minor compared to those we had—and will always have—about our son.28But I gradually realized that
just because my patients’ fears were generally not borne out, this did not diminish the validity of their original concern. Whether their problems ultimately are trivial or life threatening, patients may feel frus-trated or fearful before they have an explanation for their discomfort, even more so when their doctor can’t explain the symptom at hand, doesn’t have a treatment for it, or can’t guarantee a cure.
Improving Parent-Doctor Relationships: A Parents’ Wish List
After my son completed treatment, our family, along with several others whose children have can-cer, developed a wish list of ways that physicians can make the treatment of serious illnesses more tolera-ble for young patients and their parents (Tatolera-ble). As a parent, it is my goal to share this list with clinicians, in hopes of easing the journey of other families down the difficult path we have tread. As a physician, it is my goal to live up to it with my own patients. All those who come to see doctors deserve such consid-eration, whether they have cancer or merely a cold.
Meg Durbin, MD
Palo Alto Medical Clinic Palo Alto, CA 94301
ACKNOWLEDGMENTS
The author thanks Arthur Ablin, Martin Ernster, Virginia Ern-ster, Clinton Lewis, William Byrne, and three anonymous review-ers for their comments and suggestions.
REFERENCES
1. Durbin M. Mommy, make me better. Ladies’ Home Journal. 1996;July: 34,38,41– 42
2. Heyman J. Equal partners: A Physician’s Call for a New Spirit of Medicine. New York, NY: Little, Brown; 1995
3. Klass P. Other Women’s Children. New York, NY: Random House; 1990 4. Livingston G. Only Spring: on Mourning the Death of my Son. San
Fran-cisco, CA: Harper; 1995
5. Rosenbaum E. A Taste of My Own Medicine: When the Doctor is the Patient. New York, NY: Random House; 1988
6. Catalfo P. In the dragon’s shadow. New Age Journal. 1992;January/ February:69 –72
7. Gaes G, Gaes C, Bashe P. You Don’t Have To Die. New York, NY: Villard Press; 1992:1–318
8. Cousins N. Anatomy of an Illness as Perceived by the Patient: Reflections on
Healing and Regeneration. New York, NY: W. W. Norton and Co; 1981
9. The Center for Attitudinal Healing. Advice to Doctors and Other Big People
From Kids. Berkeley, CA: Celestial Arts; 1991
10. Greenberg LW, Jewett LS, Gluck RS, et al. Giving information for a life-threatening diagnosis. AJDC. 1984;138:649 – 653
11. Krahn GL, Hallum A, Kime C. Are there good ways to give “Bad News”? Pediatrics. 1993;91:578 –582
12. Myers BA. The informing interview. Am J Dis Child. 1983;137:572–577 13. Candlelighters Childhood Cancer Foundation is a national educational,
support, and outreach organization for families facing pediatric cancer. Internet Website “Candlelighters Childhood Cancer Family Alliance”, http://cois.corn/candle/
14. Internet Website “Cancer Related Links”, http://seidata.com/
;rmarriag/rcancer.html
15. Internet Website “Support Information for Cancer Patients”, http:// www.lib.umich.edu/chdocs/cancer/SUPPORT.HTML
16. Lerner M. Choices in Healing. Cambridge, MA: MIT Press; 1994:558 –569 17. Vastyan EA. Spiritual aspects of the care of cancer patients. CA Cancer
J Clin. 1986;36:110 –114
18. Spiegel D. Facilitating emotional coping during treatment. Cancer. 1990; 66(6 suppl):1422–1426
19. Thoma ME, Hochenberry-Easton M, Kemp V. Life change events and
coping behaviors in families of children with cancer. J Pediatr Oncol
Nursing. 1993;10:105–111
20. Hurley PM. Childhood cancer: a pilot study of assessment of parental stress. Oncol Nursing Forum. 1984;11:44 – 48
21. Uyl de Groot CA, Rutten FF, Sonsel GJ. Measurement and valuation of quality of life in economic appraisal of cancer treatment. European J
Cancer. 1994;30A:111–117
22. Berkman BJ, Sampson SE. Psychosocial effects of cancer economics on patients and their families. Cancer. 1993;72(9 suppl):2846 –2849 23. Stommel M, Given CS, Given BA. The cost of cancer home care to
families. Cancer. 1993;71:1867–1874
24. Varni JW, Katz ER, Colegrove R Jr, Dolgin M. Perceived social support and adjustment of children with newly diagnosed cancer. J Dev Behav
Pediatr. 1994;15:20 –26
25. Heiney SP, Wells SM, Ettinger RS, Ettinger S, Cannon V. Effects of group therapy on parents of children with cancer. J Pediatr Oncol
Nurs-ing. 1989;6:63– 69
26. Lynam MJ. The parent network in pediatric oncology: Supportive or not? Cancer Nursing. 1987;10:207–216
27. Suchman AL, Matthews DA. What makes the patient-doctor relation-ship therapeutic? Exploring the connexional dimension of medical care.
Ann Int Med. 1988;108:125–130
28. Van Dongen-Melman JE, Pruyn JF, De Groot A, Koot HM, Hahlen K, Verhulst FC. Late psychological consequences for parents of children who survived cancer. J Pediatr Psychol. 1995;20:567–586
Let the User Beware: Specificity
and Sensitivity Limits for In Vitro
Diagnostic Devices
ABBREVIATIONS. EBV, Epstein-Barr virus; FDA, Food and Drug Administration; PMA, premarket approval; PMN, premarket no-tification.
A
growing number of in vitro diagnostic screening tests are on the market today to diagnose numerous infectious diseases. Sim-pler to perform than the older methods of cultures or acute and convalescent serology, they promise im-mediate answers at a lower cost, which suits clinical as well as cost-containment interests in today’s health care market. Their easy processing conforms to the preferences of Clinical Laboratory Improve-ment AmendImprove-ments; the simplicity of many test kits minimizes human error. Most physicians assume that before these kits can be marketed, their reliabil-ity and validreliabil-ity have been proven. However, our recent experience with one new product, the Mono-lert,1which is promoted as a rapid screening test forinfectious mononucleosis, suggests that this general assumption is erroneous.
Starting in the early 1990s, our pediatric group sent a number of blood samples to our local hospital laboratory to identify which patients with symptoms of lethargy, fever, sore throat, headache, and lymph-adenopathy actually had early Lyme disease. Tests included a complete blood count, erythrocyte sedi-mentation rate, Lyme enzyme-linked
immunosor-Received for publication Nov 11, 1996; accepted Mar 17, 1997.
Reprint requests to (D.L.) New England Pediatrics LLP, 166 West Broad St, Suite 103, Stamford, CT 06902.
PEDIATRICS (ISSN 0031 4005). Copyright © 1997 by the American Acad-emy of Pediatrics.
COMMENTARIES 267 at Viet Nam:AAP Sponsored on August 30, 2020
bent assay, and a Monolert test. Over the next few years, very few children had serologic evidence of Lyme disease, but a surprisingly large number tested positive for infectious mononucleosis.
This was perplexing because many of these chil-dren had illnesses that were not ultimately typical of primary Epstein-Barr virus (EBV) infection. As some children’s symptoms progressed, they were found to have had a variety of other illnesses including pneu-monia and pyelonephritis. Mononucleosis was un-likely to be the correct diagnosis.
The Monolert product insert provided no obvious explanation for the many positive active infectious mononucleosis results. It stated that acute varicella, elevated rheumatoid factor, and acute cytomegalov-irus infection could cause false-positive results; how-ever, our patients’ clinical courses were not compat-ible with these diagnoses. The hospital laboratory director could identify no obvious technical prob-lems in using the kit. A conversation with the prod-uct manager at Ortho Diagnostics (Raritan, NJ), the original makers of the Monolert test kit, revealed no additional cause for test interference. Because the kit’s manufacture and sale were being transferred to Meridian Diagnostics (Cincinnati, OH), further dis-cussions would rest with the new owners.
At this point, we consulted with the Centers for Disease Control and Prevention and were referred to Dr George Miller, an expert in EBV investigation at Yale University’s School of Medicine, who agreed to test our patients’ sera for the presence of EBV mark-ers. Thirty-eight children who had initially tested positive by Monolert returned for a second veni-puncture. Dr Miller, using indirect immunofluores-cent technique, found no traces of viral capsid anti-gen immunoglobulin G in 31 of these samples. Dr Richard Tilton, founder and chief scientific officer of North American Laboratory Group Ltd, completed the EBV panel on these second serum samples (in-cluding Epstein-Barr nuclear antigen immunoglobu-lin G and early antigen) and confirmed Dr Miller’s results. This clearly indicated that these patients had not had an EBV infection in the preceding months when the Monolert test results had been positive. We also tested for antibodies to Borrelia burgdorferi and cytomegalovirus to rule those out as potential cross-reacting antibodies. We found none.
Although we had contacted the Meridian Diagnos-tics product manager to tell them about our results, the company did not respond until a Food and Drug Administration (FDA) inquiry began as a result of our findings. The director of scientific and regulatory affairs at Meridian sent us a 3-page questionnaire designed by the company to aid in its response to the FDA, a document we completed and returned.
Eight months later, we filed a Freedom of Infor-mation Act request to obtain inforInfor-mation on the re-sults of the FDA’s investigation. The documents we obtained from the Post Market Division of the FDA’s Center for Devices and Radiological Health indicated that Meridian maintained that Monolert gave accept-able results. Because the product was transferred to them from Ortho after our study was completed, Meridian denied responsibility for explaining what
happened during Ortho’s manufacturing tenure. They faulted our study design, questioned our choice of population, wondered if the laboratory had used faulty technique, and implied that we, as a group of local practitioners, had some preset prejudice against their product. The company also stated that it had received no customer complaints that it took as a sign of customer dissatisfaction. However, their files apparently contained no record of our initial com-plaint either.
Meridian officials stated in their response letter to the FDA that because the product is intended for use only in patients whose symptoms are compatible with infectious mononucleosis, its performance in any other group has not been established. That a test designed to identify an illness need be reliable in only the group of people who have classic symptoms of the illness is especially troublesome. The company volunteered to conduct clinical trials to prove the test kit’s performance. Although results were promised by May 1995, as of March 1997 we have been unable to obtain any results or to confirm that any study is ongoing or has been completed.
A further review of the medical literature revealed an article we had overlooked in our initial literature search. Published in 1991,2it concluded, as did ours,
that “the high rate of false-positive tests makes this rapid enzyme-linked immunosorbent assay unsuit-able for the diagnosis of infectious mononucleosis.” So, unknown to us, we had conducted a replication study. Yet despite two articles questioning Mono-lert’s validity, the Monolert investigation at FDA’s Post Market Division had been officially closed.
Perplexed as to how an in vitro diagnostic test kit such as this can retain FDA clearance to market, we reviewed the FDA’s process. In vitro diagnostic test kits are regulated by the FDA in the category of medical devices. Medical devices enter the US mar-ketplace for general clinical use through one of two FDA review tracks: premarket approval (PMA) or premarket notification (PMN). The most scientifi-cally rigorous path to market is the PMA process, which requires that a manufacturer provide scientific evidence demonstrating that a medical device is both safe and effective for its labelled use. This is similar to the investigational new drug application and re-view process. The second path—the PMN—is con-sidered a “me too” route to market. Most in vitro diagnostic test kits, including the Monolert, enter the US market this way. A submission is made to the FDA by the product’s sponsor to demonstrate that a medical device is substantially equivalent to another currently marketed device in its design and intended use. If FDA review determines that the device meets the criteria for a substantial equivalence determina-tion, the diagnostic test kit can be legally marketed. A medical device does not have to perform in a manner better than, or even equal to, a currently marketed product for the same labelled intended use to receive clearance. Unlike the PMA process, PMN does not require a manufacturer to supply extensive clinical trial data to support labelling claims.
Understanding this approval process clarifies a statement made by Dr David Kessler during his
years as FDA commissioner. At a Congressional hearing to study proposals to overhaul the FDA, he testified, “To require the agency to demonstrate that a product is not safe or, where appropriate, not ef-fective, is to require FDA to demonstrate something for which there may be no data because sufficient studies have not been conducted.” (New York Times. May 2, 1996:21).
Furthermore, FDA officials with whom we spoke explained that the US Congress (as the regulatory body ultimately in charge) has set no lower limits on the sensitivity and specificity needed to market a device. Basically, as long as the fine print on the insert of the product includes a disclaimer, such as a nonrandom population studied or not tested in chil-dren under x years of age or 20% specificity guaran-teed, the product may be sold. That is, as long as the product makes no false claims, it may not be denied or removed from the market, no matter how meager the criteria are or whether the performance is better than chance alone.
The officials at the FDA pointed out what has become painfully obvious. Physicians and laboratory directors who purchase and use laboratory kits from the many companies that market them need to eval-uate the fine print in the product insert carefully and critically. We may not assume that because a product is on the market it is reliable or valid.
This situation may get worse if well-meaning con-sumer groups convince Congress to adopt legislation accelerating FDA procedures for approving medical devices as well as medication and vaccines. As US Senator Edward Kennedy pointed out in a commen-tary in the Washington Post on April 22, 1996, pro-posed bills that Congress will be considering are “designed to shift responsibility for product ap-proval from the independent experts at the FDA to private businesses.” Inherent conflicts of interest are obvious.
Serious questions remain unanswered. Who, in fact, should be the watchdog? How should diagnos-tic devices be evaluated? Can the industry be legiti-mately expected to police itself? What is the role of academia here, if any? Calls for help to academic physicians in various positions around the country during this investigation generated much sympathy, but virtually no action. In fact, it seems that no
clear-cut mechanism exists for the physician community to address our concerns in a scientific manner. From our perspective, when serious concerns about prod-ucts, drugs, or vaccines have been raised, it would be beneficial to have one physician organization clearly identified whose purpose is to coordinate further studies when they are needed. Perhaps this group could also exert pressure on the FDA and manufac-turers to ensure that the appropriate steps are taken to protect public safety. This organization could be one formed solely for this purpose or it could be a branch of one already in existence–such as the AMA. It remains unclear whether in the present climate of deregulation, our presently ineffective system can become more reliable. If it is difficult to assure both the physicians and patients that in vitro diagnostic kits marketed under the current rules are sensitive and specific, one can envision even greater problems after FDA authority is lessened. Medical drugs and vaccine safety are at risk as well.
For now, physicians and laboratory directors should not assume that diagnostic test kits and other medical device products presently on the market today have been closely regulated by either business or government. In the end, we learned, let the user beware.
Dorothy Levine, MD Rosemary Klenk, MD Alan Morelli, MD Nancy Hofreuter, MD Hilary Hoffmeister, MD
New England Pediatrics LLP Stamford, CT 06902
ACKNOWLEDGMENTS
The authors wish to thank Dr James Cherry, Dr George Miller, Dr Richard Tilton, Dr Myron Levin, and Dr Alvin Rosenfeld for their review of the manuscript; and Nicole Wise, Eli Levine, and Monique Cerullo for their thoughtful editing.
REFERENCES
1. Levine D, Tilton RC, Parry MF, Klenk R, Morelli A, Hofreuter N. False-positive EBNA IgM and IgG antibody tests for infectious mono-nucleosis in children. Pediatrics. 1994;94:892– 894
2. Levin M, Weinstein M, Sumaya C, et al. The rapid diagnosis of infec-tious mononucleosis using an ELISA that detects IgM antibody to a peptide component of Epstein-Barr virus nuclear antigen. Diagn
Micro-biol Infect Dis. 1991;14:287–291
COMMENTARIES 269 at Viet Nam:AAP Sponsored on August 30, 2020
DOI: 10.1542/peds.100.2.267
1997;100;267
Pediatrics
Hoffmeister
Dorothy Levine, Rosemary Klenk, Alan Morelli, Nancy Hofreuter and Hilary
Devices
Let the User Beware: Specificity and Sensitivity Limits for In Vitro Diagnostic
Services
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DOI: 10.1542/peds.100.2.267
1997;100;267
Pediatrics
Hoffmeister
Dorothy Levine, Rosemary Klenk, Alan Morelli, Nancy Hofreuter and Hilary
Devices
Let the User Beware: Specificity and Sensitivity Limits for In Vitro Diagnostic
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