepting Recommendations made by Sarfaraz Niazi, CEO of Pharmaceutical Scientist to Modernize Regulatory Approval Process of Biosimilars
PRESS RELEASE PR Newswire
Jul. 19, 2018, 12:00 PM
CHICAGO, July 19, 2018 /PRNewswire/ -- In a quick follow-up to withdrawing a pivotal guidance on biosimilars on 21 June 2018, after Sarfaraz Niazi, CEO of Pharmaceutical Scientist, Inc., had filed a citizen petition and provided detailed advice on modernizing biosimilars regulatory process to Dr. Janet Woodcock, Head of CDER and FDA Commissioner Dr. Scott Gottlieb, the FDA has just-issued a Biosimilar Action Plan (BAP) that considers most of the recommendations made by Sarfaraz Niazi, including:
Standardized review templates tailored to regulatory dossier preparation;
Harmonization of regulatory guidance to create global regulatory dossiers;
In silico models and simulations to correlate pharmacokinetic and pharmacodynamic responses with clinical performance;
Increased use of non-U.S.-licensed comparator products to remove bridging studies;
Additional clarity and flexibility for product developers on analytical approaches to evaluating product structure and function to support a demonstration of biosimilarity, including by publishing revised draft guidance on the use of data analysis methods, including statistical approaches; identifying physical produce quality attributes that are most critical to evaluate;
Exploring ways to reduce the number of lots required for testing;
Enhanced education program to allow adoption of biosimilars for naïve patients.
The FDA is also establishing an Office of Therapeutic Biologics and Biosimilars (OTTB) to expedite review process, and to invite modern scientific approaches to demonstrate biosimilarity; FDA is further engaging in a public dialogue through a Part 15 hearing and opening a docket to request additional information from the public on what additional policy steps the FDA should consider as we seek to enhance our biosimilar program.
"This fast action by the FDA is a giant step in assuring faster approval of biosimilars and opens up new possibilities of scientific investigation to support claims of biosimilarity," said Sarfaraz Niazi, who has written the largest number of books and papers on the subject of biosimilars. He has also advised global regulatory authorities on designing their goal-specific guidance on the approval of biosimilars.
Pharmaceutical Scientist, Inc., is a consulting company that works closely with the FDA to assist biosimilar companies in securing faster approval by creating science-based, creative development plans to avoid testing in patients.
Contact: niazi@pharmsci.com.com; +1-312-297-0000; www.niazi.com; www.pharmsci.com
Citizen Petition Asks FDA to Withdraw Contentious Biologic Naming Guidance
https://www.centerforbiosimilars.com/news/citizen-petition-asks-fda-to-withdraw-contentious-biologic-naming-guidance
The FDA's updated guidance on the naming of biologics, biosimilars, and interchangeable products has caused deep concern among some proponents of biosimilars, and one stakeholder has now filed a citizen petition with the FDA in which he asks that the guidance be withdrawn.
Kelly Davio
March 26, 2019
Earlier this month, the FDA released updated draft guidance on the naming of biologics, biosimilars, and interchangeable biosimilars. The guidance holds that newly approved biologics, biosimilars, and interchangeable products will be assigned 4-letter suffixes, devoid of meaning, but it explains that the FDA no longer intends to require already approved products, including transition products, have such suffixes. The guidance caused deep concern among some proponents of biosimilars, and one stakeholder has now filed a citizen petition with the FDA in which he asks that the guidance be withdrawn.
Sarfaraz K. Niazi, PhD, 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, as well as the advisory company PharmSci, filed the petition on March 9, 2019. In the petition, he asks that the agency modify its position to state that no suffixes are required for any biologic products and instead state that brand names can be used along with National Drug Codes (NDCs).
In an interview with The Center for Biosimilars®, Niazi explained that “If you look at the labels [of biosimilars and their reference products] side by side, there is no possibility of any pharmacovigilance or traceability issue, and it has never been an issue.” He added that, for patients and prescribers, the presence of a suffix inappropriately suggests that there is a meaningful difference between the originator and the biosimilar. “In the minds of people, if you’re Mr. Johnson the third, you’re not Mr. Johnson the second,” he said.
When asked to respond to the FDA’s stated concern, expressed by FDA Commissioner Scott Gottleib, MD, that requiring already approved biologics to carry suffixes would be a costly undertaking, Niazi agreed that there would be substantial costs to innovator drug makers, from printing costs for labels to CMS coding considerations. However, he said, “there is no cost that is prohibitive to companies like Amgen.” According to Niazi, the FDA has long held that it makes its decisions on the basis of science, not cost to drug makers, a fact that makes concerns about these costs questionable.
Using suffixes for biosimilar products would be reasonable if suffixes served a purpose that could not be equally well served by using the brand names or NDCs for products, but the guidance served no purpose but to create a challenge for biosimilar acceptance and adoption, said Niazi.
Niazi’s citizen petition also asks that the FDA change its terminology used to describe biosimilars from having “no clinically meaningful differences” from the reference product to saying that products are “clinically similar.” Such a change, he said, would avoid confusion, and would keep reference product sponsors from capitalizing on potential ambiguity as a way to cast doubt on the safety and efficacy of biosimilars.
Finally, Niazi’s petition asks the FDA to warn biosimilar developers not to imply that their biosimilars are superior to other biosimilars, and to warn reference product sponsors against suggesting that the FDA is not competent to judge the safety and efficacy of these products.
The FDA has 180 days from the document’s March 14 acceptance to approve, deny, dismiss, or issue a tentative response to the petition.
The FDA Biosimilar Action Plan: Making Biologics More Accessible
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 Review, GaBI 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.
On June 21, 2018, the FDA, in an unprecedented move, withdrew its most significant and pivotal guideline, “Statistical Approaches to Evaluate Analytical Similarity” for biosimilars in line with the recommendations made in the petition. Within a few weeks of withdrawing this guidance, the FDA issued its Biosimilar Action Plan (BAP) that identified several changes coming in the biosimilars guidance.
The BAP, as currently posted by the FDA, includes a listing of 11 action items that the FDA considers to be pivotal, yet without addressing the needs of biosimilar developers in securing a faster approval by the FDA. While other stakeholders also need clarification of the FDA policies, it is the developers who will make it possible to bring lower-cost biosimilars to make a real difference. In this paper, I am providing comments on the proposed action plans of the FDA and pointing out what I believe to be the missing elements.
The BAP
Below are the key elements of the FDA’s BAP and a commentary on how these elements can be made more relevant to industry.
1. Developing and implementing new FDA review tools, such as standardized review templates that are tailored to enhance public information about FDA’s evaluation of these products.
While tools tailored to educate the public about how the FDA evaluates biosimilar Biologics License Applications (BLA) may help stakeholders better understand the process of approval, they do little to help developers unless the FDA chooses to include a molecule-specific template for developers indicating the types of studies required and how they are evaluated leading to the determination of biosimilarity. The template will help developers if it clearly defines how the FDA weighs out each step of the evaluation. It is suggested that the FDA post example templates for review by the developers before finalizing their format and content.
2. Creating information resources and development tools for sponsors of biosimilar applications. This includes tools such as in silico models and simulations to correlate pharmacokinetic (PK) and pharmacodynamic (PD) responses with clinical performance. Such tools can make biosimilar drug development more efficient.
Providing information, resources, and tools for developers is the most helpful step to avoid redundancies and repeat meetings with the FDA. Since the FDA has long emphasized that one size does not fit all, common tools that are molecule-specific are most appropriate. The tools such as in silico PK/PD modeling to predict clinical performance is likely the most impactful. The goal of this exercise should be to waive in-patient studies as much as possible.
Development tools that help developers may also include enlisting the United States Pharmacopeia (USP) to craft a new class of biosimilar monographs based on identified US-licensed products; however, the FDA has advised USP not to develop any biological monographs, fearing that changes made to these monographs over time may slow down the entry of biosimilars. Ideally, a USP monograph based on a US-reference product may allow a waiver of analytical similarity testing, a significant step in expediting development of biosimilars.
3. Enhancing the Purple Book to include more information about approved biological products, including information relating to reference product exclusivity determinations.
The BPCIA provides a 12-year exclusivity to new biological drugs; the Purple Book should indicate when this exclusivity ends and identify additional exclusivities after the first licensing of the product. The FDA can allow biosimilar sponsors to request extrapolation of indications only to those indications that are not protected by a patent.
A statement regarding indications not authorized should also be included. Additionally, the FDA needs to create a policy about any future indications for a reference product that may be approved.
While developers use the Purple Book to determine the products that are available as biosimilars, there remains an explanation due from the FDA about which products do not qualify as biosimilars, as the FDA discusses in the Biosimilar Advisory Advice. Clear advice should be given about biobetters, additional indications, new modes of action, new dosage forms or dosages.
4. Actively exploring the potential for entering into new data sharing agreements with foreign regulators to facilitate the increased use of non-US-licensed comparator products in specific studies to support a biosimilar application.
Since the BPCIA requires that a biosimilar be similar to a US-licensed originator, developers are not permitted to use a non-US licensed product as a reference. As a result, creating a global dossier requires conducting 3-way studies (ie, a US-licensed product, a non-US product, and the biosimilar candidate) to develop a regulatory dossier. To reduce the burden of additional studies, and to reduce unnecessary exposure to humans, several regulatory authorities have established clear policies on bridging studies. The most stringent default requirements are imposed by the FDA to demonstrate analytical and clinical pharmacology similarity. It is also suggested that an allowed reference product be labeled as a “qualified reference product” to remove any misunderstanding at the prescriber-level.
While data sharing with foreign regulators can be useful, it does not remove the legal restriction imposed on the FDA concerning the use of the reference product. The FDA could develop a protocol for bridging studies that are limited to abbreviated analytical similarity testing in those instances where the non-US reference product was registered using mainly the same regulatory dossier and met all other requirements of the BPCIA.
Given the high cost and time it takes to bring biosimilars to market, it would be most useful if major regulatory agencies, including the FDA, European Medicines Agency (EMA), Health Canada, Australia’s Therapeutic Goods Administration, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) work together to create a global dossier template. One of the most important efforts in the global dossier concept is the biosimilars cluster, which comprises the FDA, EMA, Health Canada, and the PDMA. Through this cluster, regulators from these 4 agencies meet 3 times a year to share information and discuss development challenges (as permitted under the intra-agency confidentiality agreements). However, the focus is on scientific alignment, not harmonization.
5. Establishing a new Office of Therapeutic Biologics and Biosimilars (OTTB) to improve coordination and support of activities under the Biosimilar User Fee Act (BsUFA) program, accelerate responses to stakeholders and support efficient operations and policy development.
This exercise is highly laudable. Whereas the BPD meetings are well organized and structured, the response time to these meetings, ranging from 60 days to 120 days, is too long and needs to be brought to 30 days. There is also a need to restructure the BPD communications by allowing sponsors to raise queries as they arise, instead of waiting for a formal meeting outcome.
6. Building on the FDA’s Biosimilar Education and Outreach Campaign, continue providing critical education to health care professionals, including releasing a series of videos that explain key concepts about biosimilar and interchangeable products.
While the FDA has done a great job in providing information on biosimilars for healthcare providers, prescribers continue to question the safety of biosimilars and even the authority of the FDA. This fact arises partly from the FDA’s practice of identifying biological products with a 4-letter suffix that could be used by originators to imply that their products are safer and even by biosimilar companies to suggest that their product stands apart from other biosimilars because of the company that manufactured it.
The FDA also needs to reprimand the companies that disseminate false information about biosimilars. A good example is the recent citizen petition filed by Pfizer against the unethical practices of multiple reference product sponsors to cast doubt on biosimilars.
7. Publishing final and revised draft guidance on biosimilar product labeling to assist sponsors in determining what data and information to include in the labeling.
The final guidance should include examples of the type of data that can be included using the prescribing information allowed in the licensed biosimilars. The FDA may also state that biosimilar developers may adopt the prescribing information of the first biosimilar with minor changes. Once a biosimilar has been approved, the label of that product could serve as a ready template for fure biosimilars of the same product.
8. Providing additional clarity for product developers on demonstrating interchangeability, including by publishing final or revised draft guidance.
The hurdles in establishing interchangeability include a legislative restriction that requires testing “in a clinical setting”; can the FDA construe this requirement to be conducted in healthy subjects? If so, can this be based on in silico or PD marker study? The best solution is to allow the biosimilar products to be tested in phase 4-type studies with approved protocols to allow a change of status.
The FDA needs to provide sample protocol outlines to demonstrate how to conduct such studies. The FDA should consider suggesting the use of markers instead of efficacy evaluations where possible.
One action that the FDA can take immediately is to issue statements that, for naïve patients, the choice of biosimilars is acceptable to enable the payors to take the reign on decision-making if the prescribers are ready. The FDA’s use of the phrase “no clinically meaningful differences,” has done more damage than good in highlighting differences. The correct statement should be “clinically similar,” to gain the confidence of the public.
9. Providing additional clarity for product developers on analytical approaches to evaluating product structure and function to support a demonstration of biosimilarity, including by publishing revised draft guidance on the use of data analysis methods, including statistical approaches.
The FDA frequently uses the term “fingerprint-like” similarity; this terminology could be replaced with “maximally similar,” and could use a quantitative approach to the degree of similarity and critical points to determine the adequacy of the demonstration of similarity. Additionally, FDA routinely uses “residual uncertainty” in describing inadequacy of similarity at different stages, a term that produces more uncertainty in the minds of developers and prescribers.
The FDA did establish a quantitative approach to the analytical similarity in its now-withdrawn guidance, wherein a 3-tier system resolved suitability of the analytical data; Tier 1 was equivalence interval based, Tier 2 was a range comparison, and Tier 3 was a visual comparison of data.
While failure to meet predefined acceptance criteria on a statistical test did not necessarily preclude determination of a highly similar status, it did create a subjective uncertainty that can be removed in a pass-or-fail system. Developers are eagerly awaiting a new data evaluation tool to allow a more rational and clinically meaningful approach for evaluating the data.
Analytical similarity testing can be made more relevant by dividing the critical quality attributes into 2 groups: release quality attributes (RQA) and structural quality attributes (SQAs).
The RQAs define the quality suitable to deliver a safe and effective product to patients. Some of these attributes are established without referring to the reference product, including protein content (proposed range, 95%-105%), bioassay (proposed range, 85%-115%), inactive components (90%-110%), or experimentally established testing reference product, more particularly surfactants, visible particles (USP <788>), subvisible particles (USP <787>), impurities (not more than 3%, matches reference product impurities), and physical properties including pH and sterility.
In the past, several RQAs statistically evaluated for side-by-side similarity testing, such as protein content and bioactivity, led to several examples where the product met the release requirement but failed analytical similarity, particularly in which a Tier 1 approach is applied based on the mean value that allows failure when the standard deviation for reference is small, and allows passing when the variability is high. All test methods used for release attributes must be validated and all lots tested must be released.
The SQAs are the integral quality elements that are related to expression, and these require testing on a side-by-side comparison with a reference product. The primary structure must match entirely, notwithstanding any terminal amino acid difference allowed. The secondary and tertiary structure is studied using methodologies that produce output that should be superimposable, without any statistical treatment of data.
Proposed testing methods include amino acid sequencing of the primary structure through peptide mapping (liquid chromatography–mass spectrometry), peptide mass fingerprint (matrix-assisted laser desorption deionization/ionization mass spectrometry), matrix-assisted laser deionization/ionization–time-of-flight, and mass spectrometry amino acid sequencing.
Exact matches should be obtained for higher order structure conformation, determined by thermodynamic fluorescence, far- and near- ultraviolet circular dichroism, differential scanning calorimetry, nuclear magnetic resonance, and ELISA.
Binding should be assessed with cell-based assays, surface plasmon resonance, ELISA (with a match within experimental variability), forced degradation profile (with no new impurities and the same relative proportion of impurities).
All test methods should be suitable and not necessarily validated since side-by-side testing of the reference product removes bias. All of the above tests that represent the basic tests used to characterize biological drugs, can be done using a smaller number of lots.
10. Providing additional support for product developers regarding product quality and manufacturing process, including by identifying physical product quality attributes that are most critical to evaluate, and by exploring ways to reduce the number of lots of the reference product required for testing.
“Additional support” means the FDA identifying quality attributes that relate to the manufacturing process; this is a significant change in how the FDA advises developers and stands to reduce the burden on developers significantly. The FDA should also allow the use of smaller lots to develop a product and then let the sponsor file for a comparability protocol after the approval of the product. This will significantly reduce the cost and time for the development of biosimilars; given the length of time and cost, creating product performance qualification lots at scale is an expensive exercise that discourages smaller companies from developing biosimilars.
Additionally, protocols related to shipping validation, leachable and extractable testing, and warnings about shaking the product should be specified.
11. Engaging in a public dialogue through a Part 15 hearing and opening a docket to request additional information from the public on what additional policy steps the FDA should consider as we seek to enhance our biosimilar program.
The FDA has always been open and responsive to receiving public advice, and creating a docket specifically for the purpose is helpful, but some stakeholders may not be eager to let their identity be known if they are in disagreement with the agency. I am recommending that the FDA allow and encourage private submission of comments to the new OTTB office.
Additional Issues Related to the BAP
Animal Toxicology
The BAP does not address a significant issue in conducting toxicology studies in animals that are more suitable for new drugs where the goal is to establish the lethal dose for 50% death. There is no scientific basis for using these studies to establish differences between a biosimilar and a reference product since the studies use a toxic dose, where the variability is high, and does not provide any useful information. The only utility of animal studies comes in conducting PK studies that may indicate any differences in the structure of the molecule. It would be appropriate for the FDA to adopt the EMA position on animal toxicology studies. However, should the FDA continue to insist on animal toxicology, then the FDA should provide more details, templates, protocol outlines, and other advice to the industry to make animal testing clinically meaningful while reducing exposure to animals.
Clinical Pharmacology
The PK/PD profile of a biosimilar is compared with a reference product using the same model as used for generic drug approval, where we conclude that 2 treatments are not different from one another if the 90% confidence interval of the ratio of a log-transformed exposure measure (AUC and/or Cmax) falls entirely within the range of 80%-125%. Since biosimilars are administered by parenteral route, where absorption is not an issue unless the product provides a delayed absorption, the correct parameters to test are the distribution volume and elimination rate constant, both of which can be sensitive to structural differences.
The FDA may also allow the use of a highly selective population that shows less variability without affecting the robustness of the testing. While in some instances the PK/PD profiles are altered in the disease state, testing in patients does not provide any additional value since using a single lot of the same product removes structural differences. Both patients and the healthy subject respond proportionally, albeit at different levels.
I am also suggesting that the FDA encourage the use of scaled-average-bioequivalence testing protocols that may allow collection of immunogenicity profiles in a single study, reducing a significant burden on developers.
In some instances, the FDA should announce that PK/PD studies are not required, such as where the route of administration (eg ocular, otic, and possibly others) does not result in a measurable concentration of the active moiety in blood; a good example is ranibizumab administered through intraocular route.
Immunogenicity Testing
There are serious ethical issues in testing biosimilars for immunogenicity; for products that are least immunogenic, such as filgrastim, testing is unnecessary, and where the product is highly immunogenic, such as some interferons, the testing is unethical as it sensitizes healthy subjects.
Both the FDA and the EMA are of the opinion that it is reasonable to develop qualified alternate tests.
The EMA provides the following statement regarding the use of alternate methods of testing immunogenicity:
“…ongoing consideration should be given to the use of emerging technologies (novel in silico, in vitro and in vivo models), which might be used as tools during development or for the first estimation of risk for clinical immunogenicity. In vitro assays based on innate and adaptive immune cells could be helpful in revealing cell-mediated responses.”
A significant advantage of in vitro methods is the ability to test multiple batches for immunogenicity, which is not possible in human subjects. A large number of companies are currently working on establishing immunogenicity testing, and I am suggesting that the FDA encourage the development of this technology by stating that “a clinical immunogenicity study can be waived, if the developer demonstrates a relevant comparison using other methods.”
Additional Clinical Studies
According to the FDA guidance, “as a scientific matter, a comparative clinical study will be necessary to support a demonstration of biosimilarity if there are residual uncertainties about whether there are clinically meaningful differences between the proposed and the reference products based on structural and functional characterization, animal testing, human PK and PD data, and clinical immunogenicity assessment.” Since all products licensed by the FDA to date submitted comparative clinical studies for approval, does this mean that all biosimilars approved by the FDA had ended up with “residual uncertainty” that required a comparative clinical study? If so, then were the comparative study or studies conducted sufficient to remove “residual uncertainty” even when the products were tested in only 1 indication, yet received extrapolation of all indications? In designing these comparative clinical studies, how were the equivalence or non-inferiority levels selected without having any data on the relationship between a response and effectiveness? These questions are pivotal to providing credence to clinical studies.
The FDA should identify drugs for which a PD parameter is acceptable instead of any testing in patients. Good examples are filgrastim and pegfilgrastim, in which the PD profile comparison in healthy subjects is sufficient in place of any additional clinical study. Many cytokines may qualify for a waiver of comparative efficacy studies if all else meets the requirements.
Finalizing FDA guidance on biosimilars—expediting approvals and acceptance
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
Category: Opinion
Page: 84-91
Author(s): Adjunct Professor Sarfaraz K Niazi, PhD, SI, FRSB, FPAMS, FACB
Visits: 4274 total, 3 today
Keywords: analytical similarity, Biosimilars, immunogenicity testing, pharmacokinetic profiling
Abstract:
Biosimilar drugs have suffered slow entrance and acceptance rates in the US market, due not only to common misperceptions among the public but also US Food and Drug Administration (FDA) licensing laws. This review offers nine major recommendations for the FDA to simplify how biosimilars are licensed and thus make biosimilars more accessible to American citizens.
Submitted: 21 May 2018; Revised: 13 July 2018; Accepted: 17 July 2018; Published online first: 23 July 2018
Background
H.R. 3590 Sec. 7002 [1], commonly known as the Biologics Price Competition and Innovation Act (BPCI Act), a part of the Affordable Healthcare Act, was enacted in 2009 to introduce biosimilars (copies of biological products coming off patent) to the market. Since then, the US Food and Drug Administration (FDA) has licensed 11 products (as of June 2018) [2], comprised of eight molecules: adalimumab, bevacizumab, epoetin, etanercept, filgrastim, infliximab, pegfilgrastim and rituximab. Under the New Drug Application (NDA) filing, insulin glargine products (Lusduna [3] and Basaglar [4]) have also been approved by FDA and from March 2020 all insulin products can be approved as biosimilars [5]. FDA has issued several draft and final guidelines to industry on demonstrating biosimilarity [6], which is the primary determinant for licensing a product, either as a biosimilar or an interchangeable biosimilar. Interchangeable biosimilars are… a separate category of biosimilar products that are additionally tested to demonstrate that automatic substitution of an originator product with the ‘interchangeable biosimilar product’ will not result in reduced efficacy or increased side effects.
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 [9–11].
The suggestions made in this paper come from decades of experience in developing biosimilar products globally, including through the biosimilars (351(k)) and NDA pathways (505(b)(2)).
The BPCI Act
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. Given below are excerpts from the BPCI Act that are relevant to guidelines for the approval of biosimilars by FDA:
(k) Licensure of biological products as biosimilar or interchangeable
§ (1) In general
§ Any person may submit an application for licensure of a biological product under this subsection.
§ (2) Content
§ (A) In General
(i) Required Information
§ An application submitted under this subsection shall include information demonstrating that
§ (I) the biological product is biosimilar to a reference product based upon data derived from
§ ‘(aa) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components;
§ ‘(bb) animal studies (including the assessment of toxicity); and
§ ‘(cc) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product;
§ (II) the biological product and reference product utilize the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product;
§ (III) the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product;
§ (IV) the route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product; and
§ (V) the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent.
§ (ii) Determination by Secretary. —The Secretary may determine, in the Secretary’s discretion, that an element described in clause (i)(I) is unnecessary in an application submitted under this subsection.
§ (4) Safety standards for determining interchangeability
§ Upon review of an application submitted under this subsection or any supplement to such application, the Secretary shall determine the biological product to be interchangeable with the reference product if the Secretary determines that the information submitted in the application (or a supplement to such application) is sufficient to show that—
(A) the biological product—
(i) is biosimilar to the reference product; and
(ii) can be expected to produce the same clinical result as the reference product in any given patient; and
(B) 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.
The statutory requirements provided in section k.2.A.i.I form the basis of biosimilar development. Remarkably, these requirements are left to the discretion of FDA, as shown in k.2.A.ii, leaving only section k.2.A.i.I–V as unchangeable by FDA [1]. Interchangeable licensing has additional legislation, as shown in k.4.A–B. A biosimilar product must demonstrate the same clinical results as the reference product, which can only be shown by patient testing. Studies using a switching-and-alternating protocol, where an originator biological product is switched with a biosimilar product and then back to the originator product, must show no diminished efficacy and no greater risk when compared to the reference product without alteration or switching. This legislation prevents FDA from making any changes to the requirements for interchangeable biosimilars; thus this paper will address issues related to the approval of biosimilars only.
Actions recommended for US FDA
To allow the faster development and adoption of biosimilar products, the following changes in the regulatory approval process are recommended:
§ Modify the current requirement for bridging studies between a US-licensed product and a non-US approved comparator, provided the non-US product meets certain specifications, such as same indications, same dosage form and approved using essentially the same dossier as the US-reference product, to establish biosimilarity.
§ Present clear scientific evidence to the public and, more particularly, prescribers that a biosimilar product has no ‘clinically meaningful difference’ from the originator product and thus should be acceptable for naïve patients, without involving the legality of substitution issue.
§ Encourage the development of in vitro immunogenicity testing methods to reduce exposure to test subjects, which would have ethical advantages and allow comparison of multiple batches of the biosimilar candidate product, improving safety evaluation.
§ Replace the current arbitrary comparisons of critical quality attributes, such as protein content or variations in known impurity profiles with clinically-relevant limits and ranges in testing analytical similarity, animal toxicology, pharmacokinetic/pharmacodynamic (PK/PD) immunogenicity, and other safety and efficacy attributes.
§ Minimize clinical studies by combining studies intended to establish immunogenicity, efficacy and PK/PD profiles to avoid unnecessary testing on patients.
§ Clarify policy on analytical method validation.
§ Change the requirement for the use of commercial-scale batches for determination of biosimilarity.
These recommendations are also, in part, the subject of a citizen petition filed by the author to FDA [11].
1. Waiver bridging studies
Developing biosimilars is costly and requires developers to formulate a global strategy where one regulatory dossier can be used to secure regulatory approvals in multiple jurisdictions. Since the BPCI Act requires that a biosimilar be similar to its locally licensed originator (that is, a product approved under Sect. 351(a) of the Public Health Service Act of 1942, as amended) [1], developers are not permitted to use a non-US product as a reference product. As a result, creating a global dossier requires three-way studies, i.e. a US-licensed product, a non-US product, and the biosimilar candidate. To reduce the burden of additional studies, and to reduce unnecessary exposure to humans, several regulatory authorities have established clear policies on bridging studies [12], as shown in Table 1.
The most stringent requirements are imposed by FDA, whose requirements include analytical similarity and PK/PD studies. It should be noted that FDA requirements for bridging studies are not clearly defined but accepted as the default position of FDA. As such, there is no legal obstacle to FDA changing its position and allowing developers to request a waiver to use a non-US-licensed product as the reference product, provided the conditions, enumerated below, are met:
§ The non-US reference product meets all statutory requirements as shown in section k.2.A.i.II–V; and
§ The non-US product received approval in its respective jurisdictions by presenting very similar original data, including clinical safety and effectiveness, as the US-licensed reference product; and
§ The regulatory filing is not intended to claim interchangeable status for the biosimilar product; or
§ The non-US reference product was judged to be equivalent to the US-licensed product in any regulatory filing that presented a bridging study, such as the recent approvals of infliximab [19] and bevacizumab [20].
FDA Commissioner Dr Scott Gottlieb agrees with the suggestions made above, however, there is wider FDA concern that legislative action would be required to make changes to current practice [21]. The author finds no legal reason why this change cannot be made by FDA.
2. Encourage substitution for naïve patients
The BPCI Act creates two categories of biosimilar products: biosimilar and interchangeable biosimilar. The latter classification was intended to allow the automatic substitution of an originator product with a biosimilar product. The labelling of an interchangeable biosimilar requires in patient studies to demonstrate similar efficacy. When a biosimilar product is repeatedly administered, the two products (biosimilar and reference) are alternated to establish that there is no reduction in efficacy or increase in side effects caused by the biosimilar. As a result of the complexity of these studies making them extremely expensive to conduct, developers have been reluctant to file for interchangeable status; and FDA is yet to approve a product as an interchangeable biosimilar. However, there is a need for a strategic approach to allow the substitution of biosimilars based on how FDA characterizes a biosimilar.
‘A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an existing the FDA-approved reference product [22]’.
From a scientific and clinical viewpoint, if a product is clinically equivalent, there is no reason why it should not be prescribed to naïve patients. This view is shared by FDA Commissioner Dr Scott Gottlieb who stated that ‘payors can also lead the way in formulary design by making biosimilars the default option for newly diagnosed patients. They can share the savings with patients, maybe by waiving co-insurance [23]’.
The author therefore requests that FDA:
§ Declare the official position that a licensed biosimilar product has no clinically meaningful difference and that it can be substituted for the originator product when the originator product is prescribed for a naïve patient.
§ Educate prescribers that biosimilars are safe and equally effective, with no risk of additional immunogenicity when used in naïve patients—the most significant barrier to the entry of biosimilars into the US market.
§ Motivate and enforce the adoption of biosimilars by payers and make the pricing structure more transparent in order to demonstrate cost savings to patients and prescribers.
3. Allow in vivo immunogenicity study waivers
Immunogenicity is defined as the propensity of biological drugs to generate an immune response to self and related proteins, which may include non-clinical effects and adverse clinical events. Immune responses to biological drugs may hamper their biological activities and result in adverse events, not only by inhibiting the efficacy of the therapeutic element but also by cross-reactions with endogenous protein, leading to loss of its physiological function. For example, neutralizing antibodies to erythropoietin can cause pure red cell aplasia by also neutralizing the endogenous protein. The effects of immunogenicity in biological drug development can be summarized as follows:
§ Effects on bio-availability, safety, efficacy and PK, including potential cross-reactivity with endogenous proteins
§ Inhibition of the function of endogenous proteins
§ Injection site reactions and other systemic reactions, mild or life-threatening
§ Formation of anti-drug antibodies, neutralizing antibodies, immune complexes and anti-idiotypic antibodies
Immunogenicity, as stated in FDA guidelines on biological drugs, must be assessed in the target population since animal testing and in vitro models cannot predict immune response in humans [24]. Immunogenicity also has a role in demonstrating product comparability following manufacturing changes. Even minor changes can potentially affect the bioactivity, efficacy or safety of a biological drug. As a result, FDA is making important advances in predicting immunogenicity [25], in particular promoting the use of in vitro immunogenicity assays.
The European Medicines Agency (EMA) provides the following statement regarding use of alternate methods of testing immunogenicity:
‘… ongoing consideration should be given to the use of emerging technologies (novel in silico, in vitro and in vivo models), which might be used as tools during development or for the first estimation of risk for clinical immunogenicity. In vitro assays based on innate and adaptive immune cells could be helpful in revealing cell-mediated responses [26]’.
The characterization and screening of biosimilars for physicochemical determinants or formulation-based factors aid both in the prediction of immunogenicity and in the development of less immunogenic therapeutic agents, considering impurities, heterogeneity, aggregate formation, oxidation and deamidation of the molecule. Moreover, predicting potential immunogenic epitopes in therapeutic biologicals is an important and useful strategy to improve their safety.
Immunogenicity testing however substantially increases the cost and time requirements for drug development and the goal of regulatory guidance should be to minimize human testing where possible. A variety of preclinical immunogenicity assessment strategies are currently used during biological development, as listed in Table 2.
A major advantage of in vitro methods is the ability to test multiple batches for immunogenicity, which is not possible in human subjects. In vitro tests can also be more useful in predicting the difference between a biosimilar product and its reference product.
There are clear ethical complications in testing for immunogenicity in healthy subjects when comparing a reference drug to a biosimilar candidate. To advance the science of in vitro immunogenicity further, FDA should:
§ Allow developers to present in vitro, in silico, or novel in vivo test methods and thus request a waiver from clinical immunogenicity testing.
§ Continue internal development efforts to find and prescribe testing modalities that reduce the need for clinical testing of immunogenicity.
4. Make pharmacokinetic profiling clinically relevant
Bioequivalence is defined in 21 CFR 320.1 (Hatch-Waxman Act) [27] as ‘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 become 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 action is not known in most cases and rarely available for sampling, level in blood was selected as a surrogate to the site of action. The PK profile characterizes two stages, absorption and disposition (distribution and elimination), making it most relevant to generic chemical (small molecule) drugs where disposition is less likely to vary. This makes the PK profile relevant to absorption, and therefore bioavailability, thus providing validation of bioequivalence.
The PK profiling of biosimilars follows the same testing protocols as used for generic drugs. However, extrapolation of testing protocols involves a significant misconception – biosimilar drugs are administered parentally, which means that while differences in absorption are unlikely, differences in disposition are likely (distribution may change due to binding effects for example, and elimination may change due to subtle structural differences). This difference between generics and biosimilars should be addressed in the selection of PK parameters and statistical models applied to demonstrate similarity.
When FDA developed guidance on biosimilars, the term ‘clinical relevance’ was introduced, which is the most crucial aspect of determining biosimilarity and addresses the step-by-step approach [1] of demonstrating: analytical similarity, non-clinical toxicology, PK/PD profile, immunogenicity profile and, if there remains any ‘residual uncertainty’, performing additional clinical studies in healthy subjects. Consideration of ‘clinical relevance’ should therefore also be part of PK/PD analysis.
The author suggests the following changes to the criteria of PK/PD profiling of biosimilars compared to a reference product:
§ Waive PK studies where the product is administered by a route (ocular, otic, and possibly others) that does not provide sufficient concentration of the active moiety in blood, such as the intraocular administration of ranibizumab [28]. However, to allow evaluation of disposition kinetics, PK studies involving intravenous administration in an appropriate animal, such as monkeys, should be required for monoclonal antibodies. This could be integrated into the non-clinical toxicology assessment. In most instances, a study population of 10–12 animals should suffice.
§ When administered parentally, as most biosimilars are, PK parameters relating to distribution such as distribution volume and parameters relating to elimination such as terminal half-life are more clinically relevant than the area under the curve (AUC) or peak plasma concentration (Cmax). Statistical modelling should include these additional parameters. Distribution volume was introduced as a determinant of clinical efficacy by the author decades ago and finds a new application in the evaluation of biosimilars [29].
§ While a confidence interval within 80–125% for the log ratio of Cmax and AUC (and for any other parameters added, as suggested above) has performed well as an acceptance criterion for generic drugs, there is no assurance that these intervals are clinically meaningful for biological drugs. Whether FDA should broaden or narrow the interval of acceptance remains to be determined once the additional parameters suggested above are taken into consideration.
§ Encourage the use of scaled average bioequivalence (SABE) testing protocols that allow collection of immunogenicity profiles in a single study. In those instances where the immunogenicity data are required from a patient population, allow PK/PD profiling in patients, reducing the number of clinical studies required.
§ Allow PK/PD studies to select a population that is likely to have minimal variation to reduce study sizes. Choosing such populations would help to demonstrate differences between the biosimilar candidate and the reference product.
5. Modify tier testing criteria for analytical similarity
FDA has recently released draft guidance on ‘Statistical Approxaches to Evaluate Analytical Similarity’ for biosimilars [30], one of the most critical components for establishing biosimilarity and a component that determines which additional studies, both clinical and CMC-related, are required. A developer identifies critical quality attributes (CQAs) and tests them using Tier 1, Tier 2, or Tier 3 statistical methods, depending on the nature of data output and the importance of the attribute to the safety and efficacy of a biosimilar product.
For CQAs in Tier 1, equivalence is established by rejecting the interval (null) hypothesis: −1.5 σR ≤ 90% CI of [μT–μR] ≤ 1.5 σ, where μT and μR are the mean responses of the test (the proposed biosimilar product and the reference product lots, respectively). This statistical testing suggests the equivalence acceptance criterion (EAC) = 1.5 × σ, where σ is the variability of the reference product (standard deviation). Statistical justification for the factor of 1.5 [31] follows the idea of the SABE criterion for highly variable generic drug products proposed by FDA. To achieve the desired power for the similarity test, FDA further recommends that an appropriate sample size is selected by evaluating the power using the alternative hypothesis μT − μR = ⅛.
There is no relevance of the factor of 1.5 used in equivalence testing of the most critical CQAs. For example, in the briefing on approval of Sandoz’s filgrastim product [32], FDA stated that one of the CQAs (protein content) initially failed, requiring additional batches to be added to the analyses. While there is a correlation between dose and effect for biological products, a small variation – as observed in the Sandoz data – should not have any clinically meaningful effect, since the release specification provides considerable variability. In essence, a test for analytical similarity may fail, yet such variation is allowed in the commercial product.
The criterion for Tier 1 testing for CQAs can produce misleading results. As an example, 10 batches (a number recommended by FDA) of a biosimilar candidate could be tested against an equal number of reference product batches for a percentage of the labelled quantity of protein. If the variation in the reference product is minimal, approaching a value of zero for σ, then all comparisons will fail, even if there is no clinically meaningful difference. The author has encountered such situations, where an attribute is tightly controlled in the originator product based on decades of manufacturing experience. The question arises if this is a clinically meaningful difference or merely a routine observation. For example, a biosimilar product may be allowed a range of 97–103% or even 95–105% in the Certificate of Analysis (COA) based on the history of manufacturing, yet all samples will fail if the σ of the reference product is minimal. On the other hand, where an attribute has high variability (σ) for the reference product, the product passes the Tier 1 test while failing a Tier 2 test, where 90% of all values fall within 3 × σ. It is for this reason that FDA requires Tier 2 testing for all Tier 1 attributes. To resolve these inconsistencies, the author suggests the following changes to the statistical modelling of CQAs in analytical similarity testing:
§ Exclude any quality attributes for testing of analytical similarity that are part of the COA. If FDA accepts the variability as shown in the ranges of acceptance provided in the COA, it is illogical to accept or reject a product based on statistical limits of analytical similarity. The COA is clinically relevant, while the tiered testing of these attributes is not. Critical quality attributes of importance are primary, secondary and tertiary structures, receptor binding and impurity profile of timed samples, in addition to many more that are pertinent to differences in the molecules, albeit subtle.
§ Allow developers to identify the CQAs and their range of variability based on clinical meaningfulness rather than using a factor of 1.5 arbitrarily to establish equivalence in a Tier 2 testing.
§ If a product fails a Tier 1 test but passes Tier 2 testing, allow this as acceptance of similarity.
6. Clarify analytical testing validation
It is clearly understood that all analytical methods, including bioanalytical methods, must be validated, as provided in a May 2018 final guidance on bioanalytical methods [33]. However, analytical similarity testing requires methods that are often difficult or impossible to validate based on the guidance provided without incurring high cost and time commitments, such as nuclear magnetic resonance techniques or mass spectrometry. While all analytical methods used in the authorization of a biosimilar should be validated, methods used to demonstrate other analytical attributes may be accepted by FDA if they are ‘suitable’, a term often used in FDA guidance but not clearly defined. There is a need for FDA to clearly differentiate between the methods that must be validated and the ones that can be used if found suitable.
7. Encourage development of novel testing methods
Current approaches to evaluating the differences between a biosimilar candidate and a reference product are based on methods for characterizing new molecules; there is a need to develop more sensitive techniques to determine differences in the structure of large molecules, both at steady state and while active within the body. Several new techniques have recently come into practice, including modified capillary electrophoresis, Chip-based (Bioanalyzer) Protein Electrophoresis Assays (CPEA), and many variations of mass spectrometry [34].
FDA defines fingerprint-like similarity as:
‘the results of integrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences (i.e. fingerprint-like analyses) permit a very high level of confidence in the analytical similarity of the proposed biosimilar product and the reference product, and it would be appropriate for the sponsor to use a more targeted and selective approach to conducting animal and/or clinical studies to resolve residual uncertainty and to support a demonstration of biosimilarity [35]’.
The introduction of new methodologies could help to demonstrate clinically meaningful similarity between products that will reduce the number of additional studies required [36, 37].
8. Accept smaller batch sizes
Unlike the development of entirely novel drugs, the development of biosimilars requires commercial-scale batches in order to begin testing for similarity. The rationale for this requirement derives from the assumption that there may not be any in patient or ‘phase III’ studies required that are historically conducted using commercial-scale batches. This requirement generates a huge cost and time burden, preventing smaller developers from entering the market. While FDA has not identified what it considers to be ‘commercial scale’, these issues were highlighted in a Type 2 formal meeting between FDA and sponsors of Biosimilar User Fee Act (BsUFA) products [38]. The author suggests that FDA requires a batch size that is adequate to provide samples for stability, clinical or other required testing, instead of making market projections to justify the size of a commercial batch. Should the developer decide to change the batch size after the product has been approved, the developer may use the Comparability Protocol for Biological Drugs [39] to make this post-approval change. This clarification by FDA would have a significant impact on industry, allowing smaller developers to offer market-ready products using smaller batches and at much lower cost.
9. Minimize clinical studies
The largest contributor to the cost and time requirements of marketing a drug are the clinical studies required to establish biosimilarity. When in patient studies are required, the cost and timeline stretch even further. The current mindset of establishing biosimilarity follows phase I to III testing, which is not relevant to establish the non-inferiority status of a biosimilar candidate with the reference product. As a result, the author makes the following recommendations:
§ If it is determined a priori that studies are required in patients, allow developers to conduct PK/PD profiling in patients as well.
§ Allow statistical models of PK/PD studies to determine immunogenicity within the same study.
§ Allow the use of in vitro models for immunogenicity testing to reduce human exposure.
§ Allow the use of animal models to establish differences in the PK (and, where possible, the PD) profile where blood concentrations are not measurable.
Summary
In developing methods for the evaluation of biosimilars, FDA has created highly specific vocabulary, such as ‘no clinically meaningful difference’ and ‘residual uncertainty’. These terms are scientifically important and represent a creative approach to assuring the safety of biosimilars. However, not all FDA guidance adequately takes these two terms into account. To improve this situation, this review makes a number of recommendations:
§ Remove the default requirement of conducting bridging studies for non-US reference products, where the reference product meets specific criteria.
§ Declare that biosimilars have no clinically meaningful difference from the originator product and, therefore, substitutions for naïve patients should be allowed.
§ Remove the default requirement of conducting in vivo immunogenicity testing and allow developers to offer alternative in vitro and in silico testing methods.
§ Modify PK/PD protocols and statistical analysis methods to make the outcomes clinically meaningful.
§ Modify testing of critical quality attributes by separating them from release specifications to demonstrate analytical similarity.
§ Minimize clinical testing by combining studies.
§ Clarify the type of validation required for analytical similarity testing.
§ Allow the approval of products based on smaller scale studies.
FDA recognizes the need for changes to its guidance. Commissioner Dr Scott Gottlieb [23] has recently expressed a willingness to respond to the urgent need to reinterpret guidelines for the increased approval and adoption of biosimilars.
In June 2018, the FDA withdrew its guidance for Analytical Similarity Testing [40] and a few days later FDA announced a new initiative, Biosimilars Action Plan that includes most of the recommendations made by the author in its citizen petition [41].
Disclaimer
This paper represents solely the views of the author and should not be understood or quoted as being made on behalf of or reflecting the position of any regulatory authority or company.
Competing interests: The author of the paper declared that he is a developer of biosimilar products. The author is founder of Karyo Biologics, LLC and Adello Biologics, which have several biosimilar products at various stages of FDA approval.
Provenance and peer review: Not commissioned; externally peer reviewed.
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Author: Adjunct Professor Sarfaraz K Niazi, PhD, SI, FRSB, FPAMS, FACB, Adjunct Professor of Biopharmaceutical Sciences, University of Illinois and University of Houston; 20 Riverside Drive, Deerfield, IL 60015, USA
In an unprecedented move, the US FDA withdrew its guidelines on the approval of biosimilar products, a multi billion dollar marketplace, after Niazi filed a citizen petition identifying the flaws in the scientific strategies of the guideline. This change will allow faster entry of biosimilars to the market and make them more accessible.
Finally, a book that distills a decade of experience of developing biosimilars; The expectations of FDA are often missed by even the most resourceful companies. Biosimilarity is what the FDA decides using a scientific approach where additional studies, particularly, the clinical studies are minimized. From statistical models, to CQA establishment, to designing bridging studies, this book is one source that no biosimilar develope should do without.
With 100+ patents in bioprocessing, biosimilars testing, NCE, new formulations, wine aging, disease management and more, I am now announcing my most pivotal patent allowed by USPTO two days ago--Windy City Hat--at that will not fly off. I designed placement of holes in the brim to overcome Bernouli's pressure using a DOD IBM Road Runner computer. Ran three clinical trials. And now you will see you Stetsons and cowboy hats that will stay on longer. I have been wearing it for over a decade now.
Now that my first US biosimilars company is fully funded and has reached the commercial stage, I am launching another company, Karyo Biologics, operating in a partnering model, to overcome the physical limitations of every company (even if you are Amgen Pfizer Sanofi Genzyme AbbVie Novartis Merck GSK Bristol-Myers Squibb Abbott Dr. Reddy's Laboratories Biocon or Celltrion)in expanding its portfolio and in overcoming the inevitable delays due to the peculiar 351(k) regulatory expectations. I am thankful to dozens of major companies around the world who are now part of Karyo and most of all to FDA for giving us prompt responses to our submissions, stating that we are ready to file INDs. We are now the first private label US biosimilars company with a fast expanding portfolio and a proven fast-to-market opportunity for a broader category of distributors. Somehow I continue to believe that we can prove the value of BPCIA to make biosimilars more accessible (available and affordable), if we keep getting creative.
In 2013, I founded Therapeutic Proteins Inc (now Adello Biologics) with a vision of making biosimilars more accessible. Today, my company has products under approval by the FDA, and these products are manufactured using my patented technology. I owe my small success to the graciousness of dozens of angel investors, who gave me a head start, Jim Berens, a man of true class, who placed his trust in my passion to help me build clean rooms, Steve and Daniel Einhorn for risking their venture capital with great heart, and finally, Chirag, Chintu and Tushar Patel, who turned a humble beginning into one of the largest funded biotechnology company in the country. It was a challenging ride, but we came through. Now my company 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 a sense of immeasurable humility.
. Invited presentation at the Regulatory and Development Strategies Biosimilars Markets Access and Commercialization Strategies Summit, Boston September 18-19, The Westin Boston Waterfront.[1] Biosimilar Market Access and Commercialization Strategies Summit provides detailed presentations, intensive case studies and collaborative panel discussions relevant to many fields including biosimilars. Dr. Niazi will be speaking on the topic of why do biosimilar filings fail and how we can manage them to assure fast to market approval, based on his 20+ years of developing biosimilars, writing the largest numbers of books on the subject and holding the largest number of bioprocessing patent in the world that help reduce the development and approval cycle.
[1] http://exlevents.com/biosimilar-market-access-commercialization-strategies-summit/
The American Statistical Association Biopharmaceutical Section Regulatory-Industry Statistics Workshop was originally a meeting for the FDA statisticians that later expanded to include all statisticians interested in statistical practices for all areas regulated by the FDA. This year over 800 people are expected to attend this workshop on Sep. 25-27, 2017 in Marriott Wardman Park, Washington D.C.
Dr. Niazi is providing a unique thermodynamic equivalence insight into Statistical Evaluation of Generic Transdermal Delivery Systems and Tropical Patches, as one of his areas of expertise and plans to participate in several sessions relating to biosimilars. The FDA provides the following comment on the Niazi's session: “With the passage of Generic Drug User Fee Act (GDUFA), there is an increased emphasis on research for generic drugs, especially in the field of statistical evaluation of generic transdermal delivery systems and topical patches (hereafter referred as TDS products). Office of Generic Drugs (OGD) in FDA CDER recommends two types of studies for TDS products Abbreviated New Drug Applications (ANDAs): one is bioequivalence (BE) with pharmacokinetic (PK) endpoints study, and the other one is the skin irritation, sensitization and adhesion study. For skin irritation, sensitization, and adhesion study, the applicant usually conducts two studies, an adhesion study and an irritation/sensitization study. To support regulatory approval, in addition to the bioequivalence of PK endpoints, the test product must adhere at least as well as the reference product, be no more irritating than the reference and be no more sensitizing than the reference. This session will discuss statistical issues, challenges and approaches in the adhesion study and irritation/sensitization study for generic TDS products.”
Pharmaceutical Scientist, Inc.: FDA Calls For Public Comments On Bioequivalence Testing
In a significant move, the US Food and Drug Administration (FDA) is asking for public comments on bioequivalence testing of generic drugs, specifically novel dissolution methods, to allow biowaivers for all types of drugs. The call comes in response to a Citizens Petition filed by Dr. Sarfaraz K. Niazi, Executive Chairman, Pharmaceutical Scientist, Inc., and Adjunct Professor of Biopharmaceutical Sciences at the University of Illinois at Chicago College of Pharmacy and author of dozens of books and research papers on the subject (www.niazi.com).
Dr. Niazi would like to speed the approval process for generic drugs to get medicine to patients as quickly and cost-effectively as possible by using a faster process called thermodynamic equivalence. The FDA has agreed to the validity of Niazi’s argument, in theory at least. In a response letter to Dr. Niazi’s petition, Dr. Janet Woodcock, Director of the Center for Drug Evaluation Research at the FDA, wrote that her department “is largely responsive to your request that we "open comment" on novel dissolution tests that can be used to establish bioequivalence…Therefore, your Petition is granted….” “It has taken years of communication with FDA to reach this stage,” said Niazi.
The focus of expanding biowaivers in the petition calls for establishing a new parameter—thermodynamic equivalence, to obviate the need for blood level studies that significant biologic variability that confounds true differences between products. The suggested change fits well within the purview of the Fair Access for Safe and Timely Generics Act of 2017 or the FAST Generics Act of 2017 and other measures taken by the FDA to allow faster approval of generic chemical and biosimilar drugs. Thermodynamic equivalence demonstration requires identifying dissolution conditions that can discriminate differences in chemical potential, a process created by Dr. Niazi. Thermodynamic equivalence can be used to assure life-cycle clinical equivalence of a generic product and provide a critical measure of GMP compliance.
Now Dr. Niazi is calling on the scientific community to send their feedback to the FDA. “I am encouraging scientists to respond to this challenge and help reduce the cost and time to approval for both chemical and biologic drugs,” said Dr. Niazi. To participate in the public comments, go to https://www.regulations.gov/comment?D=FDA-2007-P-0055-0004 and the correspondence between FDA and Pharmaceutical Scientist, Inc., a global science-driven idea company (www.pharmsci.com).
CONTACT:
At the 4th Annual Biomanufacturibg Summit, Dr. Niazi analyzes the major hurdles, never fully recognized, that have caused delays in approvals and escalated cost of development of biosimilars in USA and offers clear solutions. Read the presentation here.
Views of Professor Niazi
https://bioprocessintl.com/2019/january-february-2019/january-february-bioprocess-insider/
Biosimilar developers are targeting blockbuster “Big Pharma” biologic originator companies. Roche and AbbVie, two companies most susceptible to biosimilar erosion, have vocalized a need for stringent regulatory frameworks — calling for appropriate data, individualized labels, and unique identification for all biotherapeutics — while attempting to rebuff competition by reformulating their products and beefing up both their pipelines and intellectual property (IP). Meanwhile, several other Big Pharma companies are dominating European and US biosimilar markets: namely, Novartis, Pfizer, and Amgen, which claim some of the largest biosimilar pipelines in the industry.
Through its Sandoz division, Novartis has been marketing biosimilars in Europe for over a decade. It was first to launch a US biosimilar when its version of Neupogen (filgrastim), received approval in 2015. Pfizer has had four US approvals, including the first biosimilar version of J&J’s Remicade (infliximab). The company expanded its biosimilar pipeline in 2015 through a $17 billion ( €14.9 billion) acquisition of Hospira. And despite suffering revenue loss from an influx of first-wave biosimilars while trying to defend against versions of bestselling biologic Enbrel (etanercept), Amgen has 10 biosimilars in a portfolio that includes US-approved versions of AbbVie’s Humira (adalimumab) and Roche’s Avastin (bevacizumab).
History Repeating: Even so, Big Pharma’s interest in biosimilars may be soon to end, according to Sarfaraz Niazi, a pharmaceutical sciences and biotechnology expert with over 30 years of industry experience who founded biosimilar developer Karyo Biologics earlier this year. In his 2014 book Handbook of Biogeneric Therapeutic Proteins, he predicted that exit would occur once specialized biosimilar developers have appeared on the scene.
“This is history repeating from the generics era,” he said. “There are so many ways to cut the cost of development and manufacture, but because of their mindset and design, Big Pharma cannot do this. They can change both, but that requires a monumental shift.”
Niazi told BioProcess Insider that back in the 1980s, many large pharmaceutical companies planned to enter the generics market. “However, as the prices tanked, they all pulled out.” So far, the big companies are seeing much bigger profits from biosimilars than are sustainable, Niazi argued. “Once prices fall to below 60% of the current prices, it will no longer be feasible for the Amgens and Pfizers to stay in this market for long.”
He says their exit will accelerate when other companies from overseas bring forth products at substantially lowered costs. “Every MAb, regardless of its use, costs about $150–200/g. This price will drop by another 50% once the Indian and Chinese companies start getting approvals; at this stage, prescribers will become redundant and payers will take over.”
Biosimilar Exit? When asked for examples, Niazi cited Merck KGaA’s 2017 divestiture of its biosimilars business to Fresenius for an upfront payment of €170 million ($195 million). Last month “the other Merck” — Merck & Co. (known as MSD outside North America — dropped its Lantus (insulin glargine) biosimilar program after assessing its pricing and costs of production. And recently Sandoz, after a US Food and Drug Administration (FDA) complete response letter (CRL) demanding more data, has pulled the plug on its US rituximab program.
“It will take at least five and perhaps 10 years before the real impact of dropping prices is felt,” Niazi warned, “given that the approval of biosimilars is not fast enough, but it is coming.” He predicts that specialized biosimilar companies such as Samsung Bioepis and Coherus, both of which are already competing in the space, will take over as Big Pharma backs out. A joint venture between Biogen and Samsung BioLogics, Bioepis has a Remicade (infliximab) biosimilar competing in the United States and several other such products in Europe. And Coherus recently won US approval for its version of Amgen’s Neulasta (pegfilgrastim).
Meanwhile, the traditional generic drug companies also are lining up to take their place: Teva, which has seen success with first-wave biosimilars in Europe, is poised to enter the US market with a Celltrion-developed Rituxan (rituximab) biosimilar. Mylan already has a Neulasta biosimilar approved in the United States and boasts another 20 biosimilars and insulin analogs in its portfolio.
Economy of scale at Sandoz
Big Pharma Responds: When Merck & Co. pulled its insulin glargine product, it told BioProcess Insider that it remained committed to biosimilars. Sandoz, Pfizer, and Amgen also have dismissed the idea of any looming exit from the space.
“Pfizer is committed to biosimilars as an important treatment option for patients,” spokesperson Thomas Biegi said. “We are working hard on bringing our biosimilars to market and will continue our efforts to ensure that patients around the world have access.”
Amgen’s Kelley Davenport added: “While we can’t comment on our strategy, with 10 biosimilars in our portfolio, Amgen remains committed to its biosimilars program.”
Sandoz spokesperson Chris Lewis said his company is a “global pioneer and leader” in biosimilars and remains committed to the sector. However, he acknowledged that this is a challenging space in which “only a handful of players will succeed globally in the mid to long term.”
Nicole Fisher Contributor
And is currently listed as the largest solo holder of bioprocessing patents in the world.
In an extraordinary move, the FDA has withdrawn the draft guidance, "Statistical Approaches to Evaluate Analytical Similarity,” after receiving public comments and one citizen petition (FDA-2018-P-1876). The goal of the guidance was to provide an action plan for evaluation of similarity between proposed biosimilars and the original products. FDA Commissioner Dr. Scott Gottlieb, ordering the withdrawal of the guidance, expressed disappointment with the current pace of biosimilar development. “As the cost to develop a single biosimilar product can reach hundreds of millions of dollars, it's important that we advance policies that help make the development of biosimilar products more efficient, and patient and provider acceptance more certain," he said.
But what makes the FDA about-face on biosimilar evaluation so monumental, is that it was the direct result of the citizen petition. Filed by one man: Dr. Sarfaraz Niazi, Adjunct Professor at the University of Illinois at Chicago and CEO of Pharmaceutical Scientist, Inc. When asked about his success in influencing the FDA, the man I once wrote about as the most interesting man revolutionizing the health world, commented, “The idea of making biosimilars accessible has not worked out well to date primarily because of the complexity and redundancy in the regulatory pathway. After I pointed out the complexities and errors in the regulatory guidance and offered alternative approaches, the FDA Commissioner became motivated to make changes. This is the first time that the FDA has simply withdrawn one of its guidance.”
So, what makes the opinions of Dr. Niazi so influential? In 2003, he established Therapeutic Proteins Inc., later named Adello Biologics, with the goal of manufacturing biological drugs and supply them, “at any cost affordable by anyone across the globe.” He then went on to write the largest number of books on biosimilars and worked with the White House in developing the details of the Affordable Care Act that included the Biologics Price Competition and Innovation Act (BPCIA). And is currently listed as the largest solo holder of bioprocessing patents in the world.
Challenging Biosimilar Development Plans
Although there have been barriers to biosimilar uptake in the U.S. that range from lack of provider education to therapeutic interchangeability, the FDA and non-big pharma supporters have high hopes for the future of biosimilars. So, when Dr. Niazi contacted the FDA and told them there was a dire need to re-evaluate the scientific rationale behind the current methods of testing biosimilarity – with aim to reduce barriers including redundant analytical testing and testing in humans without compromising the quality to save significant amounts of time and money – they listened.
His basic premise is built around the FDA’s commitment to engaging scientific methods that reduce testing; in line with US 21 CFR 320.25(a), which codifies the universal belief that, “No unnecessary human testing should be performed.” In the case of biosimilars, testing in healthy subjects is unethical because of their potential of making the study subjects immunoreactive for the rest of their lives. The second premise proposed by Dr. Niazi is to invoke new technologies to establish similarity between biosimilars and reference products to remove any “residual uncertainty,” to allow faster approval of biosimilars. Dr. Niazi argues the use of “thermodynamic equivalence,” a process he created that he claims removes the need for blood-level studies to determine differences between products, can do this.
Other ideas presented included eliminating bridge testing when a non-U.S. reference is used in certain conditions (reducing the number of reference product batches required), creating a mechanism to make reference samples freely available (allowing more ethical in-vitro immunogenicity testing), minimizing non-inferiority testing in patients because of their lack of utility, and changing the pharmacokinetic testing to disposition-related parameters and allowing testing in more homogenous populations. Dr. Niazi also suggested that the FDA promote substitution of biosimilars for new patients through educational programs.
What’s Next?
Within days of the FDA withdrawing the guidance on biosimilars, Dr. Janet Woodcock, Director of Center for Drug Evaluation and Research (CDER) and the FDA Commissioner issued a July 1, 2018 Biosimilar Action Plan that considers most of the recommendations made by Dr. Niazi.
In the 1980s, the Hatch-Waxman Act created a new class of drugs – generic – that has saved American patients over a trillion dollars. If successful, biosimilars, like generics, can save a lot more by making biological drugs more affordable. The FDA has demonstrated that it listens to scientific and creative suggestions. And Dr. Niazi may finally be able to reach his dream of making healthcare more affordable. “Now that FDA is open to scientific approaches to proving biosimilarity, the burden lies on developers to design their plan more creatively. I anticipate a wave of approvals by FDA that will bring price drop of more than 50% – a threshold required to disrupt the markets by taking the decision-making from the hands of prescribers to payers. Eventually I see biosimilars becoming biogenerics, which I had predicted in my first book on the subject," he said.
The H.R. 3590 Sec. 7002, the Biologics Price Competition and Innovation Act of 2009 (BPCIA) created a new category of biological products, biosimilars, having a similar safety and efficacy profile as a US-licensed reference product. The BPCIA was approved as part of the Affordable Healthcare Act, after years of politicking in the US Congress without any resolution as big pharma kept pushing its approval. In 2008, when Barack Obama was elected President, I wrote a personal letter to him that is now in the Obama Library in Chicago, where I found the privilege of advising him on the need for this legislation and apprised him on the critical elements of the bill that needed to be kept intact. President Obama was convinced that a seven-year exclusivity period for new biologics should suffice, as I had recommended; but then the political pressure came into play, and he reluctantly agreed to a 12-year exclusivity. The frenzy that preceded the passage of the Affordable Healthcare Act, wherein the BPCIA was a minor add-on, perhaps escaped the scrutiny of many vested interests, yet, some elements that should not have been in the bill, could not be deleted—most prominently, the dual classification of biosimilars, as biosimilars and interchangeable biosimilars, the latter requiring testing that would prove to be irrelevant and scientifically irrational.
I have continued to write about the slow entry of biosimilars to the US markets and continue to hope that someday we will be able to find a rational approach to make biosimilars affordable.
This letter is in the Obama Libraray in Chicago. .
Biosimilar Regulatory Roundup: March 2019
March 2019 kicked off with a surprise, when FDA Commissioner Scott Gottlieb, MD, announced he was leaving the administration. In addition, the FDA released updated draft guidance on the naming of biologics, biosimilars, and interchangeable biosimilars; approved a Pfizer biosimilar; and more.
Allison Inserro
March 29, 2019
The man many in the biosimilar world credit with being proactive about government efforts to educate and develop the industry in the United States gave his 1-month notice early in March 2019, and that was just the start of a flurry of regulatory news this past month.
FDA Commissioner Scott Gottlieb, MD, is leaving his post, with his last day set to be April 5, just 2 days after he testifies about the FDA’s budget request to Congress. He will be replaced by Ned Sharpless, MD, who has a track record with the biotechnology industry and oncology and is said to have a friendly relationship with Gottlieb.
Still, all of the major biosimilar organizations expressed surprise and regret about Gottlieb’s decision; most observers credit him with a sea change at the FDA.
However, days later biosimilar developers were even less pleased about the FDA’s updated draft guidance on the naming of biologics, biosimilars, and interchangeable biosimilars. According to industry, the FDA’s decision to require 4-letter, nonmeaningful suffixes for biosimilars, interchangeable biosimilars, and new biologics—but not already approved biologics—could seriously hinder biosimilar uptake.
In addition, the International Generic and Biosimilar Medicines Association, a global umbrella group, called the US policy a “notable outlier” that diverges from global consensus on biosimilar naming. The draft guidance also drew the attention of an adjunct professor and founder of biosimilar companies, who filed a citizen petition with the FDA seeking that the guidance be withdrawn.
Sarfaraz K. Niazi, PhD, adjunct professor of biopharmaceutical sciences at the University of Illinois and the University of Houston, is asking that the agency modify its position to state that no suffixes are required for any biologic products and instead state that brand names can be used along with National Drug Codes (NDCs).
In other FDA news, it approved Pfizer’s trastuzumab-qyyp (Trazimera), a biosimilar referencing Herceptin. Trazimera earned EU authorization in July 2018.
The FDA also issued a Form 483 to Biocon after a February 2019 inspection of its Bangalore, India, facility. One issue documented by the FDA says that procedures designed to prevent microbiological contamination are not established or followed and points out a lack of appropriate procedures to prevent contamination on the drug product fill line. The second issue states that written records of investigations into unexplained discrepancies sometimes lacked adequate conclusions or follow-up.
Biocon acknowledged the Form 483, saying that it was related to a preapproval inspection of a new injectable manufacturing line. A representative from Biocon said that the company has already addressed the observations and made a response to the FDA.
In European regulatory news, the European Commission approved Roche’s innovator rituximab, sold in Europe as MabThera, for the treatment of pemphigus vulgaris (PV), a rare autoimmune disorder. The approval marks the first biologic approval for PV in the European Union and the first major new therapeutic option in 60 years.
In Japan, Lupin and YL Biologics received approval to manufacture and sell YLB113, a biosimilar etanercept product. The product will be Lupin’s first biosimilar to come to the Japanese market.
Back in the US capitol, 2 senators launched a bipartisan effort to address the issue of patent thickets. Senator Susan Collins, R-Maine, and Senator Tim Kaine, D-Virginia, introduced the Biologic Patent Transparency Act, which would require companies to publicly disclose the patents that protect their originator biologics, thus making it easier for competitors to evaluate and plan for the development of biosimilars.
The House Committee on Energy and Commerce held a Health Subcommittee legislative hearing on lowering the cost of prescription drugs. The 7 bills that were the subject of the hearing include several items of legislation that have long waited for congressional action as well as new proposals to address the need for increased competition. They include the Creating and Restoring Equal Access to Equivalent Samples (CREATES) Act, which would allow a biosimilar or generic developer to bring a civil action against an innovator drug company if the latter refuses to make available enough samples of a product for testing.
It also includes the Fair Access for Safe and Timely Generics (FAST Generics) Act. This proposed legislation would amend the Federal Food, Drug, and Cosmetics Act to prohibit license holders of FDA-approved drugs or biologics from restricting availability of their products for testing by competitors who seek to develop generics or biosimilars. It would also stipulate that Risk Evaluation and Mitigation Strategies cannot restrict the supply of samples to generic or biosimilar developers.
The Most Interesting Man Revolutionizing The Health World
Nicole Fisher Contributor
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He wrote his first world-renowned book at the age of 26. On weekends he recites love poems (ghazals) on Voice of America. He casually – and humbly – references his more than 70 patents that range from aging wine to chewing gum to bioreactors to air scrubbing systems at his infamous Chicago wine parties. And his mustache rules his twitter feed. In 2013 he was awarded the Star of Distinction, the highest civil award by the Government of Pakistan, for his inventions that are making significant impact in developing countries. He has written over 50 books, well over 100 research papers, and hundreds more articles in the field of science, philosophy, rhetoric, poetry and religion, drawing thousands of hits per day on his blog. Dr. Sarfaraz Niazi might just be the most interesting man in the world, but he is certainly the most interesting man pursuing biosimilars in the United States.
Throughout his career his driving principle has been to make things simpler. He did this while at Abbott Labs, as a former tenured professor at the University of Illinois at Chicago (UIC), in developing countries, and presently in his independent career at Therapeutic Proteins International, LLC (TPI) where he is working on biosimilars – or “copies” of current biologic pharmaceuticals that are about to lose their patents. Although only 17 biosimilars have been approved to date worldwide, though none in US, Dr. Niazi and TPI have nine in the pipeline to transform the entire market. According to photographer Steve Huff, Dr. Niazi is, “An amazing man, in fact the most interesting man in the world!”
Flexibility Is Key To Innovation
When asked his advice to other inventors in a recent interview, Dr. Niazi explained his philosophy that, “You should never get enamored by your thoughts. If the idea does not solve a problem or move the quality of life farther, there are many more things to be invented.” With that mentality, he is filing two products this year alone, similar to Amgen Inc.’s $6 billion molecule white blood count product, due to its expiring patent in the cancer market. Next year, the two molecules he plans to take to market are similar to AbbVie’s expiring $12 billion product Humira.
With movement like that, it’s no wonder Dr. Niazi claims that the U.S. Food and Drug Administration (FDA) is his “friend.” Nevertheless, he notes extreme complications with the rolling submission model, which can cost up to $4 million per submission in fees alone. Additionally, the four levels of the FDA’s “analytical similarity” benchmarking can be troublesome if one has a new biologic entity. This benchmarking, however, allows scientists and the FDA to work together in a predictable, step-wise fashion to move products to market quickly that have fingerprint-like similarity to existing US-licensed biologic products.
Dr. Niazi’s strategy is to create an analytical and clinical equivalent to biologics with expiring patents, which is preferred even over a Phase 3 clinical trial. By doing this, the cost of production is reduced drastically and the speed of development increases by 2-3 times. Dr. Niazi estimates an overall reduction in production costs for his biosimilars of up to 50% or higher compared to market competitors.
With movement like that, it’s no wonder Dr. Niazi claims that the U.S. Food and Drug Administration (FDA) is his “friend.” Nevertheless, he notes extreme complications with the rolling submission model, which can cost up to $4 million per submission in fees alone. Additionally, the four levels of the FDA’s “analytical similarity” benchmarking can be troublesome if one has a new biologic entity. This benchmarking, however, allows scientists and the FDA to work together in a predictable, step-wise fashion to move products to market quickly that have fingerprint-like similarity to existing US-licensed biologic products.
Dr. Niazi’s strategy is to create an analytical and clinical equivalent to biologics with expiring patents, which is preferred even over a Phase 3 clinical trial. By doing this, the cost of production is reduced drastically and the speed of development increases by 2-3 times. Dr. Niazi estimates an overall reduction in production costs for his biosimilars of up to 50% or higher compared to market competitors.
In 2003, the TPI founder committed that his work and company would stay in Chicago. He believed that from creation to manufacturing and testing to going to market, that TPI would excel in the Midwest due to Chicago’s health care ecosystem, experts and manufacturers.
Through a focus on creating “generic equivalents,” Dr. Niazi is proving that TPI can be wildly successful in the Midwest, and further, that in the same way generics revolutionized how people access pharmaceuticals, biosimilars can revolutionize the way those around the world access lifesaving treatments.
As his biosimilars enter the market with FDA approval, the ability of Dr. Niazi to impact the entire health sector grows because his biosimilars can be substituted for its reference product without provider or patient intervention. However, the FDA has not yet finalized these guidelines, and only 17 biosimilars have been approved internationally to date, of which none are by the FDA.
Ultimately, with numerous billion-dollar biologics coming off patent over the next six years, and the exorbitant cost for specialty drugs, the nine biosimilars TPI has in the pipeline stand to make a huge impact in the health sector. While Dr. Niazi could be doing many interesting things these days as an international man of mystery, he has devoted his research, time and energy to bringing high quality, cost-effective treatments to the US, and beyond. So long as he maintains his wine parties and poetry readings, its certain no one will complain.
Impact of proposed changes to FDA approach to biosimilars Posted 08/03/2019
In the Opinion article, Professor Sarfarez Niazi urges the US Food and Drug Administration (FDA) to make adjustments to its guidance on biosimilar development [1]. Niazi’s proposals are consistent with the anti-regulatory political rhetoric and administrative actions that are becoming increasingly widespread in the US. In this article, Professor Pekka Kurki comments on some of Niazi’s proposals from a global perspective [2].
Bridging studies. Most regulatory agencies require ‘bridging studies’ to demonstrate that a foreign sourced reference product and the corresponding domestic product are highly similar. Niazi proposes that bridging studies should not be required if the two products have the same composition and have been licenced based on the same documentation. Kurki agrees that some bridging studies may not be needed for products sourced from ‘highly regulated’ regions, as these have had regulatory surveillance for over 10 years and should therefore be very similar and safe. He notes that collaboration and data sharing between key regulatory agencies would facilitate the acceptance of a global reference product, and that FDA should promote this.
Clinical trials. Single-dose comparative pharmacokinetic (PK) studies are recommended by regulators where the product can be safely administered to healthy volunteers. Niazi makes several proposals to reduce the requirements of PK evaluation, and proposes PK studies in monkeys. He promotes the use of in vitro and in vivo non-clinical testing of immunogenicity in place of clinical immunogenicity studies. Kurki argues that PK studies in monkeys would be problematic from scientific, ethical and global development perspectives. He notes clinical immunogenicity studies aim to look for harmful immunogenicity and the ability of in vitro tests to entirely mimic the human immune system is inadequately documented for regulatory purposes.
Interchangeability. Fundamental to the economic benefits of biosimilars is the ability and willingness to switch between originator products and their biosimilars. Profession Kurki believes that the differing policies of leading regulatory authorities regarding interchangeability creates uncertainty among stakeholders worldwide. He argues the global market would benefit if FDA would clearly separate interchangeability without (automatic) substitution from interchangeability associated with substitution at the pharmacy level, and that this would allow prescribers and local regulatory authorities to develop safe methods for switching. He believes the requirement of specific switching studies using the local reference product discourages global development of biosimilars.
Education. Niazi believes that FDA needs to provide more information on the safety of biosimilars. By contrast, Kurki argues that the problem is not the availability of information on biosimilars, but rather that the information is likely to only reach prescribers who have a specific interest in the data. The recent consultation on FDA draft guidance on interchangeability clearly established that the views of physician societies closely follow the opinions of the innovator sector of the industry. Kurki therefore encourages FDA to engage in discussion with medical societies who publish position papers on biosimilars.
Balancing innovation with competition. Niazi criticizes FDA’s approach to manufacturing, analytical comparisons and clinical development of biosimilars. FDA has recently published a plan to revise its approach to biosimilars, the Biosimilar Action Plan (BAP) with the aim of streamlining biosimilar guidance and restoring the balance between protection of innovation, and competition and access to biologicals [3]. Many of the points raised by Niazi and Kurki will be considered as part of this plan.
Obstacles to success for biosimilars in the US market
Since 2007, the EMA has approved 31 biosimilar products1 and refused or withdrawn around five. The FDA, however, since the enactment of the Biologics Price Competition and Innovation Act (BPCIA) in 2009,2 has licensed six products under PHS 351(k) of the Public Health Service (PHS) Act; approved one product under 505 (b)(2) of the Federal Food, Drug, and Cosmetic (FD&C) Act; and sent out four Complete Response Letters (CRLs) to 351(k) Biologics License Applications (BLAs),3 including two applications each for pegfilgrastim and erythropoietin alfa (Table 1).
This commentary is based on my hands-on experience of developing biosimilars in the US and taking them to the 351(k) filing. More specifically, I will share a novel model for developing biosimilars that appears promising in overcoming many obstacles identified herein.
1. Obstacle 1: understanding the guidance
FDA writes the guidance to comply with two distinct requirements: statutory and scientific. Statutory requirements include analytical similarity, PK/PD, immunogenicity and animal toxicology, which the BPCIA mandates must be met based on scientific requirements that remain flexible and negotiable. I suggest that developers read the BPCIA carefully before reading the guide. One might be surprised to note that the FDA does not mention ‘phase 1’ or ‘phase 3’ in its guidance because human studies for biosimilars are intended to provide a comparative profile, not a measure of efficacy. This distinction is important, yet difficult to embed in the minds of scientists who are used to traditional phase 1-3 studies. Concessions such as using a development lot for a phase 1 study are not available for PK/PD studies for biosimilars, as these must be at-scale GMP lots.
The FDA uses the terms, ‘no residual uncertainty’ and ‘step-by-step’ approach, carefully and in a structured format. If you have resources that allow you to jump the steps, you should find that you are awarded a CRL; never make the mistake of doing what should not be done, such as unnecessary studies in patients.
Table 1: FDA approved biosimilars
2. Obstacle 2: not knowing your molecule
Biosimilar development requires a deeper understanding of the molecule of choice to replicate all limitations and all ‘imperfections’ of the reference product. With a new molecule, you take whatever you have and prove its safety and efficacy; in the case of biosimilars, you need to replicate, even if a feature is not clinically relevant, using a technology that may be protected by hundreds of patents designed to prevent you producing the same molecule. These scientific constraints are better addressed when the development work is outsourced to qualified teams that may not be possible to gather in-house. I strongly urge developers to explore the power of partnering with CDRMOs.
3. Obstacle 3: ignoring importance of freedom to operate
As of today, every product approved by the FDA is under litigation.4 An extensive freedom to operate analysis will teach that developers should concentrate on a wide choice of potential candidates with a market of over $120bn that have a lesser risk of litigation. Teaching science to the legal team and law to the scientists does not work well; however, there are several expert teams available to conduct these determinations. I recommend outsourcing this work, rather than doing it internally and getting constrained by the available expertise.
4. Obstacle 4: reliance on patient studies
The reason that the FDA does not mandate a patient study for the approval of biosimilars has its roots in the statutory declaration in CRF 320.25 (a) that, “no unnecessary human research should be done”. When this statute was established for the bioequivalence testing of chemical drugs, the prospect of highly potent biosimilar antibodies was not envisioned; today, the declaration applies more to biosimilars as we develop highly potent and immunogenic products whose testing in humans is riskier. In addition, we now face a new conundrum5 where it has become more difficult to find patient populations on whom to test drugs, causing delays and escalating costs in the development of biosimilars. Developers should aim to avoid all studies in patients, and that requires a different approach to designing other similarity testing studies. A fingerprint-like molecule is least likely to invoke any need for studies in patients.
5. Obstacle 5: underestimating interchangeability plan
The FDA allows two types of approvals for biosimilars and one of these grants permission to interchange without consultation with the prescriber – an interchangeability designation that requires, by statute, a patient study to demonstrate switching and alternating, demonstrating no less efficacy and no more safety issues. Given the dearth of patients, particularly for anticancer drugs, developers face difficulties in managing patient studies and, as a result, I see fewer applications for the interchangeable status coming to the FDA. My advice: stay away from interchangeable filings if you want a fast-to-market entry. My Citizens Petition to the FDA questions the scientific rationale of approval once the FDA determines that there is ‘no clinically meaningful difference’.
6. Obstacle 6: not understanding side-by-side testing
Safety and efficacy are tested side by side, with highly complex statistical modelling to prove similarity. How does one determine that there remains no ‘residual uncertainty’? How does one design studies that are sensitive to demonstrating differences rather than similarity? For example, the choice of dosing level in animal toxicology studies, whether for rodents or other mammals, should be within the escalating range of the sigmoid curve. The three statistical tiers in analytical similarity testing are not intended to make one test more important than the other. The tier 1 and tier 2 tests remain fraught with mathematical difficulties that the FDA still needs to fix. A tier 1 test where the reference product has very small standard deviation will always fail, and a tier 2 test will fail if the biosimilar products have fewer degradants or aggregates. The FDA does not allow non-inferiority testing in analytical similarity. Still, the developer needs strong statistical expertise to develop analytical similarity testing protocols. Similarly, clinical studies cannot be overpowered to obviate deficiencies in the design or testing of drugs or antibody levels. The FDA is still improving its guidance on statistical testing; the developer is advised to read the reports that the FDA has made public while approving biosimilar products.
7. Obstacle 7: GMP compliance
Unlike in the development of a new product, the FDA expects all testing to be done using at-scale lots in a GMP environment and in a CFR Part 11 compliant laboratory. This requirement comes because there is no mandatory patient trial anticipated to establish safety and efficacy of the product. The FDA guidance on GMP for investigational drugs6 is interpreted differently for biosimilars, and the FDA can audit the facility for full GMP compliance in response to an Investigational New Drug (IND) filing – an aspect that many new developers fail to realise. It is for this reason that biosimilar development works better when development work is outsourced, rather than creating a fully integrated traditional facility. Outsourcing also allows developers to bring in creative technologies7 to obtain lower cost of goods sold. In my calculations, it is more efficient and less costly to work with CDRMOs than doing the work internally.
8. Obstacle 8: FDA meetings
Formal meetings with the FDA are designed to address the issues of ‘residual uncertainty’, rather than function as teaching lessons for developers. A well-informed developer should be able to write meeting requests that result in the definite closure of issues rather than seek general advice. The FDA has made public its evaluation of the first biosimilars approved, and this information should be sufficient to write appropriate protocols, establish analytical similarity testing, select an animal toxicology model, etc. The goal of Type 2 meetings is to come out ready for the Type 3 meeting without going back to another Type 2, as most developers have done recently. Another piece of information for small companies is that while the FDA may waive the filing fee for your first application, the fee for meetings cannot be waived according to the 2017 revision of the Biosimilar User Fee Act (BsUFA). Generally, consultants hired to write and manage FDA applications have little experience and mistake this exercise for a validation of plans – the goal is to negotiate terms, not just shake hands.
9. References
1. www.ema.europa.eu
2. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ucm216146.pdf
3. www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm
4. www.healthlawpolicymatters.com/wp-content/uploads/sites/8/2016/08/Status-of-Biosimilar-A pplications-August-2016.pdf
5. www.nytimes.com/2017/08/12/health/cancer-drug-trials-encounter-aproblem- too-few-patients.html?_r=0
6. www.fda.gov/downloads/drugs/guidances/ucm070273.pdf
7. www.niazi.com/bioprocessing
10. Biography
SARFARAZ K NIAZI, PhD, SI, FRSB, FPAMS, FACB, is the Founding Executive Chairman and CSO of Karyo Biologics, LLC, the Founder of Adello Biologics, LLC, a fully integrated US biosimilar company, and Adjunct Professor of Biopharmaceutical Sciences, University of Illinois, Chicago. He has over two decades of hands-on experience in taking biosimilars to market globally. He has authored dozens of major books about biosimilars, bioprocessing, pharmaceutical formulations and regulatory
Sarfaraz K. Niazi, Founder at Karyo Biologics, Adello Biologics and Pharmaceutical Scientist, LLC
https://biotechpharmasummit.com/index.php/speaker/sarfaraz-k-niazi/
Sarfaraz K. Niazi (1), Adjunct Professor of Biopharmaceutical Sciences, University of Illinois College of Pharmacy, University of Houston and several other academic institutions, is the founder of Karyo Biologics (www.karyobio.com), Adello Biologics (www.adellobio.com) and Pharmaceutical Scientist, LLC (www.pharmsci.com). Sarfaraz is globally recognized as a pioneer of biosimilars having developed novel technology and regulatory plans to take dozens of biosimilars to the market over a period of over 30 years.
In 2014, the Forbes Magazine’s recognized him as “The Most Interesting Man Revolutionizing The Health World” (2), for his lifetime efforts in making high cost essential drugs, biosimilars and complex generics, accessible across the globe.
In 2018, the Forbes magazine reported him as “Scientist Invented A New Pathway To Approve Biosimilars, And The FDA Is Listening” (3), for his efforts to convince the US FDA to adopt a more rational approach to approve biosimilars reduce the cost of development. He is now advising the US FDA in defining the structure of their new Biosimilars Action Plan (BAP) (4) that was issued by the US FDA after Sarfaraz filed a citizen petition against the FDA (5) (FDA-2018-P-1876). The FDA has also shared the progress made in collaboration with Sarfaraz on the US government portal (6, 7). Sarfaraz’s efforts in changing the FDA approval process are widely acclaimed to be the most pivotal move to make biological drugs affordable (8-24).
To promote faster adoption of biosimilars, Sarfaraz has written dozens of major books (25), including the first book on biosimilars and coined the phrase “biosimilar” in his first biosimilars guidance advise to FDA. Other major books of Sarfaraz include the first book on single-use bioprocessing, a textbook on bioprocessing, a two-volume book on biosimilars, a six-volume set of cGMP manufacturing encyclopedia, the largest book on bioequivalence testing and the first book on preformulation of biologics and botanical drugs. He has also authored 100+ research papers and hundreds of blogs. His most recent book, Biosimilarity: The FDA Perspective, published July 2018 is dedicated to Dr. Janet Woodcock, Director, CDER at the FDA. His other books have been dedicated to Dr. James Watson, Nobel Laureate, who discovered DNA structure and President Barack Obama with White House approval, among other notable personalities.
Sarfaraz has also authored a large number of internationally published blogs on topics ranging from contemporary scientific ideas to philosophy, poetry and ironies of life.
Sarfaraz has been a keynote speaker on the topic of biosimilars including presenting the FDA viewpoints before the industry audience (26). He is a fellow of several learned societies and a widely sought-after speaker with over 500 talks across the globe. In his capacity as an academician, Sarfaraz has trained 50+ graduate students and scores of FDA inspectors.
A few notable contributions of Sarfaraz include:
Contributed to BPCIA as advisor to the US Congress and President Obama.
Received first waiver of in-patient testing of a biosimilar candidate under 351(k).
Developed a fourth-dimension analytical similarity testing to achieve fingerprint-like similarity for biosimilars.
Developed an ISO 9 bioreactor used to file the first BLA of a biosimilar.
First book authored by Sarfaraz and FDA on the topic of biosimilarity (27) and dedicated to Dr. Janet Woodcock, Head, CDER, FDA.
Published advise to the US FDA and the industry to identify and obviate the impediments to slow entry of biosimilars in the US markets (28,29).
Filed citizen petition on the subject of changing evaluation of biosimilars by the FDA (30).
Trained FDA inspectors on cGMP compliance.
Coordinated dozens of FDA audits of generic and biological manufacturers, particularly managing consent decrees.
Consultants to investment bankers, VC groups and private investors on value proposition analysis in the field of pharmaceutical and biopharmaceuticals.
Served as expert witness in IP and pharmaceutical cases.
Trained scientists on behalf of the USP.
Translated love poems of famous Asian and Persian poets into English.
Taught thousands of primary and secondary care physicians in the US on the regulatory pathways and safety features of biosimilars.
Sarfaraz is the largest solo inventor of bioprocessing inventions with over 100 inventions (31), additionally including new drugs, new dosage forms, bioequivalence testing methods and a large number of other patient-related inventions that are widely used across the globe. His patented invention of demonstrating analytical similarity methods (32) was accepted by the FDA to allow waiver of patient trials of biosimilar products.
Sarfaraz is also a licensed practitioner of the patent law at the United States Patent Office, an expertise he has used to create the FTO boundaries for biosimilars to avoid litigation under the BPCIA (33, 34). Sarfaraz provides this service free of charge to the Third World scientists and has secured over 400 patents for his clients.
The President of Pakistan conferred the high civil award, Start of Distinction (35), upon him in the field of engineering sciences, as his 100+ inventions are helping a large population around the world with more affordable drugs, clear water, new drugs, new devices, and novel disease management systems.
Sarfaraz is working with global biosimilar companies to help them secure faster approval of biosimilars as well as working with the US Congress, the FDA and the media to avoid impediments to adoption of biosimilars; recently, Sarfaraz and Pfizer have joined and advised the FDA to adopt the policies that will prevent companies like Amgen to differentiate biosimilars (36). Sarfaraz is also teaching physicians in the US on behalf of the largest biosimilar companies on the safety and regulatory paths to approvals.
Sarfaraz was born in Lucknow, India. He received as MS degree in pharmacy from the Washington State University, and a PhD in pharmaceutical sciences from the University of Illinois, where he began his academic career and continues as Adjunct Professor of Biopharmaceutical Sciences at the University of Illinois College of Pharmacy and additionally at the University of Houston and several other academic institutions around the world. Sarfaraz became a tenured professor at the age of 28, a position he left to join Abbott Laboratories International, where he was tenured as Volwiler Fellow. He left Abbott to develop biosimilars to make them accessible globally.
Sarfaraz is an avid photographer, a musician, a poet, a radio broadcaster (Voice of America, US State Department) with audience of over a billion, on literary and philosophic topics. He is also a translator of Asian love poems into English; he resides in Deerfield, Illinois.
References
http://www.fdalawblog.net/2018/05/biosimilar-approval-better-stronger-faster/
https://www.regulations.gov/document?D=FDA-2018-P-1876-0003
https://www.regulations.gov/document?D=FDA-2018-P-1876-0004
https://www.biospace.com/article/fda-withdraws-draft-guidance-on-biosimilar-development
https://seekingalpha.com/news/3367537-fda-withdraws-draft-guidance-related-biosimilar-development
http://www.fdalawblog.net/2018/05/biosimilar-approval-better-stronger-faster/
https://www.europeanpharmaceuticalreview.com/article/70987/obstacles-success-biosimilars-us-market/
https://www.jdsupra.com/legalnews/fda-to-hold-public-hearing-on-67759/
https://exlevents.com/fda-12. withdraws-biosimilar-draft-guidance-after-public-outcry/
https://www.epmmagazine.com/news/fda-is-asking-for-public-comments-on-bioequivalence-testing-/
https://www.rdmag.com/article/2014/10/biosimilars-market
https://www.niazi.com/scholar/
https://karyobio.com/news/2017/11/6/dr-niazi-invited-as-keynote-speaker-at-the-fdacms-conference
https://www.barnesandnoble.com/w/biosimilarity-sarfaraz-k-niazi/1125939292
https://www.europeanpharmaceuticalreview.com/article/70987/obstacles-success-biosimilars-us-market/
http://www.fdalawblog.net/2018/05/biosimilar-approval-better-stronger-faster/
https://sarfaraz-niazi.squarespace.com/s/biomolecule-patent.pdf
https://patents.google.com/patent/US20180024137A1/en?oq=US20180024137A1
https://www.law.cornell.edu/uscode/text/42/262
https://en.wikipedia.org/wiki/Category:Recipients_of_Sitara-i-Imtiaz
Scientist Invented A New Pathway To Approve Biosimilars, And The FDA Is Listening
Nicole Fisher Contributor
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And is currently listed as the largest solo holder of bioprocessing patents in the world.
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In an extraordinary move, the FDA has withdrawn the draft guidance, "Statistical Approaches to Evaluate Analytical Similarity,” after receiving public comments and one citizen petition (FDA-2018-P-1876). The goal of the guidance was to provide an action plan for evaluation of similarity between proposed biosimilars and the original products. FDA Commissioner Dr. Scott Gottlieb, ordering the withdrawal of the guidance, expressed disappointment with the current pace of biosimilar development. “As the cost to develop a single biosimilar product can reach hundreds of millions of dollars, it's important that we advance policies that help make the development of biosimilar products more efficient, and patient and provider acceptance more certain," he said.
But what makes the FDA about-face on biosimilar evaluation so monumental, is that it was the direct result of the citizen petition. Filed by one man: Dr. Sarfaraz Niazi, Adjunct Professor at the University of Illinois at Chicago and CEO of Pharmaceutical Scientist, Inc. When asked about his success in influencing the FDA, the man I once wrote about as the most interesting man revolutionizing the health world, commented, “The idea of making biosimilars accessible has not worked out well to date primarily because of the complexity and redundancy in the regulatory pathway. After I pointed out the complexities and errors in the regulatory guidance and offered alternative approaches, the FDA Commissioner became motivated to make changes. This is the first time that the FDA has simply withdrawn one of its guidance.”
So, what makes the opinions of Dr. Niazi so influential? In 2003, he established Therapeutic Proteins Inc., later named Adello Biologics, with the goal of manufacturing biological drugs and supply them, “at any cost affordable by anyone across the globe.” He then went on to write the largest number of books on biosimilars and worked with the White House in developing the details of the Affordable Care Act that included the Biologics Price Competition and Innovation Act (BPCIA). And is currently listed as the largest solo holder of bioprocessing patents in the world.
Challenging Biosimilar Development Plans
Although there have been barriers to biosimilar uptake in the U.S. that range from lack of provider education to therapeutic interchangeability, the FDA and non-big pharma supporters have high hopes for the future of biosimilars. So, when Dr. Niazi contacted the FDA and told them there was a dire need to re-evaluate the scientific rationale behind the current methods of testing biosimilarity – with aim to reduce barriers including redundant analytical testing and testing in humans without compromising the quality to save significant amounts of time and money – they listened.
His basic premise is built around the FDA’s commitment to engaging scientific methods that reduce testing; in line with US 21 CFR 320.25(a), which codifies the universal belief that, “No unnecessary human testing should be performed.” In the case of biosimilars, testing in healthy subjects is unethical because of their potential of making the study subjects immunoreactive for the rest of their lives. The second premise proposed by Dr. Niazi is to invoke new technologies to establish similarity between biosimilars and reference products to remove any “residual uncertainty,” to allow faster approval of biosimilars. Dr. Niazi argues the use of “thermodynamic equivalence,” a process he created that he claims removes the need for blood-level studies to determine differences between products, can do this.
Dr. Sarfaraz K. Niazi
Niazi.com
Other ideas presented included eliminating bridge testing when a non-U.S. reference is used in certain conditions (reducing the number of reference product batches required), creating a mechanism to make reference samples freely available (allowing more ethical in-vitro immunogenicity testing), minimizing non-inferiority testing in patients because of their lack of utility, and changing the pharmacokinetic testing to disposition-related parameters and allowing testing in more homogenous populations. Dr. Niazi also suggested that the FDA promote substitution of biosimilars for new patients through educational programs.
What’s Next?
Within days of the FDA withdrawing the guidance on biosimilars, Dr. Janet Woodcock, Director of Center for Drug Evaluation and Research (CDER) and the FDA Commissioner issued a July 1, 2018 Biosimilar Action Plan that considers most of the recommendations made by Dr. Niazi.
In the 1980s, the Hatch-Waxman Act created a new class of drugs – generic – that has saved American patients over a trillion dollars. If successful, biosimilars, like generics, can save a lot more by making biological drugs more affordable. The FDA has demonstrated that it listens to scientific and creative suggestions. And Dr. Niazi may finally be able to reach his dream of making healthcare more affordable. “Now that FDA is open to scientific approaches to proving biosimilarity, the burden lies on developers to design their plan more creatively. I anticipate a wave of approvals by FDA that will bring price drop of more than 50% – a threshold required to disrupt the markets by taking the decision-making from the hands of prescribers to payers. Eventually I see biosimilars becoming biogenerics, which I had predicted in my first book on the subject," he said.
222,767 viewsAug 30, 2014, 08:31am
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