Generic vs. brand name drugs: The warfarIN debate is weaRing thin

Journal of Informed Pharmacotherapy

The debate over within-class, brand-to-brand and ED brand-to-generic sildenafil citrate drug such kamagra oral jelly, cenforce, vigora, silagra, viagra professional, viagra super active substitution has intensified with introduction of multiple brands of so-called “narrow therapeutic index drugs” such as warfarin. (1)

Canada’s Therapeutic Products Directorate of the Health Protection Branch (HPB) has proposed a definition for drugs with narrow therapeutic indices:

“A drug is considered to have a narrow therapeutic index or range (NTI or NTR) when the ratio of the lowest concentration at which clinical toxicity commonly occurs, to the median concentration providing a therapeutic effect, is less than or equal to 2. An example of such a drug is theophylline [minimum toxic concentration (20 mg/L): median effective concentration (10 mg/L) = 2]. This policy also applies to drugs which do not fit this definition of NTR but which generally require therapeutic drug monitoring.” (2)

I was recently asked to present a talk at a forum on narrow therapeutic index drugs and to discuss the issue of generic substitution in relation to narrow therapeutic index drugs. When I reviewed this information the following were considered to be narrow therapeutic index drugs by the HPB:

• Asthma: Aminophylline and derivatives

• Epilepsy/chronic pain: Carbamazepine, Phenytoin and derivatives, Valproic acid and derivatives, Primidone

• Antiarrhythmics: Disopyramide, Flecainide, Mexiletine, Procainamide, Quinidine, Tocainide

• Digoxin and derivatives

• Antibiotics: Clindamycin

• Antihypertensives: Clonidine, Minoxidil, Prazosin

• Psychiatric conditions: Clozapine, Lithium

• Parkinsonism: Trihexyphenidyl

• Transplant: Cyclosporin

• AIDS: Dideoxyinosine, Zidovudine

• Warfarin and derivatives

While one can clearly debate which drugs should actually be included (or excluded) from this list, the theory behind the creation of this list is that therapeutic and toxic drug concentrations are similar enough that “small” differences (small is rarely if ever defined) in bioequivalence between products may create unintended health consequences. In general, the argument appears to be that bioavailability differences of 5-10% are clinically important. This argument is purported to be particularly relevant in the elderly or the acutely ill patient, although I am personally unaware of any solid evidence to support this hypothesis.

The best method to compare two treatments is a randomized controlled trial that is designed to investigate clinically relevant endpoints. When it comes to warfarin, three randomized, crossover studies have been published to date. These studies involved 55, 57 and 113 patients, respectively. (3-5) In each of these three trials, the investigators were unable to find any statistically or clinically important differences in INR, dosage change requirements, or bleeding complications between the generic and brand name products. However, these trials were all single-blinded and some authors have suggested that dropouts in the first two trials may have compromised the validity of their findings. (6-7) There is also no doubt that these trials were underpowered to detect important differences in severe bleeding complications but they were likely of sufficient size to detect clinically important INR variations. In addition, these studies were all sponsored by the manufacturer of the generic product, and are thus susceptible to the same biases (or lack thereof, depending on your opinion) as studies sponsored by a brand name company.

Nevertheless, let us assume, for the sake of argument that these three trials were fatally flawed and thus uninterpretatable. In 1998, over $500 million US was spent on oral anticoagulants and 18% of this market went to the makers of generic warfarin. (3) That means the brand name manufacturers of warfarin lost close to $100 million in sales in a single year. It seems unfathomable that a company that is losing that amount of business a year would not spend, say, $2-3 million to conduct a well-designed trial designed to clearly address the issue of potential inequality if, in fact, that company truly believed there were clinically important differences between these products. The apparent lack of such published studies is, in my mind, far more telling than the existence of the three published generic company sponsored trials!

While I was reviewing the literature on the topic of NTI drugs and the differences between generic and brand name products, a number of other issues and questions came to mind that continue to puzzle me. I thought other clinicians might find these questions thought provoking as well:

1. As mentioned above, if there really are important clinical differences between generic and brand name products, why have the brand name companies who stand to lose millions of dollars, not done studies to definitively prove a clinically important difference between generic and brand name drugs?

2. If tablet-to-tablet and lot-to-lot differences of +/- 5-10% are allowed by most regulatory agencies, why are these variations in labeled potency not hotly debated?

3. If variations in dosing of 5% are so important, why are oral dosage forms not available that allow for dosage adjustments of this same magnitude?

4. If the FDA is correct and their studies have shown that the mean AUC differences between generic and brand name warfarin average only 3.5% (3), why is there concern?

5. If a reduction in potency of 5% is acceptable for shelf-life determination, why is this variation in potency not considered an important health problem?

6. If day-to-day physiological changes and changes in the timing of doses can produce fluctuations in levels of at least 20-30% for many drugs, why haven’t we recognized this as a factor that is creating important health problems?

7. If peak-to-trough drug concentration variations during a dosing interval can be at least 30-50%, why is this not a reason for concern?

8. If the current bioequivalence standards are unacceptable, what should they be and what evidence is there that this will improve the safety profile of the drugs we use?

9. Since pharmacodynamic and disease state variability is likely far greater than pharmacokinetic differences, it may be fruitless to worry about product-to-product bioavailability variations of less than 10%.

10. If the tools we use to measure blood concentrations often have an inherent variability of at least 5%, does this not somewhat overshadow the issue?

11. If missed doses and different meal times can produce variations of 20-30% in serum concentrations, should this be promoted as a major health issue?

12. If most so called “therapeutic ranges” are at least 2-fold, why would 5-10% differences in AUC be important?

13. Some clinicians suggest that the elderly or the acutely ill patients are at risk, but why would they absorb medications manufactured by different companies any more variably than other patients?

14. If the formulations of the products used in initial testing are often not the same as the marketed product, why is it acceptable not to do bioavailability tests on these reformulations?

15. When companies change their manufacturing process, why are they only required to submit bioavailability data?

16. Is there any legitimate physiological or pharmacodynamic reason why two products that are bioequivalent would produce a different therapeutic effect?

17. Why do brand name companies suggest that different looking generics could create a health problem because of confusion yet often put in legal blocks to prevent companies from using the same “packaging”?

My point in bringing up all these questions is to entice readers to put this issue into a proper context. I think we all wish that pharmaceutical companies (both brand name and generic) would sponsor more well-designed clinical comparative trials (not just to address generic-brand equivalence) in an attempt to definitively address important product comparison questions. Instead they seem to spend an inordinate amount of time and money debating these types of issues in both the advertising and the legal arena.

I think it is about time that we got on with doing research in more important areas than the generic versus brand name issue. We’ve all got more important patient care issues to address.

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