Sunday, October 16, 2011

Challenges in Comparator Studies

As a statistician, I have been involved in the design and analysis of many blinded clinical trials. Being part of the clinical team, the discussion usually evolves around the choice of comparator (e.g. matching placebo or active control). If active control is used, there are usually some further considerations, e.g.:
  • which drug / dose / schedule should be used, as this may differ in terms of clinical practice and regulatory acceptance depending on the region and countries.
  • what is the treatment difference to be detected (for superiority trials) or the non-inferiority margin (for non-inferiority trials), as this would have an impact on the sample size which in turn would affect the time and cost of the trial
  • how to handle the randomisation and blinded kits in the IVRS, to ensure that the subjects receive the intended treatment; and how to deal with subjects who have not received the intended treatment.
Rarely do statisticians get into the more practical details on how to actually produce the blinded comparator treatment. Therefore it was fascinating for me to attend a conference on comparator studies and gain an insight from clinical supplies and sourcing colleagues on the technical aspects and challenges on producing blinded treatments. Ultimately their role is to ensure the integrity of the comparator is maintained and blinding can be achieved as far as possible, bearing in mind that the cost, timing and technical challenges may become a major hurdle in the process of blinding a comparator treatment.

Some of the common methods to blind an oral drug include:
  • Over-encapsulation
  • De-inking
  • Over-coating
  • Over-printing
  • Mill-and-fill
While one method may work for one oral formulation of a drug, it may not work for another oral formulation of the same drug. For example, over-encapsulation may not be appropriate for a fast-acting release of a drug product.

For other types of treatment administrations, there may be other methods such as relabelling, masking or exchanging certain secondary components.

Often there are additional aspects that need to be considered and dealt with e.g. taste, odour, consistency, colour, drug delivery device etc.

With more and more late-phase clinical trials going global, there needs to be consideration on whether to source the comparator drug direct from the original manufacturer (which may be difficult as it's a competitor product), from a generics manufacturer (only if the comparator is off-patent already and the generic form is available) or from wholesaler. The decision on whether to source the comparator drug centrally or locally should not be taken lightly: for the former, one of the challenges is the logistics of moving the comparator from the central source to different countries; while for the latter, the comparator may have slight variation in terms of formulation and availability between countries, and can become a major headache if there is a problem with meeting the demand of the drug locally.

Bearing in mind that there are so many areas to consider, it makes sense to get clinical supplies/sourcing involved early on in the clinical trial planning process once we have an idea on what are the possible comparators, even if we don't know what the comparator is going to be in the final trial design. It takes time for these guys to source, blind and repackage the comparator product. During this process, there may be additional development work required to ensure the method of blinding has no or little impact on the stability, bioavailability and dissolution profile of the comparator drug. The time and effort required in gathering all the necessary regulatory documentations should not be underestimated either.