Follow-on O Ship of State

Excellent piece by Bryan Liang in the Los Angeles Times:

Don’t Compromise the Safety of Biotech Drugs

By Bryan A. Liang

A toy plane has a handful of parts. A Boeing 747 has several million. This makes sense. Toy planes are small, simple models, while 747s are large, high-performance aircraft that travel more than 500 mph with thousands of component systems acting together. The model costs a few dollars because it's easy to manufacture. The 747 costs about $225 million because of its highly complex nature, testing and the need to ensure safety.

The comparison is worth keeping in mind as the debate heats up over "follow-on" biologics. Biologics are today's most advanced medicines, fully tested biotechnology protein drugs that provide targeted therapy to victims of cancer and other diseases. Follow-on biologics are the second or subsequent versions, but they are not identical.

U.S. spending on them reflects the importance of these drugs in medicine's arsenal. Biologics represent the fasting-growing sector in the medicines market, with more than $30 billion spent on these drugs each year. Indeed, the top five drugs in terms of Medicare expenditures administered in physicians' offices are biologics. By 2010, worldwide spending on biologics is estimated to grow to $10 billion, and biologics will make up nearly half of all newly approved medicines. Hence, many policymakers are focused on reducing the costs associated with these drugs.

Congressional legislation is pending that would allow the sale of follow-on biologics without requiring extensive testing -- essentially following the same model used for approval of generic forms of traditional prescription drugs.

But most drugs we're familiar with, like the pills we get from the pharmacy, are "small-molecule" drugs -- simple chemical compounds. They can be easily manufactured and identically copied. The anti-convulsant drug valproic acid, for example, has a total of just 26 atoms.

Identical to the brand-name version, these generics can "piggyback" on a brand-name company's testing. That's reasonable. These small-molecule drugs -- which typically are made up of a total of 20 to 100 atoms -- can be copied perfectly. So they don't need independent safety testing, cost less to make and are cheaper -- allowing more patients to obtain the medical benefits.

But biologics are far more complex. The brand-name drug Herceptin, a biologic that's widely used to treat cancer, is made up of a total of roughly 25,000 atoms. Large biologics can have millions of atoms.

Biologics aren't made by combining chemicals in a flask. They're made by life forms such as cells, yeast and bacteria. Like humans, these life forms exhibit diversity in metabolism and composition, making the final product a unique, heterogeneous mix that cannot be copied exactly. So follow-on biologic forms of a drug can only be similar to the original, not identical.

Because of the complexity of biologics, there's more regulation. In comparison with common chemical drugs that can have generic versions -- such as penicillin -- which only require 50 to 60 manufacturing tests for safety and quality, biologics require at least four times that number.

So the policy challenge is to provide incentives for innovation while also ensuring that any follow-on forms of biologics that enter the market are safe.

The key lies in something called "data exclusivity," which is a legal mechanism for allowing a company to keep confidential the data associated with a drug's development. Data exclusivity usually lasts for several years and spurs innovation by protecting new inventions. This is the current rule for small-molecule drugs, and it should be applied to biologics as well. Strong data exclusivity is critical for biologics, which are about 50% more expensive to develop than small-molecule medicines.

However, the current state of science makes ensuring safety of follow-on biologics difficult. Currently, the technology to map out the exact chemical structure and function of one large biologic versus another is not available. That makes safety reviews inexact. And follow-on forms may induce unpredictable adverse reactions.

Several years ago, a fully tested biologic created in the U.S. was cooperatively licensed overseas to be made in Europe. But the new version caused patients to suffer "pure red cell aplasia," whereby their bodies could not make red blood cells. This may have contributed to the deaths of some patients and permanent injury to others. Yet today, after eight years of research, the cause of these reactions is still unknown.

If even cooperative company efforts can result in unpredictable adverse reactions, any follow-on product that does not undergo full testing should be of concern. Recognizing this reality, the European Union has developed a system of assessment that requires clinical testing of follow-on products in Europe before approval.

U.S. policymakers should take note. Relevant clinical data and testing should be required to ensure safety of any follow-on biologic product being considered for patient use in the U.S. And appropriate data exclusivity should be put in place to foster innovation.

If chemical drugs were toy planes, biologics would be 747s, the cutting edge of medicine. Because of their complexity, any follow-on forms must be held to a higher safety standard. As we have learned in aviation, safety is no accident.

Bryan A. Liang is executive director of the Institute of Health Law Studies, California Western School of Law and co-director of the San Diego Center for Patient Safety, UC San Diego School of Medicine.