Development Milestones

Seen from the perspective of recent events, the clinical development of protease inhibitors follows rather conventional programs for drug development. The most remarkable characteristic of the clinical development of HIV-1 protease inhibitors is their rapid clinical evaluation, regulatory approval, and subsequent incorporation into standard treatment regimens. Undoubtedly, the pressure to develop new and active compounds to treat persons with HTV infection contributed to the urgency of drug development. This section will review the clinical milestones for HIV-1 protease inhibitors and discuss some of the near future clinical directions for these compounds. Peer-reviewed, published manuscripts are the basis for this review. Data presented at meetings and published in abstracts were not used. 

HIV-1 protease inhibitors were initially tested to determine dosing and interval administration (Markowitz et al., 1995 Danner et al, 1995). These studies provided key insights into the pharmacologic properties for this class of compounds. A direct result of these studies was the early recognition of resistance (since nonfully suppressive doses and intervals were initially tested) to HIV-1 protease inhibitors. The rapid clinical assessment of these medications began with an evaluation of the addition of HIV-1 protease inhibitors for patients with advanced immune destruction as defined by less than 100 CD4 cells. This was followed by HIV-1 protease inhibitor evaluation for patients with modest immune suppression, defined as less than 200 CD4 cells, and then for patients with minimal immune destruction (200-500 CD4 cells), and even exploratory studies for patients with no immune destruction (more than 500 CD4 cells). 

The findings of this study were consistent with the surrogate marker studies of the protease inhibitor saquinavir (Markowitz et al., 1995 Danner et al., 1995 Collier et al., 1996) and subsequent studies of indinavir (Hammer et al., 1997 Hirsch et al, 1999 Gulick et al., 1997). This study was different from many others that will be cited, and the clinical situation requires some explanation. First, this study did not attempt to compare strategies of multiple ART combinations. Rather, it demonstrated the value of adding a protease inhibitor various ART regimens. In addition to the study design, the patient population was critical for the conclusions of the study. Patients with the most profound immune 

The one nagging question that remained from this study was whether the optimal use of protease inhibitors should be restricted to those patients with advanced disease. The lack of a clinical effect in the substudy of patients with 50 to 200 CD4 cells did not spark a controversy in 

Issues of Ongoing Concern for the Clinical Use of HIV-1 Protease Inhibitors 

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Under the VATIP, each participating mill develops Milestones Plans for each fiber line that it enrolls in the program. Permit writers will use the Milestones Plan to incorporate enforceable... 

This chapter aims at reviewing the main development milestones of the SFA and look back at some of the most important experimental achievements in studying monolayers at interfaces with the SFA. It is structured as follows. In Section 2 the function of the basic SFA is described. This has been excellently done by several authors before [6-9] however, we feel that it is a necessary part of the review since it helps to appreciate the development of the SFA that is reviewed in Section 3. Further sections are devoted to an overview of experimental achievements obtained using the SFA. A particular emphasis is put on monolayer studies of surfactants and lipids (Chapter 4) where intriguing behaviour of hydrophobic monolayers and forces between hydrophilic monolayes, including specific interactions, are discussed. In Chapter 5 forces generated by... 

Preparing a detailed drug development plan, including designation of key points or development milestones, generating a timeline for completion, and defining the critical path... 

Milestone charts consist of a tabulation of major drug development milestones. Whereas the Go/No-Go decisions discussed previously are very project specific development milestones are much more generic and can usually be applied to a wide variety of projects. Typical milestones for pharmaceutical development are shown in Table 27.10. 

Fig. 6 The relationship of key groups, activities, and development milestones t5rpically experienced during the transfer of formulation and process technology from the pilot plant to the production facility.

As every NCE brought forward into development is unique, the exact role that reference standards take for a specific drug candidate will vary but is generally keyed to drug development milestones. At any phase of drug development, the reference standard should be assessed versus its... 

The final development milestones for a new pharmaceutical product are the submission and approval of the NDA and product launch. During this stage. 

Internal summary reports and formal proposals for management are often assembled in preparation for development milestones (e.g., candidate selection and full development decision). Research reports for critical data are written for products as they progress through development. However, reports for failing studies or discontinued programs are often not prepared and these can be equally useful since history tends to repeat itself. Because of the time and resources required to prepare such reports, a conscious decision should be made if the value added warrants the effort. 

Figure 11 The development stage in the know-how vs. applied effort plane. The principal process development milestones are shown.

Unfortunately, these documents are not highly consistent. For example, both organizations describe different FMEA methods (or several FMEA methods), which are considered to be a basis of ISO 26262. In addition, these organizations also developed milestones or maturity level concepts, which were primarily used for the synchronization of automotive manufacturers and supplier (Fig. 2.5). 

Internal summary reports and formal proposals for management are often assembled in preparation for development milestones (e.g., candidate selection, full development decision). 

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