The Sale of Unlicensed Natural Health Products, Exemption Numbers, and You!
Natural Health Products (Unprocessed Product Licence Applications) Regulations
The regulatory solution many have been waiting for may be on the horizon with the recent regulatory proposal: Natural Health Products (Unprocessed Product Licence Applications) Regulations (NHP-UPLAR). The expected impact of these regulations is to ensure continued consumer access to safe products, provide industry with some predictability in terms of going to market and enhance market stability.
What is it?
A regulatory proposal that would permit certain natural health products (NHPs), for which a product licence application has been filed with Health Canada but a decision to issue or refuse a licence has not yet been made, to be sold legally in Canada. The regulatory proposal provides qualified products with an exemption to the prohibition on sale without a valid product licence contained in the Natural Health Product Regulations (NHPR). This will allow certain NHPs to continue to be sold in Canada while Health Canada completes the full evaluation and licensing process. The proposed regulations would also assert key safety oversight measures such as adverse reaction reporting, site licensing, and the authority to suspend or stop sales if a safety issue is identified.
Why is it being proposed?
On January 1, 2004, when the NHPR came into force, there were an estimated 40,000 NHPs already being sold on the Canadian market. Health Canada provided a six-year transition period for companies to come into compliance with the regulations and submit product licence applications demonstrating the safety and efficacy of their existing products. Following review and acceptance of the data by Health Canada, product licences would be issued. Health Canada’s risk-based compliance policy allowed products without licences to be sold during this transition period provided they had submission numbers, did not pose a health risk to consumers, and were manufactured, imported, packaged and/or labelled in facilities holding valid Site Licences and complying with NHP GMPs.
When the six-year transition period ended (January 2010), the National Association of Pharmacy Regulatory Authorities (NAPRA) issued a position statement that said that “Pharmacists should not sell a marketed health product without a Drug Identification Number (DIN), Natural Product Number (NPN) or Drug Identification Number for Homeopathic Medicine (DIN-HM).” This position threatened to limit consumer access to safe NHPs and increased the current level of instability in the marketplace. As a result of industry lobbying and extensive stakeholder consultation, Health Canada identified the need for a temporary solution.
On May 8, 2010, Health Canada published a regulatory proposal that would permit certain NHPs, for which a product licence application has been filed with Health Canada but a decision to issue or refuse a licence has not yet been made, to be sold legally, with an exemption to the prohibition on sale in the NHPR.
What products are excluded?
-sterile products for ophthalmic use
-products containing ingredients prohibited from being sold under -the Food and Drug Regulations
-products with Schedule A claims
-products for use in children under 12 years of age
-products for use in pregnant or breastfeeding women
-products containing ingredients that have been subject to a recall or stop sale.
How will these regulations work?
Health Canada must assign an exemption number (EN) to any NHP to which the proposed regulations apply, before the later of 15 days after the proposed regulations come into force, or 180 days from the date the application was submitted. Applicants will be notified in writing by Health Canada of the EN and the fact that the EN, product brand name, applicant’s name and company name will be posted on the Health Canada website. As the process is voluntary, the NHPD must receive the fax-back form consenting to the EN within 30 days of its issuance.
If the NHPD does not receive consent before this deadline, it is assumed the applicant does not consent. If the applicant does not consent, the product is not legal for sale until it is issued a NPN or DIN-HM following the full review of its product licence application. An application will only be screened for completeness and safety prior to the issuance of an EN, but will continue to be evaluated in its entirety in order for Health Canada to issue (or refuse) a NPN or DIN-HM.
If the applicant consents, Health Canada receives the fax-back form before the deadline and is satisfied that safety criteria are met, they will then post the EN on the Health Canada website, making the product legal for sale in Canada. Unless specifically excluded under the regulatory proposal, all other aspects of the NHP regulations must be met, and the EN must be included on the product label within a “reasonable period of time”.
A product’s EN will be the prefix “EN” followed by the submission number it was issued by way of a Submission Receipt Acknowledgement Notice from NHPD, or, for PLAs submitted after Health Canada stops issuing submission numbers, Health Canada will provide you with a unique EN.
If approved, the proposed regulations could come into force as early as August 1, 2010, and would be repealed 30 months after they come into force.
What about compliance and enforcement?
A new Compliance and Enforcement Policy is being developed to coincide with the approval and implementation of the new regulatory proposal. There will be a six-month education and compliance promotion period with full implementation of the policy anticipated to be February 2011. An annex will be added to the policy for the length of time the NHP-UPLAR is active. This annex will provide clarification on the compliance and enforcement approach for products issued ENs. An EN may be suspended at any time in order to prevent injury to a purchaser or consumer.
It should be noted that while the existing policy considers products with submission numbers to be a lower priority for compliance and enforcement, the new policy will clearly outline the expectation for all products to have been issued NPNs, DIN-HMs or ENs to be legal for sale.
What does this mean for industry?
It is important that industry submit complete product licence applications as soon as possible in order to ensure that your products have an EN, NPN or DIN-HM prior to the full implementation of the revised Compliance and Enforcement Policy (as early as February 2011). Submission numbers will still be valid during the six-month compliance promotion period, however once this promotion period ends, products that do not have a NPN, DIN-HM or EN are not legal for sale and may be subject to compliance and enforcement activities.
Health Canada is also introducing a new Application Management Policy to coincide with the proposed regulations. This policy requires that all ingredients in a formulation be in the NHP Ingredient Database prior to the submission of the product licence application. The NHPD then has 40 days (performance standard) to issue a submission number.
Thus if you submit an application after the proposed regulations are implemented (as early as August 1, 2010), you will have to wait up to 40 days for a submission number followed by the required 180 days before your application can be considered for an EN. This will take you beyond the anticipated February 2011 date for full implementation of the Compliance and Enforcement Policy when an EN, NPN or DIN-HM will be required.
For more information, please dicentra.com
The proposed regulations were posted to the Canada Gazette on May 8, 2010. Health Canada accepted comments from stakeholders on the proposed regulations until June 7, 2010. dicentra Inc. assessed the impact of the proposed regulations and has submitted comments to Health Canada.
Science and Reasearch Updates
Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.
Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nicholson GC. JAMA. 2010 May 12;303(18):1815-22.
As an alternative to daily supplementation, a trial was conducted to determine whether a single dose of 500,000 IU of cholecalciferol administered orally to women in autumn or winter would reduce the risk of falls and fracture. This double-blind, placebo-controlled trial recruited 2256 community-dwelling women between June 2003 and June 2005. All women were aged 70 years or older and considered to be at high risk of fracture. Participants were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years, concluding in 2008. Falls and fractures were ascertained using monthly calendars, with details confirmed by telephone interview and fractures confirmed radiogically. 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels in a substudy. Women in the cholecalciferol group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times while 769 women in the placebo group fell 2512 times. Incidence relative risk (RR) for fracture in the vitamin D group was 1.26 vs the placebo group. A temporal pattern was observed in a post hoc analysis of falls where the relative risk of falling was higher in the first 3 months after dosing (1.31) and lowered during the following 9 months (1.13). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing. It was concluded that among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.
Nut consumption and blood lipid levels: a pooled analysis of 25 intervention trials
Sabaté J, Oda K, Ros E. Arch Intern Med. 2010 May 10;170(9):821-7.
Epidemiological studies have consistently associated nut consumption with reduced risk for coronary heart disease resulting in numerous dietary intervention trials to invesigate the effect of nut consumption on blood lipid levels. This analysis was conducted, pooling primary data from 25 nut consumption trials conducted in 7 countries, to estimate the effects of nut consumption on blood lipid levels and to examine whether different factors modify the effects. The studies were conducted among 583 men and women with normolipidemia and hypercholesterolemia who were not taking lipid-lowering medications. Mixed linear models to assess the effects of nut consumption and the potential interactions. With a mean daily consumption of 67 g of nuts, the following estimated mean reductions were achieved: total cholesterol concentration (10.9 mg/dL [5.1% change]), low-density lipoprotein cholesterol concentration (LDL-C) (10.2 mg/dL [7.4% change]), ratio of LDL-C to high-density lipoprotein cholesterol concentration (HDL-C) (0.22 [8.3% change]), and ratio of total cholesterol concentration to HDL-C (0.24 [5.6% change]) (P < .001 for all). Triglyceride levels were reduced by 20.6 mg/dL (10.2%) in subjects with blood triglyceride levels of at least 150 mg/dL (P < .05) but not in those with lower levels. The effects of nut consumption were dose related, and different types of nuts had similar effects. The effects were significantly modified by LDL-C, body mass index, and diet type with the lipid-lowering effects of nut consumption being greatest among subjects with high baseline LDL-C and with low body mass index and among those consuming Western diets. In was concluded that nut consumption improves blood lipid levels in a dose-related manner, particularly among subjects with higher LDL-C or with lower BMI.
Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; NASH CRN. N Engl J Med. 2010 May 6;362(18):1675-85. Epub 2010 Apr 28.
Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis for which there is currently no established treatment. 247 adults with nonalcoholic steatohepatitis and without diabetes were randomly assigned to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but there was no significant difference in the rate of improvement with pioglitazone as compared with placebo (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with both vitamin E and pioglitazone, as compared with placebo and both agents were associated with reductions in hepatic steatosis and lobular inflammation but not with improvement in fibrosis scores. Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. It was concluded that Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes.
Mirtogenol potentiates latanoprost in lowering intraocular pressure and improves ocular blood flow in asymptomatic subjects.
Robert D Steigerwalt Jr, Gianni Belcaro, Paolo Morazzoni, et al. Clinical Ophthalmology, 2010, Volume 4, Pages 471-476
The dietary supplement Mirtogenol® was previously shown to lower elevated intraocular pressure (IOP). This trial involved 79 patients with asymptomatic ocular hypertension, and examined the effects of Mirtogenol® on IOP in comparison and in combination with latanoprost eye drops. Participants were randomly assigned to three groups receiving either Mirtogenol®, latanoprost eye drops, or both in combination. Intraocular pressure and retinal blood flow were investigated in monthly intervals over 24 weeks. Mirtogenol alone lowered IOP from baseline 38.1 to 29.0 mmHg after 16 weeks, with little further improvement during the subsequent 8 weeks. Latanoprost eye drops rapidly lowered IOP from baseline 37.7 to 27.2 mmHg within four weeks, without further effects thereafter. The combination of the supplement and latanoprost lowered IOP from 38.0 to 27.3 mmHg after 4 weeks, and further decreased IOP to 24.2 mmHg after 6 weeks. After 24 weeks IOP with the combination treatment (23.0 mmHg) was significantly lower than with latanoprost alone (27.2 mmHg). With treatment duration, Mirtogenol and latanoprost individually show comparable results for their effects on increasing central artery blood flow. Combination treatment showed higher systolic blood flow velocity throughout the trial period. The diastolic blood flow velocity gradually increased with treatment duration in all three groups, however from twelve weeks onwards, the diastolic component with combination treatment was higher than with individual treatments. it was concluded that Mirtogenol lowered elevated IOP in patients almost as effectively as latanoprost, however takes much longer (24 vs 4 weeks). The combination of both was more effective for lowering IOP and the combination yielded better retinal blood flow. No serious side effects occurred during the study, apart from standard side effects in patients related to Latanoprost. These promising results warrant further research of Mirtogenol with a larger patient group.
Meta-analyses of lignans and enterolignans in relation to breast cancer risk.
Buck K, Zaineddin AK, Vrieling A, Linseisen J, Chang-Claude J. Am J Clin Nutr. 2010 May 12.
Epidemiologic studies that examined whether lignans, the most important class of phytoestrogens in the Western diet, protect against breast cancer have yielded inconsistent results. This meta-analysis included 21 studies published between 1997 and August 2009 (11 prospective cohort studies and 10 case-control studies) identified through a systematic MEDLINE seach. We calculated pooled risk estimates (REs) for total lignan exposure, dietary lignan intake, enterolignan exposure, and blood or urine concentrations of enterolactone and according to menopausal and estrogen receptor (ER) status of tumors. Lignan exposure was not associated with an overall breast cancer risk (RE: 0.92; 95% CI: 0.81, 1.02; P(heterogeneity) = 0.004). However, in postmenopausal women, high lignan intake was associated with a significant reduced risk of breast cancer (13 studies; RE: 0.86; 95% CI: 0.78, 0.94; P(heterogeneity) = 0.32). Breast cancer risk was also inversely associated with enterolignan exposure (4 studies; RE: 0.84; 95% CI: 0.71, 0.97) but not with blood or urine enterolactone concentrations. The associations were not significantly different between ER-status subgroups (6 studies). In was concluded that high lignan exposure may be associated with a reduced breast cancer risk in postmenopausal women warranting additional work to clarify the association between lignan exposure and breast cancer risk.
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