Not Grandma’s generics, ‘biosimilars’ require regulating oversight, so we know what they really contain

By Nancy Collisson

Decades ago, the most popular method American children used to assure their friends that they could be trusted in matters of utmost seriousness was to lean in and breathlessly exclaim Cross my heart and hope to die! The statement was always accompanied by a sharp criss-crossing by the speaker of his or her finger against a jelly-stained shirt.

Apparently at the time nothing better conveyed willingness to back up a promise than to vaguely let others know you were willing to hang on a cross like Jesus.

This scenario serves to remind us how little our characters change as we grow up. As adults, making life-and-death decisions about our health, we come to accept promises in the forms of scientific-sounding brand names pasted on containers stuffed inside of boxes that contain tissue paper inserts of information about the contents of these items written in size-6 fonts. 

In this case, the mutually understood difference between promiser and promisee is that if the promise falls short, the promiser crosses his or her heart against a spotless white lab coat while knowing that he or she most assuredly will not ‘die.’

Fortunately, having a world of information at our fingertips, even in the most dire and panicked of circumstances, allows us to quickly sift out and scrutinize every potential lie we may feel we’re being told or sold. In mere seconds we can find out how to live practically forever in perfect health. 

We should also, therefore, be able to figure out how best to invest in systems that claim to fulfill this dream.

Unfortunately, due to complicated technological advances and big pharma’s blatant desire to eliminate copycat generics, both the act of investigating the safest and most effective emerging health therapies and knowing which manufacturers might be best to invest in are about to become too complicated to do that at all

Patents owned by major pharmaceutical companies for gene-focused therapies called ‘biologics’ are beginning to expire, causing laboratories all over the world to rush to create not chemically identical generic equivalents, but ‘follow-up biologics’ or ‘biosimilars.’ And trying to get to the bottom of what composes a biologic to a point that dispels risk beyond a pinky promise is impossible. 

“It is difficult, and sometimes impossible,” according to the Biotechnology Innovation Organization, “to characterize a complex biologic by testing methods available in the laboratory, and some of the components of a finished biologic may be unknown.”

The fact is even original biologic manufacturers are unable to break down the components of their own therapies. Instead, they often claim to improve upon them, resulting in ‘biobetters.’ Biobetters are described by Ronald A. Rader in the BioProcessing Journal as “too dissimilar in some aspects (e.g., structure, formulation, efficacy, etc.) to be approved as biosimilar versions of corresponding reference products. Biobetters generally involve some additional innovation and are mostly produced by companies in, and targeted to, markets in more developed countries. So, when you hear about an OTC product that is ‘new and improved,’ it really is – but not for the reasons you think it is, to just improve it, but because the manufacturer cannot make the same or even a bio-identical item.

Of course, for incautious investors who may be in the habit of getting in and getting out of investments, particulary in emerging markets, the headache that could come with fully understanding precisely what’s inside these new emerging-market wonderdrugs – oops, biologics – might not seem too concerning. 

After all, a global agency has emerged that should be able to protect their investment – and the meds that we pick up. This past June, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) based in Geneva, approved membership of a regulating organization, the International Generic and Biosimilar Medicines Association (IGBA), as an assembly member. This membership reflects awareness of the rapid evolution, development, and need for oversight, regulation, and approval of biosimilar therapies manufactured within the pharmaceutical industry.

When it comes to the business of life-enhancing or life-saving therapies, big money is at stake making the manufacture of biosimilars in emerging market (EM) regions that may lack infrastructure for rigorous regulation makes the process rife for error if not misconduct. And if bad investments are made in EM manufacturers based on promises alone, investors will be lucky to get out of their positions with the designer shirts on their backs. 

Indeed, when even the FDA-approved $9-billion American company Theranos was forced to shut down its blood-testing facility after being found fradulent, who can be trusted? Who will be checking standards at facilities in Mexico, Brazil or Tanzania? What does it really mean if their potential biosimiars come under consideration of the FDA, whose authority is also continuously under attack by anti-vaccination physicians, can it really be regarded as the vanguard of trust for approving obscure and inscrutable biologics that are created under highly secretive processes?

Recipe for Disease or Disaster

In America, when we pick up a loaf of bread from a grocery store shelf, we know we’re getting a picture-perfect, soft, evenly baked loaf. We know that every aspect of its basic ingredients as well as conditions of the baking arena have been strenuously controlled to create that consistent product. Source materials; room, oven, and product temperature and moisture-content had all been acutely managed to meet demands of discerning consumers.

When word gets out that you’re a quintessential master bread-baker, others will try to replicate your recipe by reverse-engineering it. With varied amounts of analysis, time, and effort, individuals or teams of copy-cats everywhere will come very, very close to making the same types of breads to suit different penchants. In fact, their outcomes will be so similar that not even your friends will be able to tell the difference between yours and theirs.

This ideal formulation theory is the premise behind generic drug manufacturing for which especially notoriously over-charged Americans are thankful to be the recipients. 

But when it comes to laboratory scientists in depressed or even well-funded emerging markets, breaking down the formulae of original patented biologics into follow-on biologics or biosimilars is, we are told, so much more complicated that it is simply impossible.

Not Your Generic Risk

According to the Biotechnology Information Organization (BIO), “because of the complexity of biologics, the only way to establish whether there are differences that affect the safety and effectiveness of the follow-on product is to conduct clinical trials.” In other words, cross your fingers and line up the guinea pigs.

It is not possible to de-engineer a biologic the same way a drug can be. Drugs are manufactured through chemical synthesis – a process of following a recipe by mixing designated measurements of specific chemicals under sensitive conditions.

Biologics are made with pieces from living human cells or animals cells or plant cells or combinations. These micro-organisms that are incorporated into – not a drug – but a complex compound or structure that uses this recombinant – mixed up – DNA. 

This recombinant DNA is inserted into a host organism to produce new genetic combinations that target, isolate, and manipulate a defective gene. Although it is relatively easy to isolate a sample of DNA from a collection of cells, finding a specific gene within a cell is difficult because each human cell contains approximately 2 metres of sequence strands carrying information. Biologists then take these living cells and manipulate this recombinant DNA, programming it to fight a specific disesase. After that the structure is grown and multiplied until it is sufficient to be given to a patient.

To the layman and to biologists, it seems, combining living cells from plants, animals, and humans to do this job seems like a matter of crossing fingers and hoping for the best. 

According to BIO, living systems used to produce biologics are sensitive to very minor changes in the manufacturing process. “Small process differences can significantly affect the nature of the finished biologic and, most importantly, the way it functions in the body. To ensure that a manufacturing process remains the same over time, biologics manufacturers must tightly control the source and nature of starting materials, and consistently employ hundreds of process controls that assure predictable manufacturing outcomes.”

Precisely duplicating these processes to create biosimilars is impossible because process controls are established separately for each step in the process for each product, and they are always going to remain confidential to the original manufacturer who is under no obligation to release his ‘recipe.’ Thus, according to BIO, “it would be difficult or impossible for a second manufacturer to make the ‘same’ biologic without intimate knowledge of and experience with the innovator’s process.”

Adding to the difficulty of creating biosimilars is that, Just as with the original manufacturers, manufacturers of biosimilars, hundreds of millions of dollars are required by their laboratory scientists to acquire equipment, maintain consistent and pristine conditions, and to hire talent to manage the extensive research required to create precise combinations of DNA that can join with human cells to do extremely complicated tasks.

Unfortunately, despite this massive investment, they don’t always work, and, according to when they do work, the user will experience a range of ‘side’ effects.

Dr. Lawrence Steinman, MD, BA Dartmouth College and MD Harvard University, runs the Steinman Lab at Stanford University. His research led to the development of the drug Tysabri, which is used to treat patients with MS and Crohn’s disease.

In creating a biologic to treat MS, according to Steinman, the patient’s immune system is manipulated. The biologic is designed to track down the cells within the immune system that are cause the disease and attaches to those cells and destroys them.

Recognition and patents Steinman has received bespeak the exceptional discipline he has devoted to his work in this field. These include the John M. Dystel Prize from the American Academy of Neurology, the National MS Society, and the Charcot Prize for Lifetime Achievement for his MS research. He holds patents in the areas of immunology and for therapies for Huntington Disease, type-1 diabetes, and MS. Steinman co-founded Neurocrine Biosciences, Bayhill Therapeutics now named Tolerion, as well as Nuon Therapeutics, Transparency Life Sciences, and Atreca.

Because biologics can cost patients several thousand dollars each month. Demand for biosimilars is high, making investors keen to get in on the game. 

According to Rader, “to achieve analytical and clinical efficacy, and safety similarity matching that of a marketed biopharmaceutical is a significant technological accomplishment. Little, if any, detailed (and proprietary) bioproduction information is published for public access, so little is known about reference products manufacturing. Biopharmaceuticals are incredibly hard for third parties to accurately replicate, which is why, for the most part, countries that invest the most money in biopharmaceutical R&D and medical care are the ones successfully developing and adopting biosimilars.”

Presently the US lags behind Australia, Canada, Japan, and Korea in the cautious manufacture of biologics. 

Knocking on Wood

Meanwhile, however, EM countries are leaping forward to make biosimilars. According to Rader, developing countries lack biosimilar-approved pathways, but because they have long made generic drugs, they are going ahead and making them anyway. 

Any biologic product considered close enough to share the same generic International Nonproprietary Name (INN) as its reference product is considered the same or close enough, and is either approved or simply just used for the same indications as the reference drug product. Products that can be simply presumed to be biosimilar are just treated as fully biogeneric equivalents in most developing countries, and this is driven mostly by economics. Making fine distinctions among similar biopharmaceuticals is not of interest to manufacturers in these countries. Many countries commonly cited as having biosimilars may actually have zero biosimilars, but rather, biogenerics … the preferred domestic term [in India, for example]. – Ronald A. Rader

Rader states that it will be a further ten years before medical laboratories in China, India, Brazil or Cuba bring biosimilars to EU or US regulating bodies for approval or into their markets, but demand for affordability and immediacy and promotions of EM sites for medical tourism may cause consumers to toss caution to the wind and take their chances.

The Brazilian government recently licensed Protalix BioTherapeutics, a plant-expression-based biopharmaceutical company, to develop its technology in producing carrot-cell culture biologics. The government contracted with GE Healthcare and iBio, Inc., another company focused on plant-expression technology, to build a large manufacturing facility in Brazil. 

Brazil’s cautious carrot-and-stick approach is prescient and prudent, and serve well as a best-practice model for investors and consumers, alike.

Until and unless greater clarity about biosimilar manufacturing processes and their regulation is provided by global regulating body ICH and others, dealing solely with companies working with safe-as-possible and most easily understood plant-based biopharmaceutical therapies is their best bet.

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