“Before the BPCA [Best Pharmaceuticals for Children Act] and the PREA [Paediatric Research Equity Act] became law, more than 80 per cent of the drugs approved [by FDA] for adult use were being used for children, even though the safety and effectiveness had not been established in the latter. Today that number has been reduced to about 50 per cent,” a FDA blog post notes.
The effects of BPCA and PREA are already beginning to show. Janssen Pharmaceuticals, whose new drug (bedaquiline) was approved by the FDA last year for use in adults with MDR-TB disease, has already initiated steps to produce a paediatric version.
“Janssen is conducting what’s called a ‘bioavailability study’ where the pharmacokinetic and other parameters (such as taste) of two new paediatric formulations of bedaquiline (granules or water dispersible tablets) would be compared with the pharmacokinetic parameters of the current adult tablet formulation,” Daniel De Schryver, Global Communications Leader, Infectious Diseases and Vaccines, Janssen Research & Development, Belgium stated in an email to this Correspondent.
“Such a trial is normally conducted in healthy adults,” Schryver noted. “Once a suitable paediatric formulation is identified, a trial will then be conducted in paediatric MDR TB patients (up to age 18 years) to determine the safety and efficacy of bedaquiline in these patients taking either the identified paediatric formulation or the adult tablets, where appropriate.”
Once it is tested in adults, children of different age groups would be studied, starting with the oldest group — 12-18 years. This age group would be given the adult formulation as very often they tend to develop adult-type TB disease. “Based on the results from this older cohort, the trial would then proceed to the next cohort, using an age-appropriate formulation, and so on until the youngest group (as young as 6 months of age) is reached,” he explained. It is not clear when paediatric drug formulation of bedaquiline would become available for the youngest age group.
The three age groups of children (who tend to develop paediatric MDR-TB disease) to be studied are 6–12 years, 2–6 years, and 6 months–2 years respectively.
There is a compelling need to conduct clinical trials in children even when the safety, dosage and efficacy of the drug have been studied in adults. One needs to take a few steps backwards to understand this.
By default, the amount of TB drug does “not reach the same concentration in the blood of children compared with adults” for a given mg/kg body weight dosage. This results in under-dosing in children. The only way to overcome this is by increasing the dosage of TB drugs (mg/kg body weight) given to children. WHO revised upwards the dosing of TB drugs for children only in 2010!
“More science has been done and hence we are able to understand why we are not able to treat children correctly,” Dr. Denis Broun, Executive Director of UNITAID said to this Correspondent over phone from Geneva while explaining why it took a long time for WHO to revise the dosing for children. “Not that it [science of dosing] was bad before, it has become better now.”
And since the drug dosage for children has been increased, clinical trials to study pharmacokinetics and bioavailability have to necessarily be undertaken.
If the two FDA rules make it mandatory for Janssen to produce paediatric formulations of bedaquiline, UNITAID’s grant of $16.7 million to TB Alliance in December last year to accelerate the development of paediatric TB regimens has provided an additional impetus.
“Developing paediatric [TB] drugs is a not a big market for pharmaceutical companies. Have faced this in the case of HIV too,” Dr. Broun said. “The point is to put money upfront so companies would create new drugs.”
“We are working with Janssen to speed up the availability of the paediatric formulation of bedaquiline, which was approved for the treatment of MDR-TB in adults last year,” Dr. Mel Spigelman, President and Chief Executive Officer of the Global Alliance for TB Drug Development (TB Alliance) said in email to this Correspondent. “TB Alliance’s work … will aim to reduce the lag time between adult and paediatric formulations of new drugs, accelerating the availability of new TB drugs in paediatric form.”
(The Correspondent is a recipient of the 2013 REACH Lilly MDR-TB Partnership National Media Fellowship for Reporting on TB)