Efficacy Trials and Influencing Factors in Field Practice in Europe

Date:06-06-2012

1. GEP – Good Experimental Practice

In Europe there is one principle regulation, Good Laboratory Practice (GLP) that covers the requirements of laboratory data for pharmaceuticals, chemicals, biocides and plant protection products. The laboratory data is used in assessment of risk to human health and the environment. However there is a second regulation that covers plant protection products; Good Experimental Practice (GEP) which was introduced specifically for biological assessments including field studies. Field studies are typically outside the controls of a laboratory and fundamentally different because of the potential for less control and more variability. GEP was introduced in 1996 in Europe to provide a regulation of field trial data for the purpose of registration. It was introduced to provide a framework to allow experimentation and reporting on assessments of products used in the field. It is recognized there are more factors in the field that are outside control and the results from the experimentations are subject to many variables,  therefore robust statistical models are essential to interpret the results and indicate if there has been an effect or not.

The GEP framework is similar to GLP and requires formal documentation such as Protocols, SOPs, field notebooks for the collection of data, training records and job descriptions; and a formal independent quality assurance system.

In Europe GEP is separate from GLP; other territories such as Japan and the USA have only GLP covering all experimentation for regulated markets.

2. Regulation

Field Trials are typically required for new and novel:

• active ingredients,
• formulations (also known as: plant protection products),
• treatments for diseases, pests, insects or weeds, and Plant Growth Regulators (PGRs) to control growth; from original registration and marketing approval
• crops
• geographic territories and separate country applications

Typically the field trial data are included in the Biological Assessment Dossier (BAD). This is a summary of the many trials with 3 principle aims: to assess efficacy of treatment and safety to the plant, to assess risk to the environment and agriculture, and to assess economic benefit. 

Currently in Europe there are 4 main geographic areas (see figure 1) for assessment; north/west, north/east, south/west and south/east; and 3 regions for registration. Therefore trials can be done in one of the geographic regions but can be assessed in: individual countries, 1 or 2 regions; or in the whole EU community (all 4 geographic areas).

Trials are required to assess effects on target organism but can also require studies on:

• effects on yield, quality and phytotoxicity
• effects on non-target and beneficial species
• effects on adjacent and following crops

3. Field Practice

There are some parts of conducting Field Trials that are quite unique and different to the conduct for GLP; there has to be additional considerations to enable a control and consistency of field trials conducted over different geographic regions and different countries, even continents.

Weather

The weather is obviously out of control for open field studies. This has an immediate effect on the growth and management of the crop; but also has a huge effect on logistics and scheduling events such as spraying and harvesting. The planned schedules can only be best estimate at the beginning of the season; and still left to management at the local level often on a daily even hourly basis.

The weather also has an effect on the validity of the study. During 2011 there was a significant dry period throughout Europe; certain pests and diseases just didn’t appear - No assessments could be done.

Quality Assurance

Currently independent Quality Assurance is not mandatory for GEP studies presented for regulatory review. This is a cornerstone of GLP regulatory work and it is now common practice with individual companies and contract research companies to include independent QA that covers plant protection product registrations and seed assessments. It is now more common for GEP field assessments to have independent quality assurance of the GEP procedures. A protocol (also known as a study plan) is required to outline the responsibilities, the test system and the means to assess the results.

The quality assurance role has to extend outside the test facility where the Study Director is located to other remote test facilities including glasshouses, permanent test field sites, and real field sites typically rented from farmers. These facilities can be well remote from the Study Direction and yet they must be incorporated into the GEP quality system. Typically this requires appointment of Principal Field Investigators and field technicians. They must have sufficient knowledge and experience to perform the requirements of the study plans and the SOPs.

Study Director Role

The responsibilities of the Study Director are critical to choose the best test system to be able to assess the product on test. There are many ways of assessment of a single experimental factor and the results can be interpreted by a number of mathematical models and statistical tests of significance.

There are guidelines (EPPO, CBO and WHO) available to help plan a good study, but usually the Study Director has to have sufficient experience and knowledge to understand the crop and agricultural practice and of course what is to be measured in the assessment of efficacy. This is critical when planning efficacy studies because of the need to find appropriate field sites with the likely incidence of disease, pests, insects or weeds. It is also critical for the Study Director to choose an area that is acceptable to the geographic requirements of registration, to have the crop available, and at a time when the pest or disease is prevalent.  To then hope the weather will allow the conditions for the crop, pest and treatment to be assessed is truly in the hands of the gods.

Usually with good planning and experience the studies can be used for the assessment and included in the BAD. Typically it is best to have some additional spare sites in the overall study schedules. This can assure of having sufficient data to allow a meaningful assessment.

The assessments of efficacy studies requires a large field area to allow a statistical assessment; which means many assessments have to be done in the field areas to provide sufficient data to allow conclusive results  measurable by statistical means.

Principle field Investigators (PFIs)

PFIs are critical to the success of studies; the PFIs have to be consistent in the treatment and the assessment of the studies. They are often well separated in geographic terms but must be trained and informed to ensure a consistent assessment. This requires PFIs to be experienced to demand questions and details of SDs but also SDs to be able to communicate and discuss individual field conditions.

Temporary & Seasonal Staff

It is quite common for technicians to be recruited for a specific task only on a seasonal basis. This leads to an administrative problem to collect information who has worked on specific studies and to assess if they were competent to understand their responsibilities.

Field Note Books

Field notebooks are issued to PFIs and then to technicians who work in the field. The communication chain can be long in distance and therefore it is critical to have good collection of data. Field Notebooks are issued to each PFI to provide a consistent collection of relevant data. The data is specific to the field site but must all have a system to allow PFIs to record unusual events that may be critical to the assessment of efficacy.

There are now electronic formats available to allow consistent and rapid collection of field data.

Figure 1: Geographic Test Regions – Efficacy Studies for inclusion in BAD