In IVD manufacturing, design of experiments (DOE) is all about pinpointing the most efficient combination of inputs required to generate, at the lowest cost, a product that meets exacting specifications. The first part of this article (IVDT, September 1997) described the designs that are most commonly used for screening runs and response surfaces. This second part demonstrates the application of these principles, using a practical IVD manufacturing example. As the example proceeds, it will look at some of the techniques for dealing with unruly data.

Master lot testing for a serum protein to be used on an automated immunoanalyzer provides a good example of the application of designed experiments. The experiment discussed in detail here was designed and analyzed using a program called ECHIP. A description of some commercially available DOE software packages is provided in the sidebar on page 35.

Generating the Screening Design

To identify values of a control substance within a desirable range, researchers typically mix probe, conjugate, and microparticle reagents and test them using designed experiments. Table I outlines the screening design for immunochemical data representative of this example. The probe is a biotinylated antibody molecule used in standard immunologic sandwich techniques (linking two other molecules). The conjugate is a fluorescently labeled antibiotin molecule. The microparticles are antibody-coated beads. The reaction is the fluorescence generated as all of these molecules bind together with the antigen from the sample.

Table I. Immunochemical screening design. Concentrations are in arbitrary units and run order is randomized.

For the sake of simplicity, this example uses only probe, microparticle, and conjugate reagents. But in actual experiments, there are usually many more input variables than necessary. Since the number of variables should usually be reduced, the software program initially generates a screening design.

The software generates a linear-with-center-point design that includes sufficient runs to assess the replicate error, considered the noise floor. This type of design is mathematically simple, yet fully capable of accurately describing physical relevance. It is usually the screening design of choice, unless there is a compelling reason to select a more complex model. Unless otherwise requested, the order of experimental runs is randomized to control systematic error. The technicians take the design to run in the laboratory.

Excluding Insignificant Inputs

The results of the screening tests are shown in Table II. This table displays the significance of the various inputs to the output (here only the reaction rate). The stars within the table denote the significance of each effect and reflect the alpha significance values from the analysis of variance test (ANOVA) performed by the software. One star denotes the 5% significance level; two stars, 1%; and three stars, 0.1%.

Table II. Summary of results for screening design. Stars denote significance of test results (see text); LOF = lack of fit.

In this example, all main effects are considered highly important to the measured output, the reaction rate. This result is not surprising, since all the reagents are needed to generate the reaction.

If no stars were associated with a particular reagent, their absence would not necessarily indicate a lack of importance to the reaction but merely a lack of importance over the range of the reagent concentration used in the experiment. This distinction is important, because the range may need to be broadened.

The "LOF" message at the bottom of the reaction column in Table II denotes a lack of fit for this model to the data. This lack of fit is not of great concern, because most biochemical and immunochemical data are not readily fit by the overly simplistic straight line of a screening model. To verify testing adequacy, the statisticians need only examine the size of the deviations from the line in the residual table (see Table III). There they will invariably find small areas of large-enough deviation to trigger the LOF message. These residuals represent the difference between the observed data and what was calculated by the model.

Table III. Residuals from screening experiment.

The next step is to exclude those input factors found to be statistically insignificant in the screening outcome and to design a response surface experiment with only the most important factors. In this case, those factors are only the main effects: microparticle, probe, and conjugate (see Table IV).

Table IV. Response surface design. Concentrations are in arbitrary units and run order is randomized.

The experimenters may perform more runs at this stage to define the response surface more completely. In most screening experiments, however, the total number of required runs is minimized by eliminating a number of input factors (see Table V).

Table V. Response surface data. Concentrations are in arbitrary units, and run numbers correspond to the input conditions given in the design table (Table IV).

The response surface significance summary is presented in Table VI. All main effects retain significance on the reaction rate, and it can now be seen that the interaction between the probe molecule and the conjugate also exerts a significant effect on the reaction rate. The three stars next to the probe-squared row indicate that the program had to bend the response surface in proportion to the square of the value of the probe molecule concentration. The LOF message is now gone, indicating an adequate fit of the model to the data.

Table VI. Summary of response surface design showing the statistical importance of factors. Stars denote significance of test results (see text); dots indicate insignificant interactions (p<0.10).

Dealing with Lack of Fit

Had there actually been a lack of fit, several strategies could have been used to better fit the model to the data. These strategies are:

Do Nothing, and Accept the Lack of Fit. Lack of fit due to chance alone occurs about 5% of the time. The experimenters may therefore examine the residuals and, if they are sufficiently small or if the lack of fit occurs only in an area of the response surface not important to the physical process, ignore it and proceed.

Remove Certain Data. There may be cause to remove certain points due to known exceptions to the experimental protocol. The experimenters may also apply statistical tests for outlier status, but the best method is to repeat the experiment in those areas where the anomalies occurred.

Transform the Data. If there is no cause to remove data, transforming them is the easiest method. However, it is not a good idea to pull down a list of transforms and apply them one at a time to the data until the LOF message disappears. Certain transforms are most useful in certain situations. They may affect data in unwanted ways when applied in a random, shotgun fashion.

The other rule is not to go to heroic lengths to remove the lack of fit. If complex and lengthy mathematical manipulations are required, chances are the data are best left alone.

Use a More-Complex Model. Although it is sometimes of value, use of a more-complex model requires further data collection. Time and resource availability may be the deciding factors here.

Assessing Data Adequacy

Once the lack-of-fit issue is resolved, the experimenters may assess data adequacy by using standard plots (see Figure 1). In a plot of normal data versus studentized residuals (errors standardized by distance from a central point within a distribution), the straight-line relationship implies that the errors (the disparity between what was expected and what was actually observed) are normally distributed. The plot of fitted values documents that these errors are independent (the points are scattered and not clustered) with nearly constant variance (all the points lie within the standard deviation of ±3).

Figure 1. Assessment of data adequacy by residual plots.

 

Other plots are available and may yield further insights depending on the error distribution and region of interest in the data. Nevertheless, statistical testing can take researchers only so far. Continued data aberrations that arise from problems with instrumentation or chemistry may require staff engineers or immunochemists to intervene and change the design of the product.

Optimizing Outputs

Assuming that such testing and intervention are not required, the experimenter requests that the software optimize the reaction rate value to a desired number, perhaps maximizing it (see Figure 2) or requesting a specific target value. The software then generates not only the proper settings for the inputs but also a guard band for the outputs that yield the upper and lower 95% confidence limits. These limits reflect the errors of prediction and, more important, the error that will occur when a new observation is taken. A new measurement, taken at the given settings of the input variables, may therefore be expected to lie between these limits.

Figure 2. Two-dimensional response surface plot. Reaction rate as a function of probe and microparticles, with conjugate held constant (=1.00).

 

Figure 3. Three-dimensional response surface plot. Reaction rate as a function of probe and microparticles, with conjugate held constant (=1.00).

 

Figure 3 gives a three-dimensional overview of the design space, displaying how the output varies with two selected input variables. A third, off-axis variable is fixed at the value given below the graph. In Figure 2, the reaction rate is maximized under the crosshairs in the upper right corner of the design space (bounded by the red lines). This graph indicates that use of one unit of probe with two units of microparticles and one unit of conjugate will generate a reaction rate of about 9.5 units (in most cases, between 8.52 and 10.63 units).

The above methodology allows observation of input variable interactions and configuration of the system to allow derivation of a desired output variable. Many more inputs and outputs could be tested. Many variations are possible in both the design and the analytic strategy. These methodologies may even be applied to gain a better understanding of the physical mechanisms underlying the process, for example, whether antigen a is binding more strongly to antibody x or to antibody y.

Conclusion

Formal design of experiments is based on well-accepted statistics and computational algorithms that are easily implemented using commercially available software. The methodologies are flexible enough to apply to a wide variety of industries and useful in designing cost-effective strategies in many settings. DOE may enhance the experimenters' insight into many physical processes and actually speed discovery.

SOFTWARE RESOURCES

Many commercial software packages are available for formal design of experiments. The following list is far from all-inclusive; it represents those programs the author has used or examined. The commentary is meant to orient the reader rather than to be a comparative review. The particular nuances of any package may be more or less attractive to the user based on personal preference and experience.

ECHIP. The ECHIP program is devoted entirely to experimental design and is not a general statistics package. It offers many standard designs as well as the ability to create customized designs. The main design screen takes the novice step by step through the variable definitions, designs, data entry, and results analysis screens. The software includes a power/sample-size calculator that is very useful for assessing the resolving ability of an experiment, which is the ability to find a prespecified difference if one really exists. The user manual has many helpful examples. There is also a reference manual for those interested in the details behind the designs.

Contact: ECHIP, Inc., 724 Yorklyn Rd., Hockessin, DE 19707-8703, phone 302/239-5429.

Minitab. The newest version (release 11) of the Minitab statistical package has a simplified DOE interface that reduces the programming required to straightforward button-pushing. A design may be created by either of two methods. Those unfamiliar with the process may request assistance from the program. Standard as well as customized designs are available, and choices are made via familiar dialog boxes. A user manual reviews the designs via the interface, while the reference manual gives the programming steps.

Contact: Minitab, Inc., 3081 Enterprise Dr., State College, PA 16801-3008, phone 814/238-3280.

SAS. Strictly a statisticians' program, SAS in its current release allows experimental design only via programming. The methods and steps are well documented but geared to the statistically sophisticated. Presently the SAS Institute is developing a graphical user interface for its DOE system. A new release featuring this enhancement should be available soon.

Contact: SAS Institute, Inc., 100 SAS Campus Drive, Cary, NC 27513-2414, phone 919/677-8000.

SAS JMP. To more immediately address the needs of the novice designer, the SAS Institute has developed SAS JMP, a user-friendly package specifically for exploratory data analysis and experimental design. The DOE section uses JMP's colorful, interactive graphics and offers a variety of design types at the click of a button. The 2-D contours are informative. The manuals strive for clarity through a number of real-world examples.

Other Packages. The latest versions of the following programs contain DOE modules but have not been reviewed by the author: Systat (version 7.0), SPSS, Inc., 444 N. Michigan Ave., Chicago, IL 60611-3962, phone 312/329-2400; Statistica, StatSoft, 2300 E. 14th St., Tulsa, OK 74104, phone 918/749-1119.

Bibliography

Atkinson AC, and Donev AN, Optimum Experimental Designs, Oxford, England, Clarendon Press, 1992.

Myers RH, and Montgomery DC, Response Surface Methodology: Process and Product Optimization Using Designed Experiments, New York, John Wiley, 1995.

Schmidt SR, and Launsby RG, Understanding Industrial Designed Experiments, 4th ed, Colorado Springs, CO, Air Academy Press, 1997.

Wheeler B, ECHIP Reference Manual, Hockessin, DE, ECHIP, 1993.

John A. Wass is a mathematical analyst in the scientific support group at Abbott Laboratories (Abbott Park, IL).

With a single letter, FDA substantially changed the regulatory environment for blood establishments and their vendors of blood-bank software. Issued in 1994 by the agency's Center for Biologics Evaluation and Research (CBER), the letter states:

Facilities that manufacture and distribute these [blood-bank] software products are subject to the device provisions of the Federal Food, Drug, and Cosmetic Act [FD&C Act] and FDA's device regulations, including establishment registration, product listing, premarket notification or approval, current good manufacturing practices (CGMP), and adverse event reporting.¹

This sentence greatly increased FDA's regulatory control over blood-bank software. With it, CBER fully imposed medical device "general controls" upon these products and their vendors. More recently, in a legally questionable decision, FDA has required premarket submissions for, and applied its medical device quality system requirements to, certain blood-bank software developed internally by blood establishments for their own use.

The agency's regulatory oversight of blood-bank software has grown rapidly in a relatively short time, possibly outpacing the ability of blood establishments, vendors, and FDA itself to address it effectively. Although blood-bank software is regulated by CBER, clinical laboratory and other medical software (including components, accessories, and stand-alone devices) is regulated by the Center for Devices and Radiological Health (CDRH). Will clinical laboratory software be subjected to the same fate as blood-bank software? Time will tell as CDRH grapples with revising its current medical computer products policy.²

FDA's decision to apply device requirements to blood-bank software raises questions about the agency's expectations in this area of regulation. Some of the general controls traditionally used for medical devices do not apply neatly to blood-bank software, and the agency has not sufficiently elaborated on the requirements' application to it. Similar problems might occur with clinical laboratory software unless CDRH explains its expectations or limits the scope of the requirements' application. Blood establishments and vendors face many unanswered questions, placing them in the quandary of attempting to interpret what FDA requires. Clinical laboratories and their software vendors could face similar questions if CDRH is not thorough in its explanations.

This article will briefly discuss the history of FDA's regulation of blood-bank software and the present status of FDA policies in this area. It will also provide some insight into where FDA regulation of blood-bank and clinical laboratory software may be heading. Finally, it will discuss what the blood-bank software model may mean for clinical laboratory software.

History of FDA Regulation of Blood-Bank Software

As software technology has become increasingly prevalent in medical endeavors, including its use in blood establishments and clinical laboratories, FDA has asserted increasing regulatory control over it. Under the FD&C Act, FDA is responsible for the regulation of all medical devices manufactured, investigated, and marketed in the United States.³ A medical device, in relevant part, is defined under the FD&C Act as:

An instrument, apparatus, implement, machine, [or] contrivance . . . which is . . . (2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals.⁴

This definition of medical device is broad enough to encompass medical software, including blood-bank and clinical laboratory software. Despite its apparent statutory authority, however, FDA did not pay particular attention to blood-bank software until the 1980s, when data integrity and problems sensitized the agency to safety and effectiveness concerns regarding such software. One case in particular heightened FDA's interest in actively regulating blood-bank software. It involved a prominent company that produced and distributed blood-bank software as part of its blood-bank and laboratory management system. FDA learned that program deficiencies in the software had led to inadvertent release and distribution of violative blood products for patient use, creating a public health risk. The incident led FDA to increasingly perceive defective blood-bank software as a threat to the nation's blood supply.

Until the 1990s, CBER regulated computerized blood-bank systems, including their software, as equipment. As regulated manufacturers, blood establishments were obligated to maintain such equipment as safe and effective under the drug and blood-product current good manufacturing practices (GMPs).^5,6

By FDA standards, the imposition of active regulation of blood-bank software as a device happened very quickly. As late as September 1992, CBER representatives stated that there was no need for blood-bank software vendors to comply with the medical device regulations. But in October 1993, a CBER guidance document sounded a different note:

Vendors who are developers that commercially distribute software intended for use by blood establishments should be aware of the federal regulations relating to the manufacture of blood and blood components. In addition, because blood-bank software products are devices, firms manufacturing and distributing such products must comply with statutory and regulatory requirements applicable to devices.⁷

With issuance of the CBER letter of 1994 quoted at the beginning of this article, there was no question the agency had decided to impose all medical device general controls upon blood-bank software vendors and their products. In addition, the agency has interpreted this to mean that blood establishments must comply with device quality system requirements even for computer systems developed internally for their own use. They must also file premarket notifications (510(k)s) or premarket approval (PMA) applications if the software for such systems is to travel interstate (even to an affiliate or satellite site) or if interstate electronic transfer of safety-critical data occurs.

Current Status of FDA Regulation

As outlined in its 1994 letter, CBER applies the following medical device general controls to blood-bank software vendors, requiring them to:

• Register as medical device establishments and list their products with the agency as devices.⁸

   

• Follow device good manufacturing practices (now quality system requirements).⁹

   

• File reports of certain adverse events involving their products under the medical device reporting (MDR) regulation.¹⁰

   

• File 510(k)s or PMA applications for their products.¹¹

Premarket notifications or PMAs for previously marketed blood-bank software products were due on March 31, 1996, unless CBER granted a filing extension. To date, the vast majority of such filings—if not all of them—have been 510(k) submissions. While it did not say so in the 1994 letter, the agency would also expect compliance with medical device labeling requirements.¹²

Guidances. In April 1996, CBER issued its "Reviewer Guidance for a Premarket Notification Submission for Blood Establishment Computer Software."¹³ This guidance discusses many issues related to blood-bank software, including proper labeling; submitting information on the product's design, development, and functional specifications; preparing a hazard analysis for the product; and supplying information on product verification, validation, and testing. The guidance is intended as a supplement to CDRH's "Reviewer Guidance for Computer-Controlled Medical Devices Undergoing 510(k) Review," first issued in 1991.¹⁴

Besides recent guidance specific to blood-bank software, the agency has issued new draft guidances applicable to medical software generally. In the last year, CDRH has issued drafts of several software-related guidance documents that relate to blood-bank software, clinical laboratory software, and software used in in vitro diagnostic devices (e.g., software-controlled clinical analyzers). In September 1996, the device center released for comment its draft "Guidance for the Content of Premarket Submission for Medical Devices Containing Software."¹⁵ When finalized, it will replace the 1991 reviewer guidance. The new guidance is intended to apply to all types of premarket device submissions: 510(k)s, PMAs, and investigational device exemptions (IDEs). Among other things, the revision discusses the key data elements that FDA reviewers should look for in a premarket device software submission. It is also intended to further industry's understanding of FDA views on software engineering practices, quality, reliability, and safety, and especially to explain the agency's expectations for verification, validation, and testing of software devices.

Software-controlled clinical analyzers currently requiring 510(k) clearance are now subject to the 1991 guidance and will be subject to the new guidance when it is finalized. Moreover, since CBER's 510(k) guidance is a supplement to CDRH's 1991 guidance, CBER will most likely incorporate the revised guidance by reference. If CDRH calls for 510(k) submissions for all or a subset of stand-alone clinical laboratory software products, the new guidance would most likely also apply to them.

This past June 4, FDA distributed for comment a draft "Guidance for Off-the-Shelf Software Used in Medical Devices."¹⁶ When finalized, this document could affect blood-bank or clinical laboratory stand-alone software products as well as software-controlled IVD devices. Its purpose is to describe the information that should be provided in a medical device application involving off-the-shelf software. The agency states that "many of the principles outlined herein may [also] be helpful to device manufacturers in establishing design controls and validation plans for use of off-the-shelf software in their devices."

Most recently, on June 9, CDRH issued for comment a new draft guidance entitled "General Principles of Software Validation."¹⁷ The guidance is applicable to all medical device software, including blood-establishment software and software used to design, develop, or manufacture medical devices. It discusses how the general provisions of the quality system regulation apply to software, as well as the agency's current approach to evaluating a company's or establishment's software validation system.

Compliance Issues. Imposition of device controls on blood-bank software vendors significantly affects the regulatory landscape. If a vendor is noncompliant, the agency would view its software as adulterated or misbranded, making its distribution illegal under the FD&C Act.^18,19 The agency could possibly take enforcement action against the software, such as instituting a seizure of the product, an injunction against its use, or civil or criminal actions against those responsible for its manufacture and use.²⁰

Additionally, FDA has authority to issue an order requiring immediate cessation of distribution of a device it considers unsafe.²¹ Such orders also require immediate notification to relevant health professionals and user facilities, informing them of the order and directing them to stop using the device. Following an administrative hearing, the order can be upheld, amended to include a mandatory recall, or vacated. Thus, significant legal problems can result if FDA perceives that a particular blood-bank software product is violative under the FD&C Act.

Under the scenario described above, a blood establishment may be temporarily without use (or have only restricted use) of its software until the software vendor makes corrections. The establishment might even be forced to change to a new software product, suffering great business disruption and expense in the process. Even if the establishment could use the software in the interim, procurement and use of noncompliant software could leave a poor impression with the agency. IVD manufacturers that use human blood products sourced from blood banks as components in their products could find their component supply cut off or recalled as a result of such software problems.

510(k) Issues

As mentioned above, active regulation of blood-bank software comes with many unanswered questions, including premarket issues. Clinical laboratory software could face similar questions. In the area of 510(k) submissions, the role of programming bugs still needs further clarification by the agency.

Technically, a new 510(k) submission is required every time a legally marketed device is changed or modified in a way which could significantly affect its safety or effectiveness.²² This regulatory provision has often proved nebulous and difficult to apply, especially with regard to software changes. Recognizing this, FDA has published a guidance document attempting to better define when changes would or would not require the filing of a 510(k) submission.²³

Medical software products, such as blood-bank and clinical laboratory software, change continually to account for programming bugs as well as to reflect enhancements desired by customers. Addressing a bug or enhancement could be a change that the agency would view as raising new and significant safety or efficacy issues. It would not be unusual for a software vendor to make numerous product changes each year. In light of such numerous changes, an unmanageable number of 510(k)s could become necessary if the agency too conservatively defines what constitutes a significant software change. To what extent FDA will require 510(k) submissions for software bug fixes and enhancements is an open question. If it requires them too frequently, the results could be devastating for industry and the agency alike:

• Vendors would have to reallocate finite resources to prepare many 510(k) submissions for software changes. Such resource diversion could detrimentally affect day-to-day operations of blood establishments and clinical laboratories.

   

• Blood establishments and clinical laboratories would have to do without solutions to problems, or beneficial enhancements, until vendors obtained 510(k) clearance.

   

• FDA would bring upon itself an unmanageable number of 510(k) submissions which, given the agency's already stretched resources, could result in major time delays for 510(k) clearances.

Internally Developed Software

Blood establishments must also be cognizant of device controls when they are developing in-house software. In a highly controversial decision, CBER has announced that blood-bank software developed in-house at blood establishments is subject to medical device regulation, including when vendor-supplied systems are significantly modified by establishments after procurement. In addition to meeting drug and blood-product current GMPs, establishments developing such software are expected to comply with the applicable device quality system provisions, with special emphasis on design controls. This assumes no interstate movement of the software or interstate electronic transmission of safety-critical data, including, among other things, donor deferral/suitability, viral marker testing, compatibility testing, labeling, and product quarantine/release data.

Under current CBER policy, where internally developed software itself moves across state lines or where safety-critical data from the software system are electronically transmitted across state lines, the blood establishment would need premarket clearance for its software—even if the receiving site is an affiliated or satellite facility under the same corporate ownership. Some notable problems exist with this in-house blood-bank software policy:

• Relative to interstate transmission of data, it is inconsistent with the spirit and basic intent of the FD&C Act to regulate medical devices that themselves have not been shipped in interstate commerce. However, it must be noted that interstate shipment under the FD&C Act can be presumed for purposes of device enforcement actions.²⁴

   

• Under the FD&C Act, 510(k) requirements apply only when the device has been commercially distributed. CBER's policy appears to overlook the intracorporate transfer exception to commercial distribution.²⁵

   

• The policy appears somewhat at odds with FDA's current draft policy on the regulation of medical software products (including clinical laboratory software) as written by CDRH. Under CDRH policy, computer products manufactured by licensed practitioners for use in their practice are exempt from registration, listing, quality systems requirements, MDR obligations, and premarket review. The policy states that:

A medical institution where a computer product is developed will be treated similarly, provided that the product is intended only for use in that institution. This exemption applies only where there is no commercial distribution. For example, exchange of information on public "bulletin boards" would not result in a requirement for manufacturers of the software to register or list their devices.²

An apparent exception to the need for 510(k) clearance when safety-critical data travel across state lines electronically occurs when the following criteria are met: the user owns and controls the entire system (including software development and data loop); data movement does not alter the software database (e.g., satellite download to disk or read-only access); systems and controls are sufficient to identify inaccurate data and mitigate related risks; and system validation is sufficient to ensure process control and data integrity.

While current CDRH software policy does not control blood-bank software, CBER's in-house policy seems to create a potentially significant disparity between the treatment of medical software products generally (including clinical laboratory software) and blood-bank software specifically, to the detriment of the latter.

The Future of Software Regulation

CDRH is presently revising its medical computer products policy. It remains to be seen whether the device center will maintain its own position on the in-house development of software or adopt CBER's view. CDRH has stated that, at CBER's discretion, blood-bank software could be regulated under any revised device policy.

In the future, if CDRH maintains its present position and CBER follows any new CDRH software policy, internally developed blood-bank software may avoid full active regulation. Moreover, CDRH is considering means to reduce or eliminate the need for 510(k) submissions under its revised policy. If such means are instituted, blood-bank software might not require a 510(k) submission as a prerequisite to marketing.

However, if the device center adopts CBER's view, in-house clinical laboratory or other medical software could become subject to some or all of the medical device controls, despite a traditional lack of commercial distribution.

Conclusion

Obviously, FDA's active regulation of blood-bank software as a medical device raises many complex regulatory questions for blood establishments and blood-bank software vendors. In today's regulatory environment, blood establishments and commercial manufacturers must know what their regulatory obligations are in light of CBER's regulation of blood-bank software as a medical device.

Moreover, clinical laboratories and their vendors should monitor FDA regulatory developments regarding clinical laboratory and other medical software and account for possible increased regulatory scrutiny by FDA in their strategic planning.

References

1. Letter from Kathryn C. Zoon, director, FDA Center for Biologics Evaluation and Research (CBER), to blood-bank software developers and marketers, March 31, 1994.

2. "Policy for the Regulation of Computer Products," Rockville, MD, FDA, Center for Devices and Radiological Health (CDRH) 1989.

3. 21 USC 301 et seq.

4. 21 USC 321(h).

5. Memorandum from Paul D. Parkman, director, FDA's CBER, to blood establishments, September 8, 1989.

6. Code of Federal Regulations, 21 CFR 210, 211, and 606.

7. "Draft Guideline for the Validation of Blood Establishment Computer Systems," Rockville, MD, FDA, CBER, p 7, 1993.

8. 21 CFR 807.

9. 21 CFR 820.

10. 21 CFR 803.

11. 21 CFR 807 and 814.

12. 21 CFR 801.

13. "Review Guidance for a Premarket Notification Submission for Blood Establishment Computer Software," Rockville, MD, FDA, CBER, 1996.

14. "Reviewer Guidance for Computer-Controlled Medical Devices Undergoing 510(k) Review," Rockville, MD, FDA, CDRH, 1991.

15. "Guidance for the Content of Premarket Submission for Medical Devices Containing Software," Rockville, MD, FDA, CDRH, Office of Device Evaluation (ODE), 1996.

16. "Guidance for Off-the-Shelf Software Used in Medical Devices," Rockville, MD, FDA, CDRH, ODE, 1997.

17. "General Principles of Software Validation," Rockville, MD, FDA, CDRH, Office of Compliance, 1997.

18. 21 USC 351 and 352.

19. 21 USC 331(a).

20. 21 USC 332, 333(a) and (b), and 334.

21. 21 USC 360h(e)(1).

22. 21 CFR 807.81(a)(3).

23. "Deciding When to Submit a New 510(k) for a Change to an Existing Device," Rockville, MD, FDA, CDRH, ODE, 1997.

24. 21 USC 379a.

25. 21 CFR 807.3(b)(1).

David F. Weeda, Stephen D. Terman, and Neil F. O'Flaherty are partners in the law firm of Olsson, Frank and Weeda (Washington, DC).

Contrary to what many in the industrialized world believe, tuberculosis has not been eradicated. It has not even been kept under control. In fact, according to the World Health Organization (WHO), TB killed more people in 1995 than at any other time in history. In this decade alone, it is estimated that at least 30 million people will die from this disease.

In the near term, most of those victims will be from Third World countries, completely out of sight of the inhabitants of developed nations and of the majority of IVD Technology readers. But that situation is changing rapidly—and not for the better. Despite our best efforts to cleanse our countries of TB—and although an effective, low-cost treatment exists—TB is a raging epidemic on this planet. In 1993, for the first time in history, WHO declared a global health emergency because of the continued spread of TB.

One of the reasons that current conditions justify the WHO declaration is that many nations with strong economies—those in the best position to combat the disease—believe they are no longer at risk. But this is a mistaken and deadly bit of self-deception. In 1992, Nobel laureate Joshua Lederberg, PhD, said that with regard to infectious diseases, "the world really is just one village." And documented cases indicate that multidrug-resistant TB is spreading through our village at a very rapid pace. On an airline flight, remnants of a cough laden with TB bacteria drifted through the cabin, infecting passengers. In Maine, a single shipyard worker infected over 400 others with multidrug-resistant TB, most by as little as a few seconds' conversation.

For most of us, the chances of infection through such rare occurrences seem slight. But consider the fact that one-third of all humanity is already infected. And this infected population is moving around the globe as never before. In 1990, the American Medical Association estimates, nearly one-third of the 26,000 TB victims in the United States were foreign-born. The United States screens legal immigrants for active tuberculosis, but not visitors; and during 1993 there were 21.4 million nonimmigrant—and thus unscreened—arrivals in the United States. Suddenly, the chances do not seem so slight.

Tuberculosis is very good at finding the chinks in our health-care armor, and we have plenty of them, beginning with our methods for diagnosing the disease. Current work in our industry seems focused on supplying an advanced, genetic-based diagnostic for use in developed countries. Such tests cost between $8 and $20 apiece, and may require complex, automated, and very expensive instruments. So intent are companies on this goal that they have abandoned development of simple, low-cost diagnostics, fearing that these would harm present and anticipated sales of instruments and consumables.

But the high cost of genetic tests guarantees that they will never be used among the vast populations that desperately need a TB diagnostic. Indeed, cost is the major impediment to acceptance even in the United States. What is critically needed is a simple method with a very low total cost, and it is doubtful that any gene-amplifying IVD will meet these conditions in time to make a difference. It would be a pleasure, and a surprise, to hear of a company planning to sell such a test to Third World countries for a dollar or less.

We in the IVD business need to take a very hard and realistic look at this situation, because we can make a difference. WHO is engaged in an initiative to control the spread of TB. To succeed, it does not need new antibiotics, but it does need an inexpensive and rapid sputum-based IVD that can replace the acid-fast stain technique of diagnosis. Such a product would be a major contribution to the initiative.

The history of mankind's battle with TB is filled with great labors and momentous sacrifices. In 1945, for instance, George Merck returned the patents for streptomycin to Rutgers University because this antibiotic was becoming so important in fighting TB. He did so at the request of Nobel laureate Selman Waksman, who had urged that the production of streptomycin be opened to competition in order to lower the cost of treatment. In agreeing to do as Waksman asked, Merck & Co. gave up millions in profits, but maintained its resolve to do battle against TB.

But now we face the possibility of losing the battle merely for lack of resolve. We in the IVD industry need to resolve to provide the needed diagnostic at the requisite cost. And we should provide it to the entire world—not only to those who can pay for it now.

True, our corporations exist to make profits, but this sometimes requires them to take a risk—such as producing a product for a very low-paying market—in the hope of opening new opportunities. In this case, the risk seems far greater than it is. One of the payoffs of success will almost certainly be that the economic status of the affected countries will be vastly improved. The 1996 WHO report states that the Thai economy may lose $7 billion by 2015 due solely to TB. India is already losing an estimated $372 million each year. And the American Lung Association has testified that controlling TB could result in a $24-billion annual increase in economic output from developing countries. That represents new purchasing power for the people in those countries, much of which will be directed toward health care—including other diagnostics. With 98% of TB victims living in developing countries, it would be difficult to identify another market with equivalent growth potential.

Sooner or later, the world's leading economic and technological nations will be forced to do battle against the maladies that victimize the rest of humanity—if for no other reason than to protect themselves. In this case, sooner is unquestionably better, and IVD manufacturers can play a key role in leading the way.

Even if they can do nothing else, IVD manufacturers should educate themselves about the current crisis and battle to control TB. A good starting point is the list of Web sites about tuberculosis found at http://www.cpmc.columbia.edu/tbcpp/extres.html. The WHO site listed there is particularly worthy of attention.

Richard T. Root is senior project leader and head of the antibody technology laboratory at Bard Diagnostic Sciences, Inc. (Redmond, WA), and a member of the IVD Technology editorial advisory board.

For further reading

"Cost Resistance Slows Adoption of Nucleic Acid TB Tests," IVD Technol, 3(5):21—22, 1997.

Garret L, The Coming Plague: Newly Emerging Diseases in a World Out of Balance, New York, Farrar, Straus and Giroux, 1994.

Groups at Risk: The WHO Report on the Tuberculosis Epidemic 1996, New York, World Health Organization, 1996.

Kenyon TA, Valway SE, Ihle WW, et al., "Transmission of Multidrug-Resistant Mycobacterium Tuberculosis during a Long Airplane Flight," N Engl J Med, 334 (15):933—938, 1996.

Ryan F, The Forgotten Plague: How the Battle against Tuberculosis Was Won—and Lost, Boston, Brown, Little & Co., 1992.

In October, Dade International (Deerfield, IL) and the Behring Diagnostics unit of Hoechst AG (Frankfurt, Germany) completed their long-awaited merger, officially forming a new company called Dade Behring, Inc.

Announced last March, the merger was approved by the U.S. Federal Trade Commission in August and by the Commission of the European Communities in early September. The new company will be headquartered in Deerfield, IL, with a branch office in Frankfurt.

With annual sales of approximately $1.5 billion, the new company is temporarily the world's third-largest IVD firm, pending completion of the recently announced purchase of Coulter Corp. (Miami) by Beckman Instruments (Fullerton, CA). When approved, the partnership of Beckman and Coulter is expected to earn annual revenues of $1.7 billion, pushing it ahead of Dade Behring.

The hard-won achievements of diagnostics manufacturers and their suppliers could soon be in for special recognition through a new awards program designed especially for the medical device and diagnostics industries.

The Medical Design Excellence Awards will honor the accomplishments of medical product designers and publicize the industry's best technological innovations. The awards program is sponsored by Canon Communications llc, publisher of IVD Technology and Medical Device & Diagnostic Industry magazines. "As the leading publisher and trade show producer for the medical device and diagnostics industries, Canon envisions these awards as a way to distinguish the inventive contributions of designers and engineers who are leading the progress of medical technology," says Bill Cobert, president of Canon Communications.

"These awards are unique," says Amy Allen, the program's director. "Where else could a company gain recognition for bringing to market a new generation of analytes or reagents, developing an innovative automated lab system, or transferring diagnostic technologies from the clinical laboratory to point-of-care or home use? This program will make all of that possible."

The program will offer awards in two categories: finished medical devices, and components and materials intended for medical applications. "The Medical Design Excellence Awards will reward the designers and manufacturers of products that are improving health-care delivery, reducing the cost of developing and manufacturing devices, and advancing the state of the art," says Allen. "Diagnostics manufacturers have a lot to offer in all of these areas. With their products, they are making significant advances in reducing health-care costs, increasing ease of use, and bringing innovative technologies to the point of care. We hope that many IVD companies will enter the competition and receive recognition for their efforts."

The annual program was created in collaboration with the Industrial Designers Society of America (IDSA), which has elevated public understanding of industrial design in part through its sponsorship of the Industrial Design Excellence Awards published each spring in Business Week magazine. IDSA is endorsing and administering the Medical Design Excellence Awards and will oversee their judging process.

"These awards will focus attention on the complexity of product development in the medical device and diagnostics industries and will showcase examples of how that development can be done well," says Kent Ritzel, IDSA medical section chair and director of Metaphase Design Group (St. Louis). "The program will be a valuable educational vehicle that should help companies improve their competitiveness. As a result, it will foster the development of better products by encouraging investment in high-quality design and engineering."

Entries will be evaluated for their innovation, functional improvement, and business benefits. Products must be commercially available in the United States by the entry deadline of January 26, 1998. Winners will be announced at the Medical Design & Manufacturing East 98 Conference and Exposition, which will be held June 2—4 in New York City.

For further information and an entry form turn to page 18 of this issue. Or visit http://www.devicelink.com/awards, or call Kathy Leftwich of IDSA at 703/759-0100 or Amy Allen of Canon Communications at 310/392-5509.

IVD Technology Magazine
IVDT Article Index

Originally published November, 1997

The Health Industry Manufacturers Association (Washington, DC) is recommending that Japan's Ministry of Health and Welfare regulate and treat IVD products as medical devices rather than as pharmaceuticals.

The suggestion was made as part of a larger list of initiatives for the Japanese medical technology sector submitted to the Clinton administration as background for deregulation talks between the two governments.

According to HIMA, recent studies suggest that inefficiencies in the Japanese system are to blame for the high cost of many medical products in Japan. "Deregulation measures that expedite access to the Japanese market will further help lower prices and, in this case, health-care costs," says Ed Rozynski, HIMA's executive vice president.

The association says that "industry is prepared to identify some current regulations that need to be changed or relaxed for IVDs."

A new wave of patent litigation is giving increased importance to the ongoing wars over intellectual property rights in the IVD industry.

Young entrepreneurial companies are finding that the best protection against a takeover is a well-guarded idea. And market leaders are discovering that if they don't protect their patents, imitators will swamp the market.

"If a company is successful, its product will be reverse-engineered and copied," says patent attorney Stephen Glazier of Pillsbury, Madison & Sutro (Washington, DC).

Two lawsuits reflect the current trend. In late August, Vysis, Inc. (Downers Grove, IL), won a federal court ruling in San Francisco against Oncor, Inc. (Gaithersburg, MD). The court issued a broad pretrial ruling that a patent on University of California technology for fluorescent in situ hybridization (FISH) DNA probes licensed exclusively to Vysis was novel and unobvious. The court also held that Oncor's Coatosome DNA probes had infringed on the patent.

The decision was the more remarkable because it was handed down before the case went to trial. Officials for Oncor put the best face on the defeat, noting that 95% of their product base was unaffected—and that they will still have their day in court.

"It's actually very good news," says Oncor's director of diagnostics programs Patrick Muraca. "The judge has left open the question of whether the patent was procured fraudulently."

But lawyers for Vysis say it will be difficult for Oncor to prove its contention that a UC professor intentionally defrauded the U.S. Patent and Trademark Office.

According to Vysis general counsel William E. Murray, "intense research competition" is the driving force behind the latest round of patent suits. Vysis expects the FISH DNA patent to have broad application for diagnosis of cancers, heart disorders, and prenatal defects. According to Murray, a single breast cancer probe currently up for FDA approval has an estimated annual market value of $175 million.

The Vysis-Oncor suit also demonstrates the importance of patents in an age of product complexity, Murray says. Today's most valuable products have multiple components patented by different companies. The firms that triumph will be the ones that combine a group of patents for maximum clinical effect.

"Patents are trading chips," Murray says. "No one company has all the pieces."

Another important components case was filed last June by market leader Roche Diagnostics Systems, Inc. (Somerville, NJ). Roche filed to protect the cuvette component of its COBAS Mira automated chemistry test instrument after Ritter GmbH of Germany entered the European market with a competing product, Roche officials say.

The cuvette, the plastic cup that holds reagents, is hardly the jewel of the Roche patent family. But the company says that protecting it is crucial to maintaining the value of its COBAS Mira product, which represents 25% of Roche's $625-million worldwide diagnostics sales.

"We are very serious about protecting our patents," Roche public affairs director Paula Evangelista says emphatically.

European furor over the outbreak of mad cow disease in Great Britain is threatening upheaval in the U.S. IVD industry.

In July, the European Union ordered a blanket ban on all products made from cattle parts that could carry bovine spongiform encephalopathy (BSE), which is suspected as the cause of the outbreak announced in 1996. The ban will affect blood coagulant, tetanus, and other IVD tests that use calves' brains as media.

Of even greater concern to U.S. suppliers is a further EU directive authorizing its 15 member countries to require that imports be government-certified as free from BSE-risk materials. That order could drag half the U.S. IVD exports into the mad cow disease fray, says John Place, director general of the European Diagnostic Manufacturers Association (EDMA, Brussels).

The ban came as no great surprise, given the level of European outrage over the incident. In 1996, Great Britain sent shock waves through Europe by disclosing that a BSE outbreak in British cattle from 1986 to 1995 might be linked to 10 human cases of a previously unrecognized strain of Creutzfeld-Jakob or mad cow disease. Characterized by plaque formations in the brain, the disease causes severe psychiatric symptoms and dementia. Most victims of the new strain are under 30 years of age and die within a year of onset.

Under fire for bungling the crisis, European officials have promised to rid the human food chain of BSE risk.

But IVD manufacturers are mystified that they were included in the ban, since their test products are neither ingested nor injected, but rather used in a laboratory or test-tube setting. "The only way these products could transmit BSE would be if someone drank them, and I doubt anybody would do that," says Carolyn Jones, director of technology and regulatory affairs for the Health Industry Manufacturers Association (Washington, DC). "I've gotten a lot of calls from IVD companies complaining and asking for information. They're very, very scared."

Industry officials say the EU order could seriously disrupt manufacturing and international trade, and for no good purpose. A rigorous surveillance program has turned up no cases of BSE in U.S. cattle, according to United States Department of Agriculture official Linda Detwiler.

"Personally, I do not know of any risk," says Detwiler, a senior staff veterinarian with the USDA's animal and plant health inspection service.

The EU justifies the sweeping ban by citing widespread public alarm over food safety. But critics respond that the EU is pandering to political interests and emotionalism.

The European Parliament recently threatened to censure its administrative arm, the European Commission (EC), and to fire its members if food safety isn't improved. Critics charge that commission members are caving in to hysteria to avoid being sacked.

In fighting the EU ban, the IVD industry is being joined by some powerful allies. The EU directive also prohibits imports of tallow and gelatin—beef derivatives that are used in the pharmaceutical and cosmetics industries. EDMA, which is composed of European and American companies, has sent a letter of protest to the EC. The U.S. government has threatened to challenge any ban on tallow before the World Trade Organization. And FDA has sent a delegation to the commission to "air its concerns," according to Kiki Hellman, PhD, a microbiologist in the agency's Center for Devices and Radiological Health.

If the EU's certification requirement is implemented, many industry officials worry that neither USDA nor FDA has the resources to carry out the program. Manufacturers could scramble to reconfigure their products, but how? Europe first banned brain, spinal cord, and spleen material from selected cows, and then went on to place restrictions on sheep and goat parts.

"Some products are produced both within and outside the EU," says EDMA's Place. "Companies produce them wherever it is cheapest to
do so. Manufacturers could change their products— use rabbits' brains instead of calves' brains, for instance—but then those might also be excluded."

Place says he would recommend that test makers use gene technology to modify their products, but the Europeans might resist. Despite the absence of any proven risk, European countries have refused U.S. exports of genetically modified soy oil and maize.

Manufacturers will be hard-pressed to rush new diagnostics through regulatory processes and onto the market before the ban kicks in on January 1, says Frederick Clerie, director of regulatory affairs at Bayer Corp. (Tarrytown, NY). Some diagnostics makers might have to pull their products from European shelves, at least temporarily, he says.

The practical ramifications of the ban are illustrated by the recent experience of Irvine Scientific (Santa Ana, CA). In a precursor to the EU ban, Ireland is requiring the company to certify that the cattle used in its bovine serum have been in the United States for 90 days. But that's impossible.

"Nobody holds cattle for that long," says Simon Roa, production director at Irvine Scientific. "Some of the cattle come from Mexico or Canada right before slaughter."

U.S. government and trade officials would like the EU to drop its certification requirement and exempt U.S. products from the ban. Earlier this year, the EU refused to certify the United States as BSE-free, in part because of a lingering concern about the recycling of waste animal protein into feed for cattle and sheep. FDA banned the practice, which is thought to amplify BSE contamination, last summer.

But some officials fear that appeals to reason won't fly in the present climate. "The politicians are going for zero risk," says Place. "The general public doesn't understand risk. People think that by adopting laws they can reduce the risk to zero, and they can't." — G. H.