Summary Basis of Decision for INOmax ®
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
INOmax®
Nitric oxide, 100 ppm, 800 ppm, Gas, Inhalation
INO Therapeutics
Submission control no: 085333
Date issued: 2006-01-26
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), INOMAXMD (oxyde nitrique) pour inhalation, 100 ppm, 800 ppm, gaz, INO Therapeutics, No contrôle de la présentation 085333
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02270838
- 02270846
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
INOmax® is a registered trademark of INO Therapeutics.
2 Notice of decision
On September 23, 2005 , Health Canada issued a Notice of Compliance to INO Therapeutics for the drug product INOmax. INOmax contains the medicinal ingredient nitric oxide, a vasodilator. INOmax, in conjunction with ventilatory support and other appropriate agents, is indicated for the treatment of term and near-term (≥34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation (ECMO).
Inhaled nitric oxide appears to increase the partial pressure of arterial oxygen by dilating pulmonary vessels in better ventilated areas of the lung, and redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion ratios towards regions with normal ratios.
This drug submission was granted priority review as this drug product showed a significant increase in efficacy compared to existing therapies, for a condition that is not adequately managed by a drug marketed in Canada.
The market authorization was based on data from the quality, preclinical, and clinical information submitted. Efficacy of INOmax was investigated in 421 term and near-term newborns with pulmonary hypertension and hypoxic respiratory failure (oxygenation index measurements of ≥25 cm H2O/mm Hg). The overall clinical benefit of INOmax has been demonstrated with respect to the reduction of the rate of death and/or receipt of ECMO in the Neonatal Inhaled Nitric Oxide Study (NINOS) and with respect to the reduction of the rate of the receipt of ECMO based on the entire study population in the Clinical Inhaled Nitric Oxide Research Group Investigation (CINRGI) study.
In post-hoc analyses, clinical benefit was greater for the subgroups of patients who did not meet the study EMCO criteria at study entry (NINOS study) or whose baseline oxygen index was less than 40 cm H2O/mm Hg (CINRGI study). Efficacy and safety of INOmax have not been established beyond 96 hours of use, and long-term effects have not been established beyond 18-24 months. An adequate pharmacovigilance study, over a minimum of 5 years, will be carried out by INO Therapeutics to monitor and identify the long-term effects associated with the use of INOmax in neonates.
INOmax is supplied in aluminum cylinders as a compressed gas under high pressure and is available in two concentrations of nitric oxide: 100 ppm and 800 ppm. The initial dose of INOmax should be as low as possible and in no cases higher than 20 ppm for no more than 4 hours. Dosing guidelines are available in the Product Monograph.
INOmax is contraindicated for patients with the rare cardiovascular defect in which the systemic oxygenation is wholly dependent on extra-pulmonary right-to-left shunting. The use of INOmax has the potential to decrease right-to-left blood flow, which, in this condition, is potentially fatal.
Detailed conditions for the use of INOmax are described in the Product Monograph. The data submitted demonstrate that INOmax can be administered safely when used under the conditions stated in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of INOmax (nitric oxide) for inhalation, in conjunction with ventilatory support and other appropriate agents, is favourable for the treatment of term and near-term (≥34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation.
INOmax is contraindicated for patients with the rare cardiovascular defect in which the systemic oxygenation is wholly dependent on extra-pulmonary right-to-left shunting. The use of INOmax has the potential to decrease right-to-left blood flow, which, in this condition, is potentially fatal.
Detailed conditions for the use of INOmax are described in the Product Monograph. The data submitted demonstrate that INOmax can be administered safely when used under the conditions stated in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of INOmax (nitric oxide) for inhalation, in conjunction with ventilatory support and other appropriate agents, is favourable for the treatment of term and near-term (≥34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal ingredient)
Manufacturing Process and Process Controls
The drug substance is synthetically derived and the manufacturing process was considered to be adequately controlled within justified limits. The materials used are considered suitable and meet standards appropriate for their intended use.
Characterisation
Impurities and degradation products arising from manufacturing and/or storage were reported and characterised. These products were found to be within compendial limits.
Control of Drug Substance
Validation reports were satisfactorily submitted for all analytical procedures used for in-process and release testing of the drug substance. The specifications are considered acceptable for the drug substance.
Data from the batch analyses were reviewed and considered to be acceptable according to the specification of the drug substance.
Stability
Based upon the real-time and accelerated stability study data submitted, the proposed shelf-life, storage and shipping conditions for the drug substance were supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
INOmax (nitric oxide) for inhalation is a gaseous blend of nitric oxide and nitrogen (0.08% and 99.92%, respectively for 800 ppm; 0.01% and 99.99%, respectively for 100 ppm).
INOmax is supplied in aluminum cylinders as a compressed gas under high pressure (2000 pounds per square inch gauge) and is available in the following sizes:
- Size D portable aluminum cylinders containing 353 liters of nitric oxide gas in 800 ppm concentration in nitrogen.
- Size D portable aluminum cylinders containing 353 liters of nitric oxide gas in 100 ppm concentration in nitrogen.
- Size 88 aluminum cylinders containing 1963 liters of nitric oxide gas in 800 ppm concentration in nitrogen.
- Size 88 aluminum cylinders containing 1963 liters of nitric oxide gas in 100 ppm concentration in nitrogen.
The container/closure system is an aluminum alloy compressed gas cylinder, closed with a stainless steel valve with straight threads and sealed by a teflon O-ring. The cylinder meets all applicable Transport Canada regulations and guidelines for high pressure medical gas cylinders. Materials and construction are considered acceptable for this type of product.
Pharmaceutical Development
Changes to the formulation and manufacturing process made throughout the development are considered acceptable upon review.
Manufacturing Process and Process Controls
Process validation results have been reviewed and are considered acceptable for the manufacturing procedure. In-process controls detailed in the manufacturing documentation are considered to be sufficient to adequately control the process.
Control of Drug Product
Validation reports were satisfactorily submitted for all analytical procedures used for in-process and release testing of the drug product, and to justify the specification of the drug product. Nitrogen dioxide is controlled at 5 ppm in the specifications.
Data from final batch analyses were reviewed and considered to be acceptable according to the specification of the drug product.
Stability
The proposed shelf life of 36 months is considered acceptable when the product (packaged in aluminum alloy cylinders equipped with stainless steel valves and teflon seals) is stored at 25°C (77°F) with excursions permitted between 15-30°C (59-86°F).
3.1.3 Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production are considered to be suitable for the products manufactured at the site.
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Summary and Conclusion
This New Drug Submission is considered to meet the requirements of Division C.08.002 of the Food and Drug Regulations insofar as the Quality (Chemistry and Manufacturing) information is concerned. The Chemistry and Manufacturing information submitted for INOmax has demonstrated that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
No pharmacodynamic studies carried out by the manufacturer/sponsor were submitted for review.
From published information, nitric oxide relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide produces pulmonary vasodilation.
3.2.2 Pharmacokinetics
Absorption
No pharmacokinetic studies except for the pharmacokinetic-modelling study in dogs carried out by the manufacturer/sponsor were submitted for review.
From published information, nitric oxide is very rapidly inactivated by binding to hemoglobin to form methemoglobin.
The pharmacokinetic modeling study (submitted by the sponsor) of methemoglobin concentration-time was investigated in normal dogs inhaling 80, 160, 320 or 640 ppm nitric oxide. Based on an elimination half-life of 3 hours, the time to reach the steady state of percent methemoglobin concentration in anaesthetized dogs would be 12-15 hours.
3.2.3 Toxicology
Safety Pharmacology Studies
The safety pharmacology studies evaluated the effects of nitric oxide (NO) on the cardiovascular and respiratory system. The studies did not include an assessment of the effects of NO on the central nervous system (CNS). Animal studies to determine CNS toxicity were deferred on the basis of the review of the clinical data submitted assessing neurological development at 18 and 24 months. The sponsor has committed to conduct a pharmacovigilance study to assess the long-term effects of NO including neurological development.
Anesthetized male beagle dogs (13.2-14.7 kg) exposed to 0, 80, 160, 320 and 640 ppm nitric oxide for 6 hours showed dose-related increases in methemoglobinemia with results at 320 and 640 ppm being statistically significant at 1, 2, 3, 4, 5 and 6 hours post-drug administration. Mean methemoglobin levels at 6 hours for the 80, 160, 320 and 640 ppm groups were 3.0%, 6.6%, 24.1% and 78.1% respectively. These changes resulted in one death in the 640 ppm group. All NO exposed groups showed electrocardiographic changes (ventricular premature depolarizations, sinus tachycardia, and junctional rhythm).
These changes were also associated with increased heart rates in all treatment groups including the 80 ppm group. Decreased arterial oxygen tension and increased minute volume were also noted.
In contrast to the above results, a study in unanesthetized male and female beagle dogs (6.19-13.94 kg) exposed to 4 hours of NO at 40, 80, 160 or 320 ppm did not show any electrocardiogram (ECG) evidence of abnormalities of cardiac conduction, rate or rhythm. Mean methemoglobin levels at 40, 80, 160 and 320 ppm of NO for 4 hours were 2.3%, 4.5%, 10.37% and 23.5%, respectively.
Repeat Dose Toxicity Studies
The submission included only two rat studies for repeat-dose toxicity evaluation: a 7-day dose-ranging inhalation toxicity study and a 28-day inhalation toxicity study. The one-month repeat dose inhalation studies were conducted in rodents but not in non-rodents. The submission did not include juvenile animal toxicity studies, therefore, age-specific nitric oxide-induced toxicity was not determined. Toxicity studies in juvenile animals were deferred on the basis of the availability of significant neonatal human data.
The 7-day dose-ranging study showed high mortality at 300 ppm NO, considered to be due to methemoglobinemia-induced anoxia. Methemoglobinemia was noted at 80 ppm NO and showed a dose-related increase. Gross pathology showed brown discolouration of the lungs in the premature deaths which was claimed to be due to methemoglobinemia. Light microscopy of the lung showed no evidence of drug-induced toxicity. Electron microscopy of lung tissues from rats exposed to 200 ppm NO indicated oxidative injury to the respiratory epithelium. Unfortunately, similar electron microscopic determinations were not done for animals treated with the lower dose of 80 ppm.
The results of the 28-day toxicity study were similar to those of the 7-day study. No deaths were reported at 40, 80 and 160 ppm. At higher doses of 200 and 250 ppm, there was a dose-related increase in mortality. Methemoglobinemia appeared to be the major significant toxic effect of NO in this study and this was noted at the lowest dose of 40 ppm. Electron microscopy of the epithelium of the upper respiratory tract in rats treated with 200 ppm for 28 days showed changes which were similar in incidence and severity as those in the controls.
Genotoxicity Studies
Nitric oxide has demonstrated genotoxicity in some bacterial strains used in the Ames test, the mouse lymphoma test, the Chinese hamster ovary cell test, with in vivo exposure in rats, and in human lymphocytes. Since animal carcinogenicity studies were not conducted, the long-term implications of the genotoxicity findings are unknown. Therefore, INOmax should be used only after weighing the benefits against risks for individual patients.
Carcinogenicity Studies
The drug submission did not include data on carcinogenicity toxicity. This lack of data is considered acceptable based on ICH M3(M) guidelines since the recommended duration of therapy is not to exceed 96 hours. The sponsor has informed Health Canada that a 2-year rat carcinogenicity study is on-going and the report is expected to be issued during the second quarter of 2006.
Reproductive Toxicity Studies
This drug submission did not include data on reproductive toxicity. This lack of data is considered acceptable based on ICH M3(M) guidelines.
3.2.4 Summary and Conclusion
Based on the limited animal data submitted, it would appear that 40 ppm NO may be a safe dose in rats and dogs except for methemoglobinemia. It is not known whether young animals are more susceptible to NO toxicity, including methemoglobinemia. Safety pharmacology studies did not include a CNS toxicity assessment. The positive findings in the genotoxicity studies are of concern. Also, multiple dose toxicity studies in a non-rodent species are not available to determine whether the apparent difference in toxicity between rats and dogs could be considered species related.
The preclinical data submitted by the sponsor are considered inadequate for assessing fully the safety of INOmax for the proposed indication and clinical use. This is reflected in the following statements in the Product Monograph under "Toxicology":
One-month repeat dose inhalation studies have been conducted in rodents but not in non-rodents. Age-specific nitric oxide-induced toxicity has not been determined, as juvenile animal toxicity studies were not conducted. There are no reproductive animal studies or human studies to evaluate nitric oxide for effects on fertility or harm to the developing fetus. Nitric oxide has demonstrated genotoxicity in some bacterial strains used in the Salmonella (Ames Test), the mouse lymphoma test, Chinese hamster ovary cell test, in vivo exposure in rats, and human lymphocytes.
Since animal carcinogenicity studies have not been conducted, the long-term implications of the genotoxicity findings are unknown. INOmax should be used only after weighing the benefits against risks for individual patients.
INOmax is considered a life-saving drug when used as indicated for the treatment of term and near-term (≥34 weeks) neonates with hypoxic respiratory failure. Additionally, there is evidence to show that there is significant advantage over the existing therapy requiring ECMO.
According to ICH M3(M) guidelines "Pharmaceuticals under development for the indications in life threatening or serious disease without current effective therapy may also warrant a case by case approach to both toxicological evaluation and clinical development to optimise and expedite drug development. In these cases, particular studies may be abbreviated, deferred or omitted." In accordance with these guidelines, the requirements for CNS assessment in animal safety pharmacology study, the juvenile animal toxicity studies, the long-term non-rodent toxicity study and the carcinogenicity study were deferred at the time the Notice of Compliance was issued.
Animal studies to determine CNS toxicity were deferred on the basis of the review of the clinical data submitted assessing neurological development at 18 and 24 months. Additionally, the sponsor has committed to conduct a pharmacovigilance study to assess the long-term effects of NO including neurological development.
One-month repeat dose inhalation studies in non-rodents were deferred because unanesthetized male and female dogs exposed for 4 hours to NO at 40, 80, 160 and 320 ppm did not show any ECG evidence of abnormalities of cardiac conduction, rate or rhythm. Increased methemoglobin levels were noted only at 160 ppm and higher of NO.
Toxicity studies in juvenile animals were deferred on the basis of the availability of significant neonatal human data. Reproductive animal toxicity studies are not required for use in this age group of patients. A 2-year rat carcinogenicity study is ongoing and the report is expected in the second quarter of 2006.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Pharmacodynamics
Of all the clinical pharmacology and clinical pharmacokinetic studies submitted only one study (Report: CTN-NO-93-003: A dose-finding study with inhaled nitric oxide in new-born patients with persistent pulmonary hypertension and paediatric patients with pulmonary hypertension) is relevant to the proposed indication for use of nitric oxide (NO). This was an exploratory study to determine an appropriate dose of NO for a more definitive study. The significant information from this study is that in newborn and paediatric patients with oxygen index of 15-40, continuous exposure to NO between 10 and 30 ppm for 10 minutes showed improvements in oxygenation. At these doses of NO there was a plateau effect on oxygenation improvement. Only two of the 54 patients showed a methemoglobin concentration of > 2.5% with no patient > 5%.
From published information, the main pharmacodynamic response to inhaled nitric oxide (iNO) is the relaxation of lung vascular smooth muscle, causing dilation of blood vessels and consequently increased blood flow in the region reached by the compound. Nitric oxide relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation.
From published information, the pharmacodynamic response is typically seen within a few minutes from the start of treatment. A dose finding study in neonatal patients demonstrated a rapid (within 10 minutes) improvement in arterial oxygenation at doses ≤10 ppm in a majority of the patients. Inhaled NO appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion ratios toward regions with normal ratios.
3.3.2 Pharmacokinetics
Of all the clinical pharmacology and clinical pharmacokinetic studies submitted only one study is relevant to the proposed indication for use of nitric oxide (NO). See section 3.3.1 Pharmacodynamics.
From published information, inhaled NO (iNO) is absorbed systemically and the end products of NO that enter the systemic circulation are predominantly nitrate and methemoglobin.
From published information, the conversion of NO into nitrate is considered to be the major metabolic pathway. Data indicated that the inactivation of NO occurred in the red blood cells and suggested that oxyhemoglobin acted as an oxygen donor to the NO molecule in its conversion to nitrate. Over 70% of iNO was excreted as nitrate in the urine. Results also showed that up to approximately 14% of the absorbed NO may be converted directly to nitrogen oxides, which have a volume of distribution equal to about one-third of body weight and a clearance similar to the glomerular filtration rate.
3.3.3 Clinical Efficacy
Two pivotal studies were submitted in order to support the proposed indication for INOmax, the Neonatal Inhaled Nitric Oxide Study (NINOS) and the Clinical Inhaled Nitric Oxide Research Group Investigation (CINRGI) study.
NINOS was a multinational (USA and Canada), multicentre (19 sites), double-blind, randomized, placebo-controlled trial with 235 neonates; 114 in the iNO group and 121 in the placebo group. The primary clinical objective of this study was to assess the effect of inhaled nitric oxide (iNO) on the incidence of death and/or receipt of extracorporeal membrane oxygenation (ECMO) before discharge to home or 120 days, whichever came first. The secondary objectives were to assess the effects of iNO on the partial pressure of oxygen (PaO2), oxygenation index (OI) and alveolar-arterial oxygen gradient (A-aDO2) 30 minutes after initial gas treatment; as well as, length of hospital stay, duration of assisted ventilation, incidence of airleak and chronic lung disease, incidence of neonates meeting ECMO criteria, and neurodevelopmental outcomes at 18-24 months of follow-up. This study enrolled neonates who were ≥34 weeks gestational age and ≤14 days old and who required mechanical ventilation for hypoxic respiratory failure with an oxygenation index (OI) ≥25 cm H2O/mmHg. Neonates with known significant structural congenital heart disease or diaphragmatic hernia were excluded. Hypoxic respiratory failure was caused by meconium aspiration syndrome (MAS; 49%), pneumonia/sepsis (21%), idiopathic primary pulmonary hypertension of the newborn (PPHN; 17%), or respiratory distress syndrome (RDS; 11%). Patients in the iNO group received an initial dose of 20 ppm iNO and patients in the placebo group inhaled 100% oxygen at a flow equal to that of the iNO patients. Neonates who did not respond or partially responded to 20 ppm iNO (non/partial response defined as >20 mmHg increase in PaO2 after 30 minutes) had their dose increased to 80 ppm iNO or to the equal flow of the reference gas. The duration of iNO treatment was up to 336 hours (or 14 days).
CINRGI was a multicentre (18 US centres), double-blind, randomized, placebo-controlled trial. The primary objective was to examine the impact of the additional INOmax to conventional therapy on the incidence of receipt of ECMO in each treatment group. The secondary objectives of the CINRGI study were to determine the impact of the INOmax therapy on the rapid improvement in arterial oxygenation measured by the arterial-alveolar oxygen (a/A) ratio, the alveolar-arterial oxygen gradient (A-aDO2), the arterial partial pressure of oxygen (PaO2), and the oxygenation index (OI). In addition, the impact of INOmax on methemoglobin levels, blood pressure, hospital duration, the incidence of chronic lung disease, and neurological abnormalities were evaluated. A total of 212 hypoxemic term and near-term neonates (≥34 weeks gestational age and ≤96 hours of birth) with echocardiographic or clinical evidence of pulmonary hypertension and oxygenation index (OI) ≥25 cm H2O/mmHg were stratified at study entry by underlying disease and randomized to receive, in addition to conventional therapy, either nitrogen gas (placebo) or inhaled NO (97 in iNO group and 89 in placebo group) at 20 ppm, which was weaned (if PaO2 >60 ppm and pH <7.55) to 5 ppm after 4-24 hours. However, neonates with urgent need for ECMO, lethal congenital anomaly, significant bleeding diathesis, active seizures on anticonvulsants or history of prolonged asphyxia, cyanotic congenital heart disease or features that would exclude them from receiving ECMO were excluded from this study. The duration of treatment was up to 96 hours (4 days). Neonates with congenital diaphragmatic hernia (n=26) were analyzed as a separate group.
The primary objectives (i.e. the combination of death and receipt of ECMO in NINOS study and the receipt of ECMO in CINRGI study) are considered to be clinically meaningful. However, there are concerns about the sensitivity and specificity of the primary efficacy endpoints employed in the NINOS study because other factors that are not directly related to the efficacy of iNO therapy also played a role in determining whether to place an infant on ECMO.
In the NINOS study, iNO therapy significantly reduced the rate of "death and/or receipt of ECMO", however, the rate reduction was not significant in mortality but exclusively in the "receipt of ECMO" and the rate reduction of ECMO was not statistically significant in the analysis by actual gas received. Post-hoc subgroup analyses of the NINOS study further suggested that iNO reduced the rate of "meeting study ECMO criteria" for patients who did not meet ECMO criteria at study entry. Results of post-hoc analyses did not demonstrate statistically significant beneficial effect of iNO among patients who already met ECMO criteria at study entry.
The results from the CINRGI study showed that the rate of receipt of ECMO was statistically lower in the INOmax group when compared with that in the placebo group and the rate reduction remained statistically significant in the analysis by actual gas received and after adjusting for baseline oxygenation differences. In the CINRGI study, when patients were examined according to their baseline OI levels (OI <40 cm H2O/mmHg and OI ≥40 cm H2O/mmHg) in a post-hoc analysis, the statistically significant reduction of the rate of receipt of ECMO was demonstrated only among patients with baseline OI <40 cm H2O/mmHg.
In summary, the overall clinical benefit of iNO has been demonstrated in both NINOS (with respect to the reduction of the rate of death and/or receipt of ECMO) and CINRGI studies (with respect to the reduction of the rate of the receipt of ECMO) based on the entire study population. Further, greater benefit was shown among patients who did not meet the study ECMO criteria at study entry (NINOS) and among patients whose baseline OI was OI <40 cm H2O/mmHg (CINRGI). As these subgroup analyses were post-hoc and not powered to examine the statistical differences among subgroups, the efficacy of INOmax was based on the results from the entire study population of two pivotal studies. However, information concerning the results of subgroup analyses has been incorporated in the Product Monograph.
In both pivotal studies, iNO rapidly improved arterial oxygenation as measured by the alveolar-arterial oxygen gradient (A-aDO2), the arterial partial pressure of oxygen (PaO2), and the oxygenation index (OI). However, the improvement of oxygenation and the reduction of the rate of receipt of ECMO associated with the use of INOmax did not translate into clinically meaningful reductions in mortality, length of hospital stay, hospital re-admission, and other serious complications and/or adverse reactions.
In the NINOS study, about 15% (17/117) of placebo patients and 51% (57/112) of iNO patients fully responded to the therapy after the first 30 minutes which was defined by PaO2 increase > 20 mmHg. The difference between treatment groups regarding the full response rate was statistically significant (p < 0.001). Data also showed that only 5.5% of neonates who did not respond or partially responded to the initial iNO therapy at the 20 ppm dose were converted to full response with 80 ppm iNO. Additionally, the rate of receipt of ECMO between treatment groups also differed according to the initial response to 20 ppm indicating that patients who initially did not fully respond to iNO therapy in the first 30 minutes did not benefit significantly from the therapy. The CINRGI study also assessed the rate of treatment failure, which was defined as discontinuing the gas therapy due to patients "meeting ECMO criteria", "toxicity", "failure to respond", and "condition worsening". The results indicated that a higher percentage of patients in the placebo group (64.0%) discontinued the gas therapy because of treatment failure when compared with the iNO group (38.1%) (p=0.0001).
Results from the post-hoc subgroup analysis according to underlying disease in the NINOS study were similar in comparison to those in the CINRGI study with the exception of RDS. While results from the NINOS study showed that iNO resulted in a slightly increased rate of receipt of ECMO in patients with RDS, results from the CINRGI study showed that the highest reduction of the rate of receipt of ECMO was among patients with RDS who were treated with INOmax. However, the numbers of patients with RDS in both the NINOS study (n=25) and the CINRGI study (n=16) were very small. The two pivotal studies seemed to be consistent in supporting that iNO is effective in patients with pneumonia/sepsis. Data from the CINRGI study showed that that INOmax was not effective in neonates with congenital diaphragmatic hernia with respect to the reduction of the receipt of ECMO in the treatment of hypoxic respiratory failure.
3.3.4 Clinical Safety
Two pivotal studies were submitted in order to support the proposed indication for INOmax, the Neonatal Inhaled Nitric Oxide Study (NINOS) and the Clinical Inhaled Nitric Oxide Research Group Investigation (CINRGI) study. In the NINOS study, several adverse events of particular interest were collected including neurological events, pulmonary hemorrhage, prolonged oozing of blood, and GI bleeding. In the CINRGI study, all adverse events occurred during the clinical trial including hematology parameters and clinical chemistries were systematically collected. Additional information such as discharge head ultrasound, computerized axial tomographs, neurological examinations, and audiology tests were captured in the CINRGI study. For a description of the studies, see section 3.3.3 Clinical Efficacy.
Results from the NINOS study post-hoc analyses indicated that patients who were treated with iNO and who did not receive ECMO seemed to have numerical increases, although not statistically significant, in several adverse reactions including airleak, cerebral/intracranial infarct, periventricular leukomalacia, and new intraventricular hemorrhages compared to patients in the placebo group who did not receive ECMO. In particular, the presence of airleak seemed to be related to the maximum 80 ppm iNO dose. It is important to note that patients were not randomly assigned to receive 80 ppm gas therapy in the NINOS study. Patients who did not fully respond to 20 ppm gas therapy then received an increased dose of 80 ppm, therefore, neonates who received 80 ppm gas therapy may have had more severe conditions. Long-term follow-up is necessary to identify potential long-term risks associated with the use of INOmax in neonates.
In the CINRGI study, the safety profile among patients in placebo and INOmax groups were similar. Patients in the INOmax group did not show an increased number of events of abnormal electroencephalogram, cerebral hemorrhage, cerebral infarct, intracranial hemorrhage, lung edema, lung hemorrhage, and pheumothorax. However, numerical increases in some adverse events were seen in a post-hoc analysis among INOmax-treated patients who did not receive ECMO. In addition, the discharge neurologic status was further examined in a post-hoc analysis according to whether patients received ECMO or not. The results from INOmax-treated patients who did not receive ECMO (and who had a CAT scan) indicated numerical increases (based on small numbers of patients) in percentage of patients with "abnormal CAT scan" [60% (6/10) in INOmax group versus 25% (1/4) in placebo group] and "abnormal neurological examination" [18% (7/37) in INOmax versus 5% (1/19) in placebo]. There was no additional information about the type, severity, and clinical relevance of these neurologic abnormalities observed at discharge and in view of the small number of patients examined, interpretation of these data is difficult. A long-term follow up study to assess neurodevelopmental outcomes for the proposed indication is warranted.
The 1-year follow-up of the CINRGI study showed that 19% (14/74) of INOmax patients versus 14% (10/71) of placebo patients were found to have abnormal neurological examinations. The number of reports of hearing loss and cerebral palsy were also slightly higher in INOmax patients. Although not statistically significant, these numerical increases of adverse events among INOmax-treated patients after 12 months again suggest the need for a long-term follow-up study regarding potential neurological effects of INOmax.
Data from the 18-24 month NINOS follow-up study showed that patients in placebo and iNO groups were similar regarding the majority of measurements including growth parameters, neurological assessment, visual assessment, hearing assessment, audiology assessment, and the mean Bayley mental development index (MDI). However, the mean Bayley psychomotor development index (PDI) was numerically higher for placebo patients
(93.6 +/- 17.5) when compared with that for iNO patients (85.9 +/- 21.1) although not statistically significant.
A 5-year retrospective follow-up study was conducted among patients who participated in the NINOS and CINRGI studies with an overall follow-up rate of 25%. The results of the study showed that patients treated with iNO had significantly higher incidence of gait disturbance at 5-year follow-up [16% (9/55) in iNO versus 2% (1/43) in placebo, p=0.04]. Further post-hoc analysis for adverse events from 5-year follow-up data by receipt of ECMO showed that among patients who did not receive ECMO, 14.6% (6/41) of iNO-treated patients and 6.7% (2/30) of placebo-treated patients developed gait disturbance. However, the 5-year follow-up for the combined NINOS and the CINRGI studies had a very low follow-up rate; 32/206 (15.5%) and 66/186 (35.5%), respectively. Relevant data were not available to estimate the potential impact of the loss of follow-up bias, thus the results of this 5-year follow-up study were not conclusive and should be interpreted with caution. Therefore, long-term effects of INOmax, particularly with regard to pulmonary and neurodevelopment outcomes, have not been established beyond 18-24 months. There is a need for a post-marketing pharmacovigilance study to assess potential long-term effects associated with the use of INOmax.
Clinicians should be aware of the potential short-term and long-term adverse events, and the potential genotoxicity risk associated with INOmax. The Product Monograph addresses these safety concerns and informs clinicians/neonatologists about the efficacy and safety related to INOmax. The Product Monograph also includes a commitment by the sponsor to undertake a pharmacovigilance study, with a minimum of 5-year follow-up data, to identify potential long-term risks associated with the use of INOmax in neonates, particularly, related to pulmonary and neurodevelopmental outcomes.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
INOmax (nitric oxide) for inhalation has been shown to rapidly improve arterial oxygenation and reduce the need for extracorporeal membrane oxygenation (ECMO). While ECMO has been demonstrated as a life-saving therapy, neonates undergoing this surgery face several risks. A drug that can avoid the use of ECMO while having no detrimental consequences relative to altered outcomes presents a favorable benefit profile. This drug submission was granted priority review as INOmax showed a significant increase in efficacy compared to existing therapies, for a condition that is not adequately managed by a drug marketed in Canada.
The overall clinical benefit of INOmax has been demonstrated in both NINOS (with respect to the reduction of the rate of death and/or receipt of ECMO) and CINRGI studies (with respect to the reduction of the rate of the receipt of ECMO) based on the entire study population. In post-hoc analyses, clinical benefit was greater for the subgroups of patients who did not meet the study EMCO criteria at study entry (NINOS study ) or whose baseline oxygen index was less than 40 cm H2O/mm Hg (CINRGI study). Results also showed that neonates with congenital diaphragmatic hernia did not benefit from INOmax with respect to the reduction of the receipt of ECMO in the treatment of hypoxic respiratory failure.
Meeting ECMO criteria is a marker for severity of hypoxic respiratory failure. The NINOS study showed that inhaled nitric oxide prevented neonates who did not meet ECMO criteria at study entry from reaching this critical threshold of severity. Previous clinical studies have demonstrated that ECMO reduced the mortality rate by about 50% for term and near-term neonates with hypoxic respiratory failure. Therefore, a reduction in the rate of receipt of ECMO may be expected to translate into a reduction in mortality among neonates with hypoxic respiratory failure who do not have easy access to ECMO therapy. Additionally, inhaled nitric oxide provides some clinical benefit to term and near-term neonates with hypoxic respiratory failure who do not respond to standard therapy. From post-hoc analyses, the clinical benefit appears to be greater in the subgroups who did not meet ECMO criteria at baseline or whose baseline OI was less than 40 cm H2O/mmHg.
Neonates are known to have diminished methemoglobin reductase activity compared to adults and could therefore be at greater risk of developing methemoglobinemia. The concentrations of methemoglobin in the blood should be monitored, as nitric oxide (NO) for inhalation is absorbed systemically and the end products of NO that enter the systemic circulation are predominantly methemoglobin and nitrate. Methemoglobinemia increases with the dose of nitric oxide. If methemoglobin levels are >2.5%, the INOmax dose should be decreased and the administration of reducing agent such as methylene blue may be considered.
Nitrogen dioxide (NO2) rapidly forms in gas mixtures containing NO and O2, and NO may in this way indirectly cause airway inflammation and damage. The formation of NO2 has a clear relationship to NO treatment, and without proper controls in delivery and in monitoring, formation of NO2 represents a risk. The dose of NO should be reduced if the concentration of NO2 exceeds 0.5 ppm, and NO2 should be monitored as well as NO.
The use of INOmax should not be discontinued abruptly as it may result in an increase in pulmonary artery pressure (PAP) and/or worsening of blood oxygenation (PaO2). Deterioration in oxygenation and elevation in PAP may also occur in neonates with no apparent response to INOmax.
The size of two pivotal studies was not large enough to detect statistically significant differences between treatment groups regarding adverse events. Non-statistical significant numerical differences in adverse events associated with the use of INOmax, such as airleak syndrome, cerebral/intracranial infarct, new intraventricular hemorrhage, periventricular leukomalacia, gait disturbance, and psychomotor development index, were noted in post-hoc analyses, particularly, among patients who did not receive ECMO. A long-term follow-up study is needed to monitor and identify potential long-term effects associated with the use of INOmax.
A number of issues were raised during the review of this drug submission, as well as, issues regarding additional information provided by the sponsor in response to questions posed by Health Canada. In order to facilitate the drug review process, an ad-hoc Scientific Advisory Committee (SAC) was appointed to assist in evaluating the drug safety and efficacy data. Information packages along with issue statements and questions were sent to the SAC and the sponsor. The sponsor had the opportunity to provide the SAC with answers to the questions days before the teleconference, scheduled for June 10, 2005.
The following issues were discussed:
- the clinical meaningfulness of the efficacy outcomes used in both NINOS and CINRGI studies and identified subgroups of patients [i.e. already met ECMO criteria (NINOS) or whose baseline OI was greater than 40 (CINRGI)] who may not benefit significantly from the inhaled nitric oxide therapy;
- the potential intrinsic toxicity related to INOmax, particularly, with regard to pulmonary and neurological adverse events;
- long-term effects of INOmax, particularly, with respect to the neurological adverse events and genotoxicity; and
- specific management strategies for the use of INOmax for the proposed indication.
The SAC provided recommendations on each of the issues above. Based on Health Canada 's review and taking into account the comments from the SAC, important changes to the Product Monograph, as well as, specific management strategies for the use of INOmax for the proposed indication have been incorporated.
Taking into account the potential safety issues raised, Health Canada has focused on the following risk management strategies: 1) a post-market surveillance regarding long-term outcomes, particularly , neurodevelopmental and pulmonary outcomes for a minimum of 5 years follow-up with analysis done at 2 and 5 years, 2) the Product Monograph to include the sponsor's commitment to undertake a post-marketing surveillance study, under "Indication and Clinical Use" and 3) the development of the Patient Package Insert to provide information regarding INOmax to parent(s) or guardian(s) of neonates.
In full consideration of this submission and review, it is Health Canada's opinion that for the proposed indication, the benefit of INOmax outweighs the risk associated with the product. Health Canada requested that the sponsor develop a safety specification and pharmacovigilance plan to address the potential safety issues related to INOmax. Also, Health Canada required the commitment from the sponsor to undertake an adequate pharmacovigilance study, with a minimum of 5-year follow-up data, to identify potential risks associated with the use of INOmax in neonates, particularly, the risks related to pulmonary and neurodevelopmental outcomes.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of INOmax (nitric oxide) for inhalation in conjunction with ventilatory support and other appropriate agents, is favourable for the treatment of term and near-term (≥34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation (ECMO).
The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: INOmax®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2003-02-10 |
| Request for priority status | |
| Filed | 2003-05-23 |
| Approval issued | 2003-06-24 |
| Submission filed | 2003-07-02 |
| Screening 1 | |
| Quality Evaluation complete | 2004-01-24 |
| Clinical Evaluation complete | 2004-07-22 |
| NON issued by Director General (indicate safety and efficacy issues) | 2004-08-10 |
| Pre-response to NON meeting | 2004-10-27 |
| Response filed | 2004-11-30 |
| Screening 2 | |
| Screening Acceptance Letter issued | 2004-12-09 |
| Review 2 | |
| SAC Teleconference | 2005-06-10 |
| Clinical Evaluation complete | 2005-08-25 |
| Labelling Review complete | 2005-08-25 |
| NOC issued by Director General | 2005-09-23 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| INOMAX | 02270846 | INO THERAPEUTICS | NITRIC OXIDE 800 PPM / CYLR |