Stephanie Sutton was an assistant editor at Pharmaceutical Technology Europe.

Stephanie Sutton

 has written extensively about regulatory issues in the US. One of the latest regulatory developments is that generic-drug manufacturers are preparing to pay fees to FDA for the first time in the agency’s history. Application fees are already required from manufacturers when seeking regulatory approval from FDA for new prescription products, but this is the first time that such fees will also be collected from generic-drug manufacturers. The Generic Drug User Fees Amendments of 2012 (GDUFA) are scheduled to come into force in the US on October 1 2012 and will require drug manufacturers to pay annual facility fees and fees when submitting Abbreviated New Drug Applications (ANDAs) and drug maser files to FDA for generic drugs. A one-time fee will also apply to backlog applications as of 1 October. 

GDUFA was signed into law on July 9, 2012, with the aim of speeding access to safe and effective generic drugs to the public and reduce costs to industry. The program is based on an agreement negotiated between FDA and generic-drug industry representatives to address the regulatory challenges associated with the growing number of applications for generic drugs submitted to FDA. 

According to FDA, around 78% of new and refilled outpatient prescriptions in the US were for generic drugs in 2011. More than 8000 generic drugs are currently approved in the US and FDA is receiving a growing number of applications for such products. Annually, the agency receives 800 to 900 generic-drug related applications—many of which involve products manufactured outside of the US. Due to limited resources, FDA has not been able to keep pace with the increasing volume of applications, resulting in a backlog of more than 2500 applications. 

The fees will be used to fund more resources and staffing at FDA. By the fifth year of the program, FDA aims to be capable of reviewing and acting on 90% of completed generic-drug applications within 10 months of the submission date. In addition, FDA will increase its regulatory inspections of both foreign and domestic generic-drug manufacturing facilities. Currently, the agency only has the resources to conduct inspections outside of the US every 7 to 13 years. 

GDUFA will also help boost the transparency of the generic-drug manufacturing industry by establishing an identification system requiring all facilities involved in the manufacture of generic drugs and their ingredients to register. 

During the 5-year period from fiscal year 2013 through to 2017, the program is expected to provide FDA with approximately $299 million each year. 

Read more about GDUFA in these related articles:

Articles from our Regulatory Watch columnist Jill Wechsler

Generic Drug User Fees Mark a Step in the Right Direction

Enactment of FDA Reform Act Improves Drug Safety

Generic-Drug and Biosimilar-User Fees Gain Traction

GPhA Urges Congress to Move Ahead on Generic-Drug and Biosimilar User Fees

More information about GDUFA is also available on FDA’s website.

Fact Sheet: New User Fees for Generic Drugs Will Enhance Americans’ Access to Less Expensive Drugs and Generate Major Cost Savings

FDA completes work on three drug user fee programs

Guidance for Industry: Generic Drug User Fee Amendments of 2012: Questions and Answers

Articles

Generic-drug manufacturers are preparing to pay fees to FDA for the first time in the agency’s history.

Industry Gears up for GDUFA

It’s common knowledge in the pharmaceutical industry that medicines regulators do not conduct as many inspections of foreign drug-manufacturing facilities as they might like to. For a start, FDA only has a limited ability to require foreign establishments to allow inspectors into the facilities and logistical problems also mean that inspections cannot be performed unannounced.  In addition, the cost of overseas inspections can be a huge burden and regulators, like the rest of the pharmaceutical industry, are being squeezed by today’s unsettled economic environment. However, I was still surprised this week to learn at how infrequently these inspections are performed. Because of limited resources, FDA can only inspect generic-drug manufacturers outside of the US every 

		The rarity of foreign inspections has also been raised in 

 from the US Government Accountability Office (GAO). Although the number of overseas inspections conducted by FDA has increased since 2007 (when FDA inspected only 8% of foreign establishments subject to inspection), FDA has itself admitted that it still has a way to go.

		Fortunately, this situation is set to change in the near future. FDA will soon be receiving a cash boost to help fund inspections of generic-drug manufacturing facilities via the implementation of the Generic Drug User Fee Amendments of 2012 (GDUFA), which comes into force on October 1, 2012. FDA already receives fees from pharmaceutical manufacturers submitting applications for new, innovative prescription products, but GDUFA marks the first time that fees will also be collected from generic-drug manufacturers too. You can read more about GDUFA 

. In a nutshell, GDUFA will require pharmaceutical manufacturers to pay fees when submitting applications for generic drugs to FDA.

		FDA estimates that, over a 5-year period, GDUFA will provide the agency with around $299 million annually. The supplement to its budget will help to fund more frequent inspections, as well as faster reviews of applications for generic drugs. At the moment, the average review time of a new generic drug application is 31 months. FDA hopes to bring this down to 10 months in 5 years.

		The number of foreign inspections has also benefitted from increased cooperation between FDA and other regulatory agencies, such as the EMA and Australia’s Therapeutic Goods Administration (TGA). A pilot phase of a project concerning joint API inspections involving EMA, FDA and the TGA ran from December 2008 to December 2011, during which nearly 100 inspection reports were shared. The regulators are continuing their cooperation with regards to API inspections and have also opened up the project to new participants.

		PharmTech is currently running a poll about GDUFA. You can vote 

It’s common knowledge in the pharmaceutical industry that medicines regulators do not conduct as many inspections of foreign drug-manufacturing facilities as they might like to.

FDA Eyes More Foreign Inspections

The European Medicines Agency (EMA) has launched a public consultation concerning its inventory of pediatric medicines with the aim of highlighting where further R&D efforts are required. The consultation is the first of its kind in this area. 

The inventory is being developed by EMA’s Pediatric Committee (PDCO) and is based on a survey of all the pediatric uses of medicinal products in Europe, which was completed by PDCO in December 2010. By identifying the needs in different therapeutic areas, PDCO hopes that the inventory will help pharmaceutical companies to identify opportunities for new business development. In addition, the lists will enable PDCO to assess the need for medicines and studies when reviewing draft pediatric investigation plans, waivers, and deferrals. In Europe, all applications for marketing authorizations submitted to EMA must include either a product-specific waiver or pediatric investigation plan.

Healthcare professionals and patients will also be able to make use of the inventory to support their decisions in the choice of medication. 

The first list to be released includes all cardiovascular medicines for use in children and is open for consultation until Oct. 30, 2012. Details on how to participate are available on the 

. Lists for other therapeutic areas will be released for public consultation during 2012 and 2013.

Regulatory Intervention in Pediatric Medicines

The European Medicines Agency has launched a public consultation concerning its inventory of pediatric medicines with the aim of highlighting where further R&D efforts are required. The consultation is the first of its kind in this area.

EMA Seeks to Identify R&D Gaps in Pediatrics

	In most industries, businesses run the same way. You can either stick your head in the sand and pretend that everything is going fine, or you can stand up and take the feedback-whether positive or negative-and react to it. This is especially true with Quality Management Systems (QMS).

	In today’s dynamic and demand-driven world, businesses are challenged with speeding their product-to-market strategies to remain competitive. In the pharmaceutical industry, regulatory and compliance pressure add another dimension to the QMS. Organizations want to bring their products to market quickly, but need to ensure quality and compliance standards are met-it’s a paradox of “hurry up, but take your time doing so.”

	Nevertheless, no matter how much one prepares, once product is released, post-market feedback is inevitable. You may get positive feedback, but more often than not, this post-market feedback comes in the form of complaints, which can arise from consumers, doctors, patients, vendors, and many other parties. Organizations are faced with the challenge of interpreting this feedback and turning it into opportunities.

	It’s the age-old story, “We have all this data, but how do we use it?” Complaint handling systems can be very adept at collecting post-market feedback, but after the data is collected, it becomes a challenge to use the data to foster continuous improvement. You may find yourself asking:

		“How do I identify the critical adverse events from the non-critical?”

		“How can I take this data and push it back through the organization?”

		“How can I influence change and improvement quickly from this post-market feedback?”

	Quite simply put, the QMS is built for continuous improvement. Companies have Corrective and Preventive Action (CAPA) systems, complaint handling systems, and change management systems  to handle such quality events. But what can one do to turn post-market data into improvement in the next product? Below are a few tips.

	Risk-Management Filtering: The biggest challenge facing many companies has to with sorting through the data. Complaints enter the system by the hundreds or even thousands, each with varying levels of severity. The question becomes, “How can I identify the critical adverse events from the non-critical?” The answer lies in risk assessment. By using risk methods, one can filter the critical from the non-critical based on risk levels. This enables one to effectively address those events that present the largest impact on the business. Then one can open up CAPAs based on the high risk events first.

	Change Management Linked from Post-Market Events: Once a company has identified critical events and begun to correct them, how can one influence change in the product as a result? The system must be managed in a systematic way, so that R&D is able to take post-market feedback and apply it to the product. Managing the process of supplier and contract manufacturer quality is key, and it needs be done so efficiently. Change management in the QMS is ideal for this task because it includes the workflow, process automation, and integration required to enable post-market data to reach all areas of the business. By building effective change management processes, one can benchmark quality and compliance throughout the product lifecycle and reduce noncompliance as a result.

	Visibility into the data: If you aren’t one of those folks with your head in the sand, you want to be able to see how you’ve improved, or where you are not improving. You need visibility into your existing data in order to influence future strategy in product quality and compliance. Without strong reporting in the QMS, you are just looking at the data. Analysis and interpretation of the data are needed. Reporting in the QMS can help to take the temperature of the compliance effort and see whether you delivering on what you’re changing in your processes.

	QMS are designed to manage and track the drug development and manufacturing process. Post-market feedback is important to the health and success of that process and of a business. By streamlining the process of post-market feedback and reaching into the enterprise, one can quickly and effectively manage the continuous improvement process.

In most industries, businesses run the same way. You can either stick your head in the sand and pretend that everything is going fine, or you can stand up and take the feedback-whether positive or negative-and react to it.

How Post-Market Feedback Can Influence Compliance when Using a Quality Management System

Following an inquiry in 2009 that suggested the launch of various generic drugs was being delayed by anticompetitive business practices, the European Commission (EC) has been closely monitoring deals for potential breaches of the European Union's antitrust rules.  

Recently, the EC issued a Statement of Objections (a formal step in investigations into suspected violations of antitrust rules) for two separate cases. The first statement was sent to Lundbeck and several generic-drug companies with the preliminary view that agreements were formed to prevent the market entry of cheaper versions of Lundbeck's antidepressant, citalopram. After patents on citalopram expired, the EC says that Lundbeck entered into agreements that involved "substantial value transfers" from Lundbeck to its genericdrug competitors, who subsequently chose not to market any generic versions of citalopram.  

The second being scrutinized by the EC is Servier. The EC believes that Servier's agreements with several companies, coupled with acquisitions of key competing technologies, were aimed at preventing the market entry of generic versions of its cardiovascular medicine perindopril. Servier has been under close watch by the EC for potential anticompetitive practices since 2009. 

Despite these latest highprofile cases, the EC has reported a decrease in pay-to-delay deals. Results from the EC's patent monitoring activities show that the number of potentially problematic settlements stabilized in 2011, at 11% compared with the 21% noted during the sector inquiry, which  examined the period 2008–2009.  

The European Commission remains vigilant in monitoring potential pay-to-delay deals.

Europe Hones in on Antitrust Violations

Following an inquiry in 2009 that suggested the launch of various generic drugs was being delayed by anticompetitive business practices, the European Commission (EC) has been closely monitoring deals for potential breaches of the EU's antitrust rules. Recently the EC issued a Statement of Objections (a formal step in investigations into suspected violations of antitrust rules) for two further separate cases.  

The first statement was sent to Lundbeck and several generic-drug companies with the preliminary view that agreements were formed to prevent the market entry of cheaper versions of Lundbeck's antidepressant, citalopram. After patents on citalopram expired, the EC says that Lundbeck entered into agreements that involved "substantial value transfers" from Lundbeck to its generic-drug competitors, who subsequently chose not to market any generic versions of citalopram.  

"The value transfers included direct payments from Lundbeck to the generic competitors and also occurred in other forms, such as the purchase of generic citalopram stock for destruction or guaranteed profits in a distribution agreement," said an EC statement, released on 25 July. 

The second being scrutinised by the EC is Servier. The EC believes that Servier's agreements with several companies, coupled with acquisitions of key competing technologies, were aimed at preventing the market entry of generic versions of its cardiovascular medicine perindopril. Servier has been under close watch by the EC for potential anticompetitive practices since 2009. 

Despite these latest high-profile cases, the EC has reported a decrease in pay-to-delay deals. Results from the EC's patent monitoring activities show that the number of "potentially problematic" settlements stabilised in 2011 at 11% compared with the 21% noted during the sector inquiry, which examined the period 2008–2009. 

Stephanie Sutton is community manger of PharmTech Europe.

Following an inquiry in 2009 that suggested the launch of various generic drugs was being delayed by anticompetitive business practices, the European Commission (EC) has been closely monitoring deals for potential breaches of the EU's antitrust rules.