The Bioequivalence of Ketchup

May 14, 2015

I attended the Pri-Med Canada conference last week. You wouldn’t think that a lecture on bioavailability and bioequivalence would be full, but it was, and not just with pharmacists. I thought it spoke to just how poorly understood these concepts are among clinicians across the primary care spectrum.

I thought the speakers — Scott Walker and David Dubins — did a good job, but the debate-like format made it sound like there are two sides to this story. Walker took the “for” side, and Dubins took the “against” side, even though both made it clear that they favour the use of generics.

Bioequivalence is a legal term. It allows a manufacturer to apply for drug approval without doing clinical trials. The legal definition is based on principles of bioavailability. Bioavailability speaks to two things: a) the peak amount of drug is absorbed into the body; and b) what percent of the total dose is absorbed. If these 2 parameters are similar between two tablets, we assume they have the same biological effects and call them bioequivalent.

Note that the definition has nothing to do with how much drug is in each tablet. We don’t compare whether one product has 5.2 mg and whether the other has 4.8 mg for the purposes of bioequivalency. (We do under principles of good manufacturing practices (GMP)). That’s because tablet variability doesn’t matter so much if it is not absorbed in the body. This is an important distinction that I wished the speakers had emphasized more. In fact, in an audit of generic products, researchers found that the quantity of drug did not differ than more than 4–5% between brand and generic equivalents. That means a 100mg tablet doesn’t vary more than 95-105mg. That’s well within lot manufacturing tolerances for both brand and generic products.

The lecturers did a good job to point out that the definition of bioequivalence is not only for generic manufacturers. (And GMP standards are the same for both, too.) Brand companies will often change the formulation that they use in clinical trials when they start to manufacture at large scales. That new formulation must pass the bioequivalence test just like any other generic. Also, if the generic formulation is exactly the same as the brand version, there’s the possibility that bioequivalence testing can be waived.

Most people think of the 80–125% rule when they think of bioequivalence. This is for solid, oral dosage forms only, and only for drugs that do not have a narrow therapeutic window. There are other standards for different classes of drugs.

What does 80–125% mean? Remember, it’s not tablet variability. Bioequivalence is about comparing the Cmax and AUC of the generic product to the brand product in the same patient. We want be sure the ratio of the two values for the generic drug to those of the brand drug is not below 8/10=80% or above 10/8=125%. (Incidentally, I would have liked to know why the more conservative 83–120% range hasn’t been adopted, as I can’t find any rationale in the existing literature.)

Even then you might think 80–125% too large a window for these ratios. But think about it clinically. If we titrate people up or down on medications, it’s common to use a doubling rule. One tablet daily, then twice daily, then 2 bid. Start with 1/2 tablet daily for one week, then increase to one tablet. Clinically, we rarely worry about dose changes in the 20% range. So even if we had two formulations with the exact same bioavailability, a difference in blood levels is unlikely to be clinically important. And as Dubins pointed out in his talk, it certainly matters less once the patient has been on the drug for a while (i.e., steady state) and is being switched to a different formulation.

Even still, that 80–125% is not the whole story. This CADTH graphic shows how we require the measurements for bioavailability to be within 80–125% including their confidence intervals.


In other words, the measured Cmax and AUC ratios will be closer to 100% because the requirement for the confidence intervals to be contained within the 80–125% range pushes the point estimate closer to the center. In fact, in 2009 a large review of 12 years of bioequivalency data showed that the brand and generic product ratios were pretty much exact.

The speakers voiced concerns that manufacturers might game the bioequivalency definition. A larger sample size could mean a tighter confidence interval, which could mean average Cmax and AUC ratios further from parity. But again, this isn’t seen in practice and for most solid oral dosage drugs, this is unlikely to be a clinical problem. Finally, ensuring the confidence intervals of the ratios fall within 80–125% means that equivalency between generics is likely justifiable, and so switching from one generic to another is considered bioequivalent for practical purposes. This is also why demonstrating bioequivalence with the marketed brand formulation rather than the one studied in clinical trials is justifiable.

Despite all this, questions from the crowd suggested that they remained unconvinced about the quality and equivalence of generic products. Part of the problem is that the speakers did not differentiate between fabrication and manufacturing. Fabrication is the process of making the raw chemicals that go into pressing a tablet. Manufacturing involves the rest of the process of bringing that tablet to market. Manufacturers are not necessarily fabricators, and vice versa. Manufacturers are responsible for passing bioequivalencey requirements to get their products onto the Canadian market, not fabricators.

Problems in fabrication are what we see in the news and relate to quality issues such as cross-contamination and quality assurance. Reports of issues that arise from failed FDA inspections and the improper following of GMP standards is what generates hysteria and concern about generic drug safety. Quality is different from bioequivalency, and meeting one standard is not the same as meeting the other.

In truth, brand and generic manufacturers may use the same fabrication plants to source raw materials, especially for generics that are subsidiaries of brand companies. It certainly is concerning that overseas fabrication plants are failing FDA inspections whilst going undetected by Health Canada. Fraudulent documentation is even more concerning, because it suggests that known deficiencies are being purposely masked. There’s a need to beef up off-shore inspections and to hold Canadian manufacturers — brand and generic — more accountable for their fabrication sources. Health Canada’s introduction of Vanessa’s Law is only one step to ensuring Canadian pharmaceutical products are safe by quickly recalling substandard products. We need to make sure they don’t make it onto the shelves to begin with.

So that’s why it’s important for pharmacists, pharmacy technicians, and other clinicians to be aware of these definitions and procedures as they can impact patient health. People get irate over generic switching, especially when they’re not informed. Research shows that switching to your first generic is the hardest, and adherence is especially poor for patients who already have negative perceptions towards medicines. In truth, the evidence shows that switching to generic versions of cardiovascular drugs, psycotropics, clarithromycin XR, levothyroxine and others is safe and effective. Reports that patients are doing worse after being switched to generic products need to consider other factors, or even the nocebo effect.

The educational role for pharmacists here is obvious, especially in an environment of constantly changing preferred brand lists and more frequent generic switching than in the past. Encouraging brand innovation is important, but increasing generic utilization is also an important social benefit. Models for universal pharmacare rely on increased generic utilization to make it feasible, and more and more countries are implementing generic substitution laws to reduce drug expenditures. 

When people hear generic, they think of ketchup or cola. Say what you want, but generic ketchup doesn’t taste like brand. Ergo, there must be something different about generic drugs too. It’s not a safety or quality issue, it’s a “bioequivalence of ketchup” issue. It’s understandable if patients draw on those kinds of experiences and come to the same conclusion about drugs. It’s inexcusable for health care professionals. Pharmacists are entrusted by society to ensure that the products they receive are therapeutically appropriate, and speaking intelligently about bioequivalence is part of that equation.