Selection criteria for the preparation of anticancer drugs from generic drugs

Pharmaceutical criteria

We propose considering generic drugs as raw materials used in the production of chemotherapy drugs.

Accordingly, we will briefly describe Process Analytical Technology (PAT) applied to the pharmaceutical industry under the impetus of the FDA.
PAT is a dynamic, scalable process that reinforces conventional quality management tools. It allows quick feedback at all levels of production.

Like PAT, our basic premise is to consider generic drugs as an element of our continuous search for quality.

To illustrate this approach, we have asked some suppliers of generic drugs to complete a quiz.

This questionnaire covers nine technical items that illustrate the product (stability, compatibilities), the packaging (cap quality in particular) and chemical contamination (presence or absence of contamination outside the bottles or under the flip-off cap; molecule elimination test).

An analysis of the most representative discussions prompts us to propose that:

• Yes, as raw materials – and just like some of our fundamental elements (qualification, training, prerelease inspections, etc.) – generic drugs must included as essential components of our quality approach.

• As we see it, there are many technical issues that call for a joining of forces between manufacturers and producers of chemotherapy drugs (absence or poor understanding of data, cultural differences, etc.). These unresolved technical issues and the quality of the dialogue established confirm the dynamic, changing place of generic drugs in the overall quality approach, which in the future could be extended to the proprietary molecules.

Medical criteria

Generic drugs are characterised by bioequivalence studies with proprietary drugs. The challenge for the clinician is to be sure not to choose cost over efficacy and safety.

For all that, very few studies in the literature provide solutions to this issue. They differ in terms of patients, pathologies and dosages and often have low enrolment levels.

After observing Taxol®-induced neurotoxicity in our patients, which we found surprising, we searched the literature for arguments supporting a pharmacological equivalence of paclitaxel. The pharmacokinetics of Taxol® and Paxene as well as those of both Cremophors seem to be identical. The properties of the micelles are identical, as are those of the free fraction of paclitaxel. All the same, this equivalence remains the result of a bitter legal battle.

We conducted a personal study involving 17 patients being treated in our establishment. They were treated from 1 January 2012 to 30 May 2013. Our grade-3 neuropathy rate was higher than that of the pivotal studies. The neuropathies were early-onset neuropathies. Our enrolment level was low and we could not obtain this neuropathy rate with the proprietary drug.
The data in the French national pharmacovigilance database (BNPV), which are also difficult to interpret, appear to show a higher haematologic toxicity with the generic drug.

In closing, we only have bioequivalence studies with which to form an opinion on the efficacy and safety of the generic drugs. That said, we cannot expect large-scale clinical studies, as none will ever be conducted. We bear in mind the significant extra cost resulting from the proprietary molecules.