Enforcement on Steroids: FDA Delivers Twice the Drug GMP Warning Letters

Enforcement on steroids: As expected, FDA enforcement went into overdrive last year. The warning letter rate doubled and punishments were swift and harsh. But that was just the beginning. The agency expanded its field force, and after a few years of training, its new investigators will bring it on. No more dithering about Form 483 findings. Import alert hits Apotex 10 days after inspection. KV gets consent decree just four weeks after inspectors find it failed to file field alerts. Ranbaxy ANDA reviews halted by FDA's GMP concerns, even though EU and WHO saw nothing wrong. FDA's criminal investigators will coordinate more with the rest of the agency and others. Last year's 34 warning letters harped on the same issues as before, but with a new focus on foreign API makers. FDA's new foreign offices focus on data integrity in India and GMPs in China. Congress showers FDA with money but further constrains its regulatory discretion. Expect Dingell's Globalization Act to decorate 2012 PDUFA Christmas tree

The Obama administration's FDA has delivered the swift and aggressive approach to enforcement of drug GMP requirements that it promised last year.

FDA more than doubled the number of drug GMP warning letters issued in the fiscal year ending Sept. 30, 2009. And the agency did not always wait for industry to respond to warning letters or Form 483 reports before taking enforcement action.

The annual drug GMP warning letter rate went from 15 in fiscal year 2008 to 34 in FY 2009, reaching levels not seen since the 58 letters in FY 2002, the last Clinton year (see chart: " ¹ FDA Drug cGMP Warning Letters From FY 2009").

[Editors Note: Last year "The Gold Sheet" counted 18 drug GMP warning letters in FY 2008. However, three were actually issued in FY 2009 (² (Also see "Drug GMP Warning Letters, Enforcement Could Rebound in Obama's FDA" - Pink Sheet, 1 Apr, 2009.)).]

More money in the FDA budget in FY 2009 has enabled the agency to hire additional inspectors and conduct more domestic and foreign inspections. Congress approved a similar increase for the FDA FY 2010 budget, and the administration's FY 2011 budget request calls for additional increases for inspections.

FDA officials also noted some common deficiencies they are finding in their inspections of manufacturing facilities both in the U.S. and overseas, including China and India.

Swifter, harsher enforcement demonstrated

Edwin Rivera-Martinez, the acting associate director of drug quality assurance for the division of manufacturing and product quality in FDA's center for drugs, demonstrated how the agency has begun to implement the enforcement initiatives Commissioner Margaret Hamburg announced last August. (³ (Also see "Hamburg Promises Quicker Enforcement as FDA Spews Warning Letters" - Pink Sheet, 1 Aug, 2009.)).

Rivera-Martinez provided an overview of Hamburg's initiatives and discussed the activities of FDA's foreign offices at the 34 International GMP Conference in Athens, Ga. The March 15-18 conference was sponsored by the University of Georgia College of Pharmacy, the Georgia Center for Continuing Education and FDA.

The initiatives include a 15-day limit for responding to Form 483 reports of inspectional findings and a decision to have FDA's Office of Chief Counsel review only those warning letters that involve significant legal issues, speeding the issuance of routine warning letters.

He explained that "when problems arise we expect a firm to work quickly and to thoroughly correct deviations to ensure product safety. The commissioner has said if they are crossing the line they will be caught, and if they fail to act the agency will act. In terms of our strategic mission, the agency must place a greater emphasis on significant risk and on violations and use meaningful penalties to send a strong message to discourage future offenses. FDA must be quick and respond quickly. No longer will you see warning letters issued six to eight months after an inspection. You are now seeing warning letters issued on a very timely basis."

Rivera-Martinez discussed the September 2009 import alert concerning products manufactured by Apotex facilities in Canada.

"That import alert was implemented 10 days after the completion of an inspection. We've never done that before. Generally, we place companies on an import alert after a warning letter. This inspection was completed on Friday. On Monday the FDA Office of Compliance International Alert Branch was on the phone with the executive officer and asked them what they intended to do with respect to the violations. They didn't take us too seriously. ... Things are changing folks, and you need to react a lot faster because FDA is moving a lot faster."

The July 27 to Aug. 14 inspection of Apotex's Toronto drug manufacturing facility that generated the import alert also resulted in a warning letter that FDA did not issue until March 29.

The import alert also applied to Apotex's Etobicoke, Ontario, facility, which was the subject of a June 25, 2009, warning letter, issued mainly for lax investigations and belated field alert reports (⁴ (Also see "Contamination Issues Featured in Second Quarter Warning Letters" - Pink Sheet, 1 Aug, 2009.).

Failure to file field alerts results in consent decree

Another example of FDA's speedier - and harsher - enforcement stance was exhibited in the KV Pharmaceuticals consent decree issued in March 2009 (⁵ (Also see "Drug GMP Warning Letters, Enforcement Could Rebound in Obama's FDA" - Pink Sheet, 1 Apr, 2009.)).

FDA issued that consent decree just four weeks after inspecting KV Pharmaceuticals' facility, Rivera-Martinez said. "For those of you who are ex-FDAers, this is record time."

On March 3, 2010, KV's Ethex Corp. generics subsidiary pleaded guilty for failing to inform FDA about manufacturing oversized tablets of two prescription drugs.

"This is criminal prosecution," Rivera-Martinez said. "They pleaded guilty to two criminal counts of failing to file field alerts with the FDA. So folks what does that say? If you do not file field alerts with FDA on a timely basis you can now be prosecuted for this. This is the first time I've ever seen a company be prosecuted for failure to file. field alerts on a timely basis."

"They also agreed to pay $25.8 million and forfeit $1.8 million in the investigation, which by the way is a very serious consequence for failure to file field alert reports."

A similar situation was illustrated on June 25, 2009, when at FDA's request, the U.S. Marshals Service seized drug products manufactured by Detroit-based Caraco Pharmaceuticals Laboratories Ltd. "This seizure occurred six weeks after the close of the 2009 inspection" that found unresolved GMP deficiencies. (⁶ (Also see "Hamburg Promises Quicker Enforcement as FDA Spews Warning Letters" - Pink Sheet, 1 Aug, 2009.)).

Caraco estimated that the value of the seized goods was between $15 million and $20 million.

The March 11 to May 12 inspection, which FDA said in its seizure press release "found unresolved violations of cGMP requirements," covered all of the company's quality and production systems, including apparently systems for controlling digoxin tablet thickness. The inspection generated a Class I digoxin recall of March 31 due to tablet size variation.

"This action clearly shows that FDA is fully committed to taking enforcement actions against firms that do not manufacture drugs in compliance with GMPs," Rivera-Martinez said. "It also sends a clear message that firms must pay and that firms must have corporate accountability in their manufacturing operations."

He also noted that FDA issued a warning letter to McNeil Consumer Healthcare just seven days after the close of inspection. The letter was issued on Jan. 15 over the handling of odor problems at its manufacturing facility in Las Piedras, Puerto Rico (⁷ (Also see "Data Integrity Problems Continued to Surface in Recent Warning Letters" - Pink Sheet, 1 Feb, 2010.)).

He warned that "you need to move faster because if you do not move the FDA will act."

GMP concerns led FDA to halt ANDA reviews

Rivera-Martinez also described how FDA's no-nonsense enforcement policy is being played out against companies that commit data fraud, and used the Ranbaxy case an example. FDA has been involved in a four-year tangle with Ranbaxy over the Indian firm's manufacturing sites.

The agency, he noted, took the unusual step last year of invoking its application integrity policy (AIP) against the firm (⁸ (Also see "Time Waits for No Lab, Ranbaxy Learns" - Pink Sheet, 1 Mar, 2009.)).

Rivera-Martinez said the agency rarely resorts to the AIP policy, which was last invoked "decades ago" during the generic drug scandal.

"Every few months there seems to be a new chapter added to this case. ... Once a company is placed on AIP, the FDA will cease all scientific review of pending applications from that facility. At Ranbaxy this involved 25 to 30 applications in the pipeline. This means that OGD ceases to review their applications. This action was taken because essentially the company had submitted untrue statements of material fact. What does that mean? They lied to us, that is what it means. They lied to FDA in their submissions to the agency. They submitted false and misleading stability data generated at the Paonta Sahib site. Of course this is very serious."

Ranbaxy's troubles were not yet over. In September 2008, FDA issued warning letters to the firm's Paonta Sahib and Dewas sites and placed products made at these sites on an import alert, saying Ranbaxy had fabricated stability data. (⁹ (Also see "Drug GMP Warning Letters, Enforcement Could Rebound in Obama's FDA" - Pink Sheet, 1 Apr, 2009.)).

To preserve the viability of some pending applications for generic drug approvals derailed by FDA's application integrity policy, Ranbaxy changed the proposed site of manufacture from Paonta Sahib to its Ohm Labs unit based in Princeton, N.J., despite higher manufacturing costs there.

However, in September 2009, FDA issued a warning letter to Ranbaxy's Ohm Labs facility in Gloversville, N.Y., over inconsistencies in adhering to the firm's stability protocols as well as data manipulation of out-of-specification results - the same problem that concerned the agency about its operations in India (¹⁰ (Also see "Data Integrity Problems Continued to Surface in Recent Warning Letters" - Pink Sheet, 1 Feb, 2010.)).

OCI needs to do a better job

Despite the agency's toughened enforcement stance with respect to warning letters and Form 483 reports, one area that needs improvement is FDA's Office of Criminal Investigations, says a report the General Accounting Office publicly released on March 4.

The GAO report found that although OCI maintains policies to guide its investigations, FDA's oversight of OCI's investigations of individuals and companies external to FDA is limited. And though FDA is supposed to assess OCI's six field offices to ensure compliance with investigative policies, this is not being done within prescribed time frames.

In response to the report, FDA Commissioner Margaret Hamburg outlined reforms planned for the Office of Criminal Investigations, including new criteria for selecting misdemeanor prosecution cases against responsible corporate officials.

In a March 4 letter to Sen. Chuck Grassley, R-Iowa, Hamburg said the criteria have been developed and will be incorporated into revised policies and procedures. The reform is one of several recommended by senior agency officials who served on an internal committee formed last August. The committee included top officials from FDA's device and other centers, OCI, the Office of the Chief Counsel and the Offiice of the Commissioner.

Hamburg's letter says the group recommended that FDA "increase the appropriate use of misdemeanor prosecutions, a valuable enforcement tool, to hold responsible corporate officials accountable."

The committee also recommended improved procedures for information sharing between OCI and other agency offices. The goal, Hamburg told Grassley, is to keep OCI apprised of emerging risks and regulatory policies and priorities.

Enhanced information-sharing with OCI would also help FDA's product centers and its Office of Regulatory Affairs allocate resources for inspections, risk communications and regulatory activities, including civil enforcement, according to the letter.

Hiring inspectors most exciting trend

Phil Campbell of FDA's Atlanta Regional Office told the Georgia GMP meeting that "the most exciting trend" he observed in FY 2009 was the jump in domestic and foreign drug manufacturing inspections, thanks to the budget increase. "This is a very positive and encouraging trend for us."

The total number of foreign and domestic inspections for all FDA-regulated products increased from 15,245 in FY 2008 to 16,236 in FY 2009. The total number of foreign inspections went from 947 in FY 2009 to 1,232 in FY 2009, according to Campbell.

The number of domestic inspections conducted for the Center for Drug Evaluation and Research increased from 1,770 in FY 2008 to 1,869 in FY 2009 and the number of foreign CDER inspections went up from 451 in FY 2008 to 623 in FY 2009.

A trend observed by Campbell is that on the domestic front, FDA is increasingly either finding more problems in inspections or issuing more 483 reports.

FDA issued Form 483 reports in 47 percent of domestic inspections in FY 2009, up from 42 percent in FY 2008 and 45 percent in FY 2007.

On the international front, FDA issued 483s in 54 percent of foreign inspections in FY 2009, the same as in the previous two years.

Warning letters continue to cite same issues

An analysis by "The Gold Sheet" of the top warning letter citations finds that the list of the top four problems is virtually unchanged from the previous fiscal year (see chart: " ¹¹ FY 2009 Drug GMP Warning Letter Cites ").

The most frequently cited GMP provision in warning letters that FDA issued in FY 2009 was Section 211.192, production record review. This citation was observed in 20 of the 34 letters issued by FDA that year. The year before, it was also the number one citation.

Assuming second place in FY 2009 was Section 211.22, quality control unit responsibilities, observed in 13 warning letters. Last year this citation was in fourth place, so QC management issues seem to be gaining more prominence in FDA inspections.

And dropping to third place was Section 211.100, written procedures and deviations, which was cited in 11 warning letters; last year it was in second place.

And in fourth place was Section 211.160, laboratory controls, observed in nine warning letters. Last year it was in third place.

New to the top 10 list was Section 211.113, control of microbiological contamination, which was cited in nine warning letters. In FY 2008 this problem was observed in just three. And falling off the list of the top 10 is Section 211.165, testing and release for distribution.

And while citations for Section 211.67, equipment cleaning and maintenance, were down in FY 2009, citations related to Section 211.166, stability testing, increased from two warning letters in FY 2008 to seven in FY 2009.

FDA's Campbell said that in his discussions with local staff, field investigators are most concerned with lack of out-of-specification and out-of-trend investigations, product and process development, inadequate process validation, quality assurance issues and training and change controls and revalidation and follow-up to corrective and preventive actions, with OOS and QA issues topping the list of concerns.

FDA warnings hit global supply chain

FDA inspections last year identified more problems in the global supply chain. Of the 34 warning letters issued in FY 2009, seven went to API manufacturers, up from three the year before, all of whom were outside the U.S. Two were in China, while India, Japan, France and Germany each had one. Notably, they were evenly split between developing and developed economies (see chart: " ¹² Drug GMP Warning Letters By Category ").

Manufacturers of oral solid dosage forms also received the highest number of warning letters in FY 2009, seven, followed by: manufacturers of topical products, four; oral liquids, three; injectables, three; repackers, two; veterinary, one; and biologics, one.

Types of Form 483 violations little changed

Iliena Barreto-Pettit, an investigator with FDA's Florida District, noted that, as in previous years, the types of violations listed in Form 483 reports have remained essentially unchanged since last year.

She has been conducting inspections for 10 years and has been comparing trends over recent years.

"Things have not changed and I don't know the root cause of that. I have been at this conference for the last five years ... we keep finding the same types of problems. You will not be finding anything new about what I tell you today."

Citing information from FDA's Turbo Establishment Inspection Report software system, which the agency started using in 2002, Barreto-Pettit said that the 10 drug cGMP observations with the most 483 citations recorded for calendar year 2009 were:

 

• Deficient quality control unit, 211.22(d);
• Inadequate laboratory controls, 211.160(b);
• Lack of follow-up procedures, 211.100(b);
• Failure to investigate batch failures, 211.192;
• Inadequate procedures to assure quality, 211.100(a);
• Inadequate control procedures and process validation procedures, 211.188;
• Inadequate equipment cleaning and maintenance, 211.67 (a);
• Cleaning and maintenance SOPS not followed, 211.67(b);
• Inadequate employee training, 211.25(a); and
• Batch production and control records, 211.188, a newcomer to the top 10.

 

Campbell observed that "nine of the 10 citations were the same as those listed" in 2008, with the exception of the last category, batch production and control records, which is a new citation.

He also noted that citations for inadequate equipment cleaning and maintenance has been increasing over the past few years and that citations for failure to clean and maintain equipment and utensils have been increasing.

In addition, citations for 211.67 (a), failure to clean and maintain equipment and utensils, increased over the past few years.

Injunctions increased

Campbell said that the number of injunctions at all FDA's centers increased from five in FY 2008 to nine in FY 2009. At CDER the number of injunctions rose from one in FY 2008 to three in FY 2009.

FDA seizures also increased from eight in FY 2008 to nine in FY 2009.

The total number of recalls issued by CDER also increased from 379 in FY 2008 to a whopping 1,984 for FY 2009.

The top reasons for recalls were: cGMP deviations, cited in 1,604 cases; unapproved drugs, 63; tablet thickness, 56; cross contamination with other products, 31; labelling and labelling mix ups, 26; impurities and degradation products, 19; microbial contamination of nonsterile products, 19; subpotency, 19; failed USP dissolution, 18; lack of sterility assurance, 14; defective delivery systems, 12; foreign substances, 12; labelling with wrong expiration date, six; and superpotency, six.

Foreign offices face daunting challenges

On the global front, Rivera-Martinez noted that FDA faces daunting challenges in its mission to monitor foreign imports and the threats they pose. The number of foreign sites making FDA-regulated drugs has more than doubled from 1,282 in 2001 to 2,820 in 2007.

He said that "with the challenges of globalization, there was growing recognition within FDA that to do our job more effectively at home, we've got to do our job more efficiently abroad."

He noted that the melamine in pet food and infant formula in China, oversulfated chondroitin sulfate in heparin API in China, diethylene glycol in cough syrup in Panama and DEG in toothpaste in China were some of the "wake-up calls" that led FDA to establish foreign offices in 2007 and 2008.

FDA now has three FDA offices in China, in Beijing, in Guangzhou and in Shanghai, and two offices in India in New Delhi and in Mumbai. In addition, an office has been set up in Latin America in Costa Rica and in Europe in Brussels.

FDA seeks further increase in foreign staff

In recognition of these growing global threats to the supply chain, FDA has requested funding in FY 2011 to increase its foreign inspectional presence.

FDA's Office of International Programs has placed staff at new foreign posts in China, India, Europe and Latin America. Altogether, the office had 22 FDA employees working in 12 foreign posts in FY 2009. The office plans to add three posts this year and two more in FY 2011.

FDA also wants $730,000 and three staff members to help foreign drug regulatory authorities monitor drug manufacturing facilities in their countries. This will involve training those authorities, collaborating with them, sharing information with them, and gaining better access to foreign manufacturing sites.

There would also be an additional $4.9 million and 21 employees to boost FDA's foreign inspections activities. In 2014 after they complete their training, FDA expects them to conduct 115 additional inspections per year, including 46 of drug manufacturing facilities.

Meanwhile, the Office of Regulatory Affairs has augmented FDA's foreign inspection program with a dedicated foreign drug cadre. The 15-member cadre was selected in January 2009 and began conducting inspections the following month. The cadre, which consists of 12 GMP specialists, an investigative analyst, a bioresearch monitoring specialist and a microbiologist, had completed 82 GMP surveillance, pre-approval and bioresearch monitoring inspections by the end of July 2009.

Foreign offices will not focus on inspections

Rivera-Martinez noted that FDA established these foreign offices not necessarily to conduct inspections but to engage in information sharing with other local regulators and industry.

"I have often heard people say that 'great now FDA has inspectors in all these field offices overseas and that means that will double or triple the number of foreign inspections.' That is not true. The primary mission of these foreign offices is not to conduct inspections. They are there for other purposes. They are there to work with counterpart agencies in country to gather better knowledge and intelligence about production of products for transport to U.S. ports. ... They are there to engage the public sector and third parties and to help build capacity. That is probably one of their primary functions to educate not only the regulators but the industry on how to comply with FDA regulations."

In general most inspections will continue to be conducted by inspectors travelling from the United States. "It simply means if there is another heparin crisis or another diethylene glycol crisis we can have people there at the plant in hours or days and not in months. That is basically the mission of these foreign offices. Don't expect a great increase in the number of foreign inspections ... most of these inspections overseas will be conducted by FDA inspectors flying over from the continental United States."

A mixed picture on international collaboration

Rivera-Martinez said that to meet the challenge of globalization, drug regulators are collaborating more to remove unsafe medical products from the pharmaceutical supply chain.

One example of such collaboration: New Zealand's drug regulator Medsafe issued a temporary import ban on Apotex based on the FDA import alert.

"They asked us what was going on with Apotex and based on that they imposed an import ban. This is showing what close cooperation is doing not only in inspections but in enforcement."

However, the full picture is a little more complex. For example, in November 2008, Ranbaxy's Paonta Sahib site was deemed generally acceptable by a team of six inspectors from the World Health Organization, Australia's Therapeutic Goods Administration and the UK's Medicines and Healthcare Products Regulatory Agency, which was there on behalf of the European Union.

That was just two months after FDA issued a warning letter and imposed an import ban on the facility.

WHO issued a statement about the team's favorable findings on Feb. 27, 2009, just two days after FDA invoked its application integrity policy.

Indian inspections focus on data integrity

Rivera-Martinez discussed the different areas of focus that FDA inspectors look at when auditing sites in India and China.

For example, in India, inspectors look closely at application integrity with respect to records, manufacturing systems and laboratory test results; manufacturing process robustness and whether the process has been validated; whether manufacturers have monitored the impurity levels in API and inactive ingredients; whether manufacturers have conducted stability studies and investigated out of specification incidents; and whether manufacturers have ensured that their supply chains are secure.

Rivera-Martinez said that data integrity problems "may stem from committing to unrealistic specifications, lacking manufacturing capacity, unhealthy market competition, poor record-keeping practices, and deliberate manipulation of documents and data."

Other problem spots with Indian manufacturing facilities, he noted, are "inadequate development work and gaps in knowledge management with respect to batch record details, which are not stated in the batch production records but left in related standard operating procedures."

Another problem is that the results of confirmatory in-process QC tests on which process decisions are based are not shown in batch production records or are not readily accessible. Also, batch records are not always complete and accurate.

Also, Rivera-Martinez noted that "price pressure may prompt a few firms to substitute inexpensive excipients or raw starting materials intermediates and APIs from unapproved or unqualified sources. Firms need to improve their vendor qualification procedures, annual vendor performance evaluation and requalification and the vendor disqualification criteria."

GMP concerns in China

Rivera-Martinez said that in China, some concerns are that "GMP concepts are new to most manufacturers in China and that GMP concepts have not yet reached the supply chain infrastructure."

China's State FDA launched a new quality system April 10, 2009, that requires companies to assign responsibility for drug manufacturing to a drug quality administrator.

"There are also concerns that there are dual GMP practices and standards, one for domestic products and the other for foreign products."

In China there are also concerns that many manufacturers are small, inefficient and non-competitive with many of these facilities owned by the state and "many are outside the regulatory reach."

There are also concerns that manufacturers do not have adequate systems for controlling the supply chain, a point that was illustrated by the heparin crisis.

FDA inspectors are also seeing inadequate quality management systems in China with respect to the handling and investigation of OOS deviations and out of trend results.

However, he pointed out that this problem is not unique to China and is being seen at other manufacturing sites worldwide.

Rivera-Martinez noted that of the 17 warning letters and untitled letters issued to manufacturers at foreign sites in FY 2009, half cited problems with OOS investigations. "This is a common theme that we're seeing."

Doubling of warning letters to foreign sites

Of the warning letters FDA issued in FY 2009, 13 went to foreign sites in FY 2009, twice the number in FY 2008, Rivera-Martinez said.

The most common cGMP deficiencies tabulated in its Foreign Inspection Team (FIT) database in fiscal year 2009 were:

 

• deficient quality assurance system, 11 percent;
• lack of or inadequate SOPs, 11 percent;
• failure of OOS investigations, 9 percent;
• equipment cleaning and maintenance, 8 percent;
• analytical methods validation, 7 percent;
• lab records and reports, 6 percent;
• lab controls, 5 percent;
• production and record reports, 5 percent;
• process water systems, 4 percent;
• complaint investigations, 4 percent; and
• employee training, 4 percent.

 

"Lab controls continue to be the most significant in terms of cGMP deviations. This has not changed over the years as long as I have been in international compliance. Year after year this seems to be the number one GMP deficiency in the international arena. This is not that different from the domestic arena."

Infusion of money a welcome change

FDA has been more amply funded by Congress compared to past years, in recognition of the agency's need to inspect a growing inventory of product.

Peter Barton Hutt, an attorney with the Washington law firm of Covington and Burling, who held the post of chief counsel of FDA from 1971 to 1974, said that the infusion of money is a welcome change after years of flat budgets.

Hutt was one of the co-authors of a Science Board Report issued in 2008 that warned that lack of adequate funding was undermining the agency's ability to keep up with the current level of domestic and foreign inspections that is required by laws.

"The overall FDA budget was flat while user fees were going up. What do you think is the impact of that? What do you think that did to CFSAN over 20 years? They lost 15 percent of the people who were in food ... The field force which I always described is the heart of FDA. If you eviscerate the field force you eviscerate FDA."

As a result of the report, there was bipartisan agreement that FDA funding had to increase. "Today the FDA budget has doubled in appropriations from $1.3 billion in FY 2007 to $2.5 billion in appropriations, and user fees are on top of that."

FDA was given substantial increases in both the FY 2009 and 2010 budgets, allowing it to expand its inspectional capabilities. And the 2011 budget request builds on these and promotes other initiatives in the area of product safety.

FDA funding for FY 2009 increased by $325 million over fiscal 2008 levels. The FY 2009 Omnibus Appropriations Act provided FDA with a total of $2.6 billion in FY 2009, 19 percent more than the agency had to spend in FY 2008. The legislation directed FDA to spend $114.2 million of the increase on medical product safety. Direct appropriations included $413.5 million for human drugs, with $302.4 million for CDER and $111.1 million for field activities; and $183.5 million for biologics, with $148.1 million directed to CBER and $35.3 million for field activities.

FDA was given another 19 percent increase in its FY 2010 budget. A portion of the budget included a $166 million initiative aimed at ensuring supply chain safety and security for medical products. Activities targeted by the safety initiative include: development of a database to reliably inventory firms, facilities, products, product components and ingredients; more inspections of all entities in the supply chain; and better coordination with foreign regulatory authorities.

The agency's FY 2011 budget request calls for a 23 percent increase over the FY 2010 budget.

The "protecting patients" initiative, one of four in FDA's FY 2011 budget request, includes several elements in the drug manufacturing oversight arena.

Import safety is a major focus of this initiative. It includes $3.3 million and six staff members for FDA's ongoing efforts to build an electronic drug registration and listing system that will help the agency screen out illegal imports and to validate the system against the commercial Dun & Bradstreet database.

The agency is looking to win approval from Congress for generic drug user fees that will enable it to ramp up its reviews of abbreviated new drug applications at a time when many blockbusters are expected to come off patent.

The user fees are expected to generate revenue for, among other things, six inspectors who, once they are fully trained in FY 2013, will conduct 54 pre-approval inspections of domestic generic drug manufacturing facilities annually.

FDA noted in the FY 2011 budget request that it plans to propose legislation allowing the agency to collect user fees covering the cost of re-inspecting facilities after they addressed findings in FDA Form 483 reports and warning letters. This is expected to save the agency $27 million in FY 2011 alone.

The agency is budgeting $13 million and 56 employees for this function, including 21 inspectors. Once they are fully trained, they should be able to conduct 329 domestic medical product re-inspections.

Congress co-opting FDA's regulatory discretion

Despite the additional funding for FDA inspections and its stronger enforcement muscle, Hutt noted that the agency still faces resource and enforcement challenges.

He called attention to the workload Congress imposed by enacting 125 FDA-related statutes over the past 20 years.

"There is no way that any government agency can comply with six new statutes every year right across the board, food, drugs and cosmetics. ... In fact FDA has not implemented many of these statutes because it did not have the resources to do so."

Hutt said another challenge looming over the agency is the encroachment upon its regulatory discretion by congressional legislation that is increasingly prescriptive.

He noted that the original Food, Drug and Cosmetic Act of 1938, "one of the most important statutes ever enacted in America," was just 19 pages long.

The 1962 amendment that required good manufacturing practices "was 17 pages long and it transformed the way that drugs are regulated in the U.S. today and around the world."

Those groundbreaking statutes "were drafted in broad and general mandates, and FDA was told to make sure that the food and drug supply was safe. That is no longer true."

Consider, he said, that the FDA Modernization Act of 1997 is 94 pages, and the FDA Amendments Act of 2007 is 154 pages.

As an example of Congress' new, more prescriptive approach, he called attention to the 30-page provision in FDAAA that called for risk evaluation and mitigation studies, or REMS.

"The broad and general terms are no longer there." There is no need for FDA to write the regulation - it is all right there in the statute, dictated by Congress, he said. "This means the agency flexibility and discretion has been gradually reduced by Congress deciding on how FDA should be run rather than by leaving it to FDA. This is a serious impact."

Globalization Act back in play

However, not all legislation is bad in Hutt's view. He hailed Rep. John Dingell's Globalization Act, H.R. 759, as "a monumental piece of legislation."

The House Energy and Commerce Committee last year passed the food-related portion of the Michigan Democrat's bill, which is awaiting Senate action.

The committee on March 10 held a hearing as it began to work on advancing the bill's drug-related provisions.

At the hearing, Dingell got FDA Deputy Commissioner Joshua Sharfstein on the record supporting the bill's key provisions.

The bill would require drug and active ingredient manufacturers to pay an annual registration fee to defray the cost of surveillance inspections in the U.S. and abroad. Currently, FDA is supposed to inspect every domestic facility every two years. The bill would apply that requirement to foreign facilities as well. However, it would let FDA relax inspection frequency to four years for facilities it considers less risky.

The bill would allow FDA to mandate drug recalls, which have always been voluntary.

It would also allow FDA to destroy adulterated, misbranded or counterfeit drugs caught at the border.

It would add criminal penalties of up to 20 years in prison for drug counterfeiters as well as stiff fines for improper importers.

The bill would also require the use of quality risk management plans.

The most likely trajectory for passage would be for the bill to get rolled up into the next five-year reauthorization of the Prescription Drug User Fee Act, which Congress will want to pass before the current PDUFA legislation expires in 2012.

Hutt explained that PDUFA "has been known as a Christmas tree. Every member of Congress puts their own ornament on the tree and it becomes a major, major piece of legislation."

- Joanne S. Eglovitch ( ¹³ [email protected])