Approving data

The next step was to augment and expand the model to be able to predict the dose response for the comparator. Comparator data, from SBA (summary basis for approval data submitted to the FDA), yielded one model that predicted both candidate and comparator performance. The model accounted for age, disease baseline, and trial differences. Differences based on sex, weight, and other covariates were estimated to be negligible. The addition of the comparator data improved the predictive ability of the model for both drugs (Fig. 22.3). 

The part of the international classification of diseases (ICD 10) concerning psychiatric disorders identifies over 500 different diagnoses or classification terms, divided into 10 main chapters and 100 categories, including classification and diagnostic criteria. These ten main chapters will not all be covered here, because clinical trials and approval data usually do not allow such discrimination. Additionally, some of these categories, such as dementia (code FOO-09) can be covered more appropriately under neurological diseases rather than in a chapter on psychiatric diseases. 

Figure 5. Duration in months of IND (mean time from IND filing to NDA submission), NDA (mean time from NDA submission to NDA approval), and Total (mean time from IND filing to NDA approval) stages for approved NDAs by year of NDA approval. Data from U.S. and foreign companies are combined and the figures at the bottom indicate the number of NDAs approved each year for U.S. and foreign companies (13).

Given the typical 12-15 years required to discover, develop, and test a new drug (Fig. 1.2), the NDA submission and approval data will in part represent R D... 

Data sheets and prescribing information for most medicines available in New Zealand are currently published in the New Ethicals Compendium (See Appendix 5). Full text electronic copies of approved data sheets are being published on Medsafe s web site on an ongoing basis. 

Prior to use in a clinical laboratory, this kind of test must undergo regulatory approval. Data are required from several hospital labs, from numerous control and sample organisms, as well as a range of antibiotics. 

For a number of materials it is vital that propaty values are provided which have a validated accuracy and are identified as standard reference data (SRD), preferably with international approval and recognition. The prq>aration of such internationally approved data standards is a timeconsuming and delicate activity that requires a critical evaluation of all the available measurements with a detailed assessment of the accuracy of each individual datum reported. For these reasons, only results obtained in instruments characterized by high quality and a complete working equation based upon a sound theory can be employed for the establishment of standard reference data. Whenever possible the results of measurements made with different experimental techniques should be included. 

It is suggested that, to expedite processing of inquiries, a specific individual might in some cases be designated as the member responsible for liaison with SGDE. This member would be responsible for the transmission of approved data to SGDE. 

There are no official specifications for obtaining a minimum level of engine cleanliness from a fuel. However, all additives in France are subject to approval by the Direction des Carburants (DHYCA), with the objective of having data that prove, first of all, the product to be harmless, and second, the product s effectiveness. Likewise, the automotive manufacturers, in establishing their specifications, set the minimum performance to be obtained by the fuel with regard to engine cleanliness. 

At the outset, we were faced with the difficult decision whether to use the Angstrom unit or the nanometre for the dimensions of molecules. After careful consideration, we have come down firmly in favour of the Angstrom and we believe that this decision will meet with the approval of the majority of our readers. When quoting graphs and tables of data from the literature, we have retained the original units (kcal, Torr, C, tonin, etc.) in the belief that it is more reasonable to state the data in the form used by the original author—except where comparisons are being made between results presented in different units. 

ASTM committees must be balanced in that the number of voting producers must not be greater than the number of voting nonproducers. Eor petroleum products, nonproducers are regulators, consumers, and equipment manufacturers. Committee chairs must be nonproducers. Although standards must be approved by a majority, aH negative votes must be carefully considered and a response made. In practice, because aH issues are fully discussed and the discussions are based on hard data, very few negative votes are cast when standards are submitted for final approval. 

Names are necessary to report factually on available data however, the U.S. Department of Agriculture neither guarantees nor warrants the standard of the product, and the use of the name by the U.S. Department of Agriculture imphes no approval of the product to the exclusion of others that may also be suitable. 

Another reactor that was approved for development was a land-based prototype submarine propulsion reactor. Westinghouse Electric Corp. designed this pressurized water reactor, using data collected by Argonne. Built at NRTS, the reactor used enriched uranium, the metal fuel in the form of plates. A similar reactor was installed in the submarine l autilus. 

Einahy, all data, including the results of the clinical investigation, ate collected in a New Dmg Apphcation (NDA) and sent to the EDA. Once approved, the new dmg goes into production. After manufacturing begins, the new dmg products must be monitored in clinical use in the marketplace for reports of untoward reactions. This amounts to post-approval surveillance known as Phase IV. All such reports must be submitted to the EDA in a timely manner. 

The Federal Food, Dmg and Cosmetic (FDAC) Act defines dmgs as "...articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man..." and "articles (other than food) intended to affect the stmcture of any function of the body of man." In the United States and elsewhere, the introduction of a new dmg is subject to a sequence of weU-defined stages of development and approval (4). Each stage involves either scientific testing or submission and preparation of data and analysis review (Fig. 2). 

New dmg apphcation (NDA) is the process through which the U.S. Food and Dmg Administration (FDA) authorizes the marketing of a new dmg. In the NDA, the data are intended to demonstrate the safety and efficacy of the dmg in its intended apphcation. After approval, the dmg becomes available to the pubhc. Subsequendy, dosage amounts and forms may be modified according to experience, new indications may be added, and contraindications may be noted. All of the changes requite regulatory approval. A dmg in human use is subject to constant surveillance. 

Various medical devices based on Terathane have been approved by the U.S. FDA, including those used within the body. Formulators are cautioned, however, that FDA approval is not given genericaHy for these devices it must be appHed for separately by each manufacturer for each device. Additional data on safety of PTMEG may be found in the material safety and data sheets provided by the manufacturers. 

Vapor Toxicity. Laboratory exposure data indicate that vapor inhalation of alkan olamines presents low hazards at ordinary temperatures (generally, alkan olamines have low vapor pressures). Heated material may cause generation of sufficient vapors to cause adverse effects, including eye and nose irritation. If inhalation exposure is likely, approved respirators are suggested. Monoethan olamine and diethanolamine have OSHA TLVs of 3 ppm. 

Two statutory provisions of Tide 21 govern the introduction of new medical devices into the marketplace. Section 515 estabHshes a premarket approval appHcation (PMA) containing data and information demonstrating the safety and effectiveness of a device. Section 510(k) estabHshes a premarket notification process. Under this process, a manufacturer is required to file with the EDA, 90 days before a new device is to be marketed, a premarket notification demonstrating that the device in question is substantially equivalent to a device that was on the market before enactment of the 1976 Amendment and therefore marketable without formal EDA approval. 

Sample test data are either manually entered into the system or captured from analytical instmments coimected to the LIMS. The system performs any necessary calculations and compares the result to the appropriate specification stored in the database. If the comparison indicates the material is in conformance, the system can automatically provide an approval. Otherwise, the LIMS can alert lab supervision to the nonconforming sample analysis. 

Another example is the use of Tc-sestamibi, approved for use in the evaluation of coronary artery disease and myocardial infarction, in patients with breast cancer. Use in breast cancer is under investigation by a number of physicians. The data are not yet sufficient to determine the efficacy of this agent in this setting. Its safety, of course, has already been demonstrated as part of its initial evaluation for heart disease. 

In order to be approved, an NDA must include data which demonstrate that the dmg is both safe and effective. Each NDA is assigned to a division within ODER for consideration and adnunistrative control, and then assigned to the appropriate therapeutic group within the division for review. The primary team of reviewers typically consists of a physician, a pharmacologist or toxicologist, and a chemist. 

Other offices within ODER may become involved in the review process via consults. Eor example, the Office of Epidemiology and Biostatistics analyzes statistical data, the Office of Research Resources provides bioavailabiHty reviews, and the Office of Compliance determines from the results of inspections whether the firms meet EDA s Current Good Manufacturing Practice (cGMP) regulations. Advisory committees composed of independent experts are often asked to meet and further analyze the data. Often they also advise as to what additional data and information may be needed. After PDA s review is completed, PDA issues either a Summary Basis of Approval (SBA) for the dmg or a recommendation against approval. If approved, PDA releases the SBA and a summary of the safety and effectiveness data to the general pubHc. 

---