Inspectional Delays - A Continuing Problem for Timely Generic Drug Approvals
Written by Bob Pollock and Joan Janulis • January 21, 2013
According to the December 2012 Office of Generic Drugs Statistical Report, OGD received 1059 ANDAs during the 2012 calendar year. This represents a record number of ANDA receipts in a single year since the passage of Hatch-Waxman in 1984. Each ANDA typically has at least two sites that may need inspection, i.e., the primary manufacturing site and the manufacturing site of the Active Pharmaceutical Ingredient (API) supplier. But many applications have multiple API suppliers, additional packaging sites, alternate manufacturing sites or outside testing labs that may also need inspection. Thus, just the ANDAs submitted in 2012 likely have generated the need for review and or inspection of at least 3000-3500 sites. In our recent experience, many firms are experiencing significant delays in approval of their generic drug application that are waiting scheduling and completion of the required inspections.
OGD officials acknowledge that there is a significant backlog in the number of inspections. In addition, we have recently learned that there are over 100 ANDAs that have successfully completed review and are otherwise ready for approval but for the completion of a satisfactory compliance inspection. OGD estimates that some of these inspections may take up to 9 months or more for completion. Another problem for firms with ANDAs that contain multiple sites is that with a median ANDA approval time of about 34 months, waiting for a delayed inspection for one site may mean that by the time that inspection is completed, reviewed, and evaluated by headquarters, one of the other sites listed in the application may go “out of date” requiring scheduling inspection of that site, further delaying approval of the ANDA (something that we have seen with an increased frequency over the last few years).
The Office of Compliance and OGD have established a prioritization scheme for inspections that are required to support ANDA's and ANDA supplements. A general description of this prioritization scheme follows:
- Drug Shortage situations are given the highest priority for inspection. There are presently a number of current drug shortage situations whose resolutions are contingent upon approval of pending applications or supplements and these will be given highest priority.
- The next priority tier involves applications for drugs for which there is presently no generic available. Included in this group are ANDAs containing a Paragraph IV (PIV) certification, as well as ANDAs which do not. Among this second tier, OGD tries to give priority to those ANDAs that contain a PIV certification for which an potential 180-day exclusivity entitlement exists and may be in danger of forfeiture of the exclusivity due to a potential failure to obtain tentative approval within the statutory time frame (which was extended from 30 months to 40 months under GDUFA).
- The last priority tier involves applications for products that have been impacted by unforeseen circumstances that have caused a firm to stop production (i.e., acts of nature that have caused damage or obliteration of a facility).
For a pending ANDA which does fit within the prioritization tiers defined above, a firm should not expect any action to be taken in regard to the scheduling of an inspection until all other elements of the ANDA have been reviewed and have been deemed satisfactory. So if your application is not in one of these priority categories, there is a possibility (or should we say probability) that your application’s approval with be even further delayed.
OGD has stated in its experience that, once an inspection is completed, it typically takes 90 days for the result of the inspection to "get into the system", such that the status of the inspection can be verified by OGD in support of an approval action. There are presently over 200 inspection reports (for completed inspections) waiting in queue that need to be reviewed, and acted on (in other words,. there is a substantial administrative backlog, separate from the inspection queue itself.) However, our experience does not jive with this schedule. We have seen in many cases that once the inspection is completed, it may take 90 days or longer for the EIR to be written by the field and passed through the clearance channels to headquarters for review. However, we have also seen examples where the time for the EIR to be written and cleared by the field has been upwards of 120 days, and then, once the EIR is received by the Office of Compliance, it has taken (in some instances) 9 months to be evaluated and have the computer system updated to indicate the facility is acceptable.
Inspections required to be performed by the Division of Scientific Investigations are an even bigger problem, as the backlog is particularly significant for these types of inspections. For these types of inspections, it could take up to 2 years from the date that OGD requested the inspection for the inspection to be performed. With that said, if the inspection qualifies for prioritization (within the tiers defined above) and if FDA has scheduled another inspection in the same geographic region, the inspection might occur within a shorter time frame. OGD, however, has no control over this, since all of the scheduling is done within the Office of Compliance.
With delays of the nature outlined above, the Field and Headquarters need to do a better job of communicating approval and withholding recommendations; clearly there needs to be better communication with OGD, as well as a better degree of transparency relative to the status of the inspection review with the stakeholders. For those of you that have tried to gain information relative to the status of an inspection you know that getting any timely and useful information is almost impossible whether it be from OGD or the Office of Compliance. It is our understanding that even OGD has trouble obtaining status information!
We are now 4 months since the implementation of the Generic Drug User Fee Amendments and we recognize that it will take time to hire and train inspectors. But with the number of ANDAs submitted being at their highest point in history and the current problems firms are experiencing in getting their inspections cleared so their applications can be approved, perhaps it is time for FDA to reexamine what they mean by “risk-based” inspections and provide some relief until they can adequately staff up the program and meet the global inspectional demand that they now face.