Reference drug exclusivity

In order to encourage and reward the originators of new drugs the regulations contain restrictions to prevent the entry of generic copies onto the market for set time periods. 

Maximum patent extension 15 from first marketing approval 14 from marketing approval 

New therapeutic indication +1 (human) to +3 (veterinary) 3 from approval of indication 

In the US, a manufacturer may not submit an application that relies on data from an approved submission for a period of 5 years after the reference product was authorised, unless the owner of the original data has granted a right of reference. The FDA may not approve an application that relies on data submitted as a supplement (e.g. new therapeutic indication) to an authorised drug for a period of 3 years after approval ofthe supplement. These exclusivity periods will be extended by 6 months if the reference submissions contain paediatric data. The FDA will also not 

New pharmaceutical form approved 6 years after approval of the original product. 

---

Reference pricing was not introduced in Spain until December 2000. The fact that it is applied exclusively to bio-equivalent products leads, in the opinion of the authors, to the assumption that its effect on expenditure is limited, as a major market share is acquired by recently introduced drugs. The level at which the reference price is fixed is an important factor. For non-patented products, price competition should push the price towards the marginal cost, and therefore a reference price that is clearly higher than the cheapest generic could actually become a barrier to price competition in this case. 

There are two major categories of desensitization of responses mediated by G protein coupled receptors. Homologous desensitization refers to loss of responsiveness exclusively of the receptors that have been exposed to repeated or sustained activation by a drug. Heterologous desensitization refers to loss of responsiveness of some cell surface receptors that have not been directly activated by the drug in question. 

Before a drug may be tested on humans, it must first be tested on animals. Tests on humans are called clinical trials, and animal trials are often referred to as preclinical trials. Preclinical trials differ from the animal tests mentioned earlier in this chapter. The previously discussed animal tests help the drug discovery team determine and optimize the pharmacodynamic and pharmacokinetic behavior of a hit or lead. Preclinical trials, in contrast, are standardized, industrywide tests. The preclinical tests have technical names such as Segment II Reproductive Study in Rabbits or 6-Month Toxicity Study in Rats. The specific names suggest the exact nature of each study. Each trial seeks to answer predefined safety questions concerning a drug candidate. Preclinical trials do not address the therapeutic effectiveness of the drug candidate in any way. Preclinical trials examine exclusively safety issues. 

The 505(b)2 application raises some patent issues beyond the scope of this book but that need to be considered if the option is under review. Generally, the 505(b)2 provides a patent exclusivity if (and only if) the applicant conducts one or more critical studies in support of the application. If all support studies are referenced from published literature of Agency findings, the patent exclusivity will not apply. While the definition of critical studies is subject to some interpretation, in this context, it most commonly refers to studies that demonstrate the link between the applicant drug and other formulations used in outside studies or previously approved by the Agency. These studies fall under the headings of Bioequivalence (BE) or Bioavail-... 

The third category of drugs are phytotherapeutical preparations 80% of the world population use exclusively plants for the treatment of illnesses [11]. Chromatography is relied on to guarantee preparations contain therapeutically effective doses of active drug and maintain constant batch composition. A quantitative determination of active principles is performed when possible, using pure reference standards. In many phytotherapeutic preparations, the active constituents are not known, so marker substances or typical constituents of the extract are used for the quantitative determination [11]. The Applications chapter of this book (Chapter 8) contains numerous references to the use of chromatographic methods in the control of plant extracts. 

The OATP-C, also referred to as liver specific transporter 1 (LST-1) or OATP2, was cloned by number of groups (8,24,25) and was shown to be exclusively expressed in the basolateral membrane of the liver (25). As with OATP-A, OATP-C has broad substrate specificity and transports bile acids (13), sulfate and glucuronide conjugates (25), thyroid hormones (13), and peptides (16), and drugs such as pravastatin (24), methotrexate (26), and rifampin (27). Given its liver-specific expression and broad substrate... 

One of the critical factors in excipient selection and concentration is the effect on preferential hydration of the biopharmaceutical product [53, 54], Preferential hydration refers to the hydration layers on the outer surface of the protein and can be utilized to thermodynamically explain both stability enhancement and denatur-ation. Typical excipients used in protein formulations include albumin, amino acids, carbohydrates, chelating and reducing agents, cyclodextrins, polyhydric alcohols, polyethylene glycol, salts, and surfactants. Several of these excipients increase the preferential hydration of the protein and thus enhance its stability. Cosolvents need to be added in a concentration that will ensure their exclusion from the protein surface and enhance stability [54], A more comprehensive review of excipients utilized for biopharmaceutical drug products is available elsewhere [48],... 

---