PHASE I—DATA COLLECTION

The implementation phase of the data collection process takes place in the field and at the laboratory where the SAP provisions are implemented. This phase consists of Task 3—Sampling and Field Data Collection, Task 4—Laboratory Analysis, and Task 5—Field and Laboratory QA/QC. In theory, if all sampling, analysis, and QA/ QC tasks of this phase are conducted to the requirements of the SAP, the collected data will be relevant and valid. In reality, most projects have variances from the requirements specified in the SAP, hence a need for the next phase of data collection, i.e. assessment. 

This type of hADME studies using radioactive-labeled drag should be run unless phase I studies show that > 90 % of the dose is excreted unchanged in urine. In this case, a hADME study may not be required. For those drags, a urine assay should be the prerequisite for phase I trials and then mass balance may be established in trials where quantitative urine collections are performed. If phase I data indicate that cold mass balance , i.e. >90% recovery in urine cannot be obtained, a hADME study has to be scheduled for the development program. 

It may have been possible to implement very obvious waste-reduction measures already, before embarking on obtaining a material balance (even as early as at the end of Phase I). You should now consider the material balance information in conjunction with visual observations made during the data-collection period, to pinpoint areas or operations where simple adjustments in procedure could greatly improve the efficiency of the process by reducing unnecessary losses. 

These findings were further confirmed by data collected under isothermal conditions. Upon hydrogen addition at 350°C on the physical mixture previously saturated with NO species at the same temperature, no reaction products were detected. This indicated that the stored nitrates could not be regenerated by H2 at constant temperature, i.e. without a prior release in the gas phase. 

With an approved IND, the drug company can place me in humans at lower doses, mainly to observe any overt symptoms of toxicity and to evaluate my PK characteristics, and the study may use 10 to 20 healthy subjects. These data are then resubmitted to FDA (Phase 1). After my Phase I is completed, drug testing begins for my clinical efficacy, with trials at different doses and given to different populations under strict supervision. A successful study may require a few thousand patients and the involvement of several study centers across the country (or perhaps across the world) to collect extensive data. It is not unusual to have 100,000 patients take me before the data are submitted to the FDA for drug approval — the so-called marketing approval. 

For existing substances, the data collection consists of three phases. The ESR was initially concerned with the so-called HPVCs (High Production Volume Chemicals). HPVCs are those substances, which are covered by the data collection phases I and II of the ESR, i.e., those substances which have been imported or produced in quantities exceeding 1000 tons per year and produced/imported between March 23 1990 and March 23 1994. During phase I, 1884 substances were extracted from EINECS - referred to as the HPVC list these substances are listed in Annex I of ESR. The total list of substances reported under phases I and II of the Regulation is now referred to as the EU-HPVC list. 

The availability of both comprehensive SNP databases (10) and a plethora of technologies available to determine DNA variants at ever-decreasing costs has enabled the pharmaceutical industry to begin to incorporate germline DNA collection and testing into clinical trials (II). This allows for hypotheses to be developed and tested from the start of phase I testing in humans, when a direct correlation can be made between toxicity, efficacy, and pharmacokinetic variables. Furthermore, this allows the sponsor to pool data Irom several studies to significantly increase the statistical power. 

On a ternary equilibrium diagram like that of Figure 14.1, the limits of mutual solubilities are marked by the binodal curve and the compositions of phases in equilibrium by tielines. The region within the dome is two-phase and that outside is one-phase. The most common systems are those with one pair (Type I, Fig. 14.1) and two pairs (Type II. Fig. 14.4) of partially miscible substances. For instance, of the approximately 1000 sets of data collected and analyzed by Sorensen and Arlt (1979), 75% are Type I and 20% are Type II. The remaining small percentage of systems exhibit a considerable variety of behaviors, a few of which appear in Figure 14.4. As some of these examples show, the effect of temperature on phase behavior of liquids often is very pronounced. 

Equation (5.18) tells us, at last, how to obtain p(pc,y,z). We need merely to construct a Fourier series from the structure factors. The structure factors describe diffracted rays that produce the measured reflections. A full description of a diffracted ray, like any description of a wave, must include three parameters amplitude, frequency, and phase. In discussing data collection, however, I mentioned only two measurements the indices of each reflection and its intensity. Looking again at Eq. (5.18), you see that the indices of a reflection play the role of the three frequencies in one Fourier term. The only measurable variable remaining in the equation is Fhkf Does the measured intensity of a reflection, the only measurement we can make in addition to the indices, completely define Fhkp Unfortunately, the answer is "no."... 

Having obtained a suitable derivative, the crystallographer faces data collection again. Because derivatives must be isomorphous with native crystals, the strategy is the same as that for collecting native data. You can see that the phase problem effectively multiplies the magnitude of the crystallographic project by the number of derivative data sets needed. As I will show, at least two, and often more, derivatives are required. 

The AHS, a collaborative research effort between the National Cancer Institute of the National Institutes of Health and EPA, is a prospective occupational study of 89,658 pesticide appliers and their spouses in Iowa and North Carolina assembled between 1993 and 1997 to evaluate risk factors for disease in rural farm populations (Blair et al. 2005). It is being conducted in three phases—phase I (1993-1997), phase II (1999-2003), and phase III (2005)—and includes only limited biomonitoring. Data are gathered with questionnaires to determine pesticide use and exposures, work practices, and other relevant exposures from buccal cell collection with dietary surveys and with interviews to determine updated pesticide exposures (Agricultural Health Study 2005). 

---