Radiobioconjugate targetting in cancer in developing countries: Regulatory issues

Full text: The radiobioharmaceuticals for targeting cancers include radiolabelled monoclonal antibodies, peptides, anti sense nucleotides as well as intermediate molecules in pretargetting strategies. Scientists in developing countries that wish to use these agents whether for diagnosis or for therapy face formidable barriers, and this communication proposes pragmatic strategies to overcome these hurdles. Firstly such agents prior to radiolabellling have to be prepared according to Good Manufacturing Practice standards,suggested criteria for which have been formulated. Secondly, for therapy use, since centralized distribution of a high dose labeled radiopharmaceutical such as an Iodine labeled antibody is not available from a source in the country or region, and may not be feasible for logistic and economic reasons, compounded by the distances between the radiopharmaceutical manufacturing centers and the user hospitals,high dose radiolabelling has to be undertaken in house in the user centre. This necessitates understanding of the hazards especially with volatile isotopes such as radioiodine, and adequate precautions to limit these. For the addition of radioiodine remote controlled pipetting has been proposed. Another strategy is the use of resins to mop up excess radiolabel. With other radiolabels such as Rhenium, Lutecium and Gold, the problem of volatility is avoided but obtaining these at adequate specific activity and purity is sometimes difficult resulting in the need for concentration techniques. Rhenium-188 from Tungsten generators is superior to the reactor produced Rhenium-186/188 mixtures. This problem does not exist as regards diagnostic targeting where Technetium-99m is adequate and is available sterile from column generators. The use of pretargetting strategies with the final agent being a radiolabelled biotin or radiolabelled chelate may enable centralized preparation and distribution of these. Thirdly the availability of biological agents is severely hedged in by patents.Developed countries manufacturers in order to obtain local regulatory approval are chary of sharing raw material with the developing county users at any stage prior to FDA approval.After FDA approval they are exported at exorbitant costs to recover the costs of regulatory approval which are not only expensive but delay the availability of these to cancer patients in the developing countries by almost a decade!. It therefore is apparent that the developing countries need to manufacture their own therapeutic molecules,and a governmental agency is often needed to catalyse this as pharmaceutical industry is reluctant to undertake this unless the molecule is already approved and clinically successful, a Catch 22 situation! An individual research laboratory can only manufacture milligrams of an agent, and to allow investigator multicentre trials of an agent quantities of the order of 50 grams are required using biofermenters; mega kidney dialysis cartridge type systems. Individual patients need antibodies in quantities of 15-100 mg per therapy. Eventual commercial manufacture of an agent involves making kilogram quantities in air lift fermenters. Manufacture of these 50 gram quantities is estimated to cost Rs 50,000 per gram which is substantially cheaper than the Rs 10,00,000 per gram at which such agents are imported,It is therefore emphasized that developing countries need to emulate the UK story where even in a developed country the Medical Research Council set up a Therapeutic Antibody Centre initially at Cambridge and now at Oxford.Cooperation amongst developing countries is also obviously advantageous! Fourthly developing countries need to have their own regulatory standards in force and not blindly adopt those extant in developing countries. For example the costs of testing a product for minute quantities of mouse viruses or DNA is tremendous and it appears unnecessary to undertake for each batch, as multiple chromatography steps used for chemical purification eliminates these biodangers as well. It is urged that when dealing with an aggressive lethal cancer, the risk of imminent death from this is far greater than the infinitesmal risk of contracting a mouse virus infection! Already for non radiolabelled conventional chemotherapy fast track regulatory approval procedures exist as compared to noncancer drugs! Fifthly some newer manufacturing techniques for biomolecules such as those using yeast in alcoholic media for antibodies may eliminate the biohazards associated with conventional mammalian cell or bacterial routes for manufacture. Sixthly there is an alarming patent trend where not only monoclonal antibodies but also the sites against which these are directed are sought to be restricted! In conclusion, it is salutary to remember that even in the developed countries the tremendous cost of the regulatory approval process has led to available drugs being frozen in outmoded technology e.g. with a murine rather than human antibody because obtaining approval for the better molecule is considered costly and time taking! The developing countries when setting up their regulatory procedures need to keep it low cost and fast to avoid such pitfalls. (author)