The EU and US regulatory approvals process by which pharmaceutical products used to treat chronic conditions get approved is lacking in rigor, argues a new paper published in the Public Library of Science (PLoS): Medicine.
The paper, "Number of Patients Studied Prior to Approval of New Medicines: A Database Analysis," looked at approximately 200 medicinal products approved in the EU between 2000 and 2010 with the intent of assessing regulatory compliance to the International Conference on Harmonisation's E1 guideline.
That guideline, also followed by the US and Japan, sets the requirements for the size of a trial conducted to generate evidence regarding the safety of drugs intended for long-term use of non-life-threatening conditions.
Though the sample size for each product will differ depending upon its qualities and characteristics, the ICH guideline notes that the "duration of drug exposure and its relationship to both time and magnitude of occurrence of adverse events are important considerations in determining the size of the data base necessary to achieve such goals."
The other, and perhaps most, important consideration for trials of chronic disease treatments is the size of the clinical trial. The limitations of trials are well-known to most in regulatory. While trials can discover some of the more common adverse drug events (ADEs) likely to affect a population, many of those events will only be discovered when the drug is subject to long-term use in non-ideal populations and in real-world conditions.
ICH's guideline concedes this, explaining that "The safety evaluation during clinical drug development is not expected to characterize rare adverse events, for example, those occurring in less than 1 in 1000 patients." With drugs intended to be taken over a longer period of time, ICH noted a concern that "although they are likely to be uncommon, some ADEs may increase in frequency or severity over time or that some serious ADEs may occur only after drug treatment for more than six months."
"In the absence of more information about the relationship of ADEs to treatment duration, selection of a specific number of patients to be followed for 1 year is to a large extent a judgment based on the probability of detecting a given ADE frequency level and practical considerations," the guidance says.
To that end, sponsors need to make sure their trials have a sufficient number of patients to make sure those rare adverse events are discovered before the drug is released into a larger population. ICH said it anticipates that the number of patients treated should be no fewer than 1,500, and that larger populations may be needed depending on the drug's benefit profile and the population being treated. In addition, trials might also need to add more patients if the drug's effects are seen as being additive to existing morbidities.
Of those 1,500 patients, the ICH guideline recommends that at least 100 be tracked for a minimum of one year.
An Assessment of the Status Quo
The PLoS authors found that companies are generally exceeding the overall size requirement. While most standard medicines studies had an average number of 1,708 enrolled trial patients, chronic use drugs were studied in an average of 2,338 patients-far more than in anti-cancer treatments (878) or antibiotics (1,315), which are typically used on a short-term basis.
But that raises a question: Are enough patients being studied, and for the right amount of time?
The authors answer this question with an emphatic "no," arguing that, "at the time of approval of a new medicine, there are few long-term data on the medicine's benefit-risk balance."
The main problem, they said, was not the number of patients, but rather the time each patient was subjected to the product for.
"The safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least six and twelve months in 46.4% and 58.4% of new medicines, respectively," the authors of the paper wrote. "Finally, among the 84 medicines intended for chronic use, 72 were studied in at least 300 patients for six months, and 70 were studied in at least 100 patients for twelve months."
That's great if you have a medicine you only intend to take for a short amount of time; not so much if you're on an asthma medication regimen you might need to take for the rest of your life, the authors said.
A Trade-Off: More Testing, Longer Approval Times
That finding leads the authors to concede the existence of a trade-off for drug regulatory bodies: Requiring lengthier trials will lead to more expensive drugs and ones that reach patients later than they would otherwise. Still, they wrote, this tradeoff is worthwhile for those drugs intended solely for long-term use.
The authors raise the case study of GlaxoSmithKline's rosiglitazone, better known as Avandia, as one long-term use product that was later found to have an increased risk of myocardial infarction. This data was only found in post-marketing settings after the drug was given to millions of patients. The authors conceded that trial sizes would need to be enormous to be able to determine with a degree of certainty whether a product is positively associated with that level of risk, but even small signals can become useful for the purposes of postmarket vigilance and evaluation, which the authors also strongly encourage.
Thus, the authors said regulations need to be changed such that the same trial sizes required for short-term drugs are also used long-term.
"The possibility of detecting long-term adverse events from follow-up of only 300 patients for 6 months or 100 patients for 12 months, as required in the current ICH E1 guideline, is insufficient," they said. "It would be more sensible to move towards a minimum targeted long-term study size of 1,000 to 1,500 patients, comparable to the overall study size now required."
"A re-evaluation of the requirements regarding study size and long-term data for approval of new medicines seems to be merited" based on these findings, they concluded.