Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

As part of ongoing efforts to improve the quality of imported drug products, the US Food and Drug Administration is setting up shop in China. After finally receiving approval from the US State Department, FDA is making plans to establish eight full-time permanent positions at US diplomatic posts in China. The only potential hold-up is getting permission from the Chinese government.

If all goes well, FDA plans to fill the eight posts within the next 18 months. An additional five staff-all to be local Chinese nationals-will be hired to work with the new FDA staff at the US Embassy in Beijing and the US Consulates General in Shanghai and Guangzhou.

 “In an age when a border is not a barrier, the globalized economy demands nothing less than heightened regulatory interoperability, information exchange, and cooperation, especially on product quality and enforcement matters,” said FDA’s Murray M. Lumpkin, MD, deputy commissioner for International and Special Programs, in an agency release. “Along with the important 

 signed with two FDA counterpart Chinese agencies, our efforts to fill permanent FDA positions in China are a significant step toward ensuring access to safe food, drugs, and medical devices in the global market.”

 The China-based offices are only the beginning of FDA’s new “Beyond our Borders” initiative, which was 

. The program is meant to give the agency a greater presence and capacity abroad, starting with China. Four other regions will be targeted as well: India, the Middle East, Central America, and South America.

According to the agency news release, the China-based offices will also allow greater access for inspections and greater interactions with manufacturers to help assure that products imported into the US meet FDA standards. 

Senator Chuck Grassley (R-IA) supports FDA’s expansion of overseas efforts. On Mar. 11, he proposed the use of registration fees as a way to help pay for more inspections of pharmaceutical drug manufacturers abroad and to limit the number of facilities that may register with the FDA without any intention of shipping products to the US. According to a 

 he wrote to the agency’s commissioner and the US Secretary of Health and Human Services, medical device makers located outside the US are required to pay registration fees to FDA, under the Medical Device User Fee and Modernization Act (MDUFMA), and in accordance with a congressionally established schedule of registration fees. For FY 2008, MDUFMA registration fees are $1,706 and set to increase to $2,364 in FY 2012. 

“There is currently no corresponding requirement that establishments involved in the production of drugs or active pharmaceutical ingredients pay registration fees,” wrote Grassley. “Though only a beginning, requiring registration fees for these establishments may help bolster the FDA’s inspection capacity while also reducing the number of establishments that register without shipping products to the United States.” Such fees could have a potentially huge impact given than there may be as many as 6800 foreign pharmaceutical manufacturing facilities importing products into today’s US market. 

Articles

As part of ongoing efforts to improve the quality of imported drug products, the US Food and Drug Administration is setting up shop in China.

"China, Here We Come," Says FDA

With another potential “made-in-China” crisis looming over the recall of heparin, critics and the media seem to be waiting in line to take another jab at the US Food and Drug Administration. Rather than hiding behind FDA’s doors, Commissioner Andrew von Eschenbach took the opportunity to talk to the National Press Club last Friday. In a speech titled “FDA at a Turning Point: Meeting the Challenge of a Rapidly Changing World,” Von Eschenbach addressed head on FDA’s faults and what’s needed to “re-create” the agency.

single American in terms of our health and well-being,” he told the audience. “Change is affecting 

 from the food we eat to the drugs and medical devices we depend upon. These changes are impacting the Food and Drug Administration and our ability to continue to fulfill our mission to protect and promote the health of every single American.”

The Commissioner discussed how advances in science and technology, along with transportation, information, and globalization, have impacted health. “The simple truth as I see it today is that the FDA of the 20th century is not adequate to regulate the food and drugs of the 21st century.”

 He went on to describe the larger-than-life agenda set before the agency, whose staff and resources continue to be overloaded and underfunded. The American public sometimes forgets that FDA is in charge of regulating nearly all the food we eat, vitamins and dietary supplements, all types of medical products from aspirin and biologics to cardiac pacemakers and surgical masks, radiation-emitting equipment such a microwaves, cosmetics, and typical drugstore items such as toothpaste and deodorant. This list doesn’t even include the products FDA regulates for animals such as products from pet food.

To keep up this work in an efficient manner and meet growing demands, Von Eschenbach outlined a five-step transformation the agency has gone through-and will continue to go through-over the past two years. These steps are outlined below.

Focus      on the priority areas, including issues of drug safety, food protection,      the scientific foundation for regulatory decisions, work force      development, and essential infrastructure including facilities and      information technologies.

Use      a disciplined process for problem assessments and interventions.  

Develop      implementation plans for each of these strategic initiatives. One such      plan, Response to the IOM Drug Safety report, was issued last year and      some of its initiatives already have been implemented, such as the      creation of a Risk Communication Advisory Committee. A new initiative      called Safety First was launched last week to address processes for      multidisciplinary determination of risk.

Continue      a series of external and internal consultations to assess work force      numbers and skill sets. The agency plans to hire 700 new employees this      year and will be launching a two-year FDA Fellowship training program for      as many as 2000 individuals. Related projects include a $250 million      information technology infrastructure project and new integrated data      center. 

Change      policy.  “FDA can no longer be      simply a gatekeeper assessing benefit and risk before allowing a product      to be delivered to patients or the public, or to rely solely on      inspections to verify quality,” said Von Eschenbach. “It must engage in      the Total Life Cycle of the product…. Engaging in stages of discovery,      development and delivery of products we regulate will enable us to better      assure quality.” Targeting the delivery end of the life cycle, a program      called the Sentinel Initiative will soon serve to improve collaboration      between public and private partners to create a nationwide system that      will allow FDA to analyze large databases about “the safety of medical      products as they are used by large diverse populations.”

In further collaborative efforts, Von Eschenbach discussed a new “FDA beyond our Borders” program. This effort is meant to give the agency a greater presence and capacity abroad, starting with China. Four other regions will be targeted as well: India, the Middle East, Central America, and South America. The initiative will allow FDA to “regulate products where they are produced, before they arrive at our borders,” by expanding interaction with foreign regulators, among other things, he said. The same life-cycle approach will be applied to imported products with a focus on new products and high-risk products.

The work of the US Working Group on Import Safety, chaired by Health and Human Services Secretary Mike Leavitt, played a role in the “beyond borders” program idea. The working group was established last spring after several reports of contamination were tied to products made in China. 

All of these efforts are meant to “re-create” and improve the agency in a way that “enhances discovery, development and delivery of lifesaving products,” Von Eshenbach said in his closing remarks. “I am aware of the need for radical and rapid change.”

With another potential "made-in-China" crisis looming over the recall of heparin, critics and the media seem to be waiting in line to take another jab at the US Food and Drug Administration.

FDA to Undergo Transformation, Expand Borders

The US Food and Drug Administration released a final guidance on a protocol for testing sterile products. Rather than using sterility testing as part of the stability protocol, sterile product manufacturers can use container and closure system integrity tests, and therefore avoid validation tests for individual products with the same type of container. 

“If you manufacture a number of products that use the same type of container and closure system, you may validate your integrity test method using a bracketing matrix,” reads the final guidance. “It is not necessary to perform validation studies on each product.” 

Container and Closure System Integrity Testing 

 of Sterility Testing as a Component of the Stability Protocol for Sterile Products

,” provides for final clarification of the January 1998 draft guidance of the same name. 

The guidance recommends that manufacturers include container and closure system integrity tests in stability protocols for new marketing applications. Recommended tests include: validated physical or chemical container and closure system integrity methods such as bubble tests, pressure/vacuum decay, trace-gas permeation/leak tests, dye penetration tests, seal force or electrical conductivity and capacitance tests. Microbiological container and closure system integrity tests include microbial challenge or immersion tests. For media-filled containers, the guidance says, “It may be acceptable to use media-filled containers instead of product-filled containers for testing during the product’s shelf life or dating period if the product contains a material, such as a preservative, which would bias the results of the container and closure system integrity test.” 

“If you currently perform sterility testing as a stability-indicating test as part of a stability protocol, you may continue to do so,” reads the guidance. FDA states that the advantages of using container and closure system integrity tests 

Such alternate methods may detect a breach of the container and/or closure system prior to product contamination

Some of the alternate methods used to evaluate container and closure integrity can conserve samples that may be used for other stability tests 

Alternative test methods may require less time than sterility test methods which require at least seven days incubation

The potential for false positive results may be reduced with some alternative test methods when compared to sterility tests. 

Companies that incorporate a validated container and closure system integrity test to demonstrate the continued capability of containers to maintain sterility for an approved product, need to submit a “Special Supplement–Changes Being Effected (CBE)” drugs or a “Supplement–CBE” for biologics. 

The US Food and Drug Administration released a final guidance on protocol for testing sterile products.

Stability Testing Guidance Finalized

-The US Food and Drug Administration issued a draft guidance for industry titled “Good Reprint Practices” regarding the distribution of medical or scientific journal articles and reference publications that involve unapproved uses of FDA-approved drugs and medical devices.

  “Articles that discuss unapproved uses of FDA-approved drugs and devices can contribute to the practice of medicine and may even constitute a medically recognized standard of care,” said Randall Lutter, FDA deputy commissioner for policy, in an agency release. “This guidance also safeguards against off-label promotion.”

  Industry has been asking for clarification of “off-label” use since late September, when Section 401 of the Food and Drug Administration Modernization Act expired. Section 401 provided guidelines allowing the dissemination of information on unapproved uses of FDA-approved products. 

 While the new draft guidance answers this call, some individuals claim the language may be too simple, and that it has been released too quickly. Rep. Harry Waxman (D-CA), chairman of the House Oversight and Government Reform Committee, wrote FDA Commissioner Andrew von Eschenbach twice in the past few months, questioning the way in which the agency was pursuing the guidance. He said he had “significant concern” about the guidance proposal as it would “allow drug and device companies to use journal articles to promote potentially dangerous uses of drugs and medical devices without prior FDA review and approval.” Rep. Waxman and others also speculated that industry representatives have been pushing the agency to release the guidance, according to a Jan. 22 BusinessWeek article and other media reports.

 Rep. Waxman has said that the rule would give pharmaceutical companies too much leeway with off-label use and marketing. Compared to Section 401, the draft guidance seems to allow for easier dissemination of articles on unapproved uses of drugs and may encourage companies to carry out fewer clinical studies.

 Specifically, the draft guidance gives manufacturers just a few principles to follow when distributing scientific or medical journal reprints, articles, or reference publications. For example, the draft guidance calls for manufacturers to ensure that the article or reference be published by an organization that has an editorial board, and disclose any conflicts of interest for all authors or contributors to the article. In addition, articles should be peer-reviewed and published in accordance with specific procedures such as with a bibliography, but without any highlighting or summarizing by the manufacturer.

 The draft guidance does warn against distribution of special supplements or publications “that have been funded by one or more of the manufacturers of the product in the article,” as well as against articles that are “not supported by credible medical evidence.”

 FDA still has authority over whether or not a distributed article violates the Federal Food, Drug and Cosmetic Act.

 Public comments on the draft guidance are due within 60 days of its appearance in the 

(see Feb. 20 edition),  to Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD  20852.

, Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Devices.

The US Food and Drug Administration issued a draft guidance for industry titled "Good Reprint Practices" regarding the distribution of medical or scientific journal articles and reference publications that involve unapproved uses of FDA-approved drugs and medical devices.

FDA to Allow Off-Label Information

A follow-on biologics approval pathway may be on the way. US Health and Human Services Secretary Mike Leavitt accepted Sen. Charles Schumer’s (D-NY) suggestion that the US Food and Drug Administration and Congress work together to formulate legislation for such a pathway. 

President George W. Bush’s fiscal year 2009 budget-which proposed a 5.7% increase from FY 2008-included funding for a follow-on biologics approval pathway (see 

 story), which is to come from user fees. But Schumer says the pathway must also allow products to be approved as interchangeable and grant innovator products “a reasonable period of exclusivity” so that follow-on biologics, or biosimilars, can be brought to market quickly, according to the Feb. 8 

.
 
 “It is an encouraging sign that the administration not only included this proposal in its budget, but is prepared to sit down with Congress to figure out how to make the approval process work for manufacturers and the American people,” added Schumer.

A biosimilars pathway has been on the radar for some time. In early 2007, Senators sponsoring the Biologics Price Competition and Innovation Act 2007 attempted to establish a follow-on biologics approval pathway. The pathway  failed to get into the FDA Amendments Act, which passed in Sept. 2007 (see 

). The House has also introduced similar bills, such as HR 1038.

A follow-on biologics approval pathway may be on the way. US Health and Human Services Secretary Mike Leavitt accepted Sen. Charles Schumer's (D-NY) suggestion that the Food and Drug Administration and Congress work together to formulate legislation for such a pathway.

Proposed Biosimilars Legislation Makes Progress

The US Food and Drug Administration is requesting a 5.7% increase in its budget between the current fiscal year, FY 2008, and FY 2009, for a total $2.4 billion budget. The increase includes $1.77 billion in budget authority and $628 million in industry user fees, and would cover the period Oct. 1, 2008–Sept. 30, 2009.

In addition to cost-of-living increases for FDA employees, the budget proposal includes strategic increases to “strengthen food protection, modernize drug safety, speed approval of generic drugs, and improve the safety and review of medical devices,” according to an agency press release. 

“The FDA is committed to protecting and promoting the health of the American people,” said Commissioner Andrew C. von Eschenbach. “This budget enables us to continue development of the staff and programs necessary to safeguard the food we eat and improve the safety and development of drugs, vaccines, devices, and other medical products.”

Specifically, the budget proposal includes $42.2 million for FDA’s Protecting America’s Food Supply initiative, and $17.4 million ($79 million in user fees) for the agency’s medical product safety and development initiative. FDA and industry are currently discussing the terms of a generic drug user fee program that could begin in FY 2009. Also of note, approximately $9 million in the budget is being generated by recent FDA investments that the agency wishes to reinvest in priority food safety and medical product programs.

The agency is expecting an additional 526 full-time staffers in FY 2009 to focus on priority areas such as “food defense and food safety, and drug, blood, and human tissue safety programs.” FDA also plans to beef up its high-risk food inspections in the United States and abroad.

Despite the proposed increase in budget and staff, the 

  said it is disappointed in FDA’s FY 2009 proposal, according to a Feb. 5 article in 

. With 170-plus members including former FDA commissioners and former Health and Human Services secretaries, the alliance notes the recent reviews and criticisms of FDA’s work and urges a much higher number. “The amount in the administration’s proposed budget is not only inadequate, it is barely half of what FDA needs just to keep pace with inflation,” said Alliance Spokesperson William Hubbard, a former FDA Deputy Commissioner.

The President’s FY 2008 budget will be reviewed by both Congressional houses this spring. 

The US Food and Drug Administration is requesting a 5.7% increase in its budget between the current fiscal year, FY 2008, and FY 2009, for a total $2.4 billion budget.