Published February 5th, 2010
in 505(b)(2) Issues, How to: and Uncategorized.
As we have noted in this blog on several occasions, under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all new drug applications for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in all relevant pediatric subpopulations unless this requirement in waived, deferred, or inapplicable. This includes products approved via the 505(b)(2) pathway. Given that a drug developer may want to obtain approval for adults first, it is common to request that the requirement for pediatric studies be deferred until after approval of the new drug application.
The European Medicines Agency (EMEA) implemented a new “Pediatric Regulation” in January of 2007. This regulation requires an initial submission of a pediatric investigation plan (PIP) by pharmaceutical companies upon completion of adult PK studies. A PIP is required for acceptance of any marketing authorization application. Unless a waiver or deferral has been granted, all products that have not been authorized in the European Union before 16 January 2007 must include the results of pediatric studies conducted based on a PIP.
The difference in the US and European approaches has the potential to put discussions with EU regulatory agencies about pediatric clinical studies ahead of discussion with the US. For companies pursuing simultaneous drug development in the US and EU, the submission of a PIP is likely to occur before discussions would ordinarily be held with the FDA. The FDA is aware of this issue and recommends that Sponsors begin discussions about an acceptable pediatric program with the FDA when they begin discussions with the EMEA. Even if a deferral is being requested for US pediatric studies, it is wise to seek the FDA’s input before finalizing a PIP. Communication is the key to make certain that any pediatric studies meet both agencies’ requirements.
Published January 29th, 2010
in Uncategorized.
Another example of the importance CMC was reported in the news today. Warner Chilcott plc received a complete response letter from the FDA. Their “low dose” oral contraceptive NDA was the file in question. The FDA inspection of the third-party drug substance manufacturing facility and control testing laboratory used to support the application reported outstanding deficiencies which require satisfactory resolution before approval can be allowed.
Everyone in the supply chain is affected when a new drug product launch is held up. These problems can often be avoided with a proactive approach to working with third-party suppliers. The sponsor of the drug product in question must be present periodically and to inspect the sites providing critical components for their product. You should prepare a contract with the third-party that requires communication and draft a quality agreement that meets your internal standards. Confirm that it is being followed.
Neglecting these third-party sites can result in lost revenue every day the new drug product is not on the market.
Published January 27th, 2010
in Uncategorized.
Although morphine sulfate oral solution has been used for many years in pain management, it had never been approved by the FDA. As part of their ongoing unapproved drugs initiative, the FDA announced on March 30, 2009 that it was taking enforcement action against Roxane and 6 other firms selling morphine sulfate oral solution. The firms were issued warning letters giving them 90 days to correct the violation (that is, to obtain approval for unapproved product). However, on April 30, 2009, the drug companies received something of a reprieve – in the form of an FDA announcement that enforcement discretion was being extended until 180 days after any firm received approval for a morphine sulfate solution product. A loud response from the pain management community had convinced the FDA that removing these drugs from the market in July would impose unacceptable hardships on patients and caregivers. The drug companies were still under strict expectations to submit approvable applications for their products, including sufficient efficacy and safety data to meet current FDA standards. In the case of a Schedule II narcotic product like morphine, the applications particularly needed sufficient information on how to safely prescribe and use the drug, including a specific program to address the known risks of morphine misuse, abuse, and overdose.
Yesterday, the FDA announced that Roxane was the first company to receive approval of its morphine sulfate oral solution. The announcement also states that FDA has worked with Roxane to ensure that there will be enough of the approved product for patients, and that prescribers and patient organizations will be made aware that an approved version is available. Cooperation with FDA and efficiency in development of an NDA can lead to first approval for these unapproved marketed drugs. Roxane is in a great position to market its drug while its foot-dragging competitors can only watch.
The approval of the morphine oral solution paves the way for its use as an RLD for other dosage forms containing morphine.
Published January 26th, 2010
in 505(b)(2) Process and How to:.
Camargo is fully prepared to create, submit and manage the review of an NDA, either 505(b)(1) or 505(b)(2). Generally, we submit the NDA electronically, so we’re submitting an eCTD.
1. An individualized secure shared website for Camargo and the Client’s project is created for document control. A folder structure is set up according to the Client’s needs and the project management plan. The Client’s team has access for document upload, review and approval.
2. For an NDA, the individual documents are created (either by Camargo or the Client, per agreement) as designated by FDA’s Guidance on CTD Granularity. Ancillary documents, such as Batch Manufacturing records or Study Reports are uploaded to the site as well. An agreed upon series of reviews and revisions takes place. Document integrity is maintained by the check out requirement for revision (See, small green arrows in section 2.7.3 and 2.7.4 in the screenshot below) as well as a specific revisioning function, which preserves all versions and indicates when and by whom changes are made.
3. Documents which are complete and final are organized according to the appropriate Module for upload into the eCTD software.
4. Once files and required support documents are uploaded to the eCTD manager, hyperlinking and bookmarking can take place. Once complete, the eCTD is validated, and then can be published, at which point the XML backbone is installed. The NDA is ready for submission.
After submission, amendments are made using the same process. The eCTD manager maintains all of the amended changes.
In addition to NDA’s, Camargo uses the exact same process for ANDA submissions.
Published January 19th, 2010
in Uncategorized.
FDA is trying to remove unapproved new drugs from the market. This past year the FDA approved URL’s colchicine. Previously, FDA announced it was taking action against unapproved colchicine on the market. We have commented on these actions in this blog.
A recent article in Kaiser Health News questions whether the approval of these DESI drugs is good public policy. URL charges $4.50 per tablet according to the article, while the previously unapproved products could be obtained under the Wal-Mart $12 per 90-day supply. Some say that is price gouging, others say that is the price of drug development.
Clearly it costs less to make a product that is unapproved. The FDA is charged with evaluating the risk - benefit. When the FDA moved to remove the unapproved colchicine it cited 120 deaths from interactions of colchicine with other drugs. Prior to the extensive testing conducted by URL, physicians couldn’t be sure which co-administered drugs were potentially hazardous. Also, the correct dose wasn’t established. Thus, URL spent millions of dollars to obtain adequate safety and efficacy information. It would seem fair that URL should be able to recover their investment and make a profit. The law provides for exclusivity in the case where clinical trials are required for approval, as in this case. URL has 3 years to recoup their costs before facing generic competition.
Published January 15th, 2010
in Uncategorized.
Once a new drug application (NDA) has been accepted by the agency for filing, the PDUFA review clock starts. We all know the importance of the shortest time to market. Recently MannKind Corporation issued a press release stating that the FDA will not be able to complete the review of MannKind’s NDA for its ultra rapid-acting insulin therapy by the PDUFA date of January 16, 2010. The FDA’s was unable to complete the inspection of a third party supplier to MannKind. The third party was N.V. Organon, the supplier of the active ingredient recombinant human insulin.
It is not clear from the press release or publically available information, whether a last minute change was made to the file or if this was a scheduling issue for the inspectors. The N.V. Organon DMF for recombinant human insulin has been filed with the FDA since February 5, 2001. As you know, the length of time a DMF has been filed it not the important issue, what is important is whether the DMF has been referenced in any previous NDA submissions. This referencing of the DMF is the trigger for FDA review of the DMF.
Without the root cause of the delay, it remains unknown if there was anything that could be done to prevent this delay. There are steps that can be taken when identifying an API manufacturer that can have an impact on the time involved in the review of an NDA. The starting point as stated above is to find out if an active DMF is on file, and then, has any other company referenced that DMF in their NDA? What is the inspection history of the site? Review copies of recent Establishment Inspection Reports (EIRs). Have there been warning letters issued to the site? Review the responses if available. Foreign sites involve more time generally for execution of the inspections. Perform an on-site GMP and pre-approval inspection (PAI) audit well ahead of the expected agency PAI. Be as familiar and prepared with the site history as you can be prior to performing an inspection.
Once you have chosen a manufacturing or vendor site, you have to remain informed about changes occurring at the site which may impact your product and regulatory file.
News on the Biosimilar Front
Published February 8th, 2010 in News Commentary and Uncategorized. 0 CommentsTuesday, February 2nd, Teva Pharmaceuticals announced that the FDA will review its new biologic license application (BLA) to sell a biotechnology medicine, Neutroval, to boost white blood cells, which is “similar” to Amgen Inc’s Neupogen®(filgrastim). The new product is already marketed as TevaGrastim in Europe. There is a regulatory pathway for approving generic versions of biotech drugs in place in Europe. The US still does not have this option; therefore Teva treated this application like a new BLA.
The route to biosimilar approvals or generics for biologics is tied up in the U.S. Congress as part of the healthcare reform legislation, with no light at the end of the tunnel.