New molecular entities : approval

The FDA Modernization Act of 1997 contains a requirement for public disclosure and congressional reporting by October 2001 of Phase IV studies. FDA intends to meet the public disclosure requirement by posting Phase IV study commitments, the projected end of the study, and the current status of the study on their web site [102]. Sponsors whose new drug was approved with a Phase IV study requirement must submit an initial status report to FDA within one year of approval. According to data compiled by Public Citizen s Health Research Group [103], not one of the Phase IV study commitments for 107 new molecular entities approved between January 1995 and December 1999 had been completed as of December 1999. 

Figure 1 The new molecular entity approved by FDA annually in the last 28 years.

Ellison and Mullin (1997) estimated that the threat of Clinton health care reform reduced the market value of pharmaceutical firms by about 44% during the period from September 1992 to October 1993. Lichtenberg (2004a) estimated that the elasticity of R D investment with respect to market value is 0.225, that is, that a 10% decline in market value is associated with a 2.25% decline in R D investment. Combining these two estimates implies that the threat of Clinton health care reform reduced R D investment by about 9.9% (0.225 0.44). During the period 1986-2000, the average annual number of new molecular entities approved by the FDA was 28.1. Hence, the temporary reduction in R D investment attributable to the threat of Clinton health care reform may, with a lag of 12-15 years, temporarily reduce the number of new molecular entities approved by about 2.8 (9.9% 28.1) per year. 

Percentage of cohort withdrawn —A— Number of new molecular entities approved in calendar years... 

Figure 4-6-Year of First Entry to the Market for New Molecular Entities Approved in the United States, 1981-83...

Even with these extensions, however, actual review time of some drugs exceeds the statutory allowances (467). Data from the FDA do indicate that the 23 NDAs for new molecular entities approved in 1990 took an average of 30 months to approve with a median approval time of 26 months however, these numbers do not indicate how many of the drugs had amendments filed to the original NDA, thus extending the statutory 6-month approval time. Data available from the FDA and other sources do not indicate the exact percentage of NDAs that violate statutory allowances. 

The rapid physical maturation that occurs between birth and adulthood is well known. Logically, it would be anticipated that these changes would result in altered responses to xenobiotics. Within the first 5 years of life 95% of children have been prescribed medications. Yet in 1977 only one third of the new molecular entities that have potential usefulness in pediatric patients had pediatric labeling at the time of approval. 

To gain FDA approval or license for marketing, a pharmaceutical product must be shown to be safe and effective for its proposed or intended use. The drug company or sponsor must also provide evidence to show that the processes and control procedures used for synthesis, manufacture, and packaging are independently validated to ensure that the pharmaceutical product meets established standards of quality. The overall effort from the inception of a new molecular entity and the establishment of analytical, scale-up, and quality control procedures, to the collection of safety and efficacy data for consideration by the FDA as part of an NDA or BLA, is called the drug development process. 

Figure 4.17. Progression of a new molecular entity through preclinical and clinical evaluation for safety and efficacy. Preclinical and clinical study results are reviewed by FDA through several pathways, including traditional and nontraditional pathways. A majority of submitted new drug applications are approved for human use. Additional details on nontraditional clinical pathways are presented in Box 4.7. (Figure adapted from an FDA report, 1999)...

The development of a new pharmaceutical product continues to be costly and time consuming. In 1997 the FDA approved 38 new molecular entities for marketing, and the pharmaceutical industry spent about 35 billion dollars in research and development. This amounts to about 1 billion for each new drug brought to market that year. A more conservative estimate, based only... 

New Molecular Entity — An active pharmaceutical substance not previously contained in any drug product registered with the national or regional authority concerned. A new salt, ester, or noncovalent bond derivative of an approved drug substance is considered a new molecular entity for the purpose of stability testing under this guidance. 

Cross, J., H. Lee, A. Westelinck, J. Nelson, C. Grudzinskas, and C. Peck. 2002. Postmarketing Drug Dosage Changes of 499 FDA-approved New Molecular Entities, 1980-1999. Pharmacoepidemiology and Drug Safety 11 439-446. 

An NDA can be submitted for a previously unapproved new molecular entity, or for a new salt, new ester, prodrug, or other noncovalent derivative of a previously approved new molecular entity, formulated as a modihed-release drug product. The first modified-release drug product for a previously approved immediate-release drug product should be submitted as an NDA. Subsequent modified-release products that are pharmaceutically equivalent and bioequivalent to the listed drug product should be submitted as ANDAs. BA requirements for the NDA of an extended-release product are listed in 320.25(f). The purpose of an in vivo BA study for which a controlled-release claim is made is to determine if all of the following conditions are met. 

New chemical entity (NCE)/new molecular entity (NME) A 505(b)(2) application may be submitted for an NCE when some part of the data necessary for approval is derived from studies not conducted by or for the applicant and to which the applicant has not obtained a right of reference. For an NCE, this data is likely to be derived from published studies, rather than the FDA s previous finding of safety and effectiveness of a drug. If the applicant had a right of reference to all of the information necessary for approval, even if the applicant had not conducted the studies, the application would be a considered a 505(b)(1) application. 

New Drug Application (NDA) An application requesting FDA approval, after completion of the all-important Phase III Clinical Trials, to market a new drug for human use in the U S. The drug may contain chemical compounds that were previously approved by the FDA as distinct molecular entities suitable for use in drug trials. See New Molecular Entity (NME). ... 

Since the implementation of the PDUFA, the review times for NDAs for new molecular entities have dropped dramatically. In 1993, the median total approval time was 23 months, of which 21 months were used by the FDA, and 25 new molecular entities were approved. By 1996, the median time had dropped to 14.3 months for total time, with a median of 12 months for FDA review, and 53 new entities were approved. Similar reductions in review time and increases in numbers of NDAs reviewed have also occurred for supplements for manufacturing changes and for new clinical indications (16). 

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