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Biosimilars in Rheumatology
What are important differences in biosimilar vs innovator reference product manufacturing, development, and approval?
Biosimilars are not exact replicas of their originator drugs, as is the case with generic drugs. Although the US Food and Drug Administration has determined that biosimilars will not have “clinically meaningful” differences in terms of safety, purity, and potency from their reference products, there are small allowable variations in structure as a result of their derivation from living organisms. These variations between biologic progenitors and biosimilars allow for consideration of biosimilars as therapeutic options for some patients, with appropriate caution needed to protect potential drug recipients.
My experiences with biosimilars are limited because I have not fully embraced them. Let me tell you a little bit about why.
My initial concern, of course, is safety, and as with everything else, safety is a dominant driver of what propels [physicians] into embracing new molecules. [It is my belief that the] data regarding placebo-controlled, prospective experience with the reference product vs the biosimilars are grossly missing. And why is that? It’s because the biosimilar acts that have allowed biosimilars into the fray have not required that the manufacturers keep their products for the disease states for which they are being approved.
We all know that psoriatic arthritis (PsA) and rheumatoid arthritis are very different diseases, yet they are linked by commonalities including inflammatory markers and pathologic features. However, we now know that secukinumab, the human interleukin-17A antagonist, did not demonstrate efficacy for rheumatoid arthritis. It has now been only approved to treat PsA, ankylosing spondylitis, and plaque psoriasis.
Why is this important? I think it is critical that the manufacturers of the biosimilars be required to test their drug in the disease state for which it is approved. At this time, you can get approval on the basis of proximity to the indication, but not exact testing against that specific disease state. Phase 4 monitoring along with the collection of patient-reported outcomes data will be essential to learn more about these medications.
In addition, physicians should remember that biosimilars are large macromolecules. Subtle distinctions in the amino acid constitution of the drug suggest the potential for altered immunogenicity; that is to say, a human immunoresponse to the biosimilar that is lacking in the reference product, inducing allergic reactions to the biosimilar compound.
Should pharmacists be required to notify prescribers and patients when indemnity plans and pharmacy benefit managers request automatic substitution of branded biologics with a biosimilar?
Yes. What is vital in the prescribing of biosimilars is that patients and physicians are directly engaged in the decision to use these medications. Any biosimilar needs to be identified by name so the patient knows what he or she is getting and the physician knows exactly what the patient is being prescribed.
In particular, I am bothered by the notion that a patient who is currently stable on any 1 of the tumor necrosis factor drugs may be given as a substitute a biosimilar without notifying either patient or physician. If a patient later develops an adverse effect, is it because of cumulative damage brought about by the reference product or immunogenicity brought about by the new biosimilar because it has not been tested in that disease state? These are very important concerns for me.
Regardless of naming, a biosimilar is a new drug. Therefore, it is not proven in that patient with the disease for whom it is being used. Let’s say that you are giving a patient with PsA a biosimilar to the reference product approved for rheumatoid arthritis. It does not have an indication in PsA because it was not tested for PsA. But then the patient is mandated to switch. This can be problematic because the patient was previously stable on the reference drug for that disease state.
This is playing with fire, and it subjects patients to a host of concerns ranging from safety to efficacy to cost, all of which have to be taken into consideration.
Furthermore, physicians need to be aware of who the beneficiaries of the biosimilar substitutions are: the patients, the physicians, the healthcare systems? Who benefits from this? The patients may not. I’m afraid that we’re sacrificing patient safety for expediency. And that can never be appropriate.
How should clinicians approach discussions regarding biosimilar interchangeability with their patients?
Clinicians need to be organized. We need to have actual hard data sensitive to the concerns we’ve raised so that we can present it to our patients. If a patient wants to switch medications in the hope of reducing healthcare costs, rheumatologists should outline a treatment plan that safely and effectively moves a patient from one treatment to another.
Will therapeutic drug monitoring practices be changed with the adoption of biosimilars?
Therapeutic drug testing intervals may be shorter for patients initiated on biosimilars, as they are new drugs. They are not tested and they are not known. Their toxicities are not understood. This has not yet been addressed, but it needs to be addressed front and center.
Every patient needs to be looked at critically, with regular evaluation of blood drug levels to monitor for drug toxicity. In addition, complete blood counts, serum electrolytes, liver function tests, and renal function abnormalities should be monitored closely. All this needs to be very current, and right now there are no safety constraints being imposed on biosimilar recipients that separate them from the reference product.
What role will future confirmatory clinical studies have in validating biosimilar safety and efficacy?
The clinical studies are critically important because that is where you look at the pharmacokinetics, the pharmacodynamics, the absorption, the time to onset of benefit, and the potential toxicity associated with the drug. They are clearly very important and need to be instituted into the therapeutic algorithm and brought into the approval and postapproval monitoring process.
There is also an opportunity for the patient community to get involved with helping us to better understand biosimilars. They can make choices about whether they want to use a biosimilar (possibly because it will save them money or because they need a treatment option). Further, if they record their experience (patient-reported outcomes) with the medications via a registry like ArthritisPower, then researchers will be able to collate these data community-wide and conduct analysis. Understanding patient-reported outcomes combined with clinical research is vital to the uptake of these medications.
I think there needs to be pharmacovigilance in the phase 4 space that should be looking at the potential toxicity to which the patient is exposed.
I am not saying these drugs should not be approved. But they should go through the same process of approval the reference product is subjected to. These are not orphan indications.
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