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Biosimilars update: fulfilling a dire need, but at what (human) cost?

There is currently a market void for oncology products, where demand has outstripped supply, and there are millions of patients and soon-to-be-diagnosed new patients who are in need of these treatments. Add to this that certain biotherapeutic oncological immunomodulators are also being used off-label and experimentally for a variety of conditions such as arthritis, certain thyroid diseases, dermatologic conditions, and many others. This puts a further draw on the supply side, increasing the deficit of treatment availability on the demand side. How might biosimilars fill this void? And what are future-looking concerns that we should remain vigilant toward?

Current oncology landscape

There are currently over 200 drug treatments for cancer available to patients in the U.S., according to the NIH National Cancer Institute. There are also approximately 4,600 new cases of cancer diagnosed every day, which means that patient demand will not abate.

Of these treatments, there are sporadic shortages of antibody therapies of different types. But this seems to be just where the biosimilars market is best designed to fit in. That is, with recently innovated treatments, which have high demand by the consumer market, but whose patients aren't able to access the branded therapies either due to shortfalls of availability or prohibitiveness of cost. If these conditions could have wide access to biosimilars, the number of treated patients compared with today would increase by tens of millions per year worldwide. With average survivability improvements owing to the treatments of several months to years, and favorable Quality-Adjusted Life Years (QALY) profiles, this helps improve the world's battle with cancer to the tune of hundreds of millions to tens of billions of human-years added annually across the globe. But let's look at some of the downside risk of this proposition.

Approval status of biosimilars as a whole

While still considered 'new/ biosimilars aren't a new approach to therapies, but are more accurately described as still being a nascent industry. This is because the regulatory track record is still immature--only a handful of approvals--and being built, mostly by the continued and diligent hard work applied by the top companies producing these drugs and working with regulatory authorities on stabilizing the requirements. But it almost is a situation of optimism slowing market availability, and 'perfection' being the enemy of'good enough.'

Because the vast majority of polled respondents in the industry feel that biosimilars offer a wealth of benefits and value to the market, it has almost become assumed common knowledge that the future will bring a whole host of biosimilar treatments. But this optimism has also contributed to overconfidence and a loss of focus for some treatments in the biosimilar pipeline. By the very nature of biosimilars being associated with approved treatments and the success of generics for small molecule therapies, there has been an expectation that they'll 'just work' and fly through regulatory approval. Consequently, there hasn't been the same level of problem-solving and regulatory risk-reduction being implemented in all cases of biosimilar production.

I've brought into pharma a few cognitive traps from work I've done in other industries that lead to these overestimations and delays in market approval, which, by the way, come at a cost of hundreds-of-thousands to tens-of-millions in opportunity cost (USD) per day of delay.

Heuristics

Often used in computer programming to describe certain shortcuts, we have identified a number of psychological heuristics that operate in people, which in general tend to help us navigate our daily lives, but in certain cases can have extraordinarily dire consequences. These 'rules of thumb' are mental shortcuts that our brains use to keep from spending too much cognitive resources on generalizable and routine tasks; unfortunately, a'Familiarity'heuristic prevents us from allowing new information in to potentially change our course of action. Ian McCammon analyzed some of these heuristics in the field of avalanche research and found that groups with advanced training in terrain that they were familiar with exposed themselves to nearly twice the hazard level of less well-educated groups, and about the same level of hazard as parties with no avalanche training at all.

Another significant cognitive bias is the 'Consistency' heuristic, which states that once on a particular course of action, how often have you seen teams actually overcome the momentum and intertia of a bad decision and make radical changes to the outcome to guarantee success? It's actually quite rare, especially with more money and time committed to the project(s). The consistency heuristic keeps us moving on a similar path, presumably to avoid distractions and limit mental energy when distractions surround us. Research into this heuristic has shown that the level of commitment to an end goal, divorced from probabilities of success, were related to the inability to change course. Also, groups of 3 or more people, and within which there has been some level of formal training, are most susceptible to this effect of'staying the course.'

How similar?

In the medical device industry, there are special provisions and determinations made for 'substantial equivalence,' as a specific example, for a 510(k) premarket notification application, that the new device is at least as safe and effective as the predicate (device). Biosimilars have to demonstrate similarity with their innovator compound (predecessor), though how similar has been a moving target.

For biosimilars, FDA lists the following: To have a product reviewed as a biosimilar or interchangeable, manufacturers must submit a 351(k) biologies license application (BLA) that includes, among other things, information demonstrating biosimilarity based upon the following:

* Analytical studies demonstrating that the biological product is"highly similar" to the reference product notwithstanding minor differences in clinically inactive components;

* Animal studies (including the assessment of toxicity); and

* A clinical study or studies (including the assessment of immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD)) sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and for which licensure is sought for the biosimilar product.

I wonder about the 'substantial equivalence' in these cases and how "highly similar" is enough, specifically in treatments for significant disease or disorders where there is no availability of the innovator compound either because of market shortages or regional approval, or it is too expensive. For people with zero other net options, it seems beneficial to have the biosimilars widely available, but at what (human) cost? A recent review published by MedPage Today and the Milwaukee Journal Sentinel found that drug side effects reporting from the public to the FDA has skyrocketed by 500% between 2004 and 2015. And in particular cases (Zecuity migraine patch), the FDA allowed market release as long as the manufacturer reported AEs to the agency within 15 days of receiving a complaint. Effectively, this was moving the phase III trial out to Main Street.

What similar sorts of medical burden could be caused by favoring the balance of availability over rigorous safety and equivalence testing? And of course, the challenge for the regulatory agencies is also the flip side: Testing ad infinitum means that populations may be needlessly suffering without a viable treatment option available that may exist, because it is caught up in excessive review bureaucracy. Lyndsay Meyer, an FDA spokeswoman, thinks this is all part of evolving methods. She said, "It's not always necessary to wait and go through a traditional development program before making drugs available to patients."

For those attending the PDA Annual Meeting this month, or AAPS' National Biotechnology Conference 2017, these are high-impact discussion points I'd love to get your thoughts and input on. After all, we're at a place in time right now that will be looked at as history in our future: We are shaping how we want this period of time to be remembered, with respect to biosimilars and other issues in the industry. Let's make the smartest and most-informed decisions that we collectively can.

Ben Locwin

Ben Locwin, PhD, MBA, MS has worked on drug safety and efficacy of gene therapies, biologies, and small molecules. He has also designed cost models for biosimilars used by Wall Street and industry firms. He is an expert media contact for the American Association for Pharmaceutical Scientists (AAPS) and a Healthcare expert with the Association for Talent Development (ATD). He has been featured by the Associated Press, The Wall Street Journal, and Forbes. He can be reached for questions or advice at Ben.Locwin@HealthcareScienceAdvisors.com.

References

(1.) McCammon, I. (2004). Heuristic traps in recreational avalanche accidents: Evidence and implications. Avalanche News, 68.

(2.) Herbert, W. (2010). On second thought: Out smarting your mind's hardwired habits.
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Title Annotation:CLINICALLY SPEAKING
Author:Locwin, Ben
Publication:Contract Pharma
Date:Apr 1, 2017
Words:1425
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