Every medical intervention, even a very positive one, has unfortunately very often a negative offset. In other words, every benefit is counterbalanced by a risk.
It is then very difficult for those who have to decide the commercialization of a new drug (EMA in Europe and FDA in the US) to conciliate two legitimate but opposite necessities: to make a new drug available for patients as soon as possible and at the same time to be sure not to harm those same patients because of the possible toxic effects.
The question is even harder if we consider that randomized controlled trials –the studies the approval of a new drug is based on – are essentially finalized to detect benefits, but cannot identify risks. In fact, drugs toxic effects can be the strangest and most unexpected ones and they need time to be observed.
For these reasons their identification requires a higher number of patients and a much more prolonged observation than it usually happens in clinical controlled studies. Besides, whilst benefits are often evident, toxic effects can be confounded with the disease symptoms and are then more difficult to discover.
In a new drug development process, the pendulum oscillates between necessity of testing it among the patients as soon as possible (after pre-clinical studies) and caution which requires more evidences and verifications, deferring the drug availability for the clinical use.
Economic crisis and the lack of innovation have pushed the FDA to create a preferential way for all those medicines which, at least in theory, could satisfy important health needs for patients with few available alternatives. In 2011 the “fast track” procedure was granted to 16 over 35 new products presented by pharmaceutical industries. The scientific journal JAMA, official organ of US doctors, describes as an example the approval modalities for three out of the 16 drugs on fast track.
Vandenatib is a new antitumor drug which was studied in just one trial (while usually at least two trials are required) conducted on 331 patients with advanced thyroid cancer. The study showed a slow-down in the cancer progression, but the medicine – because of its toxicity - did not prolong the life of the treated patients compared to the control group. Its toxicity was probably due to QTc prolongation. The drug was nevertheless approved, even though with some restrictions.
Fingolimod is a product designed for treating multiple sclerosis which exerts its immunosuppressive activity by inhibiting the lymphocytes efflux into the lymph nodes. In one study which lasted two years the new drug diminished neurological relapses more than the placebo, as anyway did the standard drug for the disease treatment (glatiramer). However the safety profile of fingolimod raises doubts mainly because this drug is approved as a first choice treatment, whilst EMA denied this indication for Europe. Without going too much into details, the toxic effects are: atrioventricular block, reduced respiratory functionality, infections, hepatic damage, teratogenicity and cancerogenicity.
Considering its toxicity, the product was approved at lower doses than those used in the trial, until other studies will provide more results. Dabigatran is the third drug under discussion. It is an anticoagulant with many indications, including stroke prevention in patients with atrial fibrillation. One single study was enough to assess dabigatran as an alternative to warfarin, even though the overall clinical advantage and the bleeding tendency were similar. Its commercialization immediately showed that especially in elderly patients - because of renal function decline and interaction with other medicines – dabigatran induced bleeding in a much higher measure than what had been observed in the trial examined by the FDA for its approval. Besides, being an antidote not available, the bleeding caused by dabigatran is more difficult to neutralize respect to the warfarin induced one.
The conclusion is obvious: was it really necessary to approve these three drugs so quickly? Even though they were truly designed for serious diseases, could it be that patients will be receiving more damages than benefits in the end? And what about the risk to have to suspend the commercialization of a drug too superficially studied?
Shortcuts can be dangerous. There are no substitutes for the systemic study of a medicine. Doses cannot be invented, but must be determined by careful evaluation. When drugs show toxic effects, doses cannot be the same for all patients; they must be established depending on weight, renal function and other variables. This is the only way to be sure not to harm patients.
Similarly caution should be exercised, limiting the drug use for the first period only to cases where previous treatments failed and always in specialized centres. There is an exaggerated run to occupy market areas instead of helping the patients. Regulatory agencies should be cautious, knowing that pharmaceutical industries always highlight benefits in their dossiers, minimizing the risks. This is particularly important when moving from the market to the reimbursement of the new drug by the National Health Care System.
It is time that patients become the centre of attention, avoiding that profit-run and uncritical benefit desires seriously damage them.