Biosimilars: How the EMEA Got It Right (Part 1)

I don’t think anyone disagrees that:

  1. Access to life-saving medications for all patients must be granted through a patient-focused, science-based application of a logical, open, and rational process, and that
  2. For patients to gain the greatest possible benefits, biologics with patent protections that have expired should be subject to competition from appropriately safe biosimilars

However, despite some irresponsible bills that have been introduced in Congress (such as Waxman-Schumer), a science-based, patient-focused pathway to biosimilars is possible–but we MUST take into account:

  1. Information gaps in our knowledge of these complex medications–and the complex process of manufacturing them
  2. Potential threats biosimilars can pose to patients, from problems with excipients to life-threatening immunogenicity
  3. Vulnerable patient populations–such as the sick, elderly, minorities, uninsured, and underinsured–who would bear the brunt of policies that shortcut appropriate safety

“Appropriately safe”: a proper, cautious regard for patient safety

What does “appropriately safe” mean? It cannot mean taking the kinds of shortcuts that some legislation is considering when it comes to patient safety. Some people may say that that simply begs a further question: What does it mean to “take shortcuts”? Basically, any regulatory pathway that does not take into account the uniqueness of biotech medicines–the unique complexities, unique difficulties in manufacturing, and unique safety issues–is taking shortcuts and putting patient safety at risk.

There are four basic principles for an responsible pathway to biosimilars. To provide some background on these principles, and to help illustrate the outcomes to which they lead in the real world, it’s instructive to take a look at the experience of the European Union and the European Medicines Agency (EMEA). They have forged a rigorous process that tests both the structural and functional aspects of biosimilar proteins.

In other words, the EMEA proceeds with a proper, cautious regard for safety when considering applications for biosimilars. EMEA regulations show that a science-based, patient-focused pathway to biosimilars is possible. There’s no need to sacrifice patient safety for cost savings, as Henry Waxman’s latest abomination of a bill does (more on that in a later article–he is still insisting that an altered amino acid sequence is a “minor difference” between proteins). There’s no need to stifle the innovation and regard for intellectual property rights that have led the US biotechnology industry to worldwide leadership.

The EU has developed a balanced approach to biosimilars that rewards companies who develop innovative products, while allowing for competition. It’s possible to develop safe and effective biosimilars in which patients and physicians can place their trust. Because if this trust is betrayed by products that are rushed to market through a less-than-responsible regulatory pathway (and to call the Waxman bill less than responsible is a massive understatement–it’s criminally misguided and obviously the result of political calculation only), it will do irreparable harm not only to patients and the healthcare system, but also to the budding biosimilars industry. It will actually move us farther from the goal we all seek: To make life-saving biologic medications available to the patients who need them.

The EU hasn’t always gotten it right.

In fact, it came to a balanced approach, focusing on science and patient safety, in large part because of a horrific event.

First, some key background on the medication involved: EPREX is the European version of Epogen, a biotech medicine developed by Amgen that relieves anemia for patients with chronic kidney failure who are on dialysis. Epogen is a biotechnology-derived version a naturally occurring protein called erythropoietin (EPO). EPO is a “signaling protein” that tells the bone marrow to increase red blood cell production. Because of our increased understanding of signaling proteins, we know that damaged kidneys don’t make enough EPO. Normally, when blood oxygen levels are low, or when someone has lost blood in an injury, the kidneys produce and release EPO to tell the bone marrow to get started producing more red blood cells. People with kidney failure, in addition to all of their other complications, don’t make enough EPO in their kidneys. As a result, they have fewer red blood cells than normal. Using biotechnology, we can now produce large amounts of EPO to stimulate the production of red blood cells and treat chronic anemia among very sick patients, including those undergoing chemotherapy and those with chronic kidney disease.

A version of EPO—called EPREX—was introduced into the European Union by Johnson & Johnson, a large innovator company that pays careful attention to patient safety. This was essentially an intra-manufacture change, since a licensing agreement gave all companies involved full access to patents, the details of the manufacturing process, and all trade secrets. When EPREX was made in Europe, a tiny change was made that was intended to improve its safety profile. There was a concern that the ingredient used to stabilize the protein could possibly contain Mad Cow Disease, so this single stabilizing agent was changed.

Everything was done in accordance with then-current EMEA quality-control regulations that guided companies in demonstrating “comparability” of biotech medicines after a change in manufacturing. But this one small change in the manufacturing process—made by a large innovator company that pays careful attention to patient safety, not a fly-by-night biosimilars company—was enough to lead to huge consequences for patients throughout Europe. There was a significant increase in patients who developed antibodies to (or rejected) Eprex—in other words, their bodies no longer accepted this foreign protein. These antibodies even reacted with the body’s own natural erythropoietin—because the biotech medicine replicates the original, natural protein. As a result, affected patients no longer made their own red blood cells, a rare condition called “pure red cell aplasia.” They became severely anemic, requiring multiple blood transfusions and dialysis.

The key lessons of the EU experience.

Spurred on by a terrible experience, the EU established a regulatory review process for biologics that focuses on patient safety.

Because such severe immunogenic reactions cannot be predicted with pre-clinical (or non-human studies)—whether laboratory assays or animal tests—the EU has determined that clinical studies among relatively large patient populations for safety and efficacy must be conducted for all follow-on biologics. Not only are clinical studies required before approval, but robust post-marketing studies (pharmacovigilance) are required post-approval to ensure the safety of the public and track adverse events. We’re not talking about the kind of 20-person pharmacokinetic/pharmacodynamic studies done for small-molecule generics (which should not be reassuring to anyone–good specialists know that many patients, especially those taking psychotropic medications, experience worsening when switched to generics; just look up bupropion or “generic sertraline” online).

In other words, in order to ensure patient safety, the EU was saying that, first, you have to get the science right.

Next time: Getting the science right, and the relationship between good science, innovation, and improved healthcare.

The EU hasn’t always gotten it right. In fact, it came to a balanced approach, focusing on science and patient safety, in large part because of a horrific event.

First, some key background on the medication involved:

EPREX is the European version of Epogen, a biotech medicine developed by Amgen that relieves anemia for patients with chronic kidney failure who are on dialysis. Epogen is a biotechnology-derived version a naturally occurring protein called erythropoietin (EPO). EPO is a “signaling protein” that tells the bone marrow to increase red blood cell production. Because of our increased understanding of signaling proteins, we know that damaged kidneys don’t make enough EPO. Normally, when blood oxygen levels are low, or when someone has lost blood in an injury, the kidneys produce and release EPO to tell the bone marrow to get started producing more red blood cells. People with kidney failure, in addition to all of their other complications, don’t make enough EPO in their kidneys. As a result, they have fewer red blood cells than normal. Using biotechnology, we can now produce large amounts of EPO to stimulate the production of red blood cells and treat chronic anemia among very sick patients, including those undergoing chemotherapy and those with chronic kidney disease.

A version of EPO—called EPREX—was introduced into the European Union by Johnson & Johnson, a large innovator company that pays careful attention to patient safety.

This was essentially an intra-manufacture change, since a licensing agreement gave all companies involved full access to patents, the details of the manufacturing process, and all trade secrets. When EPREX was made in Europe, a tiny change was made that was intended to improve its safety profile. There was a concern that the ingredient used to stabilize the protein could possibly contain Mad Cow Disease, so this single stabilizing agent was changed.

Everything was done in accordance with then-current EMEA quality-control regulations that guided companies in demonstrating “comparability” of biotech medicines after a change in manufacturing. But this one small change in the manufacturing process—made by a large innovator company that pays careful attention to patient safety—was enough to lead to huge consequences for patients throughout Europe. There was a significant increase in patients who developed antibodies to (or rejected) Eprex—in other words, their bodies no longer accepted this foreign protein. These antibodies even reacted with the body’s own natural erythropoietin—because the biotech medicine replicates the original, natural protein. As a result, affected patients no longer made their own red blood cells, a rare condition called “pure red cell aplasia.” They became severely anemic, requiring multiple blood transfusions and dialysis.

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