Prof David Holt , St George's University of London, UK

In this free-access CardioEd resource from the recent Cardiology Update 2016 meeting organised by St George’s, University of London, Prof David Holt , Professor of Bio-Analytics at St George’s University of London, UK, talks about the most critical challenges physicians face regarding the use of generic agents.

The Cardiology Update 2016 meeting focused on heart failure management and stroke prevention in patients with atrial fibrillation.


What are the most critical challenges physicians face regarding the use of generic agents?
The main challenge in Europe, let’s put it into that context – is that for many formulations there are a lot of generic  formulations, so that you might go from one formulation to another of the same drug. And what has happened is that physicians have lost control of what they’re actually prescribing. In most settings, you’ll have to prescribe the generic formulation of the drug, so you can’t specify the formulation of the drug and then you have no idea what your patient might have received, which of several formulations they may have got.

I myself, for instance, take two generic formulations a day and when I go to get my prescriptions refilled from one form to another I will mostly get a different manufactured formulation of the same drug.

Now the problem there is that although they have all been manufactured to a high standard and will have gone through an approval process whereby they are shown bioequivalence to a reference formulation, they may not themselves be equivalent to one another.

So one generic formula may fall below the reference and another might fall above. And as we go from one generic drug to another we might end up delivering more or less of the drug.

In some clinical settings this can be a problem, for examples in narrow therapeutic index drugs where small changes in exposure to the drug result from taking that formulation. An example might be warfarin, where it has been shown – on a number of occasions now – that if you change from one formulation to another overall healthcare costs can increase, because the number of interventions that have to be made because of the differences in exposure.

I think that’s the main problem that faces physicians relating to the use of generic formulations.

How are the European drug regulatory authorities attempting to minimise the problems associated with sub-standard drug manufacture?
In Europe, and we have a similar situation in America, the regulatory authorities are trying to look at the total manufacture of the drug – the complete supply chain for both the active pharmaceutical ingredient and the excipients that go into the tablet, the capsule or the liquid formulation.

In Europe we have the European Directive on Falsifying Medicines. What this is attempting to do is to say if you buy in from outside the European community the active pharmaceutical ingredient or the excipient, they must be manufactured to the same standard of good manufacturing practice as if they have been made within the European Union.

And there are adequate guidelines on how this should be done, both in terms of what should happen in the manufacturing plant and what the inspectors should look for when inspecting formulations. But of course regulations are only as good as their observance at the point of manufacture, and how they are observed by the regulator.

So we have to ensure that the manufacturers are doing their job and the regulators are doing theirs.

Within Europe, I think that most generic drugs are manufactured to a good quality. But we need constant vigilance, and we’ve had a number of incidents where substandard medications have got into the supply chain, which is now a very complicated supply chain – most active pharmaceutical ingredients are manufactured outside the EU, mostly in China and India, so the potential for having people bypassing the regulations, not keeping to those regulations is very great. And this is what we must try to overcome.

Are all generic drugs equal with respect to safety and efficacy?
I am often asked of generic formulations are all the same in terms of efficacy and safety with respect to the originator formulation – the one that was first in the field. The thing you have to understand for the generic regulations, the procedure you go through when you produce a generic medication, they do not look at safety and efficacy. We have a process whereby they show bioequivalence for solid dose formulations – liquid formations don’t have to show that, only that they are the same drug in the same drug.

So those aspects are not looked at. And one of the main assumptions is a that bioequivalence equals therapeutic equivalence, and this is not always the case. A number of studies have shown, in particular for some of the narrow therapeutic index drugs – anti-epileptic drugs, immunosuppressives – that very small differences in exposure, those that are well within the guidelines for bioequivalence, are not adequate for interchangability when we come to look at moving from one formulation to another – in particular going backwards and forwards between generic formulations.