Diane Martire, Anamaria Jorga, Sean Donevan, New York
Submitted December 21, 2017
We read with interest, the article by Waldfogel et al. [1] The authors suggested that there was a "reporting bias," regarding pregabalin, due to the number of unpublished studies or studies without results reported on clinicaltrials.gov. Waldfogel et al. searched Pubmed and the Cochrane Database for systematic reviews from 2011 to October 12, 2015, and PubMed, Embase, and the Cochrane Central Register of Controlled Trials for primary studies from January 1, 2013 to May 24, 2016; clinicaltrials.gov was searched on March 9, 2016. [1] Given these search criteria, the authors failed to find publications describing the results of four pregabalin studies registered on clinicaltrials.gov.
Of the four studies described as unpublished in Figure 1 (NCT00785577, NCT01474772, NCT01455415, and NCT01332149), [1] one (NCT00785577) was conducted by Lilly and three were conducted by Pfizer. The Lilly-sponsored study (NCT00785577) was published in 2014. [2] Likewise, study NCT01474772 was published in 2015, [3] and study NCT01455415 was published in 2016. [4] All three publications are indexed in Pubmed. An erratum was published on the article by Waldfogel et al. to correct referenced studies NCT01474772 and NCT01455415 as published. [5] The fourth study (NCT01332149; A Study to Evaluate Efficacy, Safety and Tolerability of Lyrica in Patients with Painful Diabetic Peripheral Neuropathy) remains unpublished, but the results have been available on clinicaltrials.gov since March 2015 and a manuscript is currently under review for publication.
Pfizer published all DPN data from eighteen Pfizer-sponsored clinical trials of pregabalin (Tables 1 and 2), with the exception of the manuscript under review. This publication record is consistent with the Good Publication Practice guidelines for communicating company-sponsored medical research. [6-8] Thirteen of these studies were published as primary analyses (Tables 1 and 2). Data from the four remaining studies were included in secondary publications using pooled analyses of data (Pfizer studies 1008040, 1008173, A0081030, and A0081071). In addition, Pfizer also complied with the US Food and Drug Administration requirement that clinical results from studies initiated after September 27, 2007, or ongoing as of December 26, 2007, be posted on clinicaltrials.gov. A listing of these six studies, and their corresponding clinicaltrials.gov registration number, is provided (Table 2).
The methodology employed by Waldfogel et al. affected their summary in Table 1, [1] which was that no medication has high level strength of evidence supporting its use for the treatment of DPN. In particular, they concluded that there is weak evidence supporting the use of pregabalin. We note that their conclusion contrasts with the assessments of numerous professional societies that recommend pregabalin as one of several first-line treatments for peipheral neuropathic pain or conclude that the strength of evidence supporting its use in DPN is strong. Such societies include the American Academy of Neurology, [9] the American Association of Neuromuscular and Electrodiagnostic Medicine, [9] the American Academy of Physical Medicine and Rehabilitation, [9] the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain, [10,11] the Canadian Pain Society, [12] and the European Federation of Neurological Societies. [13]
Waldfogel et al. used an endpoint of interest, quality of life, that is different from that required for drug approval by global regulatory agencies (eg, the US Food and Drug Administration, the European Medicines Agency, and the Japanese Pharmacuetical and Medical Devices Agency). These agencies require that change in pain score be the primary endpoint in pain studies, with consideration also given to 30% and 50% responder rates (the number of patients whose pain score improves 30% or 50% from baseline to end of study). The requirement of change in pain scores as the primary endpoint requires that studies be powered and designed to detect differences in pain scores from baseline to study end for study drug compared to placebo. Quality of life measurements, such as the SF-36, are considered secondary endpoints in DPN trials by regulatory agencies; therefore, studies are not powered or designed to detect such differences. This lack of power/design increases the likelihood that analysis of secondary endpoints, including quality of life measurments, may not detect differences between the study compound and placebo. This information is necessary to place the conclusions of the article by Waldfogel et al, regarding quality of life measurements in DPN trials, in appropriate context.
ACKNOWLEDGEMENT: Editorial assistance (formatting for journal and creation of tables) was provided by Matt Soulsby, PhD, CMPP of Engage Scientific Solutions and was funded by Pfizer.
1. Waldfogel JM, Nesbit SA, Dy SM, et al. Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review. Neurology 2017;88:1958-1967.
2. Chappell AS, Iyengar S, Lobo ED, Prucka WR. Results from clinical trials of a selective ionotropic glutamate receptor 5 (iGluR5) antagonist, LY5454694 tosylate, in 2 chronic pain conditions. Pain 2014;155:1140-1149.
3. Huffman C, Stacey BR, Tuchman M, et al. Efficacy and Safety of Pregabalin in the Treatment of Patients With Painful Diabetic Peripheral Neuropathy and Pain on Walking. Clin J Pain 2015;31:946-958.
4. Raskin P, Huffman C, Yurkewicz L, et al. Pregabalin in Patients With Painful Diabetic Peripheral Neuropathy Using an NSAID for Other Pain Conditions: A Double-Blind Crossover Study. Clin J Pain 2016;32:203-210.
5. Correction: Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review. Neurology 2017;89:875.
6. Wager E, Field EA, Grossman L. Good publication practice for pharmaceutical companies. Curr Med Res Opin 2003;19:149-154.
7. Graf C, Battisti WP, Bridges D, et al. Research Methods & Reporting. Good publication practice for communicating company sponsored medical research: the GPP2 guidelines. BMJ 2009;339:b4330.
8. Battisti WP, Wager E, Baltzer L. Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3. Ann Intern Med 2015;163:461-464.
9. Bril V, England J, Franklin GM, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011;76:1758-1765.
10. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14:162-173.
11. Dworkin RH, O'Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2010;85:S3-S14.
12. Moulin D, Boulanger A, Clark AJ, et al. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag 2014;19:328-335.
13. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010;17:1113-e88.
For disclosures, please contact the editorial office at journal@neurology.org.
We read with interest, the article by Waldfogel et al. [1] The authors suggested that there was a "reporting bias," regarding pregabalin, due to the number of unpublished studies or studies without results reported on clinicaltrials.gov. Waldfogel et al. searched Pubmed and the Cochrane Database for systematic reviews from 2011 to October 12, 2015, and PubMed, Embase, and the Cochrane Central Register of Controlled Trials for primary studies from January 1, 2013 to May 24, 2016; clinicaltrials.gov was searched on March 9, 2016. [1] Given these search criteria, the authors failed to find publications describing the results of four pregabalin studies registered on clinicaltrials.gov.
Of the four studies described as unpublished in Figure 1 (NCT00785577, NCT01474772, NCT01455415, and NCT01332149), [1] one (NCT00785577) was conducted by Lilly and three were conducted by Pfizer. The Lilly-sponsored study (NCT00785577) was published in 2014. [2] Likewise, study NCT01474772 was published in 2015, [3] and study NCT01455415 was published in 2016. [4] All three publications are indexed in Pubmed. An erratum was published on the article by Waldfogel et al. to correct referenced studies NCT01474772 and NCT01455415 as published. [5] The fourth study (NCT01332149; A Study to Evaluate Efficacy, Safety and Tolerability of Lyrica in Patients with Painful Diabetic Peripheral Neuropathy) remains unpublished, but the results have been available on clinicaltrials.gov since March 2015 and a manuscript is currently under review for publication.
Pfizer published all DPN data from eighteen Pfizer-sponsored clinical trials of pregabalin (Tables 1 and 2), with the exception of the manuscript under review. This publication record is consistent with the Good Publication Practice guidelines for communicating company-sponsored medical research. [6-8] Thirteen of these studies were published as primary analyses (Tables 1 and 2). Data from the four remaining studies were included in secondary publications using pooled analyses of data (Pfizer studies 1008040, 1008173, A0081030, and A0081071). In addition, Pfizer also complied with the US Food and Drug Administration requirement that clinical results from studies initiated after September 27, 2007, or ongoing as of December 26, 2007, be posted on clinicaltrials.gov. A listing of these six studies, and their corresponding clinicaltrials.gov registration number, is provided (Table 2).
The methodology employed by Waldfogel et al. affected their summary in Table 1, [1] which was that no medication has high level strength of evidence supporting its use for the treatment of DPN. In particular, they concluded that there is weak evidence supporting the use of pregabalin. We note that their conclusion contrasts with the assessments of numerous professional societies that recommend pregabalin as one of several first-line treatments for peipheral neuropathic pain or conclude that the strength of evidence supporting its use in DPN is strong. Such societies include the American Academy of Neurology, [9] the American Association of Neuromuscular and Electrodiagnostic Medicine, [9] the American Academy of Physical Medicine and Rehabilitation, [9] the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain, [10,11] the Canadian Pain Society, [12] and the European Federation of Neurological Societies. [13]
Waldfogel et al. used an endpoint of interest, quality of life, that is different from that required for drug approval by global regulatory agencies (eg, the US Food and Drug Administration, the European Medicines Agency, and the Japanese Pharmacuetical and Medical Devices Agency). These agencies require that change in pain score be the primary endpoint in pain studies, with consideration also given to 30% and 50% responder rates (the number of patients whose pain score improves 30% or 50% from baseline to end of study). The requirement of change in pain scores as the primary endpoint requires that studies be powered and designed to detect differences in pain scores from baseline to study end for study drug compared to placebo. Quality of life measurements, such as the SF-36, are considered secondary endpoints in DPN trials by regulatory agencies; therefore, studies are not powered or designed to detect such differences. This lack of power/design increases the likelihood that analysis of secondary endpoints, including quality of life measurments, may not detect differences between the study compound and placebo. This information is necessary to place the conclusions of the article by Waldfogel et al, regarding quality of life measurements in DPN trials, in appropriate context.
ACKNOWLEDGEMENT: Editorial assistance (formatting for journal and creation of tables) was provided by Matt Soulsby, PhD, CMPP of Engage Scientific Solutions and was funded by Pfizer.
1. Waldfogel JM, Nesbit SA, Dy SM, et al. Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review. Neurology 2017;88:1958-1967.
2. Chappell AS, Iyengar S, Lobo ED, Prucka WR. Results from clinical trials of a selective ionotropic glutamate receptor 5 (iGluR5) antagonist, LY5454694 tosylate, in 2 chronic pain conditions. Pain 2014;155:1140-1149.
3. Huffman C, Stacey BR, Tuchman M, et al. Efficacy and Safety of Pregabalin in the Treatment of Patients With Painful Diabetic Peripheral Neuropathy and Pain on Walking. Clin J Pain 2015;31:946-958.
4. Raskin P, Huffman C, Yurkewicz L, et al. Pregabalin in Patients With Painful Diabetic Peripheral Neuropathy Using an NSAID for Other Pain Conditions: A Double-Blind Crossover Study. Clin J Pain 2016;32:203-210.
5. Correction: Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review. Neurology 2017;89:875.
6. Wager E, Field EA, Grossman L. Good publication practice for pharmaceutical companies. Curr Med Res Opin 2003;19:149-154.
7. Graf C, Battisti WP, Bridges D, et al. Research Methods & Reporting. Good publication practice for communicating company sponsored medical research: the GPP2 guidelines. BMJ 2009;339:b4330.
8. Battisti WP, Wager E, Baltzer L. Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3. Ann Intern Med 2015;163:461-464.
9. Bril V, England J, Franklin GM, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011;76:1758-1765.
10. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14:162-173.
11. Dworkin RH, O'Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2010;85:S3-S14.
12. Moulin D, Boulanger A, Clark AJ, et al. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag 2014;19:328-335.
13. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010;17:1113-e88.
For disclosures, please contact the editorial office at journal@neurology.org.