November 3rd, 2003
Dockets Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, Maryland 20852
Re: Docket No. 2003N-0361, Federal Register: August 26, 2003 (Volume 68, Number 165, p. 51270)
The following comments are provided by the Biotechnology Industry Organization (BIO). BIO represents more than 1,000 biotechnology companies, academic institutions, state biotechnology centers and related organizations in all 50 U.S. states and 33 other nations. BIO members are involved in the research and development of health-care, agricultural, industrial and environmental biotechnology products. BIO appreciates the opportunity to comment on the Food and Drug Administration's (FDA's) Counterfeit Drug Task Force Interim Report (Docket 2003N-0361).
BIO applauds the FDA's foresight in assembling the Counterfeit Drug Task Force and in working with a variety of stakeholders intensively over a relatively short period of time to produce a comprehensive and thoughtful interim report. We also appreciated the agency providing a public forum, on October 15th, in which various stakeholders could present their views to the agency and share them publicly with other interested parties.
Prescription drug counterfeiting, as well as criminal product tampering, adulteration and mislabeling, have serious adverse effects on our products and the patients whose lives depend on them. We agree with FDA that all avenues should be explored to prevent these activities before they become more prevalent in the United States, and to stop such already occurring activities. We also strongly agree that this is a multifaceted and complex issue that demands a multipronged approach. As stated in the Task Force interim report, there is no magic bullet. Offering the industry a multiplicity of approaches also recognizes the variations among drug products and between drugs and biological products that provide both different opportunities and different challenges to those who want to counterfeit the products. In addition, because of the implementation timelines for various anti-counterfeiting measures, BIO believes that this effort must be ongoing, starting with steps that can be taken now and implementing additional approaches over time, in a stepwise fashion that allows for adoption as appropriate throughout the system. We believe it is important to recognize that product manufacturers can incorporate sophisticated and costly technology or take other measures at the manufacturing level that will have no impact on the problem if they cannot be used in the downstream portions of the distribution system.
Because drug and biological product counterfeiting is still of relatively low prevalence in the United States, BIO believes there is time to develop and implement strategies that will take several years to be fully operational. In that regard, the United States has an advantage over some other countries, where counterfeiting and other illicit incursions into the pharmaceutical supply chain place their pharmaceutical supply and their patients in immediate and grave danger. We have an opportunity to look closely at how a system spins out of control and to learn, from steps taken (or not taken) in other parts of the world, what can work and what is less likely to be successful. BIO recommends the FDA continue along this thoughtful course, working with the manufacturing, distribution and dispensing components of the supply chain to define the U.S. problem clearly and to develop the best and most viable solutions.
Finally, we reiterate the statements made by many, including the FDA commissioner, regarding pending actions relating to prescription product importation/reimportation. We believe it is crucial for FDA not only to retain its authority to control the entry of pharmaceutical products into the United States but also to receive the resources it needs to enforce the law. BIO believes that a number of national and state actions and statements are unfortunately signaling that the United States is willing to become a marketplace for illicit prescription drug traffickers. We recommend FDA continue its opposition to efforts that weaken our border controls and invite criminal elements into our pharmaceutical distribution system.
Our comments below are organized under the general topics of Immediate Actions and Specific Comments. However, we intend, with our members, to continue analyzing these issues and developing additional information. As we do this, we want to work with the FDA and with other stakeholders so that whatever solutions evolve will be successful. We value the opportunity not only to comment on what is before us in this document, but also to continue as part of the solution to a problem that already has affected our industry and that, if unchecked, will pose serious risk to patients.
Obtaining Better Data
BIO believes an important first step is better definition of the problem, through obtaining better data. Such data is unlikely to be fully in the possession of FDA, therefore a joint effort that involves other agencies such as the Drug Enforcement Administration and the Bureau of Customs and Border Protection, as well as product manufacturers, wholesalers and others in the legitimate distribution chain, will be critical. BIO urges FDA to continue working with these other parties and to establish a communication system that can receive relevant information and an analytical process for assessing the level and nature of the problem. We believe this data will help in the development of the most appropriate longer-term strategies.
For example, if the problem is analyzed according to the risk-based approach being employed by FDA in other areas, a strategy might focus initially on the points in the distribution chain that appear to pose the highest risk to the integrity of the drug supply. We believe this offers the best opportunity to protect the public from counterfeiting. Some of the questions that might be asked include the following: What key features of the current U.S. system result in counterfeiting being substantially lower here than in some other parts of the world? How can we reinforce, capitalize on or enhance those aspects of the system? What things seem to be working less effectively in the U.S. system today, as compared with five to 10 years ago, with the result that the problem is increasing?
BIO welcomes the chance to work with FDA and other stakeholders in developing and analyzing this kind of information to determine the most strategic approach to a solution.
Rapid Alert and Response System
BIO congratulates FDA for initiating, with industry cooperation, a system of reporting that allows the agency's criminal investigations unit to learn of possible counterfeiting shortly after a manufacturer detects a potential problem. To date, the system principally has involved member companies of the Pharmaceutical Research and Manufacturers of America, many of whom are also members of BIO. BIO pledges to make this system known to all of its member companies and to encourage all BIO member companies to provide FDA with information needed to take appropriate action as quickly as possible after discovery of a potential counterfeit biological product.
Paper Pedigree/Regulation of "Unauthorized Distributors"
BIO supports the FDA's full implementation of 21 C.F.R. 203.50. This rule, which has been on hold for several years, would require "paper pedigrees" for pharmaceutical products, from which it would be possible to document the source of the product, the numbers and kinds of transactions between the initial sale by the manufacturer and the final purchase by the end user, and other key information. Although we recognize that any such paper documentation can itself be counterfeited, we believe this is not a rationale for avoiding this simple step. BIO believes that, at a minimum, requiring documentation in the form of a paper trail tracing a pharmaceutical product from its source will serve as a significant deterrent for some illicit dealers and at least a small barrier for others.
Increased Oversight of Repackaging Operations
BIO recognizes that repackaging in the wholesaler/distributor chain is a component of the distribution process for many medications (although probably less so for most biological products that are injectable, infused or intravenous and often are not dispensed to patients by retail pharmacies). Shipping in large-quantity containers for repackaging in more appropriate quantities for further distribution may be cost-effective, and total elimination of repackaging may not be feasible in the short term. However, BIO believes that repackaging operations, as outlined in the interim report, offer a prime opportunity for illicit access into the distribution chain and, as such, should be subject to far greater federal scrutiny - scrutiny of the order of that applied to manufacturers -- than is now the case. At a minimum, we believe repackagers should be required to demonstrate the same kind of "chain of custody" as is desirable for distributors and should need to employ deterrent anti-counterfeiting measures similar to those that would be considered appropriate for manufacturers.
Oversight of Various Suppliers
BIO also believes there is a need for greater oversight and additional controls regarding printing and disposal of drug labeling and packaging. This would include vendors who supply manufacturers with their materials (through, for example, qualification and audits) as well as end-user disposal (such as requiring verification of destruction and/or defacement).
BIO believes consumers need to be educated about the problem of counterfeit medicines and told what to do if they find their medicine looks, tastes or feels different (both the product or the package) or the product does not appear to have the intended effect. We believe that, as an agency trusted by consumers, FDA is in the best position to do such consumer education and most likely to have the most comprehensive and objective information about the problem and risks to consumers.
With regard to getting a better handle on the nature and extent of the problem of counterfeiting in the United States, FDA has suggested that suspect counterfeit medicines be reported via the MedWatch system. BIO believes that this mechanism for reporting would be cumbersome for the consumer and would dilute the primary purpose of the MedWatch system (to report adverse events, medical errors or complaints). It is not designed for reporting suspect criminal activity. BIO recommends that FDA establish a counterfeit product reporting system separate from MedWatch or consider setting up a counterfeit product reporting hot line.
Increased Penalties for Counterfeiters
BIO agrees with comments made by many others regarding the exceedingly low risk for those who counterfeit prescription drugs, as compared with other illicit activities such as trading in illegal drugs. We believe that not to increase penalties for criminal activities and transactions with otherwise legitimate and legal prescription drugs trivializes this activity and, furthermore, makes such criminal endeavors more attractive to those with the lowest regard for the public health and the welfare of our citizens. Although we recognize that increasing criminal penalties is not within the FDA's purview, BIO strongly believes that such a change is essential to making the overall anti-counterfeiting effort successful.
Among the suggestions made in the interim report is packaging all finished dosage forms in unit-of-use packaging. We believe such packaging, already employed for many biological products, has proven not to be the ultimate prevention against counterfeiting. Some recent examples illustrate this point. The relabeling and frank counterfeiting of the epoetin product Procrit was not deterred or prevented by the fact that this product is packaged in unit-of use vials and packages. The company has undertaken to deter counterfeiters, opting to implement sweeping anti-counterfeit measures immediately, including a new packaging technology that uses a color-changing seal to verify the authenticity of the product. It also has shored up security by using a punitive strategy with its suppliers and maintains an avenue for consumers to report suspected counterfeit Procrit batches on its Web site. This example is illustrative both of the commitment of BIO member companies to employing product-appropriate anti-counterfeiting approaches and of the fact that such technology will not in itself solve the problem. It is appropriate for companies to have individualized response plans to address incidents of counterfeiting. BIO believes that the unique expertise of each company with respect to its own products must be brought to bear on all decisions about the use of anti-counterfeiting technology and the approaches a company takes to responding to counterfeiting of its products.
Additionally, products enclosed in blister packaging also have been counterfeited. Whether such packaging combined with other anti-counterfeit measures, could prove sufficiently secure is an option that we believe, if considered, needs to be explored further. Some considerations include the question of whether the substantial cost of implementing such packaging for products now distributed in bulk or in large-quantity packaging -- costs that would accrue throughout the system -- would be balanced by a significant reduction in risk. BIO recommends that data be gathered to show the extent to which this option, where it already is in use in other countries, is viable and successful in reducing counterfeiting. Similar comments and questions apply to employing tamper-proof packaging.
The interim report recommends, as an option, that all drug products be required to employ two types of validated anti-counterfeit technologies, one overt and one covert. Because both the incorporation of such technologies and their value with regards to reaching the goal of deterring counterfeiting will be, in BIO's view, highly dependent on the product, dosage form, etc., we recommend that FDA continue to lay out the goal and allow the industry to determine, based on product types, how best to reach the goal. BIO believes that the choice of specific anti-counterfeit technology should be left to the manufacturers, who have expertise in the development, manufacture and design of both products and packaging components. Additionally, if the implementation of the technology requires regulatory approval (such as addition of deterrents integral to the product), BIO recommends that FDA consider reduced regulatory filing requirements (such as, for example, reduction of stability requirements) and regulatory reporting categories. We believe that use of taggants or chemical markers, for example, raises concerns about cost, the nature of regulatory controls and the additional time that would be required to secure FDA approval to incorporate additional chemical materials in drug products. BIO believes that it is also important to recognize that some technologies (such as taggants or other forensic technologies) may be inappropriate for use with proteins. Overall, BIO is cautious about industry wide mandates regarding technology solutions because of the sensitivity of our biotechnology products and unknown long-term cost and benefits. Technologies can prevent counterfeits from reaching the public only if downstream players in the supply chain can and do recognize them and respond appropriately.
BIO believes that the development of an electronic database for authentication purposes may be helpful and might be of practical value. However, BIO recommends substantial additional discussions to resolve some key questions before initiation of any such system. For example, who will develop and maintain the database? BIO believes FDA may well be the most appropriate site, but also recognizes the potential resource implications for the agency, which will raise concerns about whether this function would become a priority that could take resources from FDA's principal functions in the review, approval and regulation of new products. We believe a private sector organization, under FDA contract, also may be an option. That approach, however, will raise additional questions about system security and the ability to maintain the confidentiality of proprietary information as well as to prevent access into the system by counterfeiters themselves. Further, BIO believes that any such system will be only as effective as the extent of participation by manufacturers. Considerable work is needed to ensure, for any such database, that manufacturers will provide data to the system and will not be discouraged from participation by concerns about the security of their information.
With regards to the implementation of track and trace technology, BIO agrees that a truly closed system would be the primary deterrent to counterfeit medicines entering the distribution system. However, the technology is many years away from implementation - scanners would need to be installed at every step of the distribution chain, and an information technology infrastructure would need to be established from which the validity of the serialized numbers placed on each unit package would be determined; the technology for the information "tags" on each unit of distribution would need to be unfailingly read by the scanners. The current system designs have demonstrated difficulties in transmitting and receiving data from the information tags in certain standard configurations of packaging or if the product is in a liquid form. BIO believes the technology will need to be refined, the infrastructure implemented and the cost of the system absorbed.
Further, current FDA regulatory requirements, including Part 11 compliance, Stability Requirements (for example, some tags' bandwidth is UHF; are stability studies required prior to their implementation?), and Validation, may provide hurdles to employing RFID/EPC technology. Also, would the information provided in the chip be considered labeling?
BIO supports the notion that, as an initial step, low-tech solutions may be considered. We believe such low-tech approaches may prove to be appropriate for many products in the long run. FDA's recommendations regarding limiting transactions, more fully documenting transactions, etc., may be appropriate interim steps, especially in light of the fact that the high-tech approaches may be very far from feasible at this point. We also note, as mentioned earlier, that improved regulation of the so-called secondary wholesale market is a key component of such an approach.
BIO recommends that FDA pursue the development, with industry and other stakeholder input, of draft guidance documents on appropriate anti-counterfeiting steps and on physical plant and supply chain security. With regard to the former, BIO suggests that anti-counterfeiting guidances be issued as a series, in a stepwise fashion as more information becomes available and various technologies become more feasible.
Secure Business Practices
We strongly support FDA's continuing work with the National Association of Boards of Pharmacy on development of appropriate rules for licensing wholesalers. BIO also recommends that FDA, as mentioned earlier, implement its own rules applicable to unauthorized wholesalers. Strong federal oversight of the wholesale market is critical to any anti-counterfeiting effort.
With regards to business practices of individual manufacturers, BIO believes that companies should be encouraged to develop such practices voluntarily. However, we believe that it might be helpful, especially for smaller companies new to the pharmaceutical marketplace, for FDA to develop a list of voluntary activities and actions that the agency believes contribute to effective security. Such a list would constitute FDA's best assessment of optimal conditions, but such activities and actions would not be a requirement for companies seeking FDA approval of new products.
Rapid Alert and Response Systems
As noted earlier, BIO believes that any system to receive reports of possible counterfeiting should be separate from the MedWatch system, which is not - and should not be - designed for criminal activity reporting or oversight. BIO strongly supports enhancement of FDA's investigative activities, as well as response actions when the agency becomes aware of possible counterfeiting. Finally, we suggest the agency further develop its recommendation to create a "counterfeit alert network" with manufacturers, distributors, pharmacists and others participating. We believe appropriate communication among all the components of the system, will greatly facilitate early detection of problems and also serve as a real deterrent to criminal activity. BIO offers its assistance in this effort.
Education and Public Awareness
We support increased public education and believe that education of health-care providers and pharmacies is especially crucial. Counterfeits should be stopped before they reach the consumer.
Importation/reimportation is yet another uncontrolled point in the supply chain that provides an entry point for counterfeiters. BIO is opposed to loosening controls on importation and supports increased authority for FDA to access foreign manufacturer records for investigating counterfeiting cases.
In summary, BIO is eager to work with FDA on finding solutions, both interim and long term, to the still small but growing problem of drug product counterfeiting. We applaud the FDA's recognition that the problem is complex because it involves sophisticated criminals but also because it must deal with drug and biological products that are so different that single solutions cannot possibly apply equally to all of them. We believe that closed distribution systems - such as that for controlled substances, including electronic ordering systems - may be approaches worth considering. However, those systems, too, have been violated by criminals, and therefore do not offer the perfect solution.
BIO recommends FDA continue its thoughtful approach based on the assumption that there is no magic bullet. We believe FDA will provide invaluable guidance based on its comprehensive knowledge of the kinds of products in the marketplace, its global perspective on distribution and its breadth and depth of experience in both product regulation and criminal investigation. However, in the end, it will be the manufacturers, distributors and dispensers of products whose actions will determine how and whether the goal of preventing counterfeiting will be achieved. BIO pledges its help and that of its member companies to this effort.
Thank you for your consideration of these comments. Please do not hesitate to contact me should you have any questions.
Gillian R. Woollett, MA, DPhil
Science and Regulatory Affairs