Although such products will have completed the pre-marketing clinical trials, been awarded Marketing Authorisations by the regulators and been taken by perhaps hundreds of thousands or even millions of patients in real life clinical practice, there are nonetheless circumstances in which unanticipated adverse reactions can arise.
The active pharmaceutical or biological component of a medicinal product as it is received by the patient (for example as a capsule or infused solution) may sometimes only form a small fraction of the total volume of the product. The remaining volume constitutes excipients which are in theory ingredients without any effects that are simply added for consistency, stability, bulk or form. They may also be present to add flavour; as a preservative; to act as a diluent, adjuvant or lubricant; to provide a certain colour to the medication, and so on.
Excipients can vary in composition between both formulations and dose strengths of the same drug. It could be that a higher dose formulation of the same drug is manufactured as a larger tablet, for example, and therefore simply contains more excipients than the lower dose formulation. The pharmaceutical industry has placed hundreds of thousands of products on the market, all containing various excipients in varying quantities. They may change formulations and/ or excipient suppliers. Adverse reactions can occur with the excipients – for example allergies, lactose intolerance, effects of sugar in diabetic patients – and these may be difficult to detect. In the past, there have also been relative overdoses caused by new formulations of old products increasing the amount of drug that is absorbed into the body.
It is also of note that clinical trial participants (subjects or patients) have been known to experience Adverse Reactions to placebos. Within the EU, the Clinical Trial Directive (2001/20/EC, April 4, 2001) includes the word ‘placebo’ within the list of substances with the status of “an investigational medicinal product”. Therefore timely reporting of any Adverse Events applies to those found to occur after taking placebos in clinical trials conducted as post-marketing activities, if it is suspected that the reaction was caused by the placebo. Placebo reactions usually occur because of allergy to an excipient in the placebo – in the same way that excipients in medication with active ingredients can also cause allergic reactions.
Once a drug has been marketed for sufficient time to qualify for manufacture as a generic product, it is not sufficient that only the original manufacturer (innovator) of the patented drug should engage in reporting of suspected adverse reactions. Regulations require that surveillance takes place and that reports should be submitted and evaluated by whichever pharmaceutical companies made the particular generic version of the formerly patented product. Due to the types of issues with excipients stated above, there may be cases arising with suspected associations with formulation or other aspects of manufacture.
There are many examples where it has taken many years for even very serious adverse effects of products to be identified. This may be because of the rarity of their occurrence, or because the circumstances in the individual patients did not raise a suspicion that the medicine concerned was causing the problem. Examples include the identification of heart valve disease with some drugs used to treat obesity, and the occurrence of heart rhythm disturbances with some non-sedating antihistamines. In other instances, it may take many years or even decades for an adverse effect of a medicinal product to develop – for example if a drug causes cancer. In one example – stilboestrol, a synthetic female sex hormone – the adverse reaction concerned was a rare type of cancer which only manifested itself in the grown-up daughters of the women who took the drug in pregnancy. In another example, there was a change in the manufacturing process after many years on the market for a medicine used to treat depression. This change led to a toxic by-product of manufacture causing serious problems in the blood, muscles and lungs of patients receiving that make of the product, but patients receiving the original version were unaffected. Finally, as new medicines continuously come on to the market, these may have interactions with well-established use products presenting new risks to the patient previously not seen.
Globally, pharmacovigilance is of the utmost importance for pharmaceutical companies, even if a particular drug has been marketed for many years.
Please note this page is intended for interested lay readers only and therefore cannot be considered as any type of formal or informal professional advice.
1. Barton L. Cobert, MD. (2007). Manual of Drug Safety and Pharmacovigilance. Massachusetts: Jones and Bartlett.
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