Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

The Steering Committee and Expert Working Groups of the International Conference on Harmonization are meeting this week in Brussels to discuss current harmonization efforts. 

 is expected to be finalized. Q8R will provide more clarity on quality by design and specifically “design space.” In addition, the Implementation Working Group for ICH Q10 

, which is in Step 5 of the harmonization process, is discussing next steps. 

Also this week in Brussels, ICH is holding a meeting for the public to provide information on recent developments at ICH in the context of globalization and international cooperation. 

 will report on the outcome of these meetings in next week’s 

In related news, the Clinical Data Interchange Standards Consortium (CDISC) is working to harmonize information technology standards for clinical research and electronic health records. CDISC met with the Health Information Technology Standards Panel on Monday to encourage a global solution.

Articles

The Steering Committee and Expert Working Groups of the International Conference on Harmonization are meeting this week in Brussels to discuss current harmonization efforts.

ICH Leaders Meet

-The US Food and Drug Administration  issued a final rule requiring the addition of a statement and toll-free number to the labeling of certain human drug products. The statement must advise users that the number is to be used to report side effects and should not be used to seek medical advice. 

The rule, titled Toll-Free Number for Reporting Adverse Events on Labeling for Human Drug Products, was issued Oct. 28, 2008, and confirms the interim final rule of the same name that was issued Jan. 3, 2008. It applies to drug products approved under section 505 of the Food, Drug, and Cosmetic Act.

This final rule also affirms the addition of the new part 209 to current regulations requiring distribution of the side-effects statement. This final rule implements provisions of the Best Pharmaceuticals for Children Act (BPCA) and the Food and Drug Administration Amendments Act of 2007 (FDAAA).

The new statement must appear in the medication guides of the products, and pharmacies must distribute the statement with all new and refilled prescriptions in one of the following ways: 

On a sticker attached to the product’s package, vial or container

On a preprinted pharmacy prescription vial cap

By distributing the appropriate FDA-approved Medication Guide.

FDA provided a few estimates for implementing the final rule, which will impact manufacturers, distributors, pharmacies, and regulators. The agency estimates that manufacturers will spend $3000 per shelf-keeping unit (SKU) to modify labeling of a new drug application (NDA) over-the-counter (OTC) product and $1000 per SKU for an abbreviated new drug application (ANDA) OTC product. Revision of medication guides is expected to cost between $4177 to $4500 (in 2007 dollars) for an NDA prescription drug and from $1580 to $1800 for a prescription drug with an ANDA. For private OTC drug distributors and manufacturers, FDA estimates total one-time costs ranging from $38 million to $49.6 million.

The overall estimated cost of implementing the final rule ranges from $16.9 million to $52.2 million with a 3% discount rate and from $17.8 million to $53.4 million with a 7% discount rate. Most of this cost will likely be passed on to consumers, says the rule. 

The final rule takes effect Nov. 28, 2008. The compliance date is July 1, 2009. Read the complete rule 

. In May, an FDA advisory panel advised that the agency require toll-free numbers on direct-to-consumer television ads for the purposes of reporting side effects, according to a 

. This particular issue is still pending.

The US Food and Drug Administration has issued a final rule requiring the addition of a statement and toll-free number to the labeling of certain human drug products.

FDA Requires Side Effects Statement on Labeling

 How much time does your company spend on regulatory inspections? If your answer included the words "too much" followed by an agonizing sigh, you're not alone. 

In today's global marketplace, a single manufacturing site may supply more than 80 markets and spend as many as 137 days working on one inspection, according to the European Federation of Pharmaceutical Industries and Associations (EFPIA). The organization's Foreign Inspections Topic team has conducted surveys annually since 2003 among its members. Last year, 22 big and small companies, representing 644 manufacturing sites worldwide, responded. Of the 644 sites, 211, or 33%, had at least three inspections in 2007; 6 of them had more than 10 inspections.    

Some of the most interesting survey results: It typically takes about 137 work days (i.e., 8-hour days, totaling 1096 working hours) to host an inspection. This includes 80 to 100 days for preparation (e.g., reviewing, compiling, summarizing, crafting presentations); about 17 work days per inspection day (accounting for multiple employees) for inspection management during the inspection itself; and 20 days for administrative followup.  

The data also show that companies overall spent as many as 106,158 days dealing with inspections by foreign inspectorates, says EFPIA Topic Team Chair Stephan Roenninger, global quality manager at F. Hoffmann-La Roche (Basel, Basel-Stadt, Switzerland). The most active inspectorates in order of activity reported are those from the European Union, United States, Brazil, Japan, Mexico, South Korea, and Uganda.  

Considering that the average person in Europe works 220 days per year, this totals about 483 years of employee resources. In turn, inspectors spent 3054 days on foreign inspection activities in 2007 at the sites of the companies surveyed in addition to their local inspection responsibilities.   

Overall, inspection numbers are going up on both the manufacturer and regulator side. The number of days that surveyed companies spent on foreign inspections increased by 51% between 2006 and 2007. And even though the number of sites the companies had decreased by 3%, the number of foreign inspections they had increased 34% during the same period. Add to that inspections by local authorities, and there is a 130% increase in the number of inspections between 2003 and 2007, and a 172% increase in the time inspectors spent doing inspections between 2003 and 2007. In fact, many companies participating in the annual EFPIA survey have seen a 16% to 20% increase in inspections every year since 1999. 

This change may be, in part, because there are now 43 inspectorates conducting inspections outside their own borders, says Roenninger. The following countries reported to EFPIA that they recently started doing foreign inspections: Botswana, Costa Rica, Ethiopia, Morocco, Serbia, and Iraq. 

Compare the statistics compiled by EFPIA to those from a typical plant in the United States over a recent calendar year. The Pharmaceutical Research and Manufacturers Association (PhRMA) Quality Technical Group conducted a similar initial survey between 2004 and 2006 focusing on FDA's risk-based inspections. Nine companies reporting for 57 sites participated. Zena Kaufman, divisional vice-president at the Quality Center of Excellence at Abbott (Abbott Park, IL), presented data from the PhRMA group at the 2008 PDA/FDA Joint Regulatory Conference. 

A typical US plant experienced 84 days in which an inspection was occurring in one year's time.  Considering that the average plant is operational 250 days per year (52 weeks x 5 days -10 holidays), about one third of a plant operations can be tied to inspection activities, not to mention how many persons were involved in inspection activities. 

Other early results from PhRMA show that the number of inspections in the Americas increased between 2004 and 2006, but stayed relatively the same for inspections outside the region during the same period. There was a higher reported facility complexity in the Americas and the Asia-Pacific region, as compared with the European Union. The PhRMA Quality Technical Group intends to continue the survey and to possibly expand or work with EFPIA, said Kaufman.  

Both surveys beg the question: Given the amount of time and effort that go into foreign inspections, is there a better solution to assuring compliance? Can joint inspections or sharing of knowledge about sites come soon enough in a global supply chain?  

"More sharing of assessed risks to GMP and compliance at manufacturing sites between industry and/or regulators is certainly needed," say Roenninger and Kaufman. "Awareness, multi- and bilateral confidentiality agreements facilitated by harmonized training and trust between inspectorates such as membership of inspectorates in PIC/S should also be encouraged."  

Adds Roenninger, "In addition, administrative instruments (e.g., the World Health Organization's certification scheme on the quality of pharmaceutical products) providing for governmental regulatory processes for certifying manufacturing sites should be encouraged as well." 

Trends In: Foreign Inspections

 During the past five-plus years, the number of US Food and Drug Administration enforcement actions seems to have dropped significantly in the areas of seizures, permanent injunctions, and warning letters (see table). One may question whether the drop means companies are in better compliance these days, or whether FDA's drained resources are preventing the agency from following up every potential violation. Alyson Saben in the Office of Enforcement at FDA's Office of Regulatory Affairs provided some insight into this issue. 

"In many cases, agency enforcement actions are taken for matters that are of greatest public health concern and which will have the greatest impact on consumer protection," she said. "We cannot measure the agency's enforcement success—nor can we measure industry compliance—by counting warning letters and other actions, individually." 

These actions represent only a small portion of the "full spectrum of FDA's compliance efforts and the overall impact of those actions on consumer  protection," adds Saben. For example, the statistics in the table do not include the accomplishments of FDA's Office of Criminal Investigations (OCI). In fiscal year 2008 (FY 2008), as of Sept. 10, OCI initiated 405 criminal investigations, made 319 arrests, and secured 311 convictions  with fines, restitutions, and other monetary penalties totaling more than $153 million.  

In addition, FDA's efforts in the import arena have a large impact in the enforcement arena.  In 2007, the agency processed approximately 16 million lines of FDA-regulated products contained in import entries. Through the use of administrative actions such as Import Alerts and sampling efforts at the border, numerous, potentially violative, FDA-regulated products of foreign origin were prevented from reaching US consumers. And numerous other FDA "interventions," including inspections, sample collections/analyses, and issuance of 483s, take place daily, explained Saben, which result in corrective actions and consumer protection.   

"The agency also seeks to expand the impact of these actions through its communication efforts, thereby achieving a broader, potential deterrent effect industry-wide," says Saben. 

Trends In: FDA Enforcement Actions

 Washington, DC (Oct. 30)-The US Government Accountability Office (GAO) released a report last week that examines and provides recommendations for the US Food and Drug Administration’s foreign inspection process, including the agency’s data management, inspection frequency, and oversight of problems identified during inspections. According to the report, FDA’s databases contain “inaccurate information on foreign establishments subject to inspection.” Specifically, the agency’s list of establishments 

 to market drugs in the US totals around 3000 but its list of establishments that 

 drugs to the US totals closer to 6,800, states GAO. 

“The accuracy of this information is important in FDA's identification of foreign establishments subject to inspection,” says the report. “FDA inspected 1,479 foreign drug manufacturing establishments from fiscal years 2002 through 2007. Because FDA does not know the number of establishments subject to inspection, the percentage of those inspected cannot be calculated with certainty.”

GAO reviewed another list that FDA used to prioritize foreign inspections in FY 2007 to gain a better sense of how many inspections FDA is carrying out. With that list, GAO estimated that FDA inspects about 8% of foreign establishments in a given year. “At this rate, it would take the agency more than 13 years to inspect these establishments once,” says the report. Compare this with FDA’s domestic inspection frequency of at least one inspection every 2.7 years.

Additional inconsistencies in the agency’s databases are tied to how FDA classifies its inspection results. From FY 2002 to FY 2007, FDA issued 15 warning letters to foreign establishments at which it identified “serious deficiencies,” according to the GAO report. They agency’s subsequent inspections of those 15 establishments only totaled 4, and that was 2 to 5 years later. And of those 4 inspections, FDA verified that corrective actions had been taken but that additional deficiencies were present.

Considering the industry’s current environment, with reports of contamination largely based in manufacturing establishments outside the US, foreign inspections that are efficient and frequent are more critical than ever. In this regard, GAO made the following recommendations for FDA in its report:

The FDA Commissioner should enforce the requirement that establishments manufacturing drugs for the US market update their registration annually.

The FDA Commissioner should establish mechanisms for verifying information provided by the establishment at the time of registration.

The FDA Commissioner should ensure that information on the classification of inspections with serious deficiencies is accurate in all FDA databases.

The FDA Commissioner should conduct more inspections to ensure that foreign establishments manufacturing drugs currently marketed in the US are inspected at a frequency comparable to domestic establishments with similar characteristics.

The FDA Commissioner should conduct timely inspections of foreign establishments that have received warning letters to determine continued compliance.

FDA is expected to comment on GAO’s recommendations, at which time GAO will follow-up its report with updated information.
    
  Read the 

GAO Criticizes FDA’s Foreign-Drug Inspection Process 

The US Government Accountability Office (GAO) released a report last week that examines and provides recommendations for the US Food and Drug Administration's foreign inspection process, including the agency's data management, inspection frequency, and oversight of problems identified during inspections.

GAO Recommends Ways to Improve FDA Foreign Inspections

Merck plans to cut approximately 7200 positions as part of its 2008 restructuring plan, according to an Oct. 22 press release focused on the company’s third-quarter financial results. The cuts, which will include 6800 active employees and 400 vacancies, are part of the company’s efforts to reduce costs. The staff eliminations will affect all areas of the company worldwide by the end of 2011, with about 40% of total reductions taking place in the United States, about 25% affecting senior and mid-level executives.

“Merck remains confident in the progress it is making in creating a new business model that is more customer-centric, more agile, and has a variable cost structure that enables investment in key growth areas such as research and development and new products and markets,” said the release.

 The 7000+ cuts are in addition to the 10,400 positions eliminated as part of Merck’s 2005 restructuring program, which was substantially complete at the end of September 2008.  As of Sept. 30, stated the release, Merck had approximately 56,700 employees.

The company plans to “make greater use of outside technology resources, centralize common sales and marketing activities, and consolidate and streamline its operations. Merck's manufacturing division will further focus its capabilities on core products and outsource non-core manufacturing,” said the release.

As part of these goals, three research sites will close by the end of 2009: Tsukuba, Japan; Pomezia, Italy; and Seattle. 

Merck expects its global restructuring program to be completed by the end of 2011, and total pretax costs are estimated at $1.6 billion to $2.0 billion. 

Merck plans to cut approximately 7200 positions as part of its 2008 restructuring plan, according to an Oct. 22 release focused on the company's third-quarter financial results.