Biologics and Biosimilars

You may be used to the concept of substituting generic drugs for their name brand equivalents. After all, generics can save the average American family a small fortune. For example, in 2011, NPR reported that consumers could buy a month’s supply of atorvastatin, a new-to-market generic cholesterol reducer, for a $10 insurance copay. Lipitor, the name brand equivalent—and the single biggest selling drug in the United States—costs $25.

There is, however, one group of complex drugs that, when it comes to cheap substitutions, are more problematic: biologics.

Biologics Are Not Your Average Pills

A biologic is any medicinal product made using living cells that have been cultured in a lab instead of through chemical processes. Biologics are a relatively new class of drugs, but they have already become incredibly popular, accounting for up to one quarter (or $800 billion) of the nation’s total spending on prescription drugs in 2011, according to the IMS Institute. Enbrel, Humira, and Rituxin (for rheumatoid arthritis and psoriasis) and Herceptin and Avastin (to treat cancers) are some of the most widely used drugs in the biologic class—and in fact are some of the biggest selling drugs worldwide.

Biologics are very different from chemical drugs. They are extremely large and complex: the active proteins in a biologic can be up to 10,000 times the size of the active chemical compounds in a regular drug. This also means that they are extremely sensitive; almost imperceptibly small impurities in these drugs can cause serious health complications. Even the way the drug is handled after it leaves the lab can cause problems, and biologics must be rigorously monitored from the time they're produced until they are administered to patients.

The complexity of biologics means that manufacturers cannot guarantee these drugs can be reproduced with 100 percent accuracy. A 2012 paper published by drug manufacturer Amgen compares biologics to fine wines:

Much like the way in which varieties of wine have common characteristics but may vary in quality and taste depending upon region, vineyard, growing conditions and so on, the characteristics of a protein may vary depending upon the manufacturing process, including the growing conditions, for the protein.

Just like you can’t make Napa wine in Pennsylvania, you can’t make Humira in any other lab. Biologics have what can be thought of as lineages—“cell lines” that have been cultivated to best produce an effective drug. These cell lines simply cannot be recreated.

So, when the patent on a biologic drug expires, generic manufacturers have to “reverse engineer” the drug, creating their own cell line from scratch. While they cannot perfectly recreate a “generic” version of the drug, these manufacturers can come close. The results are called “biosimilars.”

Biosimilars: Almost the Same, for Almost the Same Price

For many years, the FDA refused to begin the approval process for biosimilars; the agency argued before the Senate that new legislation would be required to enable them to approve these drugs. Then, in 2010, President Obama signed into law the Patient Protection and Affordable Care Act. As part of the Affordable Care Act (commonly known as “Obamacare”), the FDA was granted specific authority to approve biosimilars. The FDA soon issued draft guidance on this class of drugs, effectively creating three categories of biologics:

  1. Originator biologic: this is the “name brand” drug
  2. Interchangeable biosimilar: this is a biosimilar that has undergone a series of tests to demonstrate that there is the expectation of the same clinical effect in any given patient, and if a doctor or pharmacist were to switch this for originator, there are no increased health risks
  3. Biosimilar: this is a drug that is highly similar to the originator and demonstrates an absence of any meaningful clinical differences, but it is not an identical product

As of 2012, no biosimilars or interchangeable biosimilars have yet been approved.  But this could change soon. In the next five years or so, the pharmaceutical companies that manufacture biologics face what is being called the “patent cliff”—a period of time during which many of these blockbuster drugs will no longer be protected by patent rights. Many expect generic drug manufacturers to jump into the biosimilar game and flood the market with cheaper alternatives.

With the patent cliff on the horizon, bills to restrict the use of biosimilars have been introduced in at least eight states in the past month alone. The proposed legislation would require that if a pharmacist wants to substitute a biosimilar, he or she must first obtain the patient’s consent and then notify the prescribing doctor of the switch. Then, both the pharmacist and the doctor are legally obligated to keep records of the switch for years.

New York Times business reporter Andrew Pollack writes that the bills were introduced only after extensive lobbying by biologic manufacturers, such as Amgen and Genentech. Pollack calls these bills “pre-emptive moves to deter the use of biosimilars even before any get to market.”

Amgen—a company that has developed originator biologics and is now working to develop biosimilars—disagrees. “We are not at all concerned with biosimilars coming to market,” said Geoff Eich, Amgen’s Executive Director of Regulatory Affairs, “and we have the greatest of confidence in the FDA and EMA (European Medicines Agency).” Eich believes the hoopla around the introduction of these state bills is due to the fact that “there’s been this sort of promise of savings with biosimilars when in reality these are very expensive to develop and manufacture.”

The data backs Eich up. The Federal Trade Commission estimates that developing a biosimilar takes seven to ten years and $200-250 million in investment; a generic chemical drug, on the other hand, costs only $1-5 million and takes two to three years to develop. In other words, there may be some cost-savings when biosimilars come to market, but they won’t be sold at the rock-bottom prices you’ve come to expect from generics. In fact, they may cost almost the same amount as the name-brand products.

So, if the bills aren’t meant to protect the profits of biotech manufacturers, what’s their purpose?

Tracking the Safety of Biosimilars

Sheldon Krimsky, a professor in the Department of Family Medicine and Community Health at Tufts University believes that tracking side effects has always been a problem in the United States. It’s not just biosimilars, or even biologics—it’s all drugs.  “We underestimate the adverse effects of drug, due to a lack of a tracking system," said Krimsky. “A doctor can report side effects of drugs to a federal database, but it turns out most doctors don't do it.”

Case studies bear this out. In 2005, the European Medicines Agency (the European Union equivalent of the FDA) enacted an approval procedure for biosimilars. In the half decade that biosimilars have been on the market, European regulators have found that, while approval standards are robust, there aren't enough safeguards in place to maintain “pharmacovigilance”—the ability to track and trace any problems that arise.

So, in 2010, the EMA passed the Pharmacovigilance Directive, which “seeks to have member states put in place the appropriate measures to ensure that patients, pharmacists, and physicians all have access to the information on which product(s) a patient has received, and that can be leveraged immediately if there is a problem of any kind, and that there is the right information to forensically attribute problems to the right product(s),” Eich explained.  Amgen and Genetech, along with other manufacturers, are working closely with the FDA to take these findings and apply them here in the States.

In other words, the new state bills do not seek to limit the use of biosimilars—their goal is to enable the FDA and manufacturers to effectively track and fix the problems that will inevitably arise. “That way,” said Eich, “patients aren’t denied access to an entire class of drugs when really there’s only a problem with one container.”

In the wake of last year's meningitis outbreak, which was caused by contamination at a compounding pharmacy that created special formulations of complex medications, consumers and regulators have reason to fret. As biologics and biosimilars become more common, their price, efficacy, and above all, safety must be carefully weighed and, perhaps, legislated.

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