1 - University of Washington
Framing the Question“A great deal of influence rests in the hands of parties who control the framing of a health issue” K.D. Brownell and K.E. Wagner, 2009IntroductionClinical decisions start with inquiries related to diagnosis, etiology, treatment, and prognosis. How can one diagnose a root fracture? Are dental caries and destructive periodontal disease infectious diseases? Does scaling and root planning reduce the morbidity associated with destructive periodontal disease? What is the prognosis of an implant-supported maxillary denture? Answers to such vague questions require the formulation of a PICO question – a specific question that defines explicitly the patient characteristics, the intervention, the control, and the outcome. 1. Specifying the patient in the clinical questionClinical questions are related to a particular patient in terms of age, dental status, concomitant diseases, medications, gender, socio-economic status, diet, tobacco use, health awareness, and family history. The need for such specificity in formulating a question may appear self-evident. A child may respond differently to a treatment than an adult. Oral cancer may be more likely in a smoker. In general, when searching for evidence, you would like to find studies that were performed on patients that share many of the characteristics of your patients. The more the characteristics of the patients in studies differ from your patient, the more questions you may have regarding the relevance of the findings.Examples where a treatment effective in one population fails to be effective in another:Vaccine for pneumonia in Alaska/Finland. Effective in Finland, not Alaska ADDIN EN.CITE <EndNote><Cite><Author>Eskola</Author><Year>1990</Year><RecNum>568</RecNum><record><rec-number>568</rec-number><foreign-keys><key app="EN" db-id="tfd9sp0eep9dede50ddx2drjxftp2w2dvdza">568</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Eskola, J.</author><author>Kayhty, H.</author><author>Takala, A.K.</author><author>Peltola, H.</author><author>Ronnberg, P.R.</author><author>Kela, E.</author><author>Pekkanen, E.</author><author>McVerry, P.H.</author><author>Makela, P.H.</author></authors></contributors><titles><title> A randomized, prospective field trial of a conjugate vaccine in the protection of infants and young children against invasive Haemophilus Influenza Type b virus.</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>1381-1387</pages><volume>323</volume><dates><year>1990</year></dates><urls></urls></record></Cite><Cite><Author>Ward</Author><Year>1990</Year><RecNum>94</RecNum><record><rec-number>94</rec-number><foreign-keys><key app="EN" db-id="tfd9sp0eep9dede50ddx2drjxftp2w2dvdza">94</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ward, J.</author><author>Brenneman, G.</author><author>Letson, G.W.</author><author>Heyward, W.L.</author><author>the Alaska H. Influenzae vaccine study group,</author></authors></contributors><titles><title>Limited efficacy of a Haemophilus Influenzae Type b conjugate vaccine in Alaska Native infants.</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>1393-1401</pages><volume>323</volume><dates><year>1990</year></dates><urls></urls></record></Cite></EndNote>(Eskola et al., 1990, Ward et al., 1990). Due to genetics?Treatments for populations at low-risk for dental caries may not work for high-risk caries populations ( ADDIN EN.CITE <EndNote><Cite><Author>Forgie</Author><Year>2000</Year><RecNum>541</RecNum><record><rec-number>541</rec-number><foreign-keys><key app="EN" db-id="tfd9sp0eep9dede50ddx2drjxftp2w2dvdza">541</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Forgie, A. H.</author><author>Paterson, M.</author><author>Pine, C. M.</author><author>Pitts, N. B.</author><author>Nugent, Z. J.</author></authors></contributors><auth-address>Dental Public Health and Health Psychology Section, Dundee Dental Hospital and School, Dundee, Scotland, UK.</auth-address><titles><title>A randomised controlled trial of the caries-preventive efficacy of a chlorhexidine-containing varnish in high-caries-risk adolescents</title><secondary-title>Caries Res</secondary-title></titles><periodical><full-title>Caries Res</full-title></periodical><pages>432-9</pages><volume>34</volume><number>5</number><keywords><keyword>Adolescent</keyword><keyword>Anti-Infective Agents, Local/pharmacology/*therapeutic use</keyword><keyword>Cariostatic Agents/pharmacology/*therapeutic use</keyword><keyword>Chi-Square Distribution</keyword><keyword>Child</keyword><keyword>Chlorhexidine/pharmacology/*therapeutic use</keyword><keyword>Colony Count, Microbial</keyword><keyword>DMF Index</keyword><keyword>Dental Caries/*prevention & control</keyword><keyword>Female</keyword><keyword>Human</keyword><keyword>Lacquer</keyword><keyword>Male</keyword><keyword>Patient Compliance</keyword><keyword>Saliva/microbiology</keyword><keyword>Streptococcus mutans/drug effects</keyword><keyword>Support, Non-U.S. Gov't</keyword><keyword>Treatment Failure</keyword></keywords><dates><year>2000</year><pub-dates><date>Sep-Oct</date></pub-dates></dates><accession-num>11014911</accession-num><urls><related-urls><url>;(Forgie et al., 2000), ADDIN EN.CITE <EndNote><Cite><Author>Hausen</Author><Year>2000</Year><RecNum>926</RecNum><record><rec-number>926</rec-number><foreign-keys><key app="EN" db-id="tfd9sp0eep9dede50ddx2drjxftp2w2dvdza">926</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hausen, H.</author><author>Karkkainen, S.</author><author>Seppa, L.</author></authors></contributors><auth-address>Institute of Dentistry, University of Oulu, Finland. hannu.hausen@oulu.fi</auth-address><titles><title>Application of the high-risk strategy to control dental caries</title><secondary-title>Community Dent Oral Epidemiol</secondary-title></titles><periodical><full-title>Community Dent Oral Epidemiol</full-title></periodical><pages>26-34</pages><volume>28</volume><number>1</number><edition>2000/01/14</edition><keywords><keyword>Child</keyword><keyword>DMF Index</keyword><keyword>Dental Caries/diagnosis/epidemiology/*prevention & control</keyword><keyword>Dental Caries Activity Tests/statistics & numerical data</keyword><keyword>Finland/epidemiology</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Observer Variation</keyword><keyword>Patient Compliance/statistics & numerical data</keyword><keyword>Prospective Studies</keyword><keyword>Random Allocation</keyword><keyword>Risk Factors</keyword><keyword>Urban Population/statistics & numerical data</keyword></keywords><dates><year>2000</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0301-5661 (Print)</isbn><accession-num>10634681</accession-num><urls><related-urls><url>;(Hausen et al., 2000) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYWxsZXN0YWw8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFy
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ADDIN EN.CITE.DATA (Kallestal, 2005) ADDIN EN.CITE <EndNote><Cite><Author>Seppa</Author><Year>1991</Year><RecNum>928</RecNum><record><rec-number>928</rec-number><foreign-keys><key app="EN" db-id="tfd9sp0eep9dede50ddx2drjxftp2w2dvdza">928</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Seppa, L.</author><author>Hausen, H.</author><author>Pollanen, L.</author><author>Karkkainen, S.</author><author>Helasharju, K.</author></authors></contributors><auth-address>Faculty of Dentistry, University of Kuopio, Finland.</auth-address><titles><title>Effect of intensified caries prevention on approximal caries in adolescents with high caries risk</title><secondary-title>Caries Res</secondary-title></titles><periodical><full-title>Caries Res</full-title></periodical><pages>392-5</pages><volume>25</volume><number>5</number><edition>1991/01/01</edition><keywords><keyword>Adolescent</keyword><keyword>DMF Index</keyword><keyword>Dental Caries/epidemiology/*prevention & control</keyword><keyword>Female</keyword><keyword>Finland/epidemiology</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Male</keyword><keyword>Oral Hygiene</keyword><keyword>Pit and Fissure Sealants</keyword><keyword>Preventive Dentistry/*standards</keyword><keyword>Program Evaluation</keyword><keyword>Risk Factors</keyword><keyword>Saliva/microbiology</keyword><keyword>Streptococcus mutans/isolation & purification</keyword></keywords><dates><year>1991</year></dates><isbn>0008-6568 (Print)</isbn><accession-num>1747891</accession-num><urls><related-urls><url>;(Seppa et al., 1991).Examples where treatments are recommended to patients with characteristics that differ from the patients enrolled in clinical trialsStatins tested in middle-aged patients with a history of a heart attack are recommended to pediatric patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BdmlzPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Avis et al., 2009). Flossing has been shown effective for caries prevention only in primary teeth, low-fluoride exposures, and only when teeth are flossed by trained personnel. Flossing is typically recommended for adults who self-floss and who use fluorides. ADDIN EN.CITE <EndNote><Cite><Author>Hujoel</Author><Year>2006</Year><RecNum>929</RecNum><record><rec-number>929</rec-number><foreign-keys><key app="EN" db-id="tfd9sp0eep9dede50ddx2drjxftp2w2dvdza">929</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hujoel, P. P.</author><author>Cunha-Cruz, J.</author><author>Banting, D. W.</author><author>Loesche, W. J.</author></authors></contributors><auth-address>Department of Dental Public Health Sciences, University of Washington, Seattle, WA 98195, USA. hujoel@u.washington.edu</auth-address><titles><title>Dental flossing and interproximal caries: a systematic review</title><secondary-title>J Dent Res</secondary-title></titles><periodical><full-title>J Dent Res</full-title></periodical><pages>298-305</pages><volume>85</volume><number>4</number><edition>2006/03/29</edition><keywords><keyword>Adolescent</keyword><keyword>Child</keyword><keyword>Controlled Clinical Trials as Topic</keyword><keyword>Databases, Bibliographic</keyword><keyword>Dental Care/*instrumentation</keyword><keyword>Dental Caries/etiology/*prevention & control</keyword><keyword>*Dental Devices, Home Care</keyword><keyword>Dental Plaque/complications/*prevention & control</keyword><keyword>Humans</keyword><keyword>Oral Hygiene/*instrumentation</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2006</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0022-0345 (Print)</isbn><accession-num>16567548</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Hujoel et al., 2006). Cholesterol lowering drug’s effectiveness in middle-aged males with abnormal cholesterol levels and extrapolated to males and females with slightly elevated cholesterol evels ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Year>1984</Year><RecNum>752</RecNum><record><rec-number>752</rec-number><foreign-keys><key app="EN" db-id="tfd9sp0eep9dede50ddx2drjxftp2w2dvdza">752</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles><title>The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease</title><secondary-title>Jama</secondary-title></titles><periodical><full-title>Jama</full-title></periodical><pages>351-64</pages><volume>251</volume><number>3</number><keywords><keyword>Adult</keyword><keyword>Cholesterol/*blood</keyword><keyword>Cholestyramine/adverse effects/*therapeutic use</keyword><keyword>Clinical Trials</keyword><keyword>Coronary Disease/blood/mortality/*prevention & control</keyword><keyword>Double-Blind Method</keyword><keyword>Human</keyword><keyword>Hypercholesterolemia/blood/drug therapy</keyword><keyword>Lipoproteins/blood</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Mortality</keyword><keyword>Support, U.S. Gov't, P.H.S.</keyword></keywords><dates><year>1984</year><pub-dates><date>Jan 20</date></pub-dates></dates><accession-num>6361299</accession-num><urls><related-urls><url>;(1984).Extrapolation of safety from one patient group to anotherTesting of safety drugs in young healthy populations and marketing to old frail populations ADDIN EN.CITE <EndNote><Cite><Author>Bodenheimer</Author><Year>2000</Year><RecNum>932</RecNum><record><rec-number>932</rec-number><foreign-keys><key app="EN" db-id="tfd9sp0eep9dede50ddx2drjxftp2w2dvdza">932</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bodenheimer, T.</author></authors></contributors><titles><title>Uneasy alliance--clinical investigators and the pharmaceutical industry</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>1539-44</pages><volume>342</volume><number>20</number><edition>2000/05/18</edition><keywords><keyword>Academic Medical Centers/economics</keyword><keyword>Authorship</keyword><keyword>*Biomedical Research</keyword><keyword>Clinical Trials as Topic/*economics</keyword><keyword>Conflict of Interest/*economics</keyword><keyword>Contracts</keyword><keyword>Disclosure</keyword><keyword>Drug Approval/organization & administration</keyword><keyword>Drug Evaluation/*economics</keyword><keyword>*Drug Industry/economics/organization & administration</keyword><keyword>Interinstitutional Relations</keyword><keyword>Publishing</keyword><keyword>*Research Support as Topic</keyword><keyword>*Social Change</keyword><keyword>United States</keyword><keyword>United States Food and Drug Administration</keyword></keywords><dates><year>2000</year><pub-dates><date>May 18</date></pub-dates></dates><isbn>0028-4793 (Print)</isbn><accession-num>10816196</accession-num><urls><related-urls><url>;(Bodenheimer, 2000).2. The comparison; the Intervention and the ControlThe essence of an answerable clinical question is a comparison. Frequency, dose, duration of both the compared interventions or exposures need to be considered when formulating a PICO question Tricks to make a novel intervention look more effective Non-expert clinicians for the delivery of the control treatment ADDIN EN.CITE <EndNote><Cite><Author>Ainamo</Author><Year>1992</Year><RecNum>727</RecNum><record><rec-number>727</rec-number><foreign-keys><key app="EN" db-id="tfd9sp0eep9dede50ddx2drjxftp2w2dvdza">727</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ainamo, J.</author><author>Lie, T.</author><author>Ellingsen, B. H.</author><author>Hansen, B. F.</author><author>Johansson, L. A.</author><author>Karring, T.</author><author>Kisch, J.</author><author>Paunio, K.</author><author>Stoltze, K.</author></authors></contributors><titles><title>Clinical responses to subgingival application of a metronidazole 25% gel compared to the effect of subgingival scaling in adult periodontitis</title><secondary-title>J Clin Periodontol</secondary-title></titles><periodical><full-title>J Clin Periodontol</full-title></periodical><pages>723-9</pages><volume>19</volume><number>9 Pt 2</number><keywords><keyword>DENTAL-SCALING. METRONIDAZOLE: tu. PERIODONTITIS: dt. PERIODONTITIS: th.</keyword></keywords><dates><year>1992</year></dates><urls></urls></record></Cite></EndNote>(Ainamo et al., 1992) (e.g., surgery not performed by expert clinician)Lowering the dose or frequency of treatment in the control group to increase apparent effectiveness of experimental treatmentSelecting a non-effective delivery method for control (e.g., oral delivery a drug which should be administered intravenously)Use of placebo-controls when effective treatments exist and violating Helsinki agreementsTricks for increasing safety profile of an exposure Filtered cigarettes can be claimed to the “healthy” when compared to unfiltered cigarettes. Sugary vitamin drinks can be claimed to be healthier than plain sugar drinks.Lowering the dose to minimize side-effects and then marketing a higher dose ADDIN EN.CITE <EndNote><Cite><Author>Finkelstein</Author><Year>2008</Year><RecNum>931</RecNum><record><rec-number>931</rec-number><foreign-keys><key app="EN" db-id="tfd9sp0eep9dede50ddx2drjxftp2w2dvdza">931</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Finkelstein, Stan N.</author><author>Temin, Peter</author></authors></contributors><titles><title>Reasonable Rx : solving the drug price crisis</title></titles><pages>xvi, 188 p.</pages><keywords><keyword>Drugs Prices United States.</keyword><keyword>Prescription pricing United States.</keyword><keyword>Pharmaceutical industry United States.</keyword><keyword>Fees, Pharmaceutical United States.</keyword><keyword>Chemistry, Pharmaceutical economics United States.</keyword><keyword>Drug Costs United States.</keyword><keyword>Drug Industry economics United States.</keyword><keyword>Drug Therapy economics United States.</keyword></keywords><dates><year>2008</year></dates><pub-location>Upper Saddle River, N.J.</pub-location><publisher>FT Press/Pearson Education</publisher><isbn>9780132344494 (hardback alk. paper)
0132344491 (hardback alk. paper)</isbn><call-num>Jefferson or Adams Bldg General or Area Studies Reading Rms HD9666.4; .F55 2008</call-num><urls></urls></record></Cite></EndNote>(Finkelstein & Temin, 2008)Evaluate safety short-term and market long-term useEvaluate safety of chewing tobacco in countries where levels of nitrosamines are low and extrapolate findings to countries where nitrosamine levels are higher.2. The OutcomeMany dental treatments are approved based on the assumption that subtle changes in dental disease markers translate into tangible patient benefit. A fraction of a millimeter improvement in tissue position, a fraction of milligram change in enamel or bone mineral density is often assumed to translate into reduced tooth loss or increased oral-health-related quality of life. Surrogate endpoint:“a laboratory sign or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives. Changes induced by therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint” (Temple, 1995). True endpoint: reflects unequivocal evidence of tangible patient benefit (Fleming, 2005). Examples of tangible events are tooth loss, speech problems, pain.The main concern related to the use of surrogate endpoints in clinical studies is that treatments may improve surrogate endpoints while negatively impacting true endpoints, or that treatments may not have an impact on surrogate endpoints, while improving true endpoints. Reliable evidence requires true endpoints.Practice questionsTreatment A is better than placebo treatment, and treatment C is worse than treatment A, Which of the following statements would be most accurateTreatment C is better than placebo treatmentTreatment C is worse than placebo treatmentTreatment C is as good as placebo treatment It is impossible to tellWhich of the following is a true endpoint? A 5 mm increase in probing pocket depthA caries lesion detected by means of a radiographThe genetic test-result identifying the IL-1 marker.PainThe cariogenicity of sweeteners can be tested by recruiting subjects and attaching a pH electrode to a tooth within each subject. The sweetener is kept intra-orally for approximately 10 minutes. If the sweetener causes the pH to remain above 5.7 for more than 30 minutes the sweetener is claimed to be caries preventive. This is an example of aTrue endpointSurrogate endpoint5. Consider a dental procedure (e.g., scaling, amalgam filling, or crown) or a diagnostic test (e.g., the electric pulp tester) that you plan to perform this week and for which you are unsure what level of evidence is available in support of the intervention. Formulate the PICO question that will allow you to do a PUBMED search for evidence specific to your patient’s situation. P:……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………I:……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………C:……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………O:……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………Tonsillectomy is sometimes recommended by orthodontists to alter facial growth. One of the goals of tonsillectomy is to prevent recurrent otitis media. A study published in a recent issue of the New England Medical Journal (Vol. 344, April 19, 2001) assessed the efficacy of tonsillectomy. Which of the following outcome measure in a clinical trial would be most convincing (most reliable) to assess efficacy of tonsillectomy Bacteriological analysis of abscess causing pathogens in middle ear fluid Prescription of antibiotics for otitis mediaHospitalization and operations related to otitis mediaDiagnosis of re-infection with H. influenza, the primary etiology of otitis mediaIn 1992, researchers at the University of Buffalo said they discovered a vaccine for preventing gum disease (Wall Street Journal, August 10, 1992). They discovered that injection of synthetic protein produced antibodies that interfered with the P. gingivalis bacterium binding to teeth.Since the presence of P. gingivalis in a periodontal pocket doubles the risk for periodontal attachment loss (J Clin Perio, 1991, 18; 744-50), this vaccine will reduce tooth loss Since the presence of P. gingivalis in a periodontal pocket doubles the risk for periodontal attachment loss (J Clin Perio, 1991, 18; 744-50), this vaccine will provide a clinically meaningful benefit to the patient.a & bNone of the abovePlease write-up brief answers to each of the following 4 questions. Formulate a PICO question on a topic that is most relevant to youClassify whether this PICO question is on the topic of treatment, diagnosis, prognosis, or etiologyGo online, type in the web address ‘’. On this page, look in the left-hand column under pubmed services and click on “Clinical Queries”. Click on the appropriate box (“etiology, therapy, prognosis, or diagnosis), enter elements of your PICO question in the search box, and hit GO.Look at the first three citations (if available) that provide abstracts. Look at the abstracts only and classify the study’s level of evidence (RCT, cohort, case-control, case-series, or biological plausibility).Answer key: 1.d, 2.d, 3.a, 4.c, 5.dRisks and rewards on trialBy Margaret McCartney Published: April 14 2008 08:48 | Last updated: April 14 2008 08:48In clinical trials, what outcomes should we be most interested in? Put simply, if a study talks about outcomes such as death or quality of life, I am likely to read on. If it doesn’t, I might not. This may be a rather crude view of what matters in research but, with so much research about – and so much of it poor – it is essential to focus on what really matters.When it comes to trials, I have expensive tastes. The kinds of trials that use my favoured outcomes as end-points tend to be costly, often prohibitively so. They also usually require large amounts of people to take part and can take a long time. As a compromise, therefore, many trials don’t look for outcomes such as death but instead seek shorter-term results, known as “surrogate markers”.A surrogate marker is potentially an excellent thing. For example, suppose we had a blood test that was a marker and could quickly reveal a problem that translated as a risk for strokes. A high score would mean a stroke was certain while a low count would imply that it was extremely unlikely. A treatment could be trialled and the levels of the marker assessed. There would be no need to wait a long time to see if the rate of strokes fell.The problem, of course, is that real life isn’t like that. Such predictive accuracy is almost unheard of. Whenever we see surrogate markers being used, therefore, we must take the results with a pinch, or possibly an ocean’s worth, of salt. This has been the case with much of the trial data on interventions designed to reduce cardiovascular mortality and morbidity.Cholesterol, high blood pressure, obesity, and type II diabetes are all used as surrogate markers for cardiovascular disease. But using these as surrogate markers assumes a definite chain of cause and effect. One expects that an intervention that reduces the risk factor will also reduce heart attacks and strokes.For example, cholesterol has long been used as a surrogate marker for the likelihood of heart attacks and stroke. Our obsession with cholesterol as a marker for the possibility of developing heart disease has reached astonishing levels; testing for it is available in high street pharmacies and gyms. Yet many of the interventions we offer for reducing it have not been shown to reduce mortality. We assume that a treatment that lowers cholesterol will also reduce heart attacks and strokes. But we can’t be sure that lower cholesterol will always give us the outcome we expect.The British Medical Journal recently reported that Merck and Schering- Plough Pharmaceuticals, which make the cholesterol-lowering drug ezetimibe, had published results relating to a clinical trial. The trial compared patients taking ezetimibe plus simvastatin, an older cholesterol lowering drug, with patients taking only simvastatin. The patients taking the two drugs did have lower cholesterol compared to the single drug. The problem again is how significant this reduction was and what effect did it have on real life outcomes, such as a reduction in heart attacks and strokes? While this trial questions the usefulness of ezetimibe and other larger trials are ongoing – it should also make us question our reliance on surrogate markers.The problem is not necessarily that of using surrogate markers. It is more that we are increasingly tempted to view surrogate markers as a satisfactory end point, rather than the beginning of a need to look for better proof of effect. Surely approval for drugs should be granted only on the basis that they are used in a way that makes it possible for these end markers to be fairly assessed. Ezetimibe was approved by the US Food and Drug Administration in 1999 and in the US is prescribed alone or in combination with other drugs more than 3m times a month. The real problem is that nine years later, we have missed millions of opportunities to fairly study their effects and the outcomes, such as death and disability, that really matter.Margaret McCartney is a GP in Glasgowmargaret.mccartney@More columns at mccartneyComment and questions: This newspaper article addresses the topic of surrogate endpoints and their usefulness in assessing treatment efficacy. To what extent are issues in dentistry similar? Can you provide 3 surrogates used in assessing periodontal treatment efficacy, orthodontic treatment outcomes, and caries treatments? For these 9 surrogates you have identified, what are the assumptions that are made when concluding that a dental treatment works based on a positive change in a surrogate? Who do you think are the decisions makers in dental research when it comes to deciding which surrogates can be used to get drugs/treatments on the market place? References ADDIN EN.REFLIST (1984). The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. Jama 251: 351-64.Ainamo J, Lie T, Ellingsen BH, Hansen BF, Johansson LA, Karring T, Kisch J, Paunio K & Stoltze K (1992). Clinical responses to subgingival application of a metronidazole 25% gel compared to the effect of subgingival scaling in adult periodontitis. J Clin Periodontol 19: 723-9.Avis HJ, Vissers MN, Wijburg FA, Kastelein JJ & Hutten BA (2009). The use of lipid-lowering drug therapy in children and adolescents. Curr Opin Investig Drugs 10: 224-31.Bodenheimer T (2000). Uneasy alliance--clinical investigators and the pharmaceutical industry. N Engl J Med 342: 1539-44.Burt BA & Pai S (2001). Sugar consumption and caries risk: a systematic review. J Dent Educ 65: 1017-23.Burt BA & Szpunar SM (1994). The Michigan study: the relationship between sugars intake and dental caries over three years. Int Dent J 44: 230-40.Deshpande A & Jadad AR (2008). The impact of polyol-containing chewing gums on dental caries: a systematic review of original randomized controlled trials and observational studies. J Am Dent Assoc 139: 1602-14.Eskola J, Kayhty H, Takala AK, Peltola H, Ronnberg PR, Kela E, Pekkanen E, McVerry PH & Makela PH (1990). A randomized, prospective field trial of a conjugate vaccine in the protection of infants and young children against invasive Haemophilus Influenza Type b virus. N Engl J Med 323: 1381-1387.Farman M & Joshi RI (2008). Full-mouth treatment versus quadrant root surface debridement in the treatment of chronic periodontitis: a systematic review. Br Dent J 205: E18; discussion 496-7.Finkelstein SN & Temin P (2008). Reasonable Rx : solving the drug price crisis, FT Press/Pearson Education: Upper Saddle River, N.J.Fleming TR & DeMets DL (1996). Surrogate end points in clinical trials: are we being misled? Ann Intern Med 125: 605-13.Forgie AH, Paterson M, Pine CM, Pitts NB & Nugent ZJ (2000). A randomised controlled trial of the caries-preventive efficacy of a chlorhexidine-containing varnish in high-caries-risk adolescents. Caries Res 34: 432-9.Forshee RA & Storey ML (2004). Evaluation of the association of demographics and beverage consumption with dental caries. Food Chem Toxicol 42: 1805-16.Gustafsson BE, Quensel CE, Lanke LS, Lundqvist C, Grahnen H, Bonow BE & Krasse B (1954). The Vipeholm dental caries study; the effect of different levels of carbohydrate intake on caries activity in 436 individuals observed for five years. Acta Odontol Scand 11: 232-64.Hausen H, Karkkainen S & Seppa L (2000). Application of the high-risk strategy to control dental caries. Community Dent Oral Epidemiol 28: 26-34.Hujoel PP, Cunha-Cruz J, Banting DW & Loesche WJ (2006). Dental flossing and interproximal caries: a systematic review. J Dent Res 85: 298-305.Kallestal C (2005). The effect of five years' implementation of caries-preventive methods in Swedish high-risk adolescents. Caries Res 39: 20-6.Lang NP, Tan WC, Krahenmann MA & Zwahlen M (2008). A systematic review of the effects of full-mouth debridement with and without antiseptics in patients with chronic periodontitis. J Clin Periodontol 35: 8-21.Lingstrom P, Holm AK, Mejare I, Twetman S, Soder B, Norlund A, Axelsson S, Lagerlof F, Nordenram G, Petersson LG, Dahlgren H & Kallestal C (2003). Dietary factors in the prevention of dental caries: a systematic review. Acta Odontol Scand 61: 331-40.Pitts NB (2005). Indiana Conference ICDAS Workshop Group Report. In: Stookey G. K., ed. Clinical Models Workshop: Remin-Demin, Precavitation, Caries. Indiana School of Dentistry: Indiana, p. 270.Pitts NB & Stamm JW (2004). International Consensus Workshop on Caries Clinical Trials (ICW-CCT)--final consensus statements: agreeing where the evidence leads. J Dent Res 83 Spec No C: C125-8.Ruxton CH, Garceau FJ & Cottrell RC (1999). Guidelines for sugar consumption in Europe: is a quantitative approach justified? Eur J Clin Nutr 53: 503-13.Seppa L, Hausen H, Pollanen L, Karkkainen S & Helasharju K (1991). Effect of intensified caries prevention on approximal caries in adolescents with high caries risk. Caries Res 25: 392-5.Vergnes JN & Sixou M (2007). Preterm low birth weight and maternal periodontal status: a meta-analysis. Am J Obstet Gynecol 196: 135 e1-7.Vettore MV, Lamarca Gde A, Leao AT, Thomaz FB, Sheiham A & Leal Mdo C (2006). Periodontal infection and adverse pregnancy outcomes: a systematic review of epidemiological studies. Cad Saude Publica 22: 2041-53.Ward J, Brenneman G, Letson GW, Heyward WL & the Alaska H. Influenzae vaccine study group (1990). Limited efficacy of a Haemophilus Influenzae Type b conjugate vaccine in Alaska Native infants. N Engl J Med 323: 1393-1401.Xiong X, Buekens P, Fraser WD, Beck J & Offenbacher S (2006). Periodontal disease and adverse pregnancy outcomes: a systematic review. BJOG 113: 135-43. ................
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