Fixed-dose combination drugs (FDCs) are bulk-produced, rather than compounded in pharmacies. They may combine active ingredients to treat a single disease (such as AIDs antiretrovirals) or several, such as Pfizer’s Caduet/Envacar, which combines the calcium antagonist amlodipine with atorvastin, a statin, to treat both high cholesterol and high blood pressure at the same time.
While FDCs bring benefits, such as potentially working faster, having better efficacy, or cancelling out adverse effects, they also have possible risks like cumulative toxicity and difficult titration, the EMA said.
To gain a marketing authorisation for an FDC, sponsor companies must justify the pharmacological and medical reasons for the combination, including dose frequency, and clearly identify the target population.
They must also show evidence for “relevant contribution of all active components to the desired therapeutic effect” and a “positive risk-benefit for the combination,” either because the combined drug has better efficacy, or because it is safer than one of the APIs alone.
Possible risks sponsors must consider in their risk-benefit analysis are the strengthening of adverse effects, and the difficulty adjusting FDCs to the needs of individual patients.
The agency added it discourages FDCs that treat two or more unrelated indications, unless companies can provide a “therapeutic rationale.”
The EMA stressed the importance of clinical data in deciding dosage levels, such as “in cases when each component of the fixed combination has several possible dosages, dosages that have shown benefit on hard clinical outcomes may be preferable for the fixed combination when compared with the dosages effective on surrogate endpoints only.”
The agency said R&D should pay careful attention to the doses of each API in combination products, ensuring ingredient levels are “scientifically justified and clinically relevant.”
Evidence for FDC authorisations can include dedicated clinical trials which use the combination product, clinical trials combining the relevant APIs but administering them separately, or literature data.
Clinical evidence for FDCs can be gathered in three situations:
- “add-on treatment of patients insufficiently responding to an existing therapy with one or more (mono-) components,”
- “substitution in patients adequately controlled with two or more mono-components used in combination,”
- “initial combination therapy for patients receiving previously neither of the substances.”
For developers of generic FDCs, bioequivalence studies are required as with any other generic. Pharmacodynamics and clinical efficacy and safety studies are not needed in this case, the EMA said, also warning they “will not rescue a failed bioequivalence study.”