For Pharmaceuticals:

An Analysis of Heparin, Accountability and
Pre-emption: Where Are We Now?
Christine Humphrey, Esq., Fuerst Humphrey Ittleman

First in a two-part series, (second part)

The “discussion draft” of the FDA Globalization Act of 2008 is the result of a congressional focus on global imports – this proposed Act was triggered by the importation from China of contaminated raw material for heparin.  The heparin tragedy was not surprising in light of the Government Accounting Office’s (GAO) reports  that the FDA has been lacking in its ability to control foreign inspections of both device and drug manufacturers. The most recent GAO reports of late, in 2007 and 2008, demonstrate a continued lack of FDA control over foreign manufacturing operations for nearly 10 years. 

The pre-approval process that drug and device manufacturers must go through will be greatly affected by the proposals found in the FDA Globalization Act of 2008 and the affects will not be limited to foreign manufacturers.  The costs associated with research and development and proposed user fees will affect domestic manufacturers’ ability to bring new products to market and obtain timely pre-approval inspections.

Another related topic concerns the recent Medtronic decision and the issue of pre-emption. The Medtronic decision affectively holds that FDA “approved” products are shielded from state tort law claims.  However, the reality is that FDA has a clear track record of being unable to effectively conduct pre-approval inspections and so the degree of consumer protection afforded by FDA “approvals” is highly suspect.  In October 2008, the Wyeth case will be heard and is a pre-emption case that this article will discuss as well.

The current pre-emption case law relies heavily on FDA’s ability to affectively “approve” the products it regulates – the heparin tragedy clearly demonstrates the agency’s inability to do this in the foreign market.  As this article discusses these issues of heparin, accountability and pre-emption -  the critical points of the “discussion draft” of the FDA Globalization Act of 2008 will be analyzed as well as how that Act that may affect pre-approval inspections and FDA’s regulatory authority.

Heparin

Beginning in January 2008, Baxter Healthcare Corporation (Baxter) recalled various lots of heparin, a blood thinning drug, following a spike in reports of adverse events, including 81 deaths and thousands of severe allergic reactions associated with the product.  

After three months of investigation, FDA working independently and in collaboration with the Centers for Disease Control and Prevention, Baxter, and many other private and public entities reported that they established a link between a contaminant found in heparin, oversulfated chondroitin sulfate, and the serious adverse events seen in patients given heparin.  

A study published online April 23 by the New England Journal of Medicine also concluded that the manmade oversulfated chondroitin sulfate, which is very hard to detect in heparin, was the likely cause of the severe anaphylactoid reactions that occurred after the intravenous heparin was administered to patients in the US and Germany.

The raw material was shipped to the U.S. from the Chinese facility, Changzhou SPL, a firm owned jointly by the U.S. firm Scientific Protein Laboratories and Techpool, a Chinese firm that gathers raw heparin from a number of workshops that extract the material from the mucus linings of pig intestines. The contaminating ingredient, oversulfated chondroitin sulfate, is now thought to have been added intentionally because the contaminating ingredient is 1000% less expensive. The Chinese government disputes that the exported product was to blame for the deaths.

Through a chain of human and computer errors, Changzhou SPL did not undergo a pre-approval inspection by the FDA in 2004, as was the agency's intention.  The FDA has “requested” the facility’s inspectional data and has “requested” expedited access to the facility and is making preparations to inspect the facility. 

The FDA cites a lack of explicit jurisdiction as limiting its ability to investigate overseas offenders that violate the FDCA because the conduct occurs entirely outside the territorial jurisdiction of the U.S.  For example, foreign firms can often deny U.S. officials access to their facilities without any adverse consequences. FDA has requested that the FDCA be amended to provide for explicit extraterritorial jurisdiction for conduct that occurs outside the US where products subject to the FD&C Act are intended to be imported into the US. 

For now, it is the FDA Globalization Act of 2008, sponsored by Congressman Dingell, that is on the table – and it attempts to address the missteps that allowed these lapses to happen by requiring, in part, all drug, medical device and food manufacturers operating within the U.S. or exporting products to the U.S. to register annually with the FDA. Registration would require the payment of a fee, and the $300 million that would result from these user fees would allow inspections to be performed once every two years.

The FDA has taken steps to address the problems, having announced in March its intention to establish an office in China.  Also, on April 30, the agency launched a hiring initiative for more than 1,300 biologists, chemists, statisticians and investigators.

Unfortunately, nearly half of the new hiring is the result of one-time increase in user fees under the PDUFA reauthorization.  However, this hiring initiative is widely misunderstood to represent a substantial increase in agency-wide resources – the reality is that this hiring will not significantly increase the  agency's abilities to inspect manufacturing plants overseas. The actual net increase in appropriated staff is probably more in the range of 200 new people. 

The heparin case demonstrates FDA’s inherent weaknesses in its ability to adequately oversee foreign drug production. The contaminant was traced to 12 different Chinese companies and it has been found in heparin batches in 11 different countries.  The suppliers of raw material to the affected facility in China were not registered with the FDA; the agency’s Information Technology systems are unable to identify and track the facilities in China and the movements of their products. Considering that 80% of all Active Pharmaceutical Ingredients (APIs) used by U.S. drug manufacturers are imported, mainly from India and China, the environment is ripe for another catastrophe. 

FDA Response to Heparin

FDA’s Janet Woodcock described FDA’s efforts as far-ranging but a significant problem is that these efforts are reactive and the use of post-marketing surveillance through adverse event reports and a reactive deployment of a team of experts and development of new test methods using state-of-the-art technologies is not a solution.  These are reactive measures and the entire premise of pre-approval inspections is to be proactive. The FDA Globalization Act of 2008 would require importers who lack documentation relating to identity, safety and purity to ship/import only through ports that have federal testing laboratories.  The Act would also require manufacturers of drugs and drug ingredients to test for contaminants.

On the domestic front, FDA effectively regulates because the FDCA requires it.  70 years ago no drugs were being made and imported into the US.  The 1938 amendments authorized FDA to examine imported drugs at the border and refuse entry to any drug that “appeared” to be in violation of the FDCA.  That law placed the responsibility on the FDA to catch a problem and stop the drug’s entry into our country, as opposed to asking the foreign manufacturer to demonstrate that they were taking care to follow established standards for drug production. So, while domestic drug manufacturers are held to a high standard of drug safety, with regular GMP inspections, foreign producers often need worry only about the remote possibility that an FDA inspector at a border crossing will find a problem and stop the drug’s entry.

FDA recently initiated an Import Alert to ensure that all imports of heparin are analyzed – it requires examination and sampling of all heparin sodium API imports – except – where FDA knows the recommended tests will be conducted. It is extremely difficult to believe the FDA could “know” when a test would be conducted when the FDA does not even “know” where APIs are coming from.  For over 400 ports of entry, FDA has only 450 inspectors, meaning that most ports are not staffed at all and many can be staffed only part time.  The use of an Import Alert that mandates required testing for one API does not address the issue of how to effectively regulate API imports as a whole.

The FDA Globalization Act of 2008 would require parity between foreign and domestic inspections – meaning that FDA would be required to inspect foreign and domestic drug and device facilities every two years and prohibit a firm from introducing a drug or device until an initial facility inspection is conducted.

Could FDA have Prevented the Problem?

FDA claims that conducting a pre-approval inspection of the Chinese facility in 2004 would not have made a difference in curtailing “intentional” contamination.  In addition, the FDA points out that the contamination was not limited to the un-inspected facility. 

Amid FDA’s contention that it could not have prevented “intentional” contamination is the issue of heparin labels.  Dennis Quaid testified on Capital Hill last month after his children were given the wrong dosage of heparin – a bottle containing 10 units of heparin looked very similar to a dark blue 10,000-unit bottle, especially when turned.

Baxter Healthcare Corporation had already submitted label changes to FDA and had sent out warning letters to hospitals, but they did not recall the products that were still on the shelves.  Could the FDA have prevented this problem? 

The FDA Globalization Act of 2008 would extend recall authority to drugs as well as provide administrative detention authority over drugs – two authorities that currently exist for the regulation of medical devices.

Accountability

A 1998 and 2008 GAO report highlights continued weaknesses in FDA databases.  FDA does not know how many foreign establishments are subject to inspection. Instead, FDA relies on databases that were not designed to capture establishments that are subject to inspection. 

The data that GAO looked at in 2007, included data from the Drug Registration and Listing System (DRLS), the Field Accomplishments and Compliance Tracking System (FACTS), and the Operational and Administrative System for Import Support (OASIS). GAO found that the data did not reflect all foreign establishments whose drugs are imported into the United States.

One database indicates there were about 3,000 foreign establishments registered to market drugs in the United States in fiscal year 2007, while another indicates that about 6,800 foreign establishments actually imported drugs in that year. Because the databases cannot exchange information, any comparisons of the data are performed manually, on a case-by-case basis.  Risk based analysis is difficult to achieve when you have inaccurate data. 

FDA inspects relatively few foreign establishments. Data from FDA suggest that the agency may inspect about eight percent of foreign establishments in a given year. At this rate, it would take FDA more than 13 years to inspect each foreign establishment once, assuming that no additional establishments require inspection.

The foreign inspection process involves unique circumstances that are not encountered domestically. For example, FDA relies on staff that inspects domestic establishments to volunteer for foreign inspections. Unlike domestic inspections to monitor the quality of a marketed drug, FDA does not arrive unannounced at a foreign establishment. It also lacks the flexibility to easily extend foreign inspections if problems are encountered, due to the need to adhere to an itinerary that typically involves multiple inspections in the same country. Finally, language barriers can make foreign inspections more difficult than domestic ones. FDA does not generally provide translators to its inspection teams. Instead, they may have to rely on an English-speaking representative of the foreign establishment being inspected, rather than an independent translator.

There really is no consideration for geographic location, manufacturing complexity and final product sensitivity.  Currently, FDA focuses generically on the product – the process and the facility.  So for example, prescription drugs are a priority over OTCs, intravenously administered drugs trump prompt release tablets and recently inspected firms are lower priority than those that have not been inspected. 

Foreign Drug Establishments

If you look at the number of foreign drug establishments and the number of establishments inspected, you can see a great disproportion.  This does not even take into account medical devices.

Many in industry have voiced great displeasure with this proposed requirement for various reasons.  In order to properly consider changes to the FDA inspection process for drugs and devices, it is important to first understand the broad range of drugs and devices.  This understanding is important as it logically leads to a view that different types of drugs and devices warrant various levels of regulation.  The law currently anticipates these differences with respect to, for example, market access.  OTC drugs and prescription drugs are regulated much differently as are Class I, II, and III devices.

It is argued that implementation of a system that mandates inspection across the board of all OTC and lower risk devices would actually harm the public health, by drastically slowing the introduction and availability of improved medical devices. For example, FDA currently conducts pre-approval inspection of approximately 50 class III devices a year, and preapproval inspection is appropriate for these high risk devices.  If FDA conducted pre-approval inspections of the 3,600+ class II devices, the approval process would likely grind to a halt.

Additionally, many in industry do not believe that the case has been made for an exponential increase in FDA inspections of domestic drug and device facilities because there is no documented public health and safety benefit. 

The generic drug industry is concerned that the increased emphasis on foreign inspections will negatively impact the timely availability of pharmaceuticals. Generic applications already are backlogged at the FDA, with the average review and approval time for Abbreviated New Drug Applications (ANDAs) now approaching 20 months, according to the Office of Generic Drugs. This is a delay of more than a year longer than the six-month statutory approval period specified by the Hatch-Waxman Act.

1 Draft Discussion of the ‘Food and Drug Administration Globalization Act of 2008’, H.R. 110th Cong. (2008).
2; See Drug Safety: Preliminary Findings Suggest FDA Initiatives Have Potential, but Do Not Fully Address Weaknesses in Its Foreign Drug Inspection Program, Before the H. Subcomm. On Oversight and Investigations, H.Comm. On Energy and Commerce, 110th Cong. (2008) (statement of Marcia Crosse, Dir. of Health Care GAO); FDA Faces Challenges in Conducting Inspections of Foreign Manufacturing Establishments, Before the H. Subcomm. On Health, H.Comm. On Energy and Commerce, 110th Cong. (2008) (statement of Marcia Crosse, Dir. of  Health Care); Challenges for FDA in Conducting Manufacturer Inspections, Before the H. Subcomm. On Oversight and Investigations, H. Comm. On Energy and Commerce, 110th Cong. (2008), (statement of Marcia Crosse, Dir. Health Care).
3 Drug Safety: Preliminary Findings Suggest FDA Initiatives Have Potential, but Do Not Fully Address Weaknesses in Its Foreign Drug Inspection Program, Before the H. Subcomm. On Oversight and Investigations, H.Comm. On Energy and Commerce, 110th Cong., 18 (2008) (statement of Marcia Crosse, Dir. of Health Care GAO)
4,; Riegel v. Medtronic, Inc., 128 S. Ct. 999 (2008).
5; Id. at 1011.
6;See Wyeth v Levine, 128 S. Ct. 1118 (2008) (granting petition for writ of certiorari).
7; Takashi Kei Kishimoto et al., Contaminated Heparin Associated with Adverse Clinical Events and Activiation of the Contact System, New Eng. J. Med. (April 23, 2008). Available at http://content.nejm.org/cgi/content/short/358/23/2457.
8; The Heparin Disaster: Chinese Counterfeits and American Failures, Before the H. Subcomm. On Oversight and Investigations, H. Comm. On Energy and Commerce, 110th Cong. (2008) (staff testimony).
9; Draft Discussion of the ‘Food and Drug Administration Globalization Act of 2008’, H.R. 110th Cong. §§ 101, 201 (2008).
10; The Heparin Disaster: Chinese Counterfeits and American Failures, Before the H. Subcomm. On Oversight and Investigations, H. Comm. On Energy and Commerce, 110th Cong. (2008) (staff testimony).
11; See Drug Safety: Preliminary Findings Suggest FDA Initiatives Have Potential, but Do Not Fully Address Weaknesses in Its Foreign Drug Inspection Program, Before the H. Subcomm. On Oversight and Investigations, H.Comm. On Energy and Commerce, 110th Cong. (2008) (statement of Marcia Crosse, Dir. of Health Care GAO); FDA Faces Challenges in Conducting Inspections of Foreign Manufacturing Establishments, Before the H. Subcomm. On Health, H.Comm. On Energy and Commerce, 110th Cong. (2008).
12; See Draft Discussion of the ‘Food and Drug Administration Globalization Act of 2008’ Legislation: Drug Safety, Before the H. Subcomm. On Oversight and Investigations, H. Comm. On Energy and Commerce, 110th Cong. (2008) (statement of Dr. Janet Woodcock, Dir. Center for Drug Evaluation and Research, FDA) available at http://www.fda.gov/ola/2008/heparin042908.html.
13; Draft Discussion of the ‘Food and Drug Administration Globalization Act of 2008’, H.R. 110th Cong. § 111 (2008).
14; Id. at § 112.
15; 21 U.S.C. § 381.
16; FDA, Import Alert 66-40 (March 10, 1998) available at http://www.fda.gov/ora/fiars/ora_import_ia6640.html.
17; Draft Discussion of the ‘Food and Drug Administration Globalization Act of 2008’, H.R. 110th Cong. § 202 (2008).
18; See GAO, Food and Drug Administration: Improvements Needed in the Foreign Drug Inspection Program, GAO/HEHS-98-21 (March 17, 1998); Drug Safety: Preliminary Findings Suggest FDA Initiatives Have Potential, but Do Not Fully Address Weaknesses in Its Foreign Drug Inspection Program, Before the H. Subcomm. On Oversight and Investigations, H.Comm. On Energy and Commerce, 110th Cong. (2008) (statement of Marcia Crosse, Dir. of Health Care GAO).
19; Drug Safety: Preliminary Findings Suggest FDA Initiatives Have Potential, but Do Not Fully Address Weaknesses in Its Foreign Drug Inspection Program, Before the H. Subcomm. On Oversight and Investigations, H.Comm. On Energy and Commerce, 110th Cong. 2-3 (2008) (statement of Marcia Crosse, Dir. of Health Care GAO).
20;Id. at 8.
21; Id.
22; Id.

Christine M. Humphrey, Esq., is a founding partner of Fuerst Humphrey Ittleman. Having 14 years of Food & Drug Administration (FDA) experience, and working inside of the FDA for 10 years, Ms. Humphrey focuses her legal practice on FDA matters, including domestic and foreign inspections of all FDA-regulated products; import and export processes; criminal, regulatory and administrative actions; risk management and regulatory due diligence. Contact her at chumphrey@fuerstlaw.com

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FDA Links:

Information on Heparin
http://www.fda.gov/CDER/drug/infopage/heparin/default.htm