Neurology -- Correspondence for French et al., 62 (8) 1252-1260

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Correspondence published:

Efficacy and tolerability of the new antiepileptic drugs: Treatment of new onset epilepsy: Gregory L Krauss (16 August 2004)

Reply to Krauss: Jacqueline A. French, MD (16 August 2004)

Reply to Holloway: Jacqueline French, Andres Kanner, MD and Gary Gronseth, MD (29 July 2004)

Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new onset epilepsy: Robert G. Holloway (29 July 2004)

Efficacy and tolerability of the new antiepileptic drugs: Treatment of new onset epilepsy 16 August 2004

Gregory L Krauss,
Department of Neurology, The Johns Hopkins University
600 N. Wolfe Street, Meyer 2-147, Baltimore, MD 21287
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Re: Efficacy and tolerability of the new antiepileptic drugs: Treatment of new onset epilepsy

gkrauss{at}jhmi.edu Gregory L Krauss

The AAN/AES therapeutics subcommittee recently assessed the treatment of primary generalized epilepsy (PGE) with the new antiepilepsy drugs (AEDs) and concluded that there is an “urgent” need for comparator treatment trials. [1]
While I agree with the conclusion, there are a number of diagnostic and regulatory barriers to the development of new therapies for PGE that need to be addressed including: 1) valproic acid (VPA) is an effective and well-established first-line therapy and it is unlikely that new AEDs will surpass the efficacy of standard treatment[2]; 2) PGE appears to consist of a group of genetically heterogeneous disorders and many patients failing VPA treatment have features atypical of PGE. For example, a successful class I study showed that topiramate was effective for treating “primary tonic clonic seizures”, however, 45% of patients had atypical seizure types—tonic, atypical absence, drop seizures [3]; 3) trials for PGE are usually done after indications for partial seizures are explored, making trials for PGE difficult to conduct, particularly within the adolescent population.
I suggest that surrogates be used to screen AEDs for possible efficacy in PGE and that promising AEDs be tested at an earlier stage in clinical development. Surrogates could include: 1) animal models of generalized epilepsy--GAERS, lh mouse; 2) acute effects on human EEG photoconvulsive responses[4]; 3) reduction in generalized spike frequency on prolonged EEGs[5]; and 4) treatment effects in Lennox-Gastaut syndrome.
It would be helpful for the FDA to encourage study of PGE. Given the rarity of remission in juvenile myoclonic epilepsy (JME), the FDA should accept comparator trials of the new AEDs with VPA as evidence of efficacy for treating PGE.
The committee made an important division between therapies for newly treated and medically resistant PGE. I also suggest that studies explicitly identify patients with syndromic and atypical PGE (e.g. onset < 3 years or >25 years, tonic clonic seizures only) so we can relate outcomes to our patients.
References
1. French JA, Kanner AM, Bautista J et al. Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new onset epilepsy. Neurology 2004; 62:1252-60
2. Nicolson A, Appleton RE, Chadwick DW, Smith DF. The relationship between treatment with valproate, lamotrigine, and topiramate and the prognosis of the idiopathic generalised epilepsies. J Neurol Neurosurg Psychiatry 2004; 75:75-79
3. Biton V, Montouris GD, Ritter F et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Neurology 1999; 52:1330-1337
4. Kasteleijn - Nolst Trenite DG, Marescaux C, Stodieck S, Edelbroek PM, Oosting J. Photosensitive epilepsy a model to study the effects of antiepileptic drugs. Evaluation of the piracetam analogue, levetiracetem. Epilepsy Research 1996; 25:225-230.
5. Gallagher MJ, Eisenman LN, Brown KM et al. Levetiracetam reduces spike-wave density and duration during continuous EEG monitoring in patients with idiopathic generalized epilepsy. Epilepsia 2004; 45:90-91.

Reply to Krauss 16 August 2004

Jacqueline A. French, MD,
Co-Chair of the Quality Standards Subcomittee, AAN
Hospital of the University of PA, 3400 Spruce St, Dept. of Neurology Ctr, Philadelphia, PA 19104
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Re: Reply to Krauss

kathy_pieper{at}urmc.rochester.edu Jacqueline A. French, MD

The AAN/AES therapeutics subcommittee committee agrees with Dr. Krauss, that trials for treatment of primary generalized epilepsy (PGE) face some very significant barriers, which he elaborated in his letter.
We also agree that screening for efficacy in primary generalized epilepsy should be performed, if possible, at some point in the development process of a new antiepileptic drug. Currently, there is somewhat of a disincentive for pharmaceutical companies to perform this screening, given the fact that no new antiepileptic drug has received FDA labeling for any idiopathic generalized epilepsy syndrome.
Although comparative trials are clinically informative, it is unlikely that the FDA will accept them as evidence of efficacy, particularly in light of the variability in seizure recurrence rate in PGE. Further consideration is needed as to how further development of antiepileptic drugs for PGE can proceed.

Reply to Holloway 29 July 2004

Jacqueline French,
Co-Chair of the Quality Standards Subcommittee, AAN,
Univeristy of PA, 3400 Spruce St., Philadelphia, PA 19104,
Andres Kanner, MD and Gary Gronseth, MD
Send Correspondence to journal:
Re: Reply to Holloway

frenchj{at}mail.med.upenn.edu Jacqueline French, et al.

The writers of the recently published AAN practice parameters on new antiepileptic drugs agree with Dr. Holloway. Disclosure of conflicts is an important issue in the development of practice parameters. Although there is no conflict of interest statement at the beginning of the article, we attempted to address potential conflicts with the following rules, which are clearly indicated in the article: “Members did not review a given AED if they had served as advisors for the pharmaceutical company that manufactured the drug and/or if they had been awarded a research grant from that company (participation in multicenter studies was not a reason for exclusion) or if they had financial interests in that company (stock ownership or employee).”
We considered delineating individual conflict disclosures for each member of the committee in the guideline. However, since a significant number of the members of this large committee are actively involved in antiepileptic drug studies, there were practical limitations on including it as part of the article.
An important point regarding these evidence based reviews, as well as others published by the American Academy of neurology, is that every attempt is made to eliminate bias by means of the rigor of the process. It is nearly impossible to select experts for guideline author panels completely free of conflicts. However, to ensure balance, the AAN guideline development oversight committees (QSS and TTA) select guideline panel members representing varied perspectives and opinions. Additionally, multiple individuals participate in the article selection and data abstraction process. Thus, it would be difficult for a single panel member to intentionally exclude articles or distort data.
Furthermore, to prevent the experts on the panel from going beyond the evidence, the process requires that recommendations and conclusions be explicitly tied to the level of the evidence found in the literature. Finally, guideline authors are required to formally consider and incorporate criticisms from AAN oversight committees, a guideline-specific reviewer network and peer reviewers from Neurology. Although nothing is foolproof, this process provides safeguards against manipulation.
The publication of these articles shortly followed a retreat held by the members of the AAN guideline development oversight committees. This retreat specifically addressed the issues of conflict of interest relating to practice parameters. It was felt, as eloquently delineated by Dr. Holloway, that there are many types of conflict of interest, including those related to the organization itself. Moreover, more subtle conflicts also exist. For example, an investigator who was in the process of writing a large grant might have a vested interest in overstating the relevance of a particular problem. Another example, included in Dr. Holloway's discussion, would be the physician whose income is directly tied to a specific procedure. There is no doubt, that we need to continue to actively discuss, consider, and review the procedures for managing and disclosing conflict of interest.

Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new onset epilepsy 29 July 2004

Robert G. Holloway,
University of Rochester School of Medicine
1351 Mt. Hope Avenue, Suite 223, Rochester, NY 14620
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Re: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new onset epilepsy

robert.holloway{at}ctcc.rochester.edu Robert G. Holloway

I was surprised that recently published practice parameters did not contain conflict of interest disclosure statements. [1,2] Authors of American Academy of Neurology (AAN) practice parameters should disclose their potential conflicts of interests. This is particularly relevant for practice parameters that review pharmaceutical agents or procedures in which the authors have a potential financial conflict of interest. The disclosures should be broad and include all types of relationships with sponsoring companies including equity holdings, contracted research and various consulting relationships. Given the stature of the practice parameters in influencing practice across multiple specialties, consideration should be given for a non-zero limit required for disclosure.
In addition, donation of remuneration from a potentially conflicting sponsor to a not-for-profit organization (e.g., charitable organization, university discretionary account or equivalent) should not preclude the need to disclose. Disclosure statements should also be considered for authors whose salaries are directly linked to the volume of procedures or devices that they are reviewing. Although not well studied, one would speculate that under such circumstances, “self-serving” bias might influence how an author seeks, interprets and reports available evidence as likely occurs with gifts. [3]
Consideration should also be given to the AAN itself to disclose its potential financial conflicts of interest when the sponsors of reviewed drugs or procedures have donated substantial amounts to the organization, even if only as unrestricted educational grants. The AAN has already made the list of not-for-profit organizations that have substantial ties to industry [4] and, I suspect, wants to avoid the negative publicity that could result from an inquisitive investigative journalist. [5]
As the public demands more accountability of the scientific enterprise, and financial conflicts of interest receive continued attention at the national level, including the recently issued guidance statement by the Department of Health and Human Services [6], it will be important for neurologists to take a proactive position, affirming to the public and patients that they are our primary interests and no others. Disclosure statements for issued practice guidelines should be one component of this affirmation. The effects of corporate sponsorship and potential conflicts of interest on the conduct and reporting of randomized controlled trials have received considerable attention.[7,8] Similar scrutiny for the development and reporting of clinical practice guidelines has only just begun, [9] but will likely increase (and should increase) given their potential to shape clinical practice, particularly those in training.
Potential conflicts of interest are so pervasive that when disclosure statements are not present, one could not be faulted for assuming that someone has something to hide. On April 26th, 2004, near the time of the release of the practice parameters addressing the new antiepileptic drugs, I received an electronic message from the AAN, which included the following: “These new evidence-based guidelines are the most comprehensive, unbiased review of the newest epilepsy drugs.” Even though I thought the guidelines were excellent, the lasting impact of the guidelines for me were “Methinks he doth protest too much” and a wish that disclosure statements were present both for the authors and for the AAN.
References
1. The TTA and QS Subcommittees of the AAN and the American Epilepsy Society. Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new onset epilepsy. Neurology 2004; 62:1252 – 1260.
2. The TTA and QS Subcommittees of the AAN and the American Epilepsy Society. Efficacy and tolerability of the new antiepileptic drugs I: Treatment of refractory epilepsy. Neurology 2004; 62:1261 – 1273.
3. Dana J, Lowenstein G. A social science perspective on gifts to physicians from industry. JAMA 2003;252–255.
4. Lifting the Veil of Secrecy. Corporate Support for Health and Environmental Professional Associations, Charities, and Industry Front Group. Integrity in Science Project. Center for Science in the Public Interest. 2003.
5. Lenzer J. Altepase for Stroke. Money and optimistic claims buttress the “brain attack” campaign. BMJ 2002; 324:723-729.
6. Department of Health and Human Services. Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subjects Protection. Federal Register 4150-36-P. May 12, 2004.
7. Schulman KA, Seils DM, Timbie JW, et al. A national survey of provisions in clinical-trial agreements between medical schools and industry sponsors. N Engl J Med. 2002 Oct 24;347:1335-1341.
8. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ. 2003 May 31;326:1167-1170.
9. Choudhry N, Stelfox H, Detsky A. Relationships between authors of clinical practice guidelines and the pharmaceutical industry. JAMA 2002; 287:612-617.