Making Registration Systems Work For Generics

Pesticide registration systems must not only ensure the quality of approved crop protection products and their reasonable safety regarding human health, the environment and crops, they must also be efficient in approving generics. Due to a decline in R&D productivity in the generation of research companies during the last two decades, along with extensive patent expirations, registration authorities are likely to receive many times more submissions for the approval of generics than for new chemical entities.

There is a global trend in national pesticide registration systems toward the adoption of registration systems based on equivalence for the approval of generic pesticides. Such systems are historically derived from the US Environmental Protection Agency’s procedure for registering equivalent (me too) generic pesticides based on substantial similarity of the Technical Grade Active Ingredient (TGAI). Such a system was based on the valid premise that products that are “substantially similar” in their chemical composition will be similar in their toxicity, eco-toxicity and field efficacy. Under such a system, generics submit an abbreviated information package related to the chemical composition of the TGAI in order to demonstrate their equivalence to a product on the market.

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In 1999, the UN Food and Agriculture Organization (FAO) published the “Manual on Development and Use of FAO Specifications for Plant Protection Products” (later jointly published with the World Trade Organization), which maps the process of determining the equivalence of TGAIs from different sources. While the FAO/WHO (World Health Organization) Manual goes into some detail into how to determine the equivalence between two TGAIs, it is not a registration guideline, per se. Registration authorities must make decisions regarding specific issues in the implementation of the system. Some critical issues will determine whether or not the registration of generic agrochemicals will be possible, and thus have major implications on agricultural production costs because competition of generic agrochemicals is the only way to break monopolies held predominantly by five large multinational corporations. Competition ultimately will bring down prices paid by farmers and consumers.

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AgroCare, the global association representing the post-patent crop protection industry, and the world’s most representative association regarding pesticide manufacturers, has surveyed the productivity of registration systems, and found that many of these systems are excessively slow or virtually paralyzed when it comes to approving generics. The two most common barriers to registering generics are: 1) lack of “reference profiles” in developing countries, and 2) lack of clarity as to what information is subject to data protection versus what is free to use.

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Reference Profiles

When countries implement registration systems based on equivalence, authorities must decide how to treat existing registrations since those approved under the prior system may have had different data requirements. The most pragmatic and scientifically sound approach is to require all registrations to be “re-validated” through a data call-in, in which the National Authority requires all registration holders to submit supplementary information to complement the information already on hand. The required information should consist primarily of the information used to determine the chemical composition of the TGAI. Registrations of formulated products should also submit the information corresponding to the TGAI used in the formulation.

Assuming a minimum purity of the active ingredient is achieved in a TGAI, the only possible difference between two TGAIs from different sources is the composition of impurities. With a five-batch analysis and the manufacturing process, the National Authority may determine the potential presence of any “relevant” impurities. Relevant impurities are those impurities that are of concern due to adverse health, environmental, pesticide stability or field efficacy effects. Relevant impurities and their tolerances are identified in FAO Specifications of pesticides as well as in literature compilations.

Any non-relevant impurities at or above 0.1% w/v (weight by volume) of the material balance must also be identified and quantified in the five-batch analysis in order to demonstrate that the TGAI material has been completely analyzed and there is no material of unknown composition that could contain relevant impurities. If there are no relevant impurities above international tolerances, the TGAI should remain on the market. This regulatory treatment of existing registrations therefore creates the necessary data base of “reference profiles” (comparison products) from the available TGAIs that satisfy the re-validation process, thereby enabling the registration system.

The lobby of the large multinational companies argues that instead of a “re-validation” process, a full “re-registration” of all existing products should be implemented, in which a full data package, including chronic toxicity studies, is required. This position makes no mention of the fact that chronic toxicity studies are usually performed on laboratory ­or pilot-plant scale production of the active ingredient to determine the toxicological and eco-toxicological properties of a new active ingredient prior to commercial production scale-up. Different studies compiled into a full dossier are often performed on material of different purity, and therefore, different impurity profiles.

Consequently, such chronic toxicity studies do not support the safety of a very specific combination of impurities found in the TGAI produced commercially, but rather the safety of the active ingredient per se. Companies often change manufacturing processes and sites, and today all companies (including all large multinational companies) source TGAIs from third parties. Chronic toxicity studies are not repeated each time the manufacturing process or site is changed.

The result of requiring a full re-registration (such as Directive 91/ 414 in Europe) has been the wholesale elimination of existing high-quality generic products with a long history of safe use that compete with other products under patent or of higher commercial interest to certain companies, thus eliminating competitive options for farmers.

Access To Registration Data

The World Trade Organization requires member countries to protect “undisclosed information” under the Trade Related Aspects of Intellectual Property Rights Agreement (TRIPS) against unfair commercial use. This does not mean countries must implement periods of exclusive use for such data.

Nevertheless, some countries have chosen to implement “TRIPS-Plus” data protection schemes that grant a period of “exclusive use” for access to registration data starting on the date of registration approval. Some countries also allow for setting new protection periods for so-called new — but in fact often old — studies that are occasionally required to evaluate a new safety issue related to an active ingredient under a “re-registration” initiative. After this period, generic producers in theory should be able to cite or use the previously protected data for the purpose of registering a competitive equivalent product. However, in practice such access is not always so clear.

While “new” studies may constitute only a small fraction of the entire data package generated for a given molecule over years, registration systems are often permissive of a very cloudy picture as to what data is defined as a new (and subject to protection in certain countries) versus old (and therefore not protected). This often leads to a “re-protection” of the entire data package, which harms farmer and consumer welfare.

Fixing this problem is technically simple. Countries with such TRIPS-Plus data protection systems should manage data bases that differentiate between previously submitted data that is not subject to any protection, and new data that is under protection. Regulatory authorities should publish the list of studies relied upon for the approval process. The list must allow full identification of the study by its full bibliographic details including author, date, exact title, report number, and the organization that carried out the experimental work.

Any data protection term should be tied to the date of the study report without consideration of later amendments or reviews. Such a simple solution would eliminate wasteful duplication of regulatory studies and especially the unethical duplication of animal studies, and reduce undue monopoly pricing in such strategic agricultural inputs.

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