Regulatory guidelines

Statistical thinking and practice is very much determined by the regulatory guidelines that are in place. Primarily it is ICH E9 Statistical Principles for Clinical Trials , published in 1998, which sets down the broad framework within which we operate. In 2001 we saw the publication of ICH ElO Choice of Control Group which contained advice on the appropriate choice of concurrent control group and in particular first introduced the concept of assay sensitivity (see Section 12.5) in active control, non-inferiority trials. 

Since that time we have seen numerous additional guidelines on specific statistical issues, for example the European (CPMP/CHMP) Points to Consider Papers  

CPMP (2000) Points to Consider on Switching between Superiority and Non- 

This guideline spelt out the circumstances where it is possible to change the objective of a trial from non-inferiority to superiority if the evidence is sufficiently strong, but clearly stated that switching in the opposite direction would unlikely be possible (see Section 12.9). 

CPMP (2001) Points to Consider on Applications with 1. Meta Analysis 2. One Pivotal Study 

Once the determinative or confirmatory method has been developed to take full advantage of the chemical properties of the analyte molecule, a study is necessary to prove that the method is valid. Criteria for method validation are outlined in guidelines from the US FDA, US EPA, and EU. A summary of the differences in regulatory requirements for method validation is provided in Table 3. The parameters addressed by all of the regulatory guidelines include accuracy, precision, sensitivity, specificity, and practicability. 

Method accuracy is defined as fhe agreemenf befween fhe measured value and fhe frue value and is usually determined by measuring fhe percenfage recovery of spiked samples. Recovery values of 70-110% are usually desired, allhough fhe EDA and the EU allow for wider ranges for analyses at low concentration levels. 

Precision is a measure of the agreement between replicate assays and is usually expressed as the coefficient of variation (CV). A CV of 15% or less is desired although, like accuracy, some leniency in this criterion is made for samples at very low concentrations. Also, the regulatory agencies give some consideration to the combined impact of accuracy and precision. For example, a method that has a recovery of less than 70% but a CV of less than 10% might be viewed more favorably than a method with a 90% recovery and a CV of 20%. 

Sensitivity is a measure of the smallest concentration that can be either measured [limit of detection (LOD)] or accurately quantitated [limit of quantitation (LOQ)]. In the USA, the method for measuring LOD or LOQ is left up to the method developer. European requirements for determining LOD and LOQ are very specific the LOD is based on the mean plus three standard deviations for 20 control blank samples, and the LOQ is defined as the lowest concentration giving an acceptable CV. 

Specificity is a measure of how selectively the analytical method measures the marker compound in the presence of other compounds. The descriptors used to establish specificity differ depending upon the guideline (see Table 3), but the purpose behind them is the same. In all cases, the method must be demonstrated to have no interference from several (at least five) confrol animals that represent variation in sex, age, and breed. Further, incurred residue samples or authentic metabolite standards must demonstrate no interference with the marker residue detection. The method must be tested with other approved dmgs for the target species to show that no interference exists if these compounds are also present. 

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Anytime hazardous materials are eneountered, the potential for a mishap to oeeur inereases. Should the hazardous materials be eonsidered waste produets, eomplianee issues beeome more important. Elazardous waste operations and work aetivities should be evaluated to determine if the operation should eomply with HAZWOPER or other regulatory guidelines. 

A number of alternative sizing methods are available, and these are described in Table 8. The American Association of Pharmaceutical Scientists, Inhalation Focus Group conducted a comprehensive review of available methods, which was published in a series of articles identified in the last column of the table. All of the methods described either have been or are currently employed in the development of aerosol products. However, at this time only the inertial samplers, cascade impactors and impingers appear in compendial standards and in regulatory guidelines [44-46], Other methods such as thermal imaging are also under development and may give complementary size information to the current methods. 

Three volumes of information on the format and content of applications for marketing authorization and relevant regulatory guidelines have been prepared by the Commission (Enterprise Directorate General) and published as the Notice to Applicants. These volumes do not have legal force, but applications that fail to follow their prescriptions can be returned to applicants as invalid. 

Volume 2A Notice to applicants—Medicinal products for human use—Procedures for marketing authorisation Volume 2B Notice to applicants—Medicinal products for human use—Presentation and content of the dossier Volume 2C Notice to applicants—Medicinal products for human use—Regulatory guidelines Commission of the European Communities, Luxembourg, 1998/1998/ 1999 (and amendments)... 

Worlds apart are the practices, yet the official policies and regulatory guidelines in developing countries show much influence from those of the developed world. While waste import bans are common in the developing world, the topography of recycling and disposal costs seems to assure a flow of e-waste out of the developed world down to the points of lowest-cost disposal. 

The degradation and formation of nonabsorbable drug complexes in the intestinal lumen is the third factor, in addition to dissolution and permeability, which could affect fraction absorption. Limitations of bioavailability due to these factors seem to be less frequent compared with the two other main factors. Regulatory guidelines for BCS-based biowaivers still ask for in vitro studies of luminal degradation in relevant test media, whereas specific binding studies are not required [17]. 

In addition, tests for mutagenicity and carcinogenicity are not likely required for most biopharma-ceutical substances. The regulatory guidelines and industrial practices relating to biopharmaceuti-cal preclinical trials thus remain in an evolutionary mode, and each product is taken on a case-by-case basis. An overview of the main preclinical tests undertaken for a sample biopharmaceutical... 

In order to understand the use and intent of the various immunotoxicology regulatory guidelines and guidance documents, the difference between two concepts familiar to toxicologists should be emphasized. Hazard, identification refers to a method which is essentially qualitative that is, it is designed to detect the ability of a test article to produce a certain (in the context of toxicology) adverse effect, without reference to exposure issues. Risk assessment, on the other hand, takes into consideration method, dose, and duration of exposure, condition(s) of the exposed population, and concurrent... 

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