Introduction



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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, 2009


Introduction

Clinical 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 question
Clinical 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 (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 ((Forgie et al., 2000), (Hausen et al., 2000) (Kallestal, 2005) (Seppa et al., 1991).

Examples where treatments are recommended to patients with characteristics that differ from the patients enrolled in clinical trials



  • Statins tested in middle-aged patients with a history of a heart attack are recommended to pediatric patients (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. (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 (1984).

Extrapolation of safety from one patient group to another



  • Testing of safety drugs in young healthy populations and marketing to old frail populations (Bodenheimer, 2000).


2. The comparison; the Intervention and the Control
The 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 (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 treatment

  • Selecting 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 agreements

Tricks 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 (Finkelstein & Temin, 2008)

  • Evaluate safety short-term and market long-term use

  • Evaluate safety of chewing tobacco in countries where levels of nitrosamines are low and extrapolate findings to countries where nitrosamine levels are higher.



2. The Outcome
Many 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 questions




  1. Treatment A is better than placebo treatment, and treatment C is worse than treatment A, Which of the following statements would be most accurate

  1. Treatment C is better than placebo treatment

  2. Treatment C is worse than placebo treatment

  3. Treatment C is as good as placebo treatment

  4. It is impossible to tell




  1. Which of the following is a true endpoint?

  1. A 5 mm increase in probing pocket depth

  2. A caries lesion detected by means of a radiograph

  3. The genetic test-result identifying the IL-1 marker.

  4. Pain




  1. The 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 a

    1. True endpoint

    2. Surrogate endpoint

5. 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:……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………




  1. 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

  1. Bacteriological analysis of abscess causing pathogens in middle ear fluid

  2. Prescription of antibiotics for otitis media

  3. Hospitalization and operations related to otitis media

  4. Diagnosis of re-infection with H. influenza, the primary etiology of otitis media




  1. In 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.

  1. 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

  2. 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.

  3. a & b

  4. None of the above

Please write-up brief answers to each of the following 4 questions.




  1. Formulate a PICO question on a topic that is most relevant to you

  2. Classify whether this PICO question is on the topic of treatment, diagnosis, prognosis, or etiology

  3. Go online, type in the web address ‘pubmed.gov’. 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.

  4. 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.d

Risks and rewards on trial

By Margaret McCartney

Published: April 14 2008 08:48 | Last updated: April 14 2008 08:48

In 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 Glasgow

margaret.mccartney@ft.com

More columns at www.ft.com/mccartney

Comment 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?

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