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Labeling for IVDs:Issues and recommendations

Patricia B. Shrader

Of the issues of greatest significance to the IVD industry, few have received more attention in recent years than labeling. Both within the United States and abroad, a proliferation of regulatory requirements involving labeling has challenged IVD companies to look for ways to reduce or harmonize requirements in the various countries where they do business. This article, developed by the IVD labeling working group of the Health Industry Manufacturers Association (HIMA) and the labeling committee of the Association of Medical Diagnostics Manufacturers (AMDM), focuses on just a few of these issues and provides recommendations for regulators worldwide.

For the past several years, "Truth in Labeling" has been a byword of FDA's Division of Clinical Laboratory Devices when discussing IVDs. There is no disagreement between FDA and regulated industry with respect to the need to provide accurate, informative, and straightforward labeling to users of IVD products and others affected by those products. However, there are differences of opinion, both within and between industry and FDA, with respect to what information is most useful and the best means of conveying that information.

Although U.S. laws and regulations pertaining to IVD labeling have not changed significantly during the past 20 or more years, the world in which these products are sold has changed significantly.¹ It is important to look at the background of the current labeling regulations, along with FDA's intent for labeling. It is also important to recognize the spread of product marketing globally, the needs of users and other customers today, and the alternative means that are available today for industry, FDA, and customers for addressing IVD labeling needs worldwide.

Although FDA has published a draft guidance recommending that medical device labeling include certain information in a specified format, the agency's regulatory requirements for the labeling of most medical devices are very limited.² By contrast, all IVDs are subject to a separate labeling regulation that specifies requirements for labels on the immediate and outer containers as well as the package insert.³

FDA's IVD labeling regulation requires manufacturers to provide a wide range of information, including general information about the intended use of the test, background information on the analyte and the technology, information on specimen collection and handling, test procedure, analysis of results, limitations, and performance characteristics for the test. Although this regulation is based on the same statutory requirements that apply to all medical devices, it was developed for reasons unique to the IVD industry. At the time it was promulgated, the IVD labeling regulation was appropriate to the state of the art, the state of industry, and the needs of users. But times and conditions have changed.

Statutory Requirements for IVD Labeling

The statutory requirements for labeling of medical devices also cover in vitro diagnostic products. IVDs are not subject to any statutory requirements different from or additional to those that apply to any other devices of the same class. Labeling is defined in the same way for all regulated products.

The statute includes a prohibition on misbranding of drugs and devices, including IVDs.⁴ In order to avoid misbranding a device, the labeler must ensure that labeling is not misleading and does not fail to reveal material facts. The affirmative requirements for device labeling include placing in the product's labeling the name of the product, the name of the manufacturer, and information about the product's contents.

There are some additional specific requirements for restricted devices. The only types of IVDs that fall into this category are analyte-specific reagents, the use of which is restricted to high-complexity laboratories as defined under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).⁵

For Class III devices, review of labeling is specified as one of the requirements for premarket approval.⁶ For such devices, the determination of safety and effectiveness is based upon the conditions of use stated in the labeling. With respect to Class I and Class II devices subject to the requirements of section 510(k) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), there is no reference to device labeling in either section 510(k) or section 513(i).

Regulatory Requirements for IVD Labeling

The labeling regulations for IVD products are found in the Code of Federal Regulations at 21 CFR 801 and 809.10. The regulations in part 801 are general requirements for all medical devices, while the regulations at 809.10 are specific to IVDs.

The labeling requirements for IVDs in section 809.10 were promulgated in 1974, prior to enactment of the Medical Device Amendments of 1976.⁷ At that time there was no premarket review for the great majority of IVD products, and some in the user community had expressed concern about the performance and consistency of IVD reagents. Other factors that encouraged FDA to regulate IVDs by promulgating a labeling regulation were the emergence and rapid acceptance of automated laboratory instrumentation, and the absence of good manufacturing practices requirements applicable to devices.

Thus, the IVD labeling regulation focused on providing users with the information needed to perform a test, and some degree of assurance regarding the performance of the products. A product whose labeling contained false or misleading information would, of course, be misbranded under the FD&C Act. In this way, FDA attempted to control the consistency and reproducibility of diagnostic tests.

Today, this key goal is accomplished by other means. The performance of IVDs and other medical devices is ensured through the agency's quality system regulation (QSR), which includes requirements for both design control and good manufacturing practices.⁸ Another goal, which is still important today, is to provide needed information to laboratories, physicians, and patients.

Global Marketing Issues

In the 1970s, when FDA first developed its labeling regulations for IVDs, most U.S. companies did business only in the United States. Today, many U.S.-based companies are participants in the global market for medical products. Expansion of this global market has led many countries to develop laws and regulations governing IVDs and, in many cases, these enactments include specific labeling and language requirements.

The European Union's IVD Directive, whose overall intent is to harmonize requirements across Europe, nevertheless permits national competent authorities to require use of their national languages in product labeling.⁹ It is anticipated that many EU member states will do so, despite the fact that professional users in the EU typically speak and read English and will gain no real benefit from the imposition of such a requirement.

Other enactments adopted by individual countries or regions may also include requirements indirectly related to labeling. The EU's Packaging and Packaging Waste Directive, for example, affects labeling because of the considerable restrictions it places on packaging.¹⁰ Thus, global regulatory requirements and constraints must be considered as factors in evaluating and establishing practical restraints on labeling.

Issues related to labeling are particularly significant for IVDs. Today, IVDs are one of the few categories of medical devices that must satisfy detailed and specific labeling requirements. These requirements include not only instructions for the performance and interpretation of tests, but also background information about the test, information about the disease or condition to which the test applies, and performance characteristics based on clinical studies. As noted above, these requirements stand as a memorial to a time when members of the clinical laboratory community were concerned about the lack of consistency in clinical chemistry reagents. For all other categories of medical devices, issues related to performance and consistency have been significantly reduced through FDA's premarket review of products and imposition of the agency's QSR.

IVD manufacturers recognize that the most valuable real estate they own is the label space on the immediate containers, packaging, and package inserts of their products. U.S. labeling requirements play a key role in determining what information must be included within this valuable space—both in the United States and abroad—so as more and more countries seek to impose specific labeling requirements, manufacturers are more and more looking for ways to reduce U.S. demands. The current regulation, covering both devices and diagnostics, states that:

(c)(1) All words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear thereon in the English language: Provided, however, that in the case of articles distributed solely in the Commonwealth of Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be substituted for English.

(2) If the label contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label shall appear thereon in the foreign language.

(3) If the labeling contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear on the labeling in the foreign language.¹¹

When it was compiled, this requirement met the needs of a U.S.-based market and ensured adequate labeling for those parts of the United States where Spanish was spoken widely. It also protected users in other countries, where such products were largely unregulated. It did not contemplate the situation today, when medical devices and diagnostics are regulated by many other countries and regions, any of which may have labeling requirements different from those of the United States.

More-recent legislation recognizes the emergence of the global market for diagnostics and devices, but sometimes with unpredicted consequences. The Export Amendments of 1996, for example, provide that certain products to be exported must meet the labeling requirements of the country to which they are being sent.¹² But the legislation did not acknowledge the potential for a conflict of requirements when the products are intended both for export and for commercial distribution in the United States. Such a conflict can place companies that manufacture in the United States in a position of potential noncompliance.

To meet U.S. labeling requirements, some companies that manufacture and label their products within the United States translate all labels and labeling information into the languages required for each country where the product will be distributed. However, in some countries, such as Japan, FDA-required labeling is not acceptable. This situation occurs either when particular information is not required in another country or when particular labeling information required in the United States would be incorrect in other countries. It can apply to certain warnings, limitations, and performance information. In such cases, companies must choose between two unpalatable alternatives: violate U.S. regulatory requirements, or label their products outside the United States.

When labeling their products outside the United States, U.S. companies commonly export the products with just enough labeling to meet export requirements, or with labeling only in English, and then relabel the products in the country of destination or at a centralized location for a particular region. This process can be more complicated for IVDs, since in many cases the package insert is sealed within an outer container (box or bag), necessitating more than a simple overlabeling operation outside the United States. In addition to sending jobs offshore, this alternative imposes a significant burden on small companies, including many IVD companies. For small companies, establishing an offshore facility and implementing adequate controls to ensure proper labeling is often onerous and sometimes cost-prohibitive.

As more countries impose specific language requirements for medical devices, the available space on labels and labeling is becoming more limited. As a result, manufacturers applying multilingual labeling in the United States must use denser and smaller typefaces, making the information more difficult to read and less useful to those requiring the information. With respect to device labels, efforts are under way to standardize the use of symbols as a replacement for verbiage. Because of the extensive information currently required in IVD labeling, however, symbols have limited utility. Symbols may alleviate manufacturer concerns about fitting required content on a reagent label of reasonable size, but they cannot adequately address package insert information.

A solution is needed that enables companies to label products with the most pertinent information at the location of their choice. At the same time, FDA must be able to regulate the information provided for IVD users so that it can ensure the safety and effectiveness of these products.

Study Group 1 of the Global Harmonization Task Force recently released a draft guidance document on medical device labeling.¹³ The guidance calls for regulators to minimize prescriptive and country-specific requirements and to eliminate such requirements as they currently exist. It also notes that "consistent worldwide labeling requirements would offer significant benefits to the manufacturer, patient or consumer, and to regulatory authorities." Regulators are advised to focus on the safe and correct use of the device, to permit the abbreviation or omission of instructions, and to encourage the use of internationally recognized symbols, consistent with safe use.

Recommendations. To replace verbiage on vials and kit labels, FDA should accept and encourage the use of symbols recommended by industry or by the International Organization for Standardization (ISO). During a transition period, the explanation of symbols could be added to the package insert, if deemed appropriate, but this requirement should be phased out as acceptance of symbols becomes universal.

To eliminate the burdens of labeling for both domestic and export use, FDA should permit companies to provide multilingual labeling and, with each language, specify the country of intended use. For example, the Japanese labeling section of a package insert would specify: "This labeling meets the requirements of the Japanese Ministry of Health and Welfare for in vitro diagnostics and is intended for use in that country." Such an approach would enable companies to provide the specific labeling required by each country, while also making it clear to laboratory and other users whether the instructions for use, interpretation of results, warnings, limitations, and so on, are approved in the United States or elsewhere. If clearly stated, such an approach to product labeling could also be appropriate for home-use products.

Implementing this recommendation would require modification of the current labeling regulation for medical devices. Alternatively, a specific exemption for IVDs could be included in 21 CFR 809. Neither modification nor exemption is prohibited by the statutory requirements for devices and diagnostics. Should FDA be interested in making this change, representatives from the IVD industry, including HIMA and AMDM member companies, would be willing to take responsibility for drafting the regulations, in conjunction with FDA. It is not anticipated that either the regulated industry or other countries would have any objection to such a modification.

Labeling Creep and Competitive Issues

A significant issue in the diagnostics industry today is labeling creep—FDA's tendency to require almost continuous modification of package insert verbiage during product reviews. Requests for changes or additions to labeling during the review process can take numerous forms.

• Addition or modification of information in the form of a limitation or warning based on information in published literature.

• Addition or modification of information based on information in another company's submission.

• Addition or modification of information based on anecdotal information provided verbally to FDA.

• Addition of information based on a medical device report or recall.

• Revision of the format for presenting preclinical or clinical data, or the addition of new information from a company's own internal or clinical studies.

Although such requests for labeling changes are sometimes appropriate, they are almost always problematic. In some cases, for example, they can cause one company's labeling to become misleading in comparison with other companies' labeling. This can occur when FDA asks a company to add a limitation statement to its package insert on the basis of data that the agency has reviewed in another company's 510(k) submission. Although such a limitation may not be applicable to the first company's product, FDA will commonly insist that it appear unless the company has generated data to show that it does not apply. The company then faces the dilemma of whether to delay product introduction while generating additional data, or to introduce the product with a limitation that can be revised only after additional data is generated and reviewed by FDA.

In some cases, FDA has required a company to change its product labeling, despite the company's concern that the change might confuse or mislead consumers—sometimes to its disadvantage in the marketplace. One company, for example, was asked to eliminate the claim that its product could be used to identify a bacterial species. Although FDA had previously permitted companies to make such claims if any data were presented for the species in question, in this case the agency said that performance of the test could only be established if at least 10 samples of each species had been tested. Implementation of this new requirement, though not unreasonable, would lead users to conclude that this product offered less capability than other companies' products.

For manufacturers, requests to add or change labeling on the basis of anecdotal information or information in peer-reviewed literature also raise concerns. Unquestionably, manufacturers have commercial motives for making the strongest possible statements on behalf of their products; but every affirmative claim that a company makes in its labeling must be based on valid scientific evidence meeting criteria defined by FDA. Through its review process, and afterward, the agency has ample opportunity to bring to light any abuses of this system. It is therefore troubling when the agency draws upon other sources of information as the basis for requesting labeling changes, but does not apply to those sources the same evidential standards as required of manufacturers.

Although it is doubtful that any outside source would deliberately provide FDA with erroneous information, competing companies, user facilities, and experts can be motivated by a variety of factors—including the need to publish, to build their reputations, or to grow their business—and these factors can influence their thinking. Moreover, most of these sources are subject to much less stringent oversight than are FDA-regulated manufacturers. FDA should recognize that the best-regulated source isn't necessarily the least credible, and should ensure that appropriate standards of evidence are applied to all information used as the basis for labeling regulated products.

The format and content of performance data contained in product labeling is likewise a concern to manufacturers. Because these elements of product labeling vary from manufacturer to manufacturer, it can be difficult for users and others interested in product characteristics to compare products. Even when labeling information is accurate and not misleading with respect to one product, such variations among manufacturers can become misleading all by themselves. If comparable information could be presented in the same way, users would be able to more easily compare the performance of similar products. However, in many cases such standardization is not possible because different companies follow different clinical study protocols, provide different types of clinical samples, use different comparative methodologies, and so on. For all these reasons, it is important that FDA consider product labeling requirements in the context of all similar products.

Recent evidence suggests that FDA has become much more sensitive to the issues addressed above. In October 1997, for instance, FDA sent a letter to all manufacturers of tests for antibodies to Borrelia burgdorferi; the letter requested a labeling change for all such products, but provided 18 months for the changes to be made. In the future, manufacturers should expect consistency in labeling requests over a longer period of time, as well as an industrywide approach to the need for immediate or short-term changes.

Recommendations. Before requiring manufacturers to add information to their product labeling, FDA should ensure that such information has been substantiated in some appropriate fashion. If the information involves all products within a generic class, all companies marketing such products should be required to add the same information at the same time. FDA could readily accomplish this goal by using its authority to impose special controls, as provided by the Safe Medical Devices Act of 1990.¹⁴

Guidance documents that cover product review requirements and include pertinent labeling requirements are of enormous value to industry. They provide predictability for the review process, which is especially significant for companies that are planning and budgeting new product development and launch. FDA can improve the utility of such guidances by making certain that they are applied consistently, and that they are regularly reviewed and updated as appropriate.

FDA should acknowledge that other countries do not have the same interest in requiring manufacturers to provide detailed clinical information as part of their product labeling. For a variety of reasons, data and information generated during carefully controlled clinical studies of IVD devices may not be representative of what users will achieve in their own laboratories. However interesting and informative they may be, such data have little value for users. In determining what information a product's labeling should include, FDA and other regulators should focus on ensuring that manufacturers provide the minimum information necessary to enable laboratories to perform assays correctly and analyze their results properly.

Information Technology and Access to Information

In 1972, when FDA first proposed its labeling regulations for IVDs, the methods available for conveying information to users were as limited as the audience that needed to be reached. Since then, of course, the explosion of the global marketplace has dramatically increased the size of the audience needing information about medical products. Fortunately, the available communication technologies have also expanded, and there are today many more means of providing information to such audiences. Nevertheless, FDA's expectations of the ways that manufacturers and others should convey labeling information to users have changed very little.

Package inserts are among the primary tools that FDA expects IVD manufacturers to use in communicating with users. But even within FDA's Center for Devices and Radiological Health (CDRH) there is some disagreement over the requirements for such inserts. The FD&C Act defines labeling as "all labels or other written, printed, or graphic matter (1) upon any article or its containers or wrappers, or (2) accompanying such articles."¹⁵ There is long-standing case law to support the notion that labeling includes pamphlets, circulars, and other types of information shipped separately from an article and even at different times.¹⁶ Following this case law, the CDRH Office of Device Evaluation (ODE) accepts the proposition that written material provided with a product as part of an integrated commercial transaction should be considered labeling. But the CDRH Office of Compliance (OC) takes the position that in order for labeling to accompany a product, the package insert must travel in the same box as the instrument, reagent, or kit. During inspections, FDA investigators have questioned companies about their labeling practices and have advised them that they are required to put a package insert in each box.

There have been a few notable exceptions to OC's enforcement of its interpretation. FDA's labeling regulation itself provides one such exception, offering reduced requirements for "a multiple purpose instrument used for diagnostic purposes, and not committed to specific diagnostic procedures or systems," or for "a reagent intended for use as a replacement in a diagnostic system."¹⁷ Over the years, FDA has also granted some additional exemptions in specific instances. In the late 1970s, for example, several manufacturers of prepared plated media received FDA approval to provide new users with a published manual for these products, in lieu of placing a package insert into each container. More recently, ODE has given some companies permission to provide a package insert, a computer disk, or a CD-ROM as a supplement to an instrument manual for a newly cleared set of reagents. Manufacturers of chemistry analyzers that use proprietary reagent cartridges may also provide a manual instead of enclosing the same paper package insert with each reagent order. Other companies have employed similar means of conveying information, without enclosing a package insert in each box, and have so far not been challenged by OC or by their district offices.

Despite OC's continued reliance on the use of package inserts, a survey of users suggests that such inserts are not the most effective way to convey information. In one instance, an irate laboratory customer sent a company photographs showing the large number of package inserts that the lab had discarded in order to conserve space and provide easier access to the reagents. For laboratories that maintain a laboratory manual, as required by CLIA, discarding unneeded copies of package inserts should cause no problems. The package insert for every FDA-cleared product provides all the information the laboratory should require. The laboratory simply puts one copy of the package insert in its manual and discards all additional copies.

Another mounting problem is the failure of labeling to reach the end-user. This can occur when a central receiving department removes products from their packaging, as in the case of purchasing groups and consolidated clinical laboratories. Because the users of the product are often remote from the purchasing group, they are less able to obtain labeling information.

A final complication is provided by other countries' efforts to develop regulations that will reduce the amount of waste associated with medical products. For example, the EU's Packaging and Packaging Waste Directive will require manufacturers to exercise control over both packaging and labeling materials for devices and diagnostics.¹⁰ To comply with these requirements, companies must look for new and innovative ways to package and label products, while continuing to ensure that users have access to the information they need.

Recommendations. FDA's goal is to ensure that users and other consumers have access to the information they need to purchase, order, and perform appropriate tests; analyze results; and provide information back to the ordering physician as required. Companies likewise want to provide their customers with the information they desire. FDA should, of course, continue to regulate the content of labeling for regulated products. However, strict control of the means used to convey information is not appropriate and should not be required.

Rather than prescribing how labeling information should get to users, FDA should permit companies to demonstrate that alternative methods can be effective in communicating that information to users. Meeting this requirement would require a company to establish a system for disseminating information that would likely be more effective than current methods. FDA could accomplish this goal by issuing a guidance on 21 CFR 809.10 that would clarify the means by which labeling may "accompany" a product and would enable manufacturers to establish controlled systems that could be detailed in product submissions or reviewed during inspections. HIMA and AMDM member companies are preparing a draft guidance document for this purpose.

The ongoing proliferation of Internet use offers one possible means of disseminating such labeling information. A company could post all labeling information on its Web site and include on the kit box or reagent outer container the Internet address for labeling information. For consumers without access to the Internet, a technical services telephone number or fax-back number could also be provided.

Conclusion

To ensure timely provision of information to users and advance the goal of global harmonization, the time is appropriate for FDA to change some of its positions on labeling for IVD products. Industry encourages FDA to consider the ideas presented herein and to work in partnership with manufacturers to update requirements for IVD labeling.

References

1. 21 United States Code 352, and 360e(d)
(2)(D).

2. Code of Federal Regulations, 21 CFR 801.

3. 21 CFR 809.10.

4. 21 USC 352.

5. 42 CFR 493.25.

6. 21 CFR 814.20(b)(10), and 814.45 (a)(2).

7. 21 CFR 809.10.

8. 21 CFR 820.

9. "Council Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on In Vitro Diagnostic Medical Devices," Official Journal of the European Union L331 (December 12, 1998).

10. "Council Directive 94/62/EC of the European Parliament of 20 December 1994 on Packaging and Packaging Waste," Official Journal of the European Union L365 (December 31, 1994).

11. 21 CFR 801.15(c).

12. 21 USC 801, 802.

13. Global Harmonization Task Force Study Group 1, "Labelling for Medical Devices," in Global Harmonization Task Force Main Page (Bethesda, MD: 1999 [cited 24 June 1999]).

14. Pub. L. No. 101-629, 104 Stat. 4511 (1990).

15. Federal Food, Drug, and Cosmetic Act, sect. 201(m), 21 USC 321(m).

16. Kordel v. United States, 335 U.S. 345, 350 (1948).

17. 21 CFR 809.10(b).

Patricia B. Shrader is director of corporate regulatory affairs at Becton Dickinson (Franklin Lakes, NJ), and is currently working with Becton Dickinson Microbiology Systems (Sparks, MD). She is also president of the Association of Medical Diagnostics Manufacturers (Washington, DC).