Ici les documents relatifs à la confrontation avec la FDA du 12 mai 2010:
et notamment le document A CHARGE:
En introduction (Traduction auto):
Les AINS sont utilisés à la fois leurs propriétés anti-inflammatoires et analgésiques. Il existe des risques pour la sécurité relatives aux classes, notamment cardiovasculaires graves événements
thrombotiques et de graves événements gastro-intestinaux (GI). D'autres risques liés à la classe comprennent l'hypertension, la rétention d'eau, des
lésions hépatiques, des lésions rénales, l'anaphylaxie et les réactions
Selon le requérant, le naproxcinod a été développé pour répondre à deux toxicité liées aux AINS : gastropathie et les élévations de la pression artérielle. La molécule mère est métabolisée en deux fractions actives, le naproxène et l'oxyde nitrique (NO), la molécule active contenant des nitrates dans les vasodilatateurs tels que la nitroglycérine et le dinitrate d'isosorbide.
L'avantage supposé de la composante NO de la drogue est une réduction de la
gastropathie due aux AINS, et une atténuation de l'élévation de la pression
artérielle après le début de l'AINS.
Toujours selon la requérante, la libération de NO de naproxcinod est destiné à contrer la hausse des TA vue avec les AINS chez les patients normotendus et hypertendus,
À l'appui de l'étiquetage (la notice) lié aux systèmes GI et CV , le requérant a effectué des études d'endoscopie digestive et des études automatisées de la pression artérielle (MAPA).
Le Demandeur a tenté de montrer que l'efficacité du naproxcinod n'est pas différente du naproxène tandis que la sécurité est meilleure.
Lors de la réunion, la discussion se concentrera sur de savoir si le requérant a réussi à démontrer qu'il existe un avantage cliniquement significatif dans la sécurité du naproxcinod par rapport au naproxène et s'il y a une efficacité comparable.
Concernant la non-infériorité par rapport au Naproxène:
The Division has identified several deficiencies in the Applicant’s approach to the noninferiority analysis:
1. There was no scientific justification provided for the choice of the non-inferiority margin
The selection of an acceptable non-inferiority margin is critical in assuring that
there is little clinically meaningful difference between naproxcinod and naproxen treatments.
2. The treatment effect size of naproxcinod as reported in Phase 2 dose ranging studies was of the order of 12 mm for WOMAC pain and function endpoints and 0.4 for patient overall rating of disease status.
The Applicant’s established margins for WOMAC pain and function are nearly
70% of the treatment effect size.
3. Non-inferiority of naproxcinod to naproxen for all three co-primary endpoints was not demonstrated in replicated studies.
1. Naproxcinod, at doses of 750 mg and 375 mg twice a day, is efficacious in the relief of signs and symptoms of osteoarthritis.
2. Naproxcinod has not been demonstrated to be non-inferior to naproxen.
3. The general safety profile of naproxcinod is consistent with that of the NSAID drug class.
Concernant les effets cardio-vasculaires:
Following treatment with naproxcinod, BP was not consistently less than baseline through the dosing interval. Although less of an effect was noted compared to naproxen in general, this was not sustained through the inter-dosing interval. More than two-fold changes in peak-trough effects were noted in some ABPM recordings. Hence, this reviewer’s conclusions are as follows:
• Based on information available to date a consistent effect on both systolic and diastolic BP is mainly present at peak.
• The effect through the dosing interval is variable.
• Typically drugs with meaningful effects on cardiac outcomes have an effect on systolic and diastolic BP that persists through the dosing interval. In this case the potential impact on cardiac outcomes is unclear.
• Potential safety issues due to hypotensive effect at peak in vulnerable subjects would have to be considered. Caution should be advised regarding concomitant use with PDE-5 inhibitors like sildenafil, nitroglycerin and antihypertensive treatments especially at first dose.
Final comments related to labeling will be addressed after the advisory committee meeting.
1. As discussed in the review only peak effects were evaluated in the phase 3 studies and a consistently lower BP effect at trough with naproxcinod compared to naproxen has not been demonstrated in the ABPM studies. Hence we recommend that all promotional statements and data (e.g. mean 24 hour BP from the ABPM study and data depicting peak BP from the pooled phase 2/3 studies) that imply beneficial effects be removed.
2. Statements regarding potential exaggerated hypotension-related AEs in the elderly and with concomitant PDE-5 inhibitors like sildenafil, nitroglycerin and antihypertensive therapy especially at first dose should be included under warning and precautions.
Concernant les effets gastro-intestinaux:
DGP Medical Reviewer’s Response:
DGP recommends that the proposed labeling language in Section 14.3 be removed because of the following issues:
(1) The outcome of Study 0005, the single study with an appropriate efficacy endpoint, was not statistically significant, and the observation should not be shown in the labeling. It is also not clear that the absolute difference in percentage of patients who developed ulcers between the Naproxen and Naproxcinod arms of this large trial, 4%, is clinically meaningful.
(2) Because erosion is a transient lesion and can heal spontaneously through normal mucosal turnover, erosions should not be used as an endpoint for ulcer risk reduction studies and erosion data should not be included in the label.
(3) The treatment duration of all three studies (0002, 0027, and 0005) was inadequate. All were conducted for less than 6 months. In fact, two of the studies proposed for the labeling were only of two weeks duration.
If the difference between Naproxen and Naproxcinod observed in Study 005 is considered potentially clinically relevant, the Applicant should conduct well designed 6-month studies of Naproxcinod-induced peptic ulcers. They should consider studying a population that is H. pylori negative at baseline.
Draft Discussion Points for the Committee
1. Discuss whether the data support the claim that naproxcinod has similar efficacy to Naprosyn and whether their chosen non-inferiority margin was appropriate.
2. Discuss the public health impact of the Applicant’s findings regarding the effects of naproxcinod on blood pressure.
3. Discuss the public health impact of the Applicant’s findings regarding the effects of naproxcinod on the proximal gastrointestinal tract.
FDA staff: NicOx drug's heart benefit unclear
Mon May 10, 2010 4:53pm EDT
* FDA releases documents ahead of May 12 meeting
Stocks | Regulatory News | Global Markets | Healthcare
* Agency reviewer: heart effect not consistent
WASHINGTON, May 10 (Reuters) - NicOx SA's (NCOX.PA) pain drug appears safe and effective for arthritis patients, but the impact on patient's cardiovascular risks is less clear, U.S. Food and Drug staff reviewers said in documents released on Monday.
The French drugmaker is seeking Food and Drug Administration approval to sell its drug, a non-steroidal anti-inflammatory drug (NSAID) called naproxcinod, to treat osteoarthritis. The company is hoping the agency will recognize its drug's potential blood-pressure benefits, setting it apart from rivals in an already-crowded field.
But an FDA staff reviewer said, based on information to date, the drug's effect on patients' blood pressure is variable.
"Typically, drugs with meaningful effects on cardiac outcomes have an effect on systolic and diastolic (blood pressure) that persists through the dosing interval," an FDA staff reviewer wrote. "In this case, the potential impact on cardiac outcomes is unclear."
Naproxcinod aims to be an improved version of naproxen, a widely used NSAID that can increase blood pressure and cause stomach problems. NicOx's drug is a nitric oxide-releasing version designed to avoid such side effects.
The FDA staff will present their reviews to an FDA panel of outside experts that meets Wednesday to discuss whether the drug is safe and effective for the joint disease.
A final agency decision is due by July 23. (Reporting by Susan Heavey; Editing by Steve Orlofsky)
Ici les documents relatifs à la confrontation avec la FDA du 12 mai 2010: