Jill Wechsler is Pharmaceutical Technology Europe's Washington Editor, jillwechsler7@gmail.com.

Jill Wechsler

The American Society of Mechanical Engineers' Council on Codes and Standards established an ad hoc committee to examine whether a standard to create uniformity and consistency in the bioprocessing industry is needed. This article describes the goals and current activities of the standards committee and its subcommittees.	

On 20 June 1989, the American Society of Mechanical Engineers' (ASME) Council on Codes and Standards issued a directive to the Board on Pressure Technology Codes and Standards to form an 

 committee to investigate and catalogue the biopharmaceutical industry's concerns about inconsistencies. Thus, the Bioprocessing Equipment (BPE) Standards Committee was formed and immediately met to establish a path forward. The committee, consisting of end-users, equipment manufacturers or suppliers, drug manufacturers, distributors and engineers, met in New York City at the ASME headquarters to discuss the need for a standard that could bring clarity and consistency to the bioprocessing industry and end miscommunications, misunderstandings, misinterpretations and ambiguities in the applicable entities. 	

It was agreed that the six parts of the new standard would be identified by the following titles and subcommittee designations:	

Dimensions and tolerances for stainless steel automatic welding and hygienic clamp tube fittings

Stainless steel and higher alloy interior surface finishes

The first edition of the ASME BPE standard was issued on 17 October 1997, followed by a second edition in 2002. The standard gives the industry a level playing field for the sector's engineers, manufacturers and end-users. It addresses the needs of those who purchase, specify and manufacture biopharmaceutical production equipment. The standard also provides a method of ensuring that the design, production and installation of bioprocessing equipment, tubing, fittings and components are consistent and uniform. 	

The number of subcommittees has recently increased from the original six to 10, with the addition of the European, Polymers and Elastomers, Accreditation, and Metallic Materials of Construction subcommittees. What follows is an update regarding their current activities and a look ahead at their future challenges.	

 This subcommittee is developing a list of documentation that may be included in a turnover package. Contractors and owners will be able to review this list and decide which documents are needed.				

 The focus of this subcommittee is both clean-in-place and pure-water systems. Its goal is to record and depict solid designs that are agreed upon by the industry. The basics will be covered in the 2005 edition of the standard.	

 Subcommittee members are reviewing the standardization of face dimensions of hygienic clamp fittings, hygienic clamp nominal envelopes and angles. They are considering the same angle/slope on concentric/eccentric reducing fittings as are the Deutsche International Norm (DIN) and the International Organization for Standardization (ISO) for generating a shorter overall dimension. Members are also evaluating the need for a shorter ferrule length and are working with the Equipment Seals Subcommittee to establish seals dimensions to lessen or mitigate seal intrusion into the pipe stream.	

 This subcommittee is developing a standardized weld log for consistent, recordable data and formatting. This log will be similar to the standardized ASME Section IX, "

Weld Procedure Specification and Procedure Qualification Record

," because it will lessen the need to search the form for specific data. Thus, required data and their locations will be consistent.	

 Members of this group are evaluating the need to create colour photographs that depict various defects found on process surface finishes. This action will simplify the interpretations of written standards across the industry.	

 This subcommittee is working on defining the criteria for integrating hygienic clamps into pipe streams. These criteria will be created in conjunction with a hygienic clamp type-fitting standard that is being developed by the Dimensions and Tolerances Subcommittee.	

 A section about polymers and elastomers will be the standard's newest addition. It will describe practices for the use of polymer-based materials that have demonstrated the ability to attain cleanability and sterility as they relate to bioprocessing equipment. The committee is currently working on the application of polymer materials and how they relate to fire codes and fire safety issues in compliance with regulations for all new buildings.	

In addition, the committee is interested in incorporating these codes and standards into the BPE and is adding other items such as flexible hoses that will have additional applications (silicon rubber or tubing type applications, for example). This new section will be included in the 2004 addendum to the standard.	

 Buying equipment from a manufacturer that is well versed in the standard's requirements is essential for establishing clear communication. However, some manufacturers claim to conform to the requirements, when in fact they do not. For this reason, a subcommittee has been established that will research the methods of accrediting manufacturers. Similar to the way in which ASME authorizes manufacturers that produce ASME Section VIII pressure vessels to hold a "U Stamp," companies that claim to provide equipment and components to the BPE standard will be required to pass an accreditation process.	

 This newly formed subcommittee was created to address European philosophies and methods and to evaluate issues that are of concern to the European biopharmaceutical industry. Its intent is to add European design, installation methods, philosophies, and terms and definitions to the standard.	

 A new section of the standard that will address metallic construction materials is under development. This subcommittee will help clarify weld and surface finish criteria for metals other than 316L stainless steel. This will include nickel-based alloys as well as stainless steels that are more commonly used in Europe. 	

In addition, the committee is researching whether recommendations for improvements to pharmaceutical equipment design are needed, particularly in the areas of active pharmaceutical ingredients and personal care products.	

The next edition of the BPE standard is scheduled to be released in 2005 and will continue to provide uniformity and consistency for international biopharmaceutical equipment and system design. However, significant challenges will accompany the committee's plans for a wider scope and global expansion. For instance, the standard must gain worldwide recognition and acceptance while existing in harmonization with other recognized regulations. 	

Articles

The American Society of Mechanical Engineers' Council on Codes and Standards established an ad hoc committee to examine whether a standard to create uniformity and consistency in the bioprocessing industry is needed. This article describes the goals and current activities of the standards committee and its subcommittees.

Uniformity of Bioprocessing Equipment Manufacturing

The US Food and Drug Administration (FDA) is proposing a multifaceted approach to halt the spread of counterfeit drugs in the US that centres on establishing an electronic tracking system able to ensure product integrity. At the same time, FDA is requiring drug manufacturers to add linear barcodes to containers and packages of drugs going to hospitals (see sidebar "FDA requires barcodes on hospital drugs"). The barcode initiative aims to promote patient safety, but could delay efforts to adopt e-chip tracking technology. Moreover, the voluntary nature of the anticounterfeit initiative has raised complaints that it is inadequate to ensure the safety of the nation's drug supply. Ironically, successful implementation of this plan to identify and block distribution of bogus medicines could remove obstacles to broader importing of lower-cost prescription products. 	

The task of implementing these policies will fall to others at FDA, following the appointment of commissioner Mark McClellan to be administrator of the Centers for Medicare and Medicaid Services (CMS) in the Department of Health and Human Services (HHS). A top priority for the Bush administration has been to name a knowledgeable and credible individual to begin implementing the Medicare prescription drug benefit and quell complaints from seniors before the November elections. 				

A physician and economist, McClellan knows a lot about drug pricing and reimbursement and their impact on biomedical innovation. He shaped health policy for the White House as a member of the Council of Economic Advisors before coming to FDA in late 2002 and advised the administration in crafting the Medicare bill. 	

In shifting McClellan to CMS, the administration also calculated that FDA could weather the change. Deputy commissioner Lester Crawford served as FDA acting commissioner before McClellan's arrival, a period that saw him launch FDA programmes to modernize good manufacturing practices (GMPs) and consolidate biotech therapies with drugs. Recently, he has been heading up food and animal safety and antibioterrorism initiatives - prime HHS concerns. 	

McClellan made the smart move last autumn of detailing Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), to the Office of the Commissioner (OC) to help implement many of his risk management and strategic plan initiatives. Now Crawford has asked Woodcock to remain as one of three acting deputies instead of returning to CDER in April as planned. Woodcock will be deputy for operations; Murray Lumpkin deputy for special programmes; and Amit Sachdev deputy for policy.	

Woodcock says she can extend her OC stay because CDER is in good hands under acting director Steven Galson. The main priorities for Galson are to continue integrating biologics staffers into CDER, plan for the centre's move to new offices next year and to deal with the constant lawsuits related to generic drugs. Among many initiatives, Woodcock remains in charge of GMP modernization, developing guidance on protein characterization, and crafting a policy for generic - or follow-on - biologics, which is expected this spring. 	

Although FDA will continue to function well, McClellan's departure leaves a big hole at the agency. An outspoken and highly visible commissioner, he advocated for policies to spur medical innovation and gain more equitable global drug pricing. He did not shy away from controversial issues, as seen in his campaign to block drug importing and illegal Internet sales. He leaves FDA with a mountain of unfinished business, but with its drug approval and oversight systems in good shape. He also sets a high standard for future commissioners who want to leave a mark on FDA and the pharmaceutical industry. 	

FDA's report, "Combating Counterfeit Drugs," combines incentives for adopting new product authentication and tracking technologies with proposals to stiffen legal authorities and expand educational efforts to stem the flow of bogus drugs into the US supply system. The centrepiece of the plan is to encourage manufacturers, distributors and pharmacists to adopt a new drug "track and trace" system in 4 years. The envisioned system would use embedded radio frequency identification (RFID) chips that would record data on a drug product's movement from plant to pharmacist and ultimately to the patient. In addition to thwarting illegal operators, the e-tracking system could improve inventory control programmes for all parties and make it easier to recall products that develop safety problems.				

FDA sidesteps some of the more controversial issues that arose at its October 2003 open meeting on drug counterfeit proposals (Pharm. Technol. Eur. 15(12) 22–24 [2003]). Most notably, the agency is not requiring manufacturers to put finished dosages in unit-of-use packaging, as advocated by some pharmacists and providers. FDA officials acknowledge that such a change could enhance patient safety, but decided that it would not control counterfeiting enough to warrant the cost for manufacturers. For now, FDA is encouraging manufacturers to analyse the costs and benefits of unit-of-use packaging, starting with newly approved drugs, injectibles and the products most likely to be counterfeited. FDA also supports independent efforts to develop standards on the size, shape and organization of unit packaging that could reduce costs. 	

Similarly, FDA is not requiring manufacturers to adopt any specific anti-tampering packaging or product authentication systems, such as holograms, coloured labels and chemical markers. Such approaches may be helpful in preventing counterfeiting, but FDA believes that there is no one "magic bullet" able to foil illegal operators sufficiently to justify specific mandates. Moreover, agency officials fear that recommending any one product authentication technology would only alert counterfeiters to industry practices, and could also stifle further innovation. Manufacturers, instead, should explore the range of anticounterfeiting technologies to determine which best fits the specific product and dosage form and the company's capabilities. 	

To spur adoption of new technologies for existing products, FDA says it will review its policies on postapproval manufacturing changes. The agency plans to issue guidance on how companies can adopt anticounterfeit packaging and labelling changes without the need to obtain prior FDA approval, possibly through a changes-being-effected supplement or notification in an annual report. 	

The prospect of establishing a national electronic tracking system for all prescription drugs in four years is prompting FDA to once more postpone plans to implement the paper pedigree system required by the Prescription Drug Marketing Act (PDMA) of 1987. After several delays because of high costs and technical difficulties, FDA was scheduled to launch the paper pedigree system on 1 April. Instead, the agency is backing this new electronic approach as a better way to meet PDMA objectives, but will reassess in 2006 whether industry is progressing sufficiently to keep paper pedigrees on hold. 		

Manufacturers and wholesalers have begun feasibility studies of RFID systems, notably a pilot test by wholesaler McKesson for Wal-Mart. RFID tracking involves inserting tiny electromagnetic chips with unique mass serialization numbers that carry an electronic product code (EPC) in drug labels and packages. When incorporated into systems with data readers and computer information bases, the chips automatically authenticate and track products moving through the distribution system, creating a de facto electronic drug pedigree. RFID chips can hold much more data than barcodes and do not have to be read manually by scanners. 	

Next year, FDA expects that manufacturers will begin applying RFID chips to pallets, cases and packages of pharmaceuticals most likely to be counterfeited, and that wholesalers, chain drug stores and some hospitals will begin acquiring and installing information systems able to read and use this tracking information. An FDA timeline calls for these actions to be extended in 2006 to more products, pharmacists and hospitals so that there is a full RFID tracking system in place in 2007. 	

During this process, FDA will examine whether it needs to revise rules for labelling, electronic records and adherence to good manufacturing practices (GMPs) to accommodate new technologies. Another task is to ensure that any electronic tracing system complies with patient privacy protection policies. FDA and manufacturers are also examining whether RFID systems present any pharmaceutical safety issues. Researchers are conducting stability tests on drugs with labels or containers that have chips and will test if frequency emissions from chips could affect sensitive biotech products. 	

In announcing the anticounterfeit plan, McClellan noted that the private sector - and not FDA - should establish and maintain the e-tracking database. FDA expects all stakeholders will help develop standards for unique mass serial numbers to identify a pallet, case or package; protocols for reading tags; and compatible software requirements to ensure system interoperability. Manufacturers should also work with FDA and other members of the supply chain to address regulatory and economic issues that could delay adoption of the RFID tracking approach. 	

In addition to encouraging technological innovation, FDA proposes changes in laws and policies to further deter production and distribution of counterfeit products. These include 				

Stiffer criminal penalties. FDA is asking the US Sentencing Commission to increase jail terms for drug counterfeiters. Currently, making a counterfeit drug brings only a 3 year maximum sentence, compared with up to 10 years for counterfeiting a drug label. 

Stronger state wholesaler regulation. The National Association of Boards of Pharmacy (NABP) has issued revised model rules for wholesalers that FDA would like states to adopt. 

Broader input on counterfeit activity. A counterfeit alert network will collect reports on counterfeit incidents from national health organizations, consumer groups and industry, and disseminate FDA alerts to members and subscribers. 

Identification of likely counterfeit targets. Some states and organizations are developing lists of those high-priced, high-volume and scarce products most likely to attract counterfeiters. Pharmacists and providers feel that such lists should also include therapies likely to cause the most harm if counterfeited, such as AIDS and cancer treatments and injectibles. FDA supports compilation of a national list by NABP and other stakeholders to avoid redundancies and to help the public identify suspect products, but prefers that private organizations lead this effort. 

Heightened security. FDA is promoting secure business practices and expects to develop guidance for industry on securing facilities and production sites. FDA also plans to increase site inspections of drug re-packagers, which have served as an avenue for counterfeits to enter the supply chain. FDA advises firms to name a high-level individual or team to co-ordinate anticounterfeiting activities and to check the legitimacy of suppliers and other business partners.

International co-operation. FDA also plans to collaborate with international organizations in identifying counterfeiters and establishing tracking systems. The agency is supporting efforts headed by the World Health Organization and will work more closely with the Permanent Forum on International Pharmaceutical Crime and the Interpol Intellectual Property Crimes Action Group to implement worldwide anticounterfeit drug strategies.

Another FDA goal is to increase public information on the dangers of counterfeit drugs. The agency plans to issue more advisories on buying drugs safely through the Internet, an activity that also supports its campaign to halt the sale of illegally imported drugs through the Internet. 				

While not all illegal imports are counterfeits, Internet purchasing opens the door for bogus products to enter the US market (see sidebar "Counterfeit or just illegal?"). The surge in shipments of unauthorized drugs to US customers has prompted an FDA crackdown. An agency "sting" operation in January netted evidence of counterfeit and misbranded products being mailed to Americans and led to actions against Texan importers. The tension heated up in February when several state and local governments launched new efforts to help citizens obtain drugs from Canada. Members of Congress threatened to block McClellan's appointment to CMS until he explained his anti-import stance. 	

Data from IMS Health shows that sales of prescription drugs reimported from Canada to the US topped $1 billion in 2003 compared with $500 million in 2002. The growth trend may level off as manufacturers limit sales to Canadian mail order pharmacies shipping products to the US. Pfizer informed several Canadian firms in February that it would cut off supplies, similar to earlier action by GSK.	

While Congress debates drug import proposals, FDA analysts are examining what resources the federal government would need to make drug reimporting safe, as required by the new Medicare reform legislation. HHS established a drug import task force to examine these issues publicly. A main argument against importing is that FDA has no way to ensure that a product from Canada is genuine and has been shipped and handled correctly, and an electronic tracking system could reduce this concern.  	

FDA relies on e-chips to thwart bogus products, and drops paper pedigrees and unit-of-use packaging.

McClellan Moves to Block Counterfeits and Require Barcodes Before Leaving FDA

Federal health officials are taking steps to establish national electronic medical records and health information systems. The aim is to improve patient care by making it easier for health care professionals to access information regarding medical products and patient health issues. Prescribing drugs electronically is a key element, critical in reducing medication errors and improving compliance. 	

The US Food and Drug Administration (FDA) has launched an ambitious programme to support these efforts, beginning with a new rule requiring drug manufacturers to file product labelling information electronically. The agency is developing systems for the e-submission of applications for testing and marketing new drugs, and for capturing new drug use information. These initiatives will help build databases on product safety, efficacy and quality to provide the public with timely information concerning medication use through the National Library of Medicine.	

These programmes build on a series of FDA policies issued during recent years to clarify how industry may submit required regulatory documents in electronic format. In January 1999, FDA published a guidance regarding formatting e-submissions, which was updated in a new draft guidance published last October (2003). A November 1999 guidance addresses submitting abbreviated new drug applications (ANDAs) electronically. Last August (2003), the agency issued recommendations for electronic filing of the common technical document (CTD); this establishes a novel format for registering new drugs around the world based on recommendations from the International Conference on Harmonization (ICH). ICH agreements are also changing FDA policies for the e-submission of postmarketing expedited safety reports and for periodic adverse drug event (ADE) reports. In addition, the agency expects that a recent clarification of its electronic records and signatures policy under Part 11 will help manufacturers develop electronic record keeping and filing systems. Separately, the Bush administration seeks to improve  public health by encouraging lower drug prices, an issue that has entered international trade talks (see sidebar "Trade negotiations"). 	

Until now, FDA e-submission programmes have been voluntary for pharma companies. The agency has been working to formulate uniform standards and terminologies for submitting electronic data to help manufacturers develop information systems that can interrelate. The aim is to be able to capture complex information regarding medical products, practices and health conditions, and transfer the data over secure networks. 				

FDA officials are moving forward with mandated electronic data submissions, starting with drug labelling information. The agency issued a final regulation in December (2003) requiring manufacturers to submit the content of the package insert or professional labelling in electronic format, including all text, tables and figures (www.fda.gov/OHRMS/DOCKETS/98fr/03-30641.htm). The rule establishes a standard format for filing market applications and supplements for new drugs and biologics, including generic drugs. 	

The aim is to improve the review process and speed up dissemination of labelling changes and important product information to doctors and patients. The data will become part of an electronic library of labelling information for all FDA regulated products, which will make it easier for people to search for information on drug side-effects, comparisons with other drugs and product benefits. FDA is collaborating with the National Library of Medicine's DailyMed project, which will provide medication information to the public. 	

In announcing the e-labelling requirement at the December (2003) meeting of the National Council on Patient Information and Education (NCPIE), FDA commissioner Mark McClellan observed that "using modern information technology (IT) to improve public health is no longer optional at FDA." He expects the new programme will allow manufacturers to quickly provide FDA with updated information on drug risks and benefits. That information will then help physicians and consumers make "head-to-head comparisons between drugs so that they can make the best choices," he noted. The new initiative is "the first step in developing an e-library of all FDA labels that can be readily searched and used by professionals and consumers alike," and reduce the need for doctors to search through thousands of pages in reference books. 	

As far as new mandates go, this one is not highly controversial. Most large pharma companies have been voluntarily submitting labelling information electronically for some time, and the technical process for doing so uses portable document format (PDF), which is inexpensive and widely available. FDA reserves the right to recommend new file formats and software in the future in response to technological advances, but promises to consult with industry and to provide ample warning before making any changes. 	

The agency published a proposed e-labelling rule last May, received only a few comments and finalized the proposal with little change. The e-labelling requirement becomes effective in June and only applies to the content of the package insert, including references in annual reports, and not to all the various types of labels on packages and containers or those submitted with advertising material.		

FDA officials anticipate that this policy will greatly facilitate its review of thousands of labelling changes submitted each year. When a manufacturer files even a minor change in professional labelling, the agency has to conduct a manual word-for-word comparison using two paper copies.	

Still to come are further regulations for restructuring the content of professional drug labelling to make it more readable and useful to prescribers. A related initiative aims to replace paper package inserts with electronic information. Pharmaceutical manufacturers back this campaign and have been working to reduce opposition from pharmacists. Tests of a paperless labelling system are under way. 	

The e-labelling rule is just one part of a broader FDA strategy for spurring development of a national electronic health information system. At a speech before the Urban Institute in Washington DC, McClellan described his vision for using modern IT to collect and analyse ADE information and thus deliver "safer, higher value and less costly medical care." These initiatives include the following:				

Electronic data systems for clinical trials. FDA is collaborating with the National Cancer Institute (NCI) to establish the Cancer Biomedical Informatics Grid featuring an electronic system for submitting and evaluating cancer trial information. A first step, announced in November (2003), is to implement a system for electronically submitting investigational new drugs (INDs) for cancer therapies to FDA. This will build a system that will link cancer researchers across the US to FDA, allowing e-submission of clinical data. FDA will be able to review these applications faster, speeding new treatments to patients at a lower cost. 	

The larger goal for FDA is to use this experience with NCI and cancer therapies "as a model for how we manage information across all the different therapeutic areas and in every clinical trial," McClellan said. Working in the cancer area will further this effort because many cancer researchers and NCI cancer co-operative groups currently use advanced information systems. Investigators in these groups are already entering clinical information electronically, providing evidence of how this process can speed up the clinical trial process and more readily provide information to drug developers and FDA reviewers. 	

In addition to enhancing FDA's review process, e-information from clinical trials will accelerate clinical research by allowing researchers to quickly obtain answers to questions regarding test treatments. Research information data banks can also provide useful information concerning the benefits and risks of drugs to patient subgroups, including racial and ethnic minorities, women, children, seniors and others. 	

Pharmacogenomic information analysis. FDA issued a proposal in November (2003) to encourage drug researchers to share with it information on how genetic differences cause patients to respond differently to therapies (www.fda.gov/cber/gdlns/pharmdtasub.pdf). Drug manufacturers are collecting more pharmacogenomic (PG) data, but are reluctant to submit it for fear that it might raise "red flags" for the regulators. The draft guidance clarifies when such data should be filed as part of a new drug application (NDA) or biologic licence application (BLA). 	

The agency also defines another pathway for providing research information, separate from official submissions, to help improve regulatory processes and inform the research community. This involves using electronic information systems to analyse large amounts of data that can then be made available to the medical community. FDA says it will combine PG information submitted electronically to camouflage the sponsor while generating useful information on which treatments are likely to be more effective or more safe for certain patients. 	

Tracking drug products. FDA is finalizing a proposal issued last year requiring national product codes on all prescription drugs, biologics and blood products to prevent errors in dispensing and administering them. Implementation requires establishing large data banks to collect and distribute product identification information. The regulation is expected to encourage hospitals and clinics to adopt barcode readers and electronic record systems able to scan and interpret drug barcode information.	

Drug barcoding may also help curb the distribution of unapproved and illegal drug products. FDA's counterfeit drug task force is encouraging a number of technologies, including electronic "track and trace" systems that are able to follow a drug from manufacturer to end-user. Use of radio-frequency identification systems and barcodes to establish electronic pedigrees is being encouraged, replacing cumbersome paper-based systems. Manufacturers are testing new tracking technologies and exploring approaches for establishing integrated databases that can be used at all stages of the drug distribution system. 	

Increased information on ADEs. To ensure the safe use of medical products after approval for market, FDA is expanding its current spontaneous ADE reporting system and adopting innovative statistical methods that are able to identify "signals" of drug problems more quickly. However, because this voluntary reporting system is fairly limited, the agency also wants to establish broader active surveillance systems to improve its capacity for detecting drug safety issues. Some initiatives involve linking directly into the electronic medical record systems of health care plans to scan medical records for signals that could indicate problems with new products. Once hospitals and physicians establish electronic medical records systems, ADE reporting could become automatic. 	

Electronic prescribing systems. The emergence of low cost web technologies and increased use of palm-sized devices among physicians promises to boost e-prescribing, thereby reducing errors and improving treatment decisions. Although e-prescribing is currently used for less than 10% of drug prescriptions, McClellan estimates that its implementation across the US could eliminate more than 2 million ADEs annually. 	

FDA's e-labelling policy will encourage e-prescribing, McClellan believes. In addition, an important but less noticed provision in the recently approved Medicare reform bill supports development of e-prescribing programmes. Although the legislation stops short of mandating that health plans and providers adopt such systems, the measure provides strong incentives to do so. It instructs the Department of Health and Human Services (HHS) to establish e-prescribing standards, the first of which will be developed in 2 years with input from standards organizations, providers, pharmacists and pharmacy benefit managers (PBMs). HHS will conduct a one-year pilot in 2006 to test the system and issue final standards in 2008 (see sidebar "New faces at HHS"). 	

The bill also provides grants to assist prescribers with installing e-prescribing programmes and, more importantly, allows Medicare managed care plans and pharmacy plan operators to pay bonuses to doctors and hospitals that participate in e-prescribing. One year after adoption of final standards, all Medicare providers will have to follow the new standards if they want to use e-prescribing systems. E-prescribing is expected to encourage physicians to comply with drug formularies to improve patient safety, quality of care and yield cost savings.  	

FDA is expanding electronic data submission programmes to improve regulatory operations, and ensure appropriate and safe drug use.

Electronic Information Systems Promote Drug Development and Patient Safety

This year has been one of tremendous activity at the US Food and Drug Administration (FDA) and other government agencies involved with health care, biomedical research and national security. Scientists completed sequencing the human genome, setting the stage for a period of important new medical therapy development. Efforts to protect the nation from biological warfare created pressures to produce new vaccines and medical treatments able to counter biological, chemical and radiological attacks (see sidebar "Combating bioterrorism"). 	

The need to make prescription drugs more affordable for all Americans has shaped a wide range of policy initiatives. Leaders in Congress and the White House tackled the daunting task of crafting a prescription drug benefit for the nation's 40 million plus Medicare beneficiaries. FDA has taken steps to bring new generic drugs to market, while also struggling to stem public access to less expensive but unregulated medicines from abroad. The overarching goal is to make it easier for manufacturers to translate new biomedical discoveries into safe and effective treatments that will be more affordable for consumers. 	

In his first year in office, FDA commissioner Mark McClellan tackled a host of thorny issues head-on. He unveiled a raft of initiatives designed to streamline FDA internal regulatory procedures, encourage innovation in pharmaceutical manufacturing and clarify requirements for testing new therapies (see sidebar "Consolidating drug oversight"). A prime goal has been to reverse the recent slowdown in new drug applications (NDAs) for important new treatments. FDA approved only 17 new molecular entities (NMEs) in 2002, a drop compared with previous years; the numbers are up so far this year, spurring hopes for further gains. 				

In January, the commissioner announced the Improving Innovation in Medical Technology plan, which aims to reduce the costs and delays in drug development by clarifying the regulatory standards and test data required by FDA to approve an NDA in only one review cycle.1 A key element of the scheme is "root cause analysis," designed to help manufacturers develop and submit sufficient test data in initial applications to reduce the need for lengthy and costly multicycle reviews of market applications. The agency is also writing more guidance documents to better define requirements for testing new treatments for diabetes, cancer and obesity - top priority disease areas for all government health agencies. 	

At the same time, FDA officials continued to implement a 2 year campaign to overhaul agency regulations governing good manufacturing practices (GMPs). Launched in August 2002, FDA unveiled several new initiatives in February (2003), followed by further announcements in September.2–4 The GMP update is revising policies governing electronic records and signatures; manufacturing plant inspection programmes; and post-approval manufacturing changes. It aims to encourage manufacturers to adopt new production technologies that can reduce manufacturing costs and better ensure product quality. 	

An overriding theme in McClellan's initiatives is to apply risk management methods to FDA policies and programmes, a concept that he explained further in FDA's Strategic Action Plan, issued in August (2003). Risk management involves targeting FDA's limited resources to best protect public health at the least cost. The agency wants to focus more oversight on higher risk products and processes, while also crafting policies that encourage voluntary compliance. Initiatives that reduce the time, cost and uncertainty of new drug development can improve public health, according to McClellan, by reducing the cost of medical product development and thus helping consumers access effective new treatments. 	

FDA seeks to apply risk management approaches to ensure the safe use of medical products by patients. In April, the agency held a 3 day workshop to examine ways of discovering and managing potential adverse drug events (ADEs). FDA officials, manufacturers and health professionals commented on agency proposals for testing new products more extensively before they reach the market to better identify and study possible safety problems. Participants also discussed how manufacturers could develop pharmacovigilance plans to detect and analyse safety issues that appear after a product reaches the market. FDA wants sponsors to do more to identify risk "signals" and to develop postmarketing risk management programmes for drugs that pose increased safety concerns for patients. 						

Another strategy for reducing potential medication errors is for manufacturers to print barcodes on drug packages, and even individual dosage forms, to ensure that the right patient receives the right dose at the right time. FDA issued a proposed rule in March requiring manufacturers to print barcodes on prescription drug packages.5 The rule compromises in calling only for national drug codes on packages, as opposed to more extensive data indicating lot number and expiration date. 	

FDA said it hoped to publish final rules on preapproval and postapproval drug safety policies, as well as barcoding requirements, by the end of the year. Meanwhile, the agency is linking up with broader health system databases that can help it identify ADEs more rapidly. FDA is also working with the National Library of Medicine to establish an electronic product label system for quickly distributing updated and comprehensive medication information to patients and health care providers. 	

To further facilitate public access to more affordable medicines, FDA is streamlining its generic drug oversight process and promoting the quality and interchangeability of generics to encourage more prescribing. The agency has beefed up resources for its Office of Generic Drugs, has launched a consumer advertising campaign to promote the safety and equivalence of generics, and has backed legislative changes to clarify the rules governing patent listings and challenges. One aim is to reduce the endless litigation between innovator firms and generic competitors regarding patent violations.				

A controversial issue is whether FDA has the authority to approve generic versions of biotech therapies, which appears open to interpretation under current law. In October, FDA issued a lengthy response to several citizens' petitions opposing approval of  "follow-on" versions of brand-name therapies under the "paper NDA" process. A letter from the Center for Drug Evaluation and Research (CDER) claims that FDA may approve certain products based on published studies of the innovator drug as a way of bringing new therapies to market more quickly and without the need to duplicate research. At the same time, FDA fears that too much investment in "copy cat" products could divert industry resources from innovative research. The agency may begin a public process to gain more input from manufacturers, health care providers and consumer groups on how to balance these concerns.	

Consumer efforts to obtain less expensive prescription drugs from Canada and other nations erupted this year into a contentious battle on Capitol Hill and in the media. Despite strong pressure from consumers and health insurers, McClellan insists that reimporting could bring unsafe and untested products into the US. FDA officials testified before Congress about the dangers of escalating drug purchases via Internet pharmacies, many of which operate overseas. Despite such opposition from FDA and the White House, the House approved a bill in July that permits reimporting of low-cost drugs from other countries - with no requirement that FDA first certifies that such activity will not harm consumers.6 Supporters of the measure aim to add it to legislation establishing a Medicare drug benefit. 	

The debate escalated in September when FDA asked the Department of Justice to file suit against a leading pharmacy website, Rx Depot, for arranging drug imports from Canada despite a March warning letter from FDA calling for the firm to cease and desist. FDA claimed that such imports "pose a serious threat to public health" because the agency cannot ensure the safety of these illegally imported medicines from unregulated sources. FDA's warnings appear to be falling on deaf ears as several states and local governments are devising plans to buy medicines from Canada to cut spending on drugs for Medicaid and local pharmacy benefit programmes. 	

The broader problem, according to FDA and manufacturers, is that illegal reimporting opens the door for counterfeit and unsafe products to enter the US market. FDA's counterfeit drug task force issued an interim report on 1 October that describes how counterfeit products slip into the US drug distribution system. To retaliate against the growing trend, the report proposes a mix of:	

stricter licensing standards for wholesalers and distributors

technological innovations that manufacturers can incorporate into actual products or add to packaging to identify bogus as well as legitimate drugs

public education to help health professionals and consumers look for and identify counterfeits more readily.

FDA sponsored a well-attended meeting on 15 October to discuss these proposals and view anticounterfeiting technologies. Not surprisingly, manufacturers urged tighter controls on distributors, including requirements for maintaining detailed pedigree records that track drug origin and distribution; wholesalers, in turn, asked FDA to require manufacturers to include authentication devices and markers in drug products and packages.	

The problem for manufacturers is that the public generally believes that drugs from Canada are just as safe and effective as those made in the US. A recent poll shows that consumers oppose efforts by the government and the US pharmaceutical industry to prevent them from obtaining less expensive foreign medicines, and that a growing number are purchasing them or would like to shop abroad for prescription drugs. 	

Intensified concerns regarding counterfeit drugs and illegal imports are focussing attention on the drug distribution system. One major wholesaler has been investigated for illegally diverting drugs to boost profits. FDA analysis identifies secondary wholesalers and repackagers as a common route of entry for counterfeit products. Florida has adopted a more stringent licensing and oversight policy for drug wholesalers, and other states are looking to follow suit. FDA is talking to Congress about revising a 1988 law that sets rules for tracking and documenting the source and movement of drugs through the distribution system. Manufacturers of products that appear attractive to counterfeiters are tightening up distribution by limiting sales to certain wholesalers or shipping directly to specific pharmacies. New electronic tracking systems may provide better ways to monitor and control the drug supply system.	

One way to deter illegal and dangerous importing, according to McClellan, is to reduce the differences between US and foreign pharma prices. At a September colloquium on generic medicine in Cancun (Mexico), McClellan pointed to international pricing disparities for escalating the battle over whether US consumers may reimport less expensive medicines from Canada.				

And because the US pays higher prices, McClellan commented, other nations do not shoulder a "fair share" of the cost of bringing new medicines to the world. Americans account for approximately half of all pharmaceutical spending worldwide, whereas Germany pays less than 5%, he noted, warning that such price controls abroad may "grind the global development of new drugs to a halt." 	

The commissioner's remedy is to relate drug prices to a nation's income, with rich nations paying more to support R&D so that developing nations can pay less. There's little chance, of course, that political leaders in Europe, Japan and Canada will agree to boost pharmaceutical prices - particularly when they are having trouble coping with escalating health care costs at home. But relating the reimporting problem to wide international differences in pharmaceutical prices gets at the heart of the issue and raises important questions about who will finance future biomedical R&D. 	

1.	J. Wechsler, "Standards for Supplements," Pharm. Technol. Eur. 15(3), 18-20 (2003).				

2.	J. Wechsler, "Overhauling Compliance and GMPs," Pharm. Technol. Eur. 15(4), 19-22 (2003).	

3.	J. Wechsler, "GMP Update: Reducing Obstacles to Innovation," Pharm. Technol. Eur. 15(10), 21-25 (2003).	

4.	J. Wechsler, "FDA Seeks Risk-Based Inspection Programme," Pharm. Technol. Eur. 15(11), 18-21 (2003).	

5.	J. Wechsler, "Drug Safety in the Limelight," Pharm. Technol. Eur. 15(5), 19-22 (2003).	

6.	J. Wechsler, "Counterfeiting, Compliance and Controls," Pharm. Technol. Eur. 15(9), 21-25 (2003).  	

This year has been one of tremendous activity at the US Food and Drug Administration (FDA) and other government agencies involved with health care, biomedical research and national security. Scientists completed sequencing the human genome, setting the stage for a period of important new medical therapy development. Efforts to protect the nation from biological warfare created pressures to produce new vaccines and medical treatments able to counter biological, chemical and radiological attacks (see sidebar "Combating bioterrorism").

Drug Pricing Concerns Shape Policy Decisions

In April, scientists worldwide celebrated the 50th anniversary of the discovery of the double helix by announcing the successful completion of the Human Genome Project (HGP). As they unveiled the nearly finished version of the human genome sequence, leaders of this landmark project outlined plans for tackling the next stage: translating genomic research into medical treatments to improve public health. This will involve identifying variations in DNA sequences that contribute to disease and defining how the proteins produced by each gene control cellular operation. 	

Turning the genomics vision into reality	

HGP accomplished a great deal beyond producing a 99.9% accurate sequence. It mapped the genome of comparative organisms (rat and mouse) and developed new technologies that will facilitate further exploration and development. The project identified more than 1400 disease genes and studied the ethical, legal and social issues raised by expanded knowledge regarding human genetic make-up. The next stage of utilizing genome-based discoveries in product development will involve pharmaceutical manufacturers more directly and will require the US Food and Drug Administration (FDA) and other government agencies to address pertinent regulatory and legal issues.	

In marking the completion of HGP's stated task, Francis Collins, director of the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH), declared it was time to move from large-scale DNA sequencing to more specific research projects. Collins and other HGP leaders outlined new research and development (R&D) opportunities in a recent article.1 This blueprint for future genomics research describes the resources and technological developments critical to developing "powerful new therapeutic approaches to disease" (see sidebar "Turning the genomics vision into reality").				

An ongoing issue is the need to balance timely access to new discoveries with protection of intellectual property (IP). Without an understanding of how complex patent and licensing policies influence private sector investment in new technologies, many diagnostic and therapeutic advances based on genomics may never reach the clinical setting where they can benefit patients (see sidebar "Patent protection and public access to data").		

Patent protection and public access to data	

A major concern for manufacturers is that gathering more genomic data will affect policies governing the testing and approval of new drugs and medical products. Industry is already investing more resources in pharmacogenomics (PG) to better understand how and why individuals respond differently to pharmaceuticals, a key issue in identifying candidate compounds and in testing them for safety and efficacy. This information promises to streamline animal and human studies by				

developing new sets of biomarkers for toxic responses in animals and humans 

predicting who will respond to a drug based on genetic differences in pathogenesis 

predicting who will have serious side-effects based on toxicogenomic analysis 

rationalizing drug dosing by using genetic/phenotypic tests for metabolizer status.

Such analyses have the potential to revolutionize drug development processes and lead to the production of more effective, less toxic drugs more quickly and efficiently, commented Janet Woodcock, director of FDA's Center for Drug Evaluation and Research (CDER), during the April meeting of FDA's Science Board. However, FDA officials are concerned that companies are not presenting PG analysis to the agency because of fears that it may lead to requests for even more data and tests, and further delay new product approvals. Woodcock wants to clarify FDA regulatory policies to encourage PG analysis and to gain access to information that could advance scientific discovery.	

In a sense, this concern among manufacturers that innovative research will complicate product regulation is similar to the "don't use" and "don't tell" attitude hindering industry adoption of new manufacturing technologies. Manufacturers worry that installing new online methods to control pharmaceutical production and drug quality will raise additional questions from plant inspectors and FDA staffers who review chemistry, manufacturing and controls data. To overcome these obstacles, FDA has launched the Process Analytical Technology (PAT) initiative, which aims to encourage manufacturers to install more efficient production systems, which are able to reduce costs and better ensure product quality. 	

Similarly, Woodcock seeks to develop several PG guidances to clarify agency approaches for using PG information. The aim is to overcome industry reluctance to disclose data from exploratory PG studies used by researchers to identify target compounds and to evaluate cellular and animal responses to drug candidates. The guidances will address 	

when PG data will have a "regulatory impact" 

co-development of drugs and diagnostic tests

The first step will be to develop "concept papers" regarding these topics, followed by draft and final guidances, which FDA hopes to issue by the end of 2004. 	

One of the main goals is to distinguish between PG data that may affect product regulation and should be submitted to FDA, and data that will not be required in filings for investigational new drugs (INDs) and new drug applications (NDAs). One "threshold" for submission might be genomic information that represents a valid biomarker with known predictive characteristics. FDA is likely to request that certain PG information be filed in applications, such as 	

studies supporting enrollment in clinical trials by genotype to enrich responders or avoid adverse outcomes

dose selection data based on metabolizer genotype

animal genomic data that explains why a toxic finding is unique to that species

data that may influence the course of the clinical development process.

Alternatively, FDA wants to define a "research information package" that manufacturers would share with FDA, but would not have any impact on application review. Such data would be discussed separately by a new Interdisciplinary Pharmacogenomic Review Group (IPGRG), composed of representatives from all FDA Centers. Data collected for "research use" that would not affect regulatory and approval decisions might include	

evaluation of new transporter gene diversity versus response in clinical subjects

genomic single nucleotide polymorphism (SNP) data collected in clinical trial subjects

gene expression microarray screening in trial subjects or in animal toxicology studies. 

Woodcock anticipates plenty of public discussion of PG issues through the guidance development process, beginning with a public workshop this autumn. Manufacturers are already expressing concerns regarding new FDA rules in this area. Brian Spear, director of pharmacogenomics at Abbott Laboratories, told the Science Board that most pharmaceutical companies are exploring how PG analysis may help design clinical trials and interpret study data. Gene expression studies can predict toxicity of candidate compounds and identify biomarkers for toxicity and drug response. Analysing patient genotypes may help define study populations and avoid overloading trials with inappropriate patients. Although such approaches may reduce potential patient injury and make studies safer, they may also be challenged as attempts to merely improve study results. A prime objective is to establish superior methods for validating conclusions derived from modern microarray and genomic analysis, which industry fears could be misinterpreted by regulatory officials. 				

Spear supported FDA's idea of establishing a central PG review group of experts to review PG studies separate from the review process, but emphasized the need for clearer definitions of "pharmacogenomic data" and "research exemption." Without a more explicit policy, manufacturers will worry that FDA and other regulatory authorities could expand requirements later for what studies and data analysis they require for product registration. And whereas clarification of research approaches may appear useful, increased standardization also carries the risk of encouraging both regulators and manufacturers to favour certain procedures, which may inhibit innovation in the long run. 	

Another manufacturing concern is that PG data could be used to narrow product marketing opportunities. A genetic study showing, for example, that 30% of patients could fail to respond to a certain treatment may lead to restrictive product labelling, even if the drug appears safe and effective for a general population. Or, data indicating that certain patients respond to a treatment might lead to required diagnostic testing of participants in clinical trials and of potential patients. In the end, industry willingness to underwrite more PG studies may prompt FDA to require genetic analysis as a regular component of drug development programmes.	

These are difficult issues, and FDA is building its internal capacity and expertise for analysing and understanding genomic data, explained Frank Sistare, acting director of CDER's Office of Testing and Research. CDER has established an internal Non-clinical Pharmacogenomics subcommittee and is expanding reviewer training in this area. The panel will help develop standards for submission, review and integration of PG data, and will also work with other government agencies and international scientists to further develop these initiatives. FDA is seeking input from advisory committees and experts concerning ways to better understand and assess relevant information as genomics discoveries evolve.	

The task of clarifying FDA regulatory policies related to PG is an important challenge for FDA commissioner Mark McClellan. A key strategy for improving public health is to make more new cost-effective therapies available to those patients who can benefit most from them, McClellan told industry leaders during the March annual meeting of the Pharmaceutical Research and Manufacturers of America. To this end, FDA is undertaking a "concerted effort" to use PG information effectively, he said, but needs more help from industry to better understand the issues and make FDA's regulatory process more efficient.	

McClellan made similar remarks during the April Science Board meeting, calling for action to integrate genomics information into product development and medical practice. He acknowledged that drug developers fear that data from molecular genomics doesn't "fit" the regulatory process and may "raise red flags" with reviewers. But he urged industry to share results with FDA so that these issues can be discussed openly and collaboratively. 	

1.	F. Collins et al., "A Vision for the Future of Genomics Research," Nature 422(6934), 835–847 (2003).				

2.	F. Collins, M. Morgan and A. Patrinos, "The Human Genome Project: Lessons from Large-Scale Biology," Science 300(5617), 286–290 (2003).	

The US Food and Drug Administration is working with manufacturers to establish new policies for incorporating genomic information into the regulatory process and simultaneously encourage pharmacogenomic research.

From Genome Exploration to Drug Development

The US Food and Drug Administration (FDA) is proposing that barcodes be used on drug packages, and that new error reporting standards should be introduced as part of the campaign to reduce medication errors.

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