By Ralph Tarantino, PhD
Pharmaceutical Consultant and Principal, SteriTech Solutions, LLCMiddletown, NJ
Let’s not forget the reason for the FDA’s existence. The agency was formed to assure the purity of food and drug products (1906). They went on to regulate drug safety (1937) and then drug efficacy (1962). The efficacy regulations were in response to what was truly a safety issue—the use of thalidomide in pregnant women. The FDA is the institutionalized embodiment of the Hippocratic Oath to “first do no harm.” They are cautious because that is their job. Safety does come first. You can always replace a drug that’s not working, but you cannot replace a patient who has died. Suggesting biosimilars could be approved without clinical data is not a very cautious position to take and leads one to wonder about the possible motivation of the FDA in taking that position.
Of course companies are not impartial bystanders on this issue. However, the figure below, which appears on a leading biopharmaceutical company’s website,* does nicely represents the situation at hand. The complexity and size differences between small organic molecules and biopharmaceuticals are enormous. Complete physico-chemical characterization is probably never truly achieved for a biopharmaceutical product. They are not small molecules.
By definition, within the realm of biotechnology, microorganisms are used to produce drugs, hence the term biopharmaceuticals. These microscopic “chemists” are not following any prewritten procedures or SOPs; they don’t have lab notebooks. They are living organisms, greatly affected by their environment and the process conditions under which they “work.” The biopharmaceuticals they produce have three or four levels of structure. These therapeutic proteins can fold; they can aggregate; they take the form of alpha helixes in some regions and beta sheets in others. In addition, they are equally if not more susceptible to all chemical degradation processes that can inactivate small molecules or make them toxic. Plus, they can be immunogenic.
Sometimes small changes in biopharmaceuticals are not readily detectable by analytical methods and sometimes they can affect the safety and efficacy of the final product. In many cases animal data regarding safety and efficacy is not very reliable since for many biological substances there are species-specific structural differences in the biopharmaceuticals they produce.
In essence, the complexity of biopharmaceuticals as drug molecules plus the inherent variability in how they are produced make them difficult to duplicate. This difficulty is sometimes encountered within the same company when transfer between different manufacturing sites is attempted. Imagine how much more challenging it will be to validate that successful duplication has occurred between the reference company and a new biopharmaceutical company. Imagine trying to conduct this validation without clinical testing. I don’t believe it is very likely.
In their communications, the FDA highlights the fact that they can waive the requirement for clinical studies for biosimilars, but would they? Could they? Would you want them to? What argument would convince them not to test a biosimilar in humans and remain true to their mandate of safety first?
The whole issue reeks of political hokeyness, unbefitting serious healthcare issues. Biopharmaceutical sales comprise about 15% to 20% of overall pharmaceutical sales; therefore, savings in this area will not have a dramatic effect on the health care bottom line. Biopharmaceutical products are usually critical care or life-saving treatments administered in a hospital by injection or infusion. Manufacturing and testing of biopharmaceuticals is complex and will remain complex. Only large, well-funded companies will be able to afford to make them—a vastly different situation than banging out millions of acetaminophen tablets on an industrial press to generically replace Tylenol. Biosimilars are not generics, could never be and any suggestions to the contrary should be avoided.
A company on the path for approval of a biosimilar will always have to face the prospect of long and expensive clinical studies. The process will be beyond the capabilities of a mom and pop operation, and costs will go up.
I don’t think the FDA wants to look like the bad guy here. They would like to avoid the appearance of stifling competition or of being unresponsive to health care reform. The FDA states they will judge each biosimilar on a case-by-case basis, which is good but is also a way of avoiding accountability.
So why the big fuss? The risks here will be borne by the investor and the patient, and I am not sure what the benefits will be. The litigation scenarios are almost limitless. The government should make some clear regulations about exclusivity, since patent issues with natural products are complex, and let it go at that.
Since in reality the hurdles to approving a new biopharmaceutical will not change much, the complexity and cost of producing new biopharmaceuticals will not change much, and their impact on the overall cost of healthcare will not be significant, the furor and anticipation surrounding issuance of the biosimilar guideline . . . is, unfortunately, much ado about nothing.
*Genentech’s web page on biosimilars.
Related site: click here for a good executive summary of biosimilars.
To read Part 1 of this blog, click here.