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European Medicines Agency and United States Food and Drug Administration to share manufacturing site inspections
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The European Medicines Agency and the United States Food and Drug Administration (FDA) are launching an initiative to share work on inspections of manufacturing sites in each other's territories. The initiative, starting in January 2012, will enable the two authorities to rely on each other's inspection outcomes rather than carrying out separate inspections in duplicate. This is expected to:
- enable better use of the two authorities' inspection resources;
- reduce the burden of inspections for medicines manufacturers;
- shift the authorities' inspection capacity to other regions.
The initiative will apply to inspections of manufacturing sites of human or veterinary medicines in the European Economic Area or United States of America. It will focus on sites that are already known to the two authorities and have a history of compliance with good manufacturing practice (GMP) following previous inspections.
This is the latest step in increased collaboration between European authorities and the FDA. In August this year, the authorities announced the successful completion of two pilot projects involving the sharing of information on inspections.
The outcomes of the initiative will be reviewed after three years.
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*Article written by PharmaNews on 12/12/11
Interesting article from the WSJ - 11/2/11 This IS the solution - allow companies to make money on products in demand.
The Bush-Obama Rx Shortages
Critical cancer drugs are in short supply thanks to price controls.
This week President Obama finally confronted a major U.S. health-care disgrace—the growing shortages of lifesaving drugs, especially anticancer therapies. For some reason the White House lumped its executive order with its "we can't wait" campaign against House Republicans, but the pity is that we will have to wait, because the only genuine fix is a liberal anathema: market prices.
Shortages have more than tripled since 2005, according to the University of Utah's Drug Information Service, and by the end of the year more than 300 products are likely to be back-ordered, in short supply or totally unavailable. Some are anesthetics and pain therapies, others emergency room "crash cart" drugs. But most—about 70% in 2010—belong to the class of drugs known as "sterile injectables" that are mainstays of the chemotherapy arsenal, such as paclitaxel or cytarabine.
The result is that more and more patients are receiving substandard care—relying on less effective or more expensive substitutes or else forced to postpone treatment. In oncology, delays of weeks or even days can be fatal.
Most sterile injectables have been off-patent for decades, but unlike other cheap generic drugs with low profit margins, production is complex and requires special facilities. Nonetheless, George W. Bush and the Republican majority decided that Medicare was "overpaying" for these cancer drugs and included a 6% cap on price increases every six months in the 2003 prescription drug bill. These new price controls (which apply to the providers that purchase the drugs) took effect in 2005, when the shortages began.
In a rational market, sterile injectable prices would now be rising to encourage more supply, since the demand for cancer drugs is inelastic. The old reimbursement system, called "buy and bill," was imperfect, but at least it allowed prices to float and wasn't producing the scarcity that central planning always does. The sterile injectables that are in short supply currently sell for $37.88 a dose on average, and modest price increases could make the market economic.
The problem is compounded because Food and Drug Administration rules cause pointless delays. It takes as long as two and a half years to receive FDA manufacturing approval for a generic, so other drug makers can't ramp up production if a company cancels a product line due to these disincentives or even if the fragile supply chain for sterile injectables is contaminated and manufacture is delayed.
Mr. Obama's executive order will do little if any good since it doesn't address or even mention this underlying distortion that Medicare has created. Instead, it merely expands the FDA reporting requirements about production interruptions or terminations. This is supposed to be an early warning system, but the scandal is that the availability of basic medicines could be allowed to become an emergency.
The order also tells the Justice Department to crack down on the "grey markets" that have sprung up to deliver supplies to doctors and hospitals, albeit with the inevitable markups. So rather than allow price signals to govern supply and demand, Mr. Obama wants to suppress them further.
The larger danger apart from the risks to the patients forced to receive compromised treatment is to the future of cancer progress. The common chemotherapy drugs are critical in clinical trials as the standard regimen or in combination with new options, and the Coalition of Cancer Cooperative Groups reports that as many as half of all ongoing trials require the drugs that are vanishing. This is a delay that really is killing people.
WSJ - November 2nd, 2011
FY 2009
•859 ANDAs submitted in FY 2009
•263 PIV submissions
409 eCTD submissions
242 CTD submissions
30 paper CTD submissions
178 Gateway submissions
8 ANDA's RTR's (Refuse to Review) in FY 2009
FY 2010
•813 ANDAs submitted in FY 2010
•262 PIV submissions
119 CTD submissions
271 eCTD submissions
12 paper CTD submissions
411 Gateway submissions
13 ANDA's RTR'd in FY 2010
FY 2011
•853 ANDAs submitted (as of 9/26/2011)
•211 PIV submissions
60 CTD submissions
177 eCTD submissions
5 paper CTD submissions
611 Gateway submissions
•48 ANDAs RTR’d (as of 9/26/2011)
Relevance of numbers
100% of Original ANDAs being submitted are in CTD format (eCTD+paper CTD+Gateway)
Approximately 95% (or more) of original submissions are now electronic
Gateway submissions have continued to surge tremendously
58=(2008) 178=(2009) 411=(2010) 611=(2011)
RTR's as a percent of submissions is about 17% (data is incomplete as all of FY 2011 submissions have not been reviewed) FY 2008=15%, FY 2009=9%, FY 2010=14%
FDA currently has approximately 2500 ANDA's under review
FDA currently has approximately 4900 CMC Supplements under review
*All information above from GPhA Technical Conference held in Bethesda, MD - Oct 3-5 Kwadwo Awuah, Pharm D., R.Ph,. Regulatory Support Management Officer, Office of Generic Drugs, FDA
Industry average ANDA approval times are approximately 33 months, industry has done an excellent job converting to electronic ANDA filings from paper.
The focus for industry remains to provide the FDA 'well written' ANDA applications, this will assist the FDA with more efficient review times.
Custopharm filed the 1st eCTD ANDA in 2004, have filed over 100 since. Custopharm assists companies by through Regulatory assistance, when we fully write eCTD ESG ANDA's the average approval time is significantly faster than the industry average.
Best,
Dave McCleary
dmccleary@custopharm.com
On September 19th, 2011 the FDA announced a revision to its 2006 guidance titled “Marketed Unapproved Drugs-- Compliance Policy Guide Sec. 440.100, Marketed New Drugs Without Approved NDAs or ANDAs” (CPG 440.100). This revised guidance clarifies that any unapproved new drug introduced onto the market after September 19, 2011 will be subject to immediate enforcement action, without prior notice and without regard to the enforcement priorities set out in CPG 440.100.
Custopharm can assist with filing ANDA's and NDA's. We filed the 1st eCTD ANDA in 2004, have filed over 100 ANDA's since, approved for the Electronic Submission Gateway (ESG) in 2008, responded to over 100 deficiencies in 2010. Custopharm will make you feel comfortable knowing that your submission is of the highest quality.
Custopharm can also assist with Drug Listings, Establishment Registrations, and SPL filings.
Best,
Dave McCleary
dmccleary@custopharm.com
Consider these points:
Compliance has 192 foreign inspections scheduled, resources to complete 62 in 2011. The number of facilities that require inspections has increased in the last 5 years. Consider only 6 years ago there were less than 20 Chinese facilities inspected and approved for API, now there are over 200. A wave of Chinese Dosage facilities have filed ANDA's which will require inspections and additional effort. Numbers in India have also grown with API manufacturers and Dosage facilities over the last 6 years. The additional overseas work created for the Compliance group is significant.
Most likely Federal funding will be cut back in 2012, talks of up to 10%.
Assuming a reduction in the number of inspections and headcount in 2012, the average ANDA approval time could continue to increase.
The possibility of User Fees for Generic applications can generate additional revenue, but will these fees be channeled directly to CDER or will a portion go to the General Accounting Fund? Additional dollars could potentially reduce the average ANDA approval times, or these fees could balance out the potential cuts to the budget.
None of us know how this will balance out next year, companies must think of ways to be most effective and efficient in order to manage the change ahead.
A key to success will be the Regulatory strategy, a 'well written' eCTD ESG ANDA will minimize the efforts of the reviewer.
Don't try to 'save money' with a low cost Regulatory Consultant, now is the time to work with an experienced company that knows what they are doing. A poorly written, poorly managed ANDA can cost a company in excess of 24 months of review time, not to mention creating an unnecessary burden on the reviewer.
Custopharm filed the first eCTD ANDA in March 2004. We have filed over 100 eCTD ANDA's, over 500 ESG filings. We file 'well written' eCTD ESG ANDA's, you can be confident that a quality application has been filed with the reviewer's needs in mind.
Best,
Dave McCleary
dmccleary@custopharm.com
Regulatory approval time lines should be a key focus for all Generic companies, even more important than development time lines. Companies must understand a poorly written application could potentially cost them 12-18 months of time on the market.
Average ANDA approval times are approaching 34 months, most blame the FDA. But is this the case? We don't think so.
The FDA receives applications from a vast array of companies, many from overseas. Custopharm has reviewed documents from over 35 companies, many of the applications we see are 'data dumps' to the FDA. Too much information is submitted to the FDA reviewers which clogs up the system and wastes the reviewers time. Another critical issue is how the ANDA is written, every company has a different style of formatting the application, this also adds time to the review. Language barriers can create confusion to the reviewer, this adds additional questions to the sponsor of the application. Last but not least, many applications are not complete which creates additional cycles of review adding to the work load of the FDA reviewer.
Custopharm can assist with review of the development to assure the ANDA is complete, we can then write a 'well written' application with the FDA reviewer in mind, we also assist with deficiency responses. Custopharm has filed over 100 eCTD ANDA's and over 500 ESG filings, we filed the 1st eCTD ANDA in March 2004. We are good at what we do and are fair to our customers.
A new easy to use eCTD software is entering the final phases of beta testing and we are looking for volunteers to evaluate and provide input crucial to the finalization and completion of the software.
This software is based on the principles that software should be easy to pick up and use and therefore does not require extensive training and is designed to be "Mac" like in its ease of use. However, if anybody needs instructions we are more than happy to help.
Currently, we are looking for volunteers to evaluate the capabilities of the software and make recommendations as to how to improve it. Ideal beta testers would be regulatory consultants working on a variety of submissions types for the US market; however direct pharmaceutical employees are requested to register as well. This is a rare opportunity to use an eCTD software package at no cost.
We feel this is the first eCTD software to actually do what software is supposed to do and simplify the process for preparing eCTD submissions.
To be considered as a Beta tester please contact us directly by completing the form. Once we have made our selections we will advise you that you were chosen and provide instructions regarding the software installation.
Having just returned from the DCAT meeting in New York City, all the buzz was about the seemingly imminent "Generic Drug User Fees." Everyone had questions, opinions, suggestions and speculated about the upcoming fees. The main questions were how big the fees would be (especially from smaller companies with limited resources), the impact the fees would have on ANDA approval times and when they would start. It seems everyone had a different answer or idea for the various questions. I heard people discuss feels as small as $20,000 per ANDA to upwards of $100,000 per ANDA. Timelines seemed to range from sometime during the second quarter of 2011 to sometime in 2012. Nobody had an answer to the impact that the fees would have on approval timelines but consensus seemed to be that a target of 18 month approvals would be ideal. The only thing that wasn't in question was whether or not the fees would happen. Everyone agreed that they would happen and most were optimistic to their success.
User fees have been implemented with varying success at the difference divisions at FDA. CDER has implemented PDUFA fees for NDA submissions with success in sticking to the review times in most instances. However, if you read the statistics regarding the decreasing number of new drugs being approved, the real question revolves around the cause of the timelines being kept is it due to the number of filings or due to the fees. Additionally, PDUFA fees for NDA are very large and have created a secondary issue. The FDA would love to remove all unapproved "Grandfathered" products from the market, however the large PDUFA fees make it cost prohibitive to submit an NDA for these products.
On the other side of the coin, CVM has issued reasonably sized filing fees for veterinary drug products but has placed the money in the general reserve fund (or at least so I have been told) and therefore approval times have not improved since implementing the fees. From what I hear, CVM makes OGD look good with the 30 month ANDA approval times.
One other question that poses itself is how do you address, the more than 2,000 ANDA that are currently backlogged once the fees start. Do they keep their place in line or do the get bumped for "priority" paid submissions.A definite concern on industry is if the fees are used to supplement or replace the current Federal Government's funding for OGD. If it replaces, I do not think things will get better quickly if ever. If it supplements the fees, then I think eventually we will get to a much better system wherein timely approvals are possible and to be expected.
In conclusion, it seems not matter what the FDA does, the problem will not be solved overnight. And if you read my previous blog; in Custopharm's opinion one of the primary reason for much of this backlog is poorly written applications that recirculate through the FDA over and over again.
We welcome any comments, thoughts, opinions and theories you may have on this subject matter. Please feel free to comment in the space below.
As the title illustrates this article will apply mainly to ANDA approval times since currently there are no PDUFA or User Fees for generic drug products. Even when and if the user fees reach generics there is no assurance that they will work the same way as they do for NDAs with action dates that are essentially adhered to.
During product development and submission preparation. everyone is familiar in at least some regard with the use of Gantt charts as a project management tool. Gantt charts are a great tool to track and plan in-house or contracted activities for which the sponsor has at least some direct control. Additionally, most Gantt charts I have seen go on to predict expected dates for FDA application acceptance, deficiencies and approval times. However these times were essentially based on empirical evidence or examples that is outdated due to ever changing conditions at the FDA.
We have divided the FDA review process into four main areas; FIFO cue time, review time, deficiency response time and approval time. Everyone's target is to get to the approval time as quickly as possible, however to get there it is essential to manage the three other phases as effectively as possible. Today I will address the FIFO Cue time.
The FDA operates most applications in a First In First Out procedure or FIFO. There are some exceptions such as expedited application or products on the drug shortage list. However, those are out of the scope of this discussion. Our definition of FIFO cue time is the time your submission sits around waiting for it to be picked up for review.
There are not many things that an individual can do to improve the FIFO cue time for a filing since, it is a general issue that effects all companies. The only things that you as an individual company can do to improve your cue time is to get your submission in the cue as quickly as possible. This means filing the submission earlier and ensuring that your company is using the Electronic Submission Gateway (ESG) to submit your filings.
Beyond these two things, the only ways to improve FIFO cue time is to have fewer submissions enter the FDA (which we all know isn't going to happen) or for the industry as a whole to submit higher quality filings that actually have a single cycle approval process. The key contributor for long FIFO cue times are applications that are essentially stuck in the system. By this I mean filings that have received multiple rounds of similar deficiencies and are not prepared in a manner that is easy to review. Typically these submissions are filed by companies that are not familiar with FDA processes or do not place emphasis on regulatory.
To improve this the industry needs to start looking at the regulatory function as an integral part of the product development process. Submitting an application to the FDA is much more than just following guidance documents and providing the data to the FDA. THe process is based on experience from previous applications, working with reviewers, and providing the information to the FDA in a logical easy to follow pattern. Keep in mind that each additional deficiency cycle add months to your product launch date.
Everyone who works in regulatory affairs is always under constant pressure to get submissions out as soon as possible. No matter which eCTD preparation software or EDMS system you utilize; the process always begins with Microsoft Word documents. Everyone is familiar with the basic functions of Word. Everyone has opened or created a document and started typing. However, the more effectively one utilizes Word's more advanced features the more effective and efficient you can be in preparing your submissions. Actually this goes beyond just submission preparation but extends itself into any word processing requirements.
Some of the key tasks that can speed up your work are automating processes, selecting text and repetitive text entry. We will describe some simple way you can use Word more efficiently. At Custopharm, we use these and many others to speed up our submission preparation to ensure timely delivery of our work product. The instructions provided below are for Word 2007 but similar procedures have been utilized for previous versions.
- Automating Processes - The most common form of process automation we use is through the use of cross references and numbering.
- Cross References are a link to a particular paragraph, figure, table, etc. The main benefit using cross references is that if section numbers, tables or figures are modified due to changes in the document; the cross reference will update automatically. For example, if you have a cross reference to Table 2 in a file and you add another table to your document which changes Table 2 to Table 3. The cross reference will automatically updates the reference to list the table as Table 3. To add a cross reference, place your cursor where you want the cross reference placed, click on insert on the ribbon and then in the link section select Cross Reference. Select the desired reference type (figure, table, numbered item) and what you want to reference (i.e. page number, paragraph number, etc.). Then click on your desired target and click insert. The cross reference will be added at your cursor position.
- Numbering or Outline Numbering plays an integral part in submission or any complex document formatting. To utilize this feature in the home tab of the ribbon click on Numbering or Multilevel List in the Paragraph Section. Many clients that we work with manually enter numbers and then when creating a table of contents or adding sections the numbers also get out of order. Both types of numbering allow you to define what your number looks like. You can precede all the numbers with the module number followed by the section number. To customize you layout click on the "Define New ..." which is displayed when you click on the drop down arrow. In this section you can define the numbering style (font, font size, bold, etc), you can design how the numbers and associated text are formatted within word including fonts, paragraph spacing, layout, etc. Custopharm's typical practice is to utilize the multilevel List and associate the various levels with headings 1, 2 , 3. etc. This facilitates the preparation of the table of contents when the document is completed, which is another process that can be easily optimized once style sheets are properly used.
- Selecting text is frequently utilized in all sorts of document editing. Most people will use their mouse to select text by clicking on the first letter and dragging through the last word. This is by far the most inefficient method of selecting text. It may not seem like much time can be saved by selecting text more efficiently but with the frequency of this activity saving a few seconds each time will really come to be a significant time, especially for complicated selections. We will describe the easy ways to perform selection of various items.
- To select a word: double click on the word.
- To select a line: single click in the white space next to the line.
- To select a sentence: hold down "Control" and click on any word in the sentence.
- To select a paragraph: triple click on a word in the paragraph.
- To select a table: hold down "Alt" and double click on any cell in the table. Alternately, click on the little box with two arrows that is displayed on the upper left corner of the table when your cursor is in the table. (Single clicking on a word with "Alt" brings up the research tab)
- Repetitive Text Entry is useful for repeated entry of the same set of text. This is especially helpful for drug names, manufacturing facilities or any block of text that needs to be entered frequently within a document. For this we utilize Words' Quick Parts. This is located in the Insert tab of the ribbon under the text section. To add a selection to Quick Parts, simply select your text, press the drop down arrow of the Quick Parts Section and click "Save Selection to Quick Part Gallery." Another way to easily add repetitive words is to use the auto correct feature in word. To do this go to Word Options, go to the proofing tab and click on "AutoCorrect Options..." Here you can define a combination of letters to be replaced with your complete text. This is how word converts (r) to the registered symbol. The only thing to keep in mind for this is to not use letters that will be normally in sequence. This feature has created numerous problems for analytical chemists trying to abbreviate acetonitrile as ACN only to have it change to CAN automatically.
We welcome comments for any other tips or trick for Word you may have.