Difference between revisions of "Double blind trial"

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The '''double-blind test''' is an elaborate instrument for estimating the size of the [[specific effect]] of a drug. It represents the core of [[evidence-based medicine]]. The need for such an instrument arises from the fact that people might become healthy independently of any therapy (spontaneous remission) and by non-specific effects like expectations, environmental stimuli and other influences ([[placebo effect]]).
  
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The double-blind test is a differentiated instrument for estimating the size of the specific effect of a drug. It represents the core of [[Evidence-based_medicine|evidence-based medicine]]. The need for such a differentiated instrument arises from the fact that people can become healthy independently of any therapy (spontaneous remission) and that non-specific effects such as expectations, environmental stimuli and other influences can lead to improvement ([[Placebo_effect|placebo effect]]).
+
In the double-blind trial, patients receive either the drug to be tested (verum) or a sham drug with the same appearance ([[Placebo|placebo]]). They are randomly assigned to the check or control group ([[Randomization|randomization]]). Both groups should not differ too much in their characteristics (severity of the disease, age and sex of patients, etc.). If patients do not know whether they are receiving a verum or a placebo, the trial is called ''blinded''. If the therapists and all other persons involved do not know it either, in order not to influence the result by unconscious signals, one talks of a ''double-blind setting''. This basic scheme exists in various modifications. If the therapeutic effect of the substance to be tested is stronger than in the 'placebo arm', an effective therapy is assumed. The double-blind test has some fundamental shortcomings that significantly limit its significance for therapies.
  
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In the double-blind trial, patients receive either the drug to be tested (verum) or a sham drug with the same appearance ([[Placebo|Placebo]]). They are randomly assigned to the check or control group ([[Randomization|Randomization]]). Both groups should not differ too much in their characteristics (severity of the disease, age and sex of patients, etc.). If patients do not know whether they are receiving a verum or a placebo, the trial is blinded. If the therapists and the other persons involved do not know, in order not to influence the result with unconscious signals, one speaks of double-blind. This basic scheme undergoes various modifications. If the therapeutic effect of the substance to be tested is greater than in the'placebo arm', effective therapy is assumed. The double-blind test has some fundamental weaknesses that significantly limit its significance for therapies.
+
*Randomization is based on certain criteria or markers ([[Surrogate_Parameters|surrogate parameters]]) that are thought of representing the disease. For other events, the double-blind test is more or less blind. The best known example was Sildenfali (Viagra©). In a double-blind test on hypertension, the substance proved hardly better than the placebo. Only a burglary at the company headquarters made the company aware that they had a potent agent.<ref>Der Spiegel, 18.5.98</ref>
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*Patients in  double-blind trials are generally highly selected and have clear diagnoses and symptoms. In general, they do not correspond too much to the general population to be treated later.
 +
*Patients in double-blind trials usually receive a monotherapy. As a consequence, it is always doubtful in how far emerging results can be transferred to multimorbid patients.
 +
*Since double-blind tests are very time-consuming, they are usually only carried out for 3 to 6 months. Longer tests are rather an exception. However, longer observation times can reverse the results. Therapies can be helpful short term, but harmful long term.<ref>Ivanovas G (2009): Kritik der reinen Evidenz. Homöopathie in der evidenzbasierten Medizin – Teil 1, Homöopathie KONKRET 3.9: 10–18</ref>
 +
*With a double-blind test, it is not possible to distinguish whether the robustness or resilience of the patient is increased or not.<ref>Ivanovas G, Tomaras V, Papadioti V, Paritsis N (2007): Human robustness and conscious purpose in contemporary medicine, Kybernetes 36; 7/8: 972-984</ref> Quite often the regulatory capacity is restricted by drugs, which might have a damaging effect under changing circumstances. For example, beta-blockers have a wide therapeutic spectrum, but they lead to a reduced adaptability towards heat. This might lead to higher incidences of heat stroke and death during a heat wave.<ref>Bouchama A, Knochel JP (2002): Heat stroke, N Engl J Med 346: 1978 - 1988</ref> That is, a therapy with a significantly lower effect under constant conditions might be much more effective under changing conditions.
 +
*The double-blind tests make statements about collectives, not about individuals.<ref>Niroomand F (2004): Evidenzbasierte Medizin: Das Individuum bleibt auf der Strecke, Dtsch Arztebl 101: A 1870–1874</ref> The question to what extent a result is relevant cannot be statistically assessed. In a double-blind study on mattress hardness, it was found that a medium-soft mattress provided the best result for the majority of people. But a not insignificant number of people slept better on a hard or a soft mattress.<ref>Kovacs FM, Abraira V, Peña A, Martín-Rodríguez JG, Sánchez-Vera M, Ferrer E, Ruano D, Guillén P, Gestoso M, Muriel A, Zamora J, del Real MTG, Mufraggi N (2003): Effect of firmness of mattress on chronic non-specific low-back pain: randomised, double-blind, controlled, multicentre trial. Lancet 362: 1599-604</ref> What is the cosequence of that knowledge? Should everybody sleep on middle hard matresses?
 +
*In statistics, there is a fundamental uncertainty as to what helps whom and under what circumstances. This was somewhat sarcastically summarized as follows: ''"Large numbers provide a statistically accurate result, of which one does not know to whom it concerns. Small numbers provide a statistically unsuitable result, but one knows better whom it concerns. Hard to decide which kind of ignorance is more useless.''"<ref>Beck-Bornholdt HP, Dubben HH (2003): Der Schein der Weisen. Rowohlt, Reinbek bei Hamburg</ref>
  
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*Randomization is based on certain criteria or markers ([[Surrogate_Parameters|surrogate parameters]]) that are to map the disease. For other events, the double-blind test is more or less blind. The best known example was Sildenfali (Viagra©). The substance proved to be hardly effective in the treatment of high pressure in the double-blind test. Only a break-in at the company headquarters made the company aware that they had a potent agent.<ref>Der Spiegel, 18.5.98</ref>
+
The inadequacy of the double-blind test can be observed even in such a simple and standardized disease as 'Otitis media'. In the first major studies on the therapeutic effect of antibiotics in this disease, it was found that they were no more effective than a placebo, but increased the number of recurrences.<ref>Hendley JO (2002): Otitis media, N Engl J Med 347; 15: 1169-1174; Rovers MM, Signs AGM, Zielhuis GA, Rosenfeld RM (2004): Otitis media, Lancet 363; 9407: 465-473</ref> First of all, this result showed that the effect of an antibiotic therapy in otitis media was significantly overestimated. But a uselessness of antibiotics did not necessarily make too much sense physiologically. After certain criteria for otitis media were established (redness and protrusion of the eardrum, pain and fever), in later studies antibiotic therapy was somewhat more effective than a placebo, but still associated with more complications.<ref>Tähtinen PA, Laine MK, Huovinen P, Jalava J, Ruuskanen O, Ruohola A. (2011): A Placebo-Controlled Trial of Antimicrobial Treatment for Acute Otitis Media; N Engl J Med. 364(2):116-26.</ref> Moreover,these studies did not consider the question of resilience and/or long-term impacts of the therapy,  on the intestinal flora, for example.
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*Patients selected for double-blind trials are generally highly selected and have clear diagnoses and disease symptoms. Thus they usually do not correspond very much to the general population to be treated later.
 
−
*Patients in double-blind trials usually receive monotherapy. These results cannot be transferred so easily to patient groups with multiple therapies.
 
−
*Since double-blind tests are very time-consuming, they are usually only carried out for 3 to 6 months. Longer tests are rather the exception. However, longer observation times can reverse the results. Therapies can be useful in the short term, but harm in the long term.<ref>Ivanovas G (2009): Kritik der reinen Evidenz. Homöopathie in der evidenzbasierten Medizin – Teil 1, Homöopathie KONKRET 3.9: 10–18</ref>
 
−
*Within the double-blind test, it is not possible to distinguish whether the robustness or resilience of the patient.<ref>Ivanovas G, Tomaras V, Papadioti V, Paritsis N (2007): Human robustness and conscious purpose in contemporary medicine, Kybernetes 36; 7/8: 972-984</ref> Very often the regulatory capacity is restricted by drugs, which can have a damaging effect under changed circumstances. Thus, beta-blockers have a wide therapeutic spectrum, but they lead to less adaptability to heat, which can lead to heat stroke and death in a heat wave.<ref>Bouchama A, Knochel JP (2002): Heat stroke, N Engl J Med 346: 1978 - 1988</ref> A therapy with a significantly lower effect under constant conditions can be much more effective under changing conditions.
 
−
*The double-blind tests make statements about collectives, not about individuals.<ref>Niroomand F (2004): Evidenzbasierte Medizin: Das Individuum bleibt auf der Strecke, Dtsch Arztebl 101: A 1870–1874</ref> The question to what extent a result is relevant cannot be statistically assessed. In a double-blind study on mattress hardness, for example, it was found that a medium-soft mattress provided the best result for the majority of people. But a not insignificant number of people slept better on a hard or a soft mattress.<ref>Kovacs FM, Abraira V, Peña A, Martín-Rodríguez JG, Sánchez-Vera M, Ferrer E, Ruano D, Guillén P, Gestoso M, Muriel A, Zamora J, del Real MTG, Mufraggi N (2003): Effect of firmness of mattress on chronic non-specific low-back pain: randomised, double-blind, controlled, multicentre trial. Lancet 362: 1599-604</ref>  
 
−
*There is a fundamental statistical uncertainty as to what helps whom and under what circumstances. This was somewhat sarcastically summarized as follows:"''Large numbers provide a statistically accurate result, of which one does not know who it applies to. Small numbers provide a statistically unusable result, but one knows better who it applies to. Hard to decide which of these kinds of ignorance is the more useless.''"<ref>Beck-Bornholdt HP, Dubben HH (2003): Der Schein der Weisen. Rowohlt, Reinbek bei Hamburg</ref>
 
  
−
The inadequacy of the double-blind test can be observed even in such a simple and standardized disease as 'Otitis media'. In the first major studies on the therapeutic effect of antibiotics in this disease, it was found that they were no more effective than a placebo, but increased the number of recurrences.<ref>Hendley JO (2002): Otitis media, N Engl J Med 347; 15: 1169-1174; Rovers MM, Signs AGM, Zielhuis GA, Rosenfeld RM (2004): Otitis media, Lancet 363; 9407: 465-473</ref> This result showed that the effect of antibiotic therapy was significantly overestimated but did not necessarily make physiological sense. When the criteria of otitis media were clarified (redness and protrusion of the eardrum, pain and fever), in later studies antibiotic therapy was somewhat more effective than the administration of placebo, but was associated with more complications.<ref>Tähtinen PA, Laine MK, Huovinen P, Jalava J, Ruuskanen O, Ruohola A. (2011): A Placebo-Controlled Trial of Antimicrobial Treatment for Acute Otitis Media; N Engl J Med. 364(2):116-26.</ref> These studies did not consider the question of resilience and/or long-term effects, for example the effects on the intestinal flora. Double-blind studies thus provide clues that can and should influence therapeutic action under the above-mentioned reservations. However, they cannot be regarded as a gold standard and therapeutic imperative. In any case, the overall situation of the patient must be assessed and considered as the basis for therapeutic action.
+
Double-blind studies thus provide clues that could and should influence the therapeutic action, but under the above-mentioned reservations. However, they cannot be regarded as a gold standard and therapeutic imperative.The overall situation of the patient must be assessed and considered and taken as the basis for any therapeutic action.
  
 
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Latest revision as of 09:34, 20 August 2018

The double-blind test is an elaborate instrument for estimating the size of the specific effect of a drug. It represents the core of evidence-based medicine. The need for such an instrument arises from the fact that people might become healthy independently of any therapy (spontaneous remission) and by non-specific effects like expectations, environmental stimuli and other influences (placebo effect).

In the double-blind trial, patients receive either the drug to be tested (verum) or a sham drug with the same appearance (placebo). They are randomly assigned to the check or control group (randomization). Both groups should not differ too much in their characteristics (severity of the disease, age and sex of patients, etc.). If patients do not know whether they are receiving a verum or a placebo, the trial is called blinded. If the therapists and all other persons involved do not know it either, in order not to influence the result by unconscious signals, one talks of a double-blind setting. This basic scheme exists in various modifications. If the therapeutic effect of the substance to be tested is stronger than in the 'placebo arm', an effective therapy is assumed. The double-blind test has some fundamental shortcomings that significantly limit its significance for therapies.

  • Randomization is based on certain criteria or markers (surrogate parameters) that are thought of representing the disease. For other events, the double-blind test is more or less blind. The best known example was Sildenfali (Viagra©). In a double-blind test on hypertension, the substance proved hardly better than the placebo. Only a burglary at the company headquarters made the company aware that they had a potent agent.[1]
  • Patients in double-blind trials are generally highly selected and have clear diagnoses and symptoms. In general, they do not correspond too much to the general population to be treated later.
  • Patients in double-blind trials usually receive a monotherapy. As a consequence, it is always doubtful in how far emerging results can be transferred to multimorbid patients.
  • Since double-blind tests are very time-consuming, they are usually only carried out for 3 to 6 months. Longer tests are rather an exception. However, longer observation times can reverse the results. Therapies can be helpful short term, but harmful long term.[2]
  • With a double-blind test, it is not possible to distinguish whether the robustness or resilience of the patient is increased or not.[3] Quite often the regulatory capacity is restricted by drugs, which might have a damaging effect under changing circumstances. For example, beta-blockers have a wide therapeutic spectrum, but they lead to a reduced adaptability towards heat. This might lead to higher incidences of heat stroke and death during a heat wave.[4] That is, a therapy with a significantly lower effect under constant conditions might be much more effective under changing conditions.
  • The double-blind tests make statements about collectives, not about individuals.[5] The question to what extent a result is relevant cannot be statistically assessed. In a double-blind study on mattress hardness, it was found that a medium-soft mattress provided the best result for the majority of people. But a not insignificant number of people slept better on a hard or a soft mattress.[6] What is the cosequence of that knowledge? Should everybody sleep on middle hard matresses?
  • In statistics, there is a fundamental uncertainty as to what helps whom and under what circumstances. This was somewhat sarcastically summarized as follows: "Large numbers provide a statistically accurate result, of which one does not know to whom it concerns. Small numbers provide a statistically unsuitable result, but one knows better whom it concerns. Hard to decide which kind of ignorance is more useless."[7]

The inadequacy of the double-blind test can be observed even in such a simple and standardized disease as 'Otitis media'. In the first major studies on the therapeutic effect of antibiotics in this disease, it was found that they were no more effective than a placebo, but increased the number of recurrences.[8] First of all, this result showed that the effect of an antibiotic therapy in otitis media was significantly overestimated. But a uselessness of antibiotics did not necessarily make too much sense physiologically. After certain criteria for otitis media were established (redness and protrusion of the eardrum, pain and fever), in later studies antibiotic therapy was somewhat more effective than a placebo, but still associated with more complications.[9] Moreover,these studies did not consider the question of resilience and/or long-term impacts of the therapy, on the intestinal flora, for example.

Double-blind studies thus provide clues that could and should influence the therapeutic action, but under the above-mentioned reservations. However, they cannot be regarded as a gold standard and therapeutic imperative.The overall situation of the patient must be assessed and considered and taken as the basis for any therapeutic action.

 

Sources

  1. ↑ Der Spiegel, 18.5.98
  2. ↑ Ivanovas G (2009): Kritik der reinen Evidenz. Homöopathie in der evidenzbasierten Medizin – Teil 1, Homöopathie KONKRET 3.9: 10–18
  3. ↑ Ivanovas G, Tomaras V, Papadioti V, Paritsis N (2007): Human robustness and conscious purpose in contemporary medicine, Kybernetes 36; 7/8: 972-984
  4. ↑ Bouchama A, Knochel JP (2002): Heat stroke, N Engl J Med 346: 1978 - 1988
  5. ↑ Niroomand F (2004): Evidenzbasierte Medizin: Das Individuum bleibt auf der Strecke, Dtsch Arztebl 101: A 1870–1874
  6. ↑ Kovacs FM, Abraira V, Peña A, Martín-Rodríguez JG, Sánchez-Vera M, Ferrer E, Ruano D, Guillén P, Gestoso M, Muriel A, Zamora J, del Real MTG, Mufraggi N (2003): Effect of firmness of mattress on chronic non-specific low-back pain: randomised, double-blind, controlled, multicentre trial. Lancet 362: 1599-604
  7. ↑ Beck-Bornholdt HP, Dubben HH (2003): Der Schein der Weisen. Rowohlt, Reinbek bei Hamburg
  8. ↑ Hendley JO (2002): Otitis media, N Engl J Med 347; 15: 1169-1174; Rovers MM, Signs AGM, Zielhuis GA, Rosenfeld RM (2004): Otitis media, Lancet 363; 9407: 465-473
  9. ↑ Tähtinen PA, Laine MK, Huovinen P, Jalava J, Ruuskanen O, Ruohola A. (2011): A Placebo-Controlled Trial of Antimicrobial Treatment for Acute Otitis Media; N Engl J Med. 364(2):116-26.
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