Our consultancy services include supporting manufacturers of natural health products (NHPs) with clinical trial applications, NHP master files (NHP-MF), product and site licensing as well as post license management. We also support packagers, labelers and importers of NHPs with Health Canada requirements for site licensing and site license renewals. Below are some strategies by which we help applicants to effectively navigate through the various regulatory streams and overcome regulatory hurdles to reduce cost & time to market and to further product innovation.
While this article primarily discusses NHPs, the same principles may in future apply to non-prescription drugs as the NHPD seeks to align their pre-market review with their approach toward NHPs. This is because the review of non-prescription drugs and disinfectants were transferred to NHPD in July 2013.
Product Licensing for NHP Manufacturers
The first step prior to filing a natural health product license application (PLA) to Health Canada's Natural Health Product Directorate (NHPD) is to
determine if the product is indeed a NHP. While it may be common knowledge that NHPs include substances such as plant materials, alga, fungi, essential fatty acids, vitamins, minerals and
probiotics, there are exceptions. For instance, if vitamin A is to be sold at a daily oral dose of > 10, 000 IU it would be regulated as a prescription drug and not a NHP which falls under the
non-prescription over-the-counter drug category. An antibiotic prepared from an alga, a bacterium or a fungus or a synthetic duplicate of that antibiotic is also not a NHP. Changing the dosage
form from oral to intravenous can also change a product from NHP to prescription drug status. We evaluate products for manufacturers, classifying the products and determining the regulatory
pathway – the NHP class and type of PLA (e.g. compendial, traditional, non-traditional, etc.).
To understand NHP regulation in Canada, one has to understand the risk based approach to medical product regulation adopted by Health Canada and international regulatory agencies such as US Food and Drug Administration (FDA) and European Medicines Agency (EMA). NHPD's risk based approach can be seen through their 3 tier risk based classification system for NHPs (classes I, II, III) as well as through their implementation of a post license quality audit that will verify that a NHP on the market is properly substantiated by evidence of safety, quality and efficacy when used per manufacturer recommendations.
To ensure NHP manufacturers successfully pass Health Canada audits, we evaluate all labeling, available safety, efficacy and quality evidence to identify and monitor regulatory gaps in the evidence till all compliance requirements are met. For instance, we would advise manufacturers of seal oil of the risk of polychlorinated dibenzo-para-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) contaminants and the analytical methods and acceptance criteria expected by NHPD [Environmental Protection Agency (EPA) method No. 1613 revision B; total PCDD and PCDF toxicity limit of 2.0 pg TEQ TEF/g oil]. In this case, we would work with the manufacturer and monitor compliance to this product specific quality gap. However, in addition to ensuring that a robust PLA gets filed, we simultaneously engage with manufacturers to employ strategies that would reduce their regulatory burden.
In general, the class of a NHP depends on the degree to which a manufacturer can attest that their NHP complies with one or more NHPD monographs and to the NHPD ingredients database. NHPD target review time is dependent on the risk class of the NHP and can vary from as little as 10 days for a Class I NHP to 180 days for a Class III NHP. We initially survey the NHPD databases and monographs and may suggest labeling or formulation modifications or supplementary quality tests that can bring the NHP into compliance with NHPD approved monograph(s) as this is the shortest regulatory route possible. Where the safety-efficacy profile of the NHP, its' ingredients or conditions of use (e.g. indication, dose, dosage form, route or administration, etc.) are not deemed as well established by the NHPD, the PLA would need to be supported with additional evidence.
In general, NHPD expects that the safety, efficacy and quality evidence presented in a PLA be risk and product specific. The example of seal oil above serves to demonstrate how quality evidence can be product specific. We work with NHP manufacturers to reduce the cost and time to market by reducing the risk class and thereby the level of the safety, efficacy and quality evidence expected by NHPD. As an example, consider how adjusting the label claim or indication can impact the risk category and evidence expected of the NHP by the NHPD. Generally, anxiety and memory loss have been both associated with depressive disorders in scientific literature. If the NHP was indicated for the 'treatment of depressive disorders' the NHP would be in the high risk category. However, if the indication or label claim was 'to help restore cognitive function / memory,' the NHP would be medium risk, whereas reducing the claim to 'help reduce nervousness' would place the NHP in the low risk category.
While a variety of evidence may be considered such as meta-analyses, peer reviewed scientific literature, epidemiological studies and other regulatory agency product approvals; NHPD expects a minimum level of safety and efficacy evidence that is commensurate to the risk. For instance, while two pilot studies may suffice as minimum evidence in support of efficacy for a high risk NHP, two phase II clinical studies are required for a medium or moderate risk NHP. Phase III randomized, controlled and well-designed clinical trials are expected for high risk NHPs. Moreover, evidence presented must be product specific or linked to the recommended conditions of use. For instance, the reference dosage form (in the evidence supplied) should be comparable to that recommended and a justification made to show that the difference in dosage form is unlikely to affect product efficacy. By revealing the various marketing options, we help start-up manufacturers determine and meet their business goals.
Clinical Trial Applications (CTAs) for NHP Manufacturers
Where a clinical trial is needed to support safety, efficacy or a new condition of use in a PLA, we will take care of the entire clinical trial regulatory process including preparing the pre-clinical trial application (CTA) consultation meeting package and liaising with NHPD at the pre-CTA meeting. Based on our knowledge of product compliance gaps, regulatory goals and NHPD expectations, we can contribute toward clinical trial design. We provide technical writing support for key documents such as the investigator brochure, informed consent and product labeling used in the clinical trial. We prepare and file the entire CTA with NHPD, assess changes and file CTA amendments or notifications as needed.
Pipeline Innovation for NHP Manufacturers
We can significantly contribute toward the business development plans of manufacturers, even to the identification of new NHP markets. For example, a quick search of Health Canada’s licensed NHP database reveals no product for the treatment of prostate cancer or cerebrovascular disease. According to the American Cancer Society, evidence is available that supports the use of flax seed for prostate cancer, but this needs further clinical research1. Our comprehensive research reports with regulatory analyses provide manufacturers with available options to further product innovation.
Should a manufacturer wish to switch their NHP to a prescription drug so as to have benefits including exclusive patent rights, 8 year data protection or provincial re-imbursement in Canada, we will suggest changes to the formulation or product conditions of use as needed and propose a new regulatory strategy to accomplish these goals.
NHP Master Files (NHP-MF) for NHP Ingredient Manufacturers
Our consultancy services also extend to NHP master file (NHP-MF) preparation for manufacturers of medicinal and non-medicinal ingredients that are used in the manufacture of NHPs. NHP-MFs can be cross-referenced by one or more NHP-MFs in support of PLAs or clinical trial applications. We work with ingredient manufacturers to address any compliance gaps in the data they need to provide. In general, this includes the manufacture process flow with details such as in process quality controls, reactants, solvents, reaction conditions, ingredient structure elucidation and confirmation & physicochemical properties, impurities, reference standards, specifications and safety / efficacy evidence.
Site Licensing for NHP Manufacturers, Packagers, Labelers and Importers
We provide a comprehensive suite of site licensing services to start-up NHP manufacturers, packagers, labelers and importers. Initial site license applications (SLA) can be complex especially for Canadian importers dealing with multiple foreign sites. We can simplify this process by liaising with each foreign site to address compliance deficiencies (e.g. inadequate complaint handling, recall procedures) and to clarify the SLA process. For instance, a Quality Assurance Report (QAR), signed by the quality assurance person in charge or a third party auditor, is submitted as part of a SLA but Health Canada accepts several alternatives to this document. For instance, for a manufacturing facility in India, a US FDA Establishment Inspection Report (EIR) within the last 3 years would be a suitable alternative to the QAR.
We also evaluate changes post site licensing and accordingly file either site license amendments or notifications. We are vigilant of site license renewal time frames to ensure that site licenses once acquired are not suspended or canceled. Our competencies provide our customers with peace of mind.
In conclusion, we offer a comprehensive, in-depth suite of consultancy services pre and post licensing for all ingredient and NHP manufacturers, packagers, labelers and importers. We think of both your bottom line and future pipeline growth by utilizing regulatory strategies to reduce cost and time to market while furthering product innovation opportunities. We remain on top of an ever changing regulatory landscape, scaling the regulatory heights for our customers.
- Flaxseed. American Cancer Society. Oct14, 2011. URL: http://www.cancer.org/Treatment/TreatmentsandSideEffects/ComplementaryandAlternativeMedicine/HerbsVitaminsandMinerals/flaxseed