The Prescription Drug User Fee Act (PDUFA) is due to be reauthorized by the end of September this year. Along with the usual increases in fees, the latest version of the act (PDUFA V) includes some new initiatives. One of these is a program for enhanced review transparency and communication which will apply to all New Molecular Entity (NME) New Drug Applications (NDAs) and original Biologics License Applications (BLAs). This includes applications that are submitted following a Refuse-To-File action.
Included in the program are specific meetings between the Agency and the Sponsor (e.g. pre-submission meeting, late-cycle meeting) as well as other communications. One very important change to this program affects the overall review timeline for a submission. For NME NDA and original BLA submissions that are filed by FDA under the program, the PDUFA review clock will begin at the conclusion of the 60 calendar day filing review period that begins on the date of FDA receipt of the original submission. What this means is that sponsors who submit NME NDAs and original BLAs on or after October 1, 2012 will have a two month longer review period than those submitted prior to that date. For sponsors looking at a filing date near the September 30th deadline, this new program provides additional incentive to file before the new timeline takes effect.
Posted by Marla Scarola, Senior Consultant. For more information, please contact Marla at email@example.com.
Another of the widely held misconceptions about GRAS status is that it means that an ingredient is considered safe by the FDA, irrespective of how much is used and for what purpose. This interpretation is, however, quite different than what is stated in Section 201(s) of the Federal Food Drug & Cosmetic Act wherein GRAS refers to a conclusion regarding safety of a food substance “under the intended conditions of use.” Thus, GRAS is a conditional designation rather than a broad acknowledgment of safety. The intended conditions of use under which a substance is considered to be GRAS are noted in the CFR in Sections 182, 184, and 186. These sections pertain to direct addition to foods in order to achieve a physical, nutritional, or other technical effect in the food (Sections 182 and 184 of the CFR) or indirect incorporation in foods as result of use of the substance in food manufacturing, processing, or packaging (Sections 182 and 186 of the CFR). In some cases, GRAS substances are broadly characterized by the type of intended effect and in other cases very specific limits on the type of use considered to be GRAS are specified. Irrespective of whether the use description is broad or narrow, it is a stipulation of the GRAS designation that when a substance is directly added to food for an intended purpose, the amount used is not greater than what is needed to achieve the intended effect. In most cases the CFR does not specify what use levels are acceptable for a specific use, leaving the discretion about how much to use to the food manufacturers. However, many substances are determined to be GRAS only when used at levels below a certain maximum. If a manufacturer uses a GRAS-designated substance for purposes other than those described in the CFR or in amounts much greater than what is reasonably needed to achieve the specified effect described in the CFR, the substance may no longer be considered GRAS. Even substances designated as GRAS for multiple purposes were given GRAS status taking into consideration the total potential exposures based on known uses in foods at the time that the designation was made. New uses or amounts of use that deviate significantly from those envisioned at the time that the GRAS determination was made may not necessarily be considered GRAS; even for those substances with a multipurpose GRAS designation. Limitations on exposure are often found for GRAS substances that have the potential to migrate into foods during manufacturing, processing, or packaging. Consistent with the concept of not using more of a GRAS substance than is needed for an intended effect when that substance is intentionally added to foods, the FDA stipulates that the amounts of GRAS substances that indirectly migrate into foods should be minimized. Thus, even though maximum use levels are not stipulated in most cases in Sections 182, 184, and 186 of the CFR, potential exposure is a principal determinant of whether a substance is considered to be GRAS. Potential exposure should also be considered when citing a substance’s GRAS status as evidence of safety of a substance for a non-food use. Any conclusion regarding the safety of a substance that relies on GRAS status should consider the route and extent of exposure for the non-food to assure that it does not deviate in significant ways from the GRAS food use cited in the CFR.
Posted by Carrie Rabe, Senior Consultant. For more information, please contact Carrie at firstname.lastname@example.org.
In a recent FDA Drug Safety Communication, the Agency announced that the Celexa (citalopram hydrobromide) label now has revised dosing recommendations based on evaluations of post-marketing reports related to QTc prolongation and thorough QTC studies. The label reasonably stresses the importance of routine ECG monitoring and provides an upper level of prolongation that would necessitate discontinuation of the drug due to cardiac risk of arrhythmia.
In our opinion, somewhat lost in all the good intention is the notion that measurement of QTc, and identification of prolongation that rises to the level of requiring action, is not all that simple. Big pharma, in support of clinical trials, may send out ECGs to accredited cardiovascular consultants and specialist CROs for evaluation, programs that have high level training and quality control programs; this is not always the case for a typical general practitioner. Numerous known confounding variables (Barbey JT. 2012. Clin Pharm Therapeut 91:580) and technical issues related to measurement of the QTc can introduce considerable uncertainty in the final result.
Drug treatment decisions, based on label-designated blood test abnormalities, are generally supported by the high quality of accredited diagnostics laboratories. Similarly, required genomics screening for selection of candidate patients, now a common component of many approved drug labels, by default takes place in qualified settings outside the doctor’s office. We wonder if FDA’s appropriate focus on drug risks of arrhythmia may not be fully addressing the problems inherent in the way in which patients at risk are now being identified. Specifically, FDA may not fully be taking into account the extent to which the benefit of a medically appropriate decision may be counterbalanced by erroneous data driving that decision.
Posted by Bob Roth, Vice President and Worldwide Medical Director. For more information, please contact Bob at email@example.com.