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Scientific evidence requirements for nutritional adequacy of a term infant formula

A guidance document for infant formula manufacturers
2021

Table of Contents

1.0 Introduction

In Canada, infant formulas are regulated under the Food and Drugs Act (FDA) and Division 25 of the Food and Drug Regulations (FDR). Manufacturers must submit a premarket submission prior to selling or advertising any new infant formula or an infant formula that has undergone a major change. A premarket submission must contain detailed information on the composition and manufacturing of the infant formula and its packaging and labelling, as well as evidence to establish that the new or changed infant formula is safe and nutritionally adequate to promote acceptable growth and development in infants for whom it is intended when consumed according to the directions of use.

This document provides additional guidance to infant formula manufacturers on the evidence required to support the nutritional adequacy of infant formula as per Division 25, Sections B.25.046 (2) (i) and B.25.048 (2) (d) of the FDR. Other Health Canada guidance documents such as Guide for the Preparation of Infant Formula and Human Milk Fortifier Premarket Submissions and Good Manufacturing Practices for Infant Formula should also be consulted in conjunction with this document.

This guidance document describes the type of evidence required by Health Canada before selling or marketing:

This document identifies the circumstances that require clinical or other types of testing; identifies the evidence (clinical, biochemical, animal etc.) that should be submitted for the premarket evaluation of infant formula; and aligns the circumstances that require testing with the recommended types of tests.

2.0 Nutritional adequacy for term infant formula

A nutritionally adequate diet for infants is one that fulfills a set of dietary recommendations for infants 0 to 12 months of age. In Canada, we use the dietary recommendations (Dietary Reference Intakes) from the National Academy of Sciences, Engineering and Medicine. A nutritionally adequate infant formula must comply with the compositional requirements specified in Division 25 Section B.25.054 of the FDR and Table II in this Division. In addition, compliance with the nutritional composition specified for infant formula in Codex Alimentarius (1,2), the Life Science Research Office (3) and European Society for Paediatric Gastroenterology, Hepatology and Nutrition (4) are highly recommended.

Nutritional adequacy is substantiated by two quality factors that must be met:

An infant formula is nutritionally adequate if it promotes normal physical growth in infants when consumed in accordance with the directions for use. Clinical trial evidence is usually used to determine whether a given infant formula is nutritionally adequate.

3.0 Key terms used in the Food and Drugs Act (FDA) and Food and Drug Regulations (FDR), and internationally for use in infant formula assessment

An adverse outcome that occurs during or after the use of a drug or other intervention but is not necessarily caused by it (5).

An experiment to compare the effects of two or more healthcare interventions. Clinical trial is an umbrella term for a variety of designs of healthcare trials, including uncontrolled trials, controlled trials, and randomized controlled trials (6). A clinical trial is a research study that assigns individuals or groups of participants to one or more health-related interventions and follows them over a specific period of time to evaluate the effects on health outcomes. It is designed to answer a specific question. Participants receiving the intervention are called the experimental group. The others serve as controls. The effects and clinical significance of the intervention on a health-related outcome are assessed by comparing the two groups. It is the role of institutional review boards to ensure that such studies are ethical and safe. In the case of infants, their legally accepted representatives must give informed consent for them to take part.

Manufacturers are encouraged to consult Health Canada's Growth and Tolerance Clinical Trial Protocol – Healthy Term Newborn Infants for more details on the clinical trial protocol for infant formula.

Means relevant information gathered from high quality scientific research to address a well-defined question. Evidence should be factual, bias-free, balanced, valid (measuring what it is supposed to be measuring), reproducible and accurate. A clinical growth and tolerance study of infant formula should include a complete study report with individual raw data. It should include a balanced assessment of the benefits and harms, with emphasis on the study's limitations and generalizability. Evidence from individual studies make up a body of evidence. The evidence must be sufficiently convincing and strong to support a decision to allow the marketing of the infant formula.

Evidence for the safety and nutritional adequacy of infant formula may come from data on infants, animal models and other data, and should include, but is not limited to:

The evidence must be in line with the following requirements:

Healthy growth of an infant broadly includes "all aspects of physical growth and normal development, including the development of organ systems and the normal functional development of motor, neurocognitive, and immune systems"(7). These growth and developmental processes are major predictors of an infant's ability to reach their biological potentials and they can be affected by the infant's nutritional status (7). Infant formula must therefore support nutritional well-being. This is particularly important during the first 6 months of life when it is the sole source of nutrition, as well as after 6 months when it comprises a major source of nutrition, for many infants.

Means an infant delivered between the gestational ages of 37 to 42 weeks, a birth weight of ≥2.5 kilograms, and without disease (7).

Means a person who is under the age of one year.

Means, in respect of an infant formula or a human milk substitute, any change of an ingredient, the amount of an ingredient or the processing or packaging of the infant formula where the manufacturer's experience or generally accepted theory would predict an adverse effect on the levels or availability of nutrients in, or the microbiological or chemical safety of, the infant formula.

Examples of major changes for an infant formula include:

Means a human milk substitute that is:

Is a food substance (for example nutritional, microbiological) that is:

The World Health Organization's Child Growth Standards (2006) are the standards used for physical growth assessment.

Means

  1. a substance, including a microorganism, that does not have a history of safe use as a food;
  2. a food that has been manufactured, prepared, preserved or packaged by a process that
    1. has not been previously applied to that food; or
    2. causes the food to undergo a major change;
  3. a food that is derived from a plant, animal or microorganism that has been genetically modified such that
    1. the plant, animal or microorganism exhibits characteristics that were not previously observed in that plant, animal or microorganism;
    2. the plant, animal or microorganism no longer exhibits characteristics that were previously observed in that plant, animal or microorganism; or
    3. one or more characteristics of the plant, animal or microorganism no longer fall within the anticipated range for that plant, animal or microorganism.

The manufacturer of a new infant formula, or one that has undergone a major change in composition, manufacturing, packaging, or processing, must notify Health Canada of the intention to sell or advertise for sale the new or changed infant formula.

This must be done at least 90 days before the sale or advertisement (refer to Health Canada's Guide for the Preparation of Infant Formula and Human Milk Fortifier Premarket Submissions).

The amount and quality of protein in the infant formula must be appropriate to the intended use of the infant formula. Protein quality may be demonstrated using existing Protein Efficiency Ratio (PER) methods (Association of Official Analytical Chemists or Health Canada’s Method FO-1). The PER is currently the best method for demonstrating protein quality for infant formula for young infants (below 6 months of age). Methods based on Protein Digestibility Corrected Amino Acid Score (PDCAAS) and Digestible Indispensable Amino Acid Score (DIAAS) are currently not sufficiently developed for use in young infants, especially for plant-based infant formulas which usually contain anti-nutritional factors. In addition, the essential and conditionally essential amino acid profile should align with that of human milk (refer to Codex Standard 72, Annex I).

When in the view of either the investigator or sponsor it results in any of the following outcomes: death, a life threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions (9).

An adverse event for which the causal relation between the intervention and the event is at least a reasonable possibility (10).

4.0 Clinical studies to support the premarket evaluation of infant formula

In general, clinical studies are used to determine:

The following types of clinical studies may be required to determine the safety and nutritional adequacy of infant formula for term infants.

4.1 Clinical growth and tolerance study

This study assesses the effects of the experimental infant formula on measures of physical growth and tolerance as compared to a concurrent control using a marketed infant formula in Canada that has been clinically tested and proven safe and nutritionally adequate, and to an accepted international growth standard.

Tolerance is the physiological response or effect the infant formula has on the respiratory system, skin and the gastrointestinal tract (for example, fussiness, colic, cramps, regurgitation, stool characteristics and allergic reactions).

Physical Growth is measured by assessing the weight growth rate parameter over a 16 week interval starting during the first 14 days of life, expressed as grams per day, in healthy term newborn infants fed the experimental infant formula as compared to the weight growth rate of infants fed a concurrent control of a marketed infant formula in Canada.

Gain in weight per unit of energy intake can be determined when infant formula intake is measured along with weight over a period of weeks or months.

Further details on the above parameters are outlined in Health Canada's Growth and Tolerance Clinical Trial Protocol -Healthy Term Newborn Infants.

4.2 Nutrient bioavailability studies

4.2.1 Serum indices of protein adequacy of the formula

Serum albumin levels increase predictably in normal term infants in their early months of life. Lower than normal increases may indicate inadequacy of protein in the diet. To assess protein adequacy using serum albumin in a clinical study, serum albumin should be assessed between 90 and 120 (± 4) days of age in both the experimental group (given the new infant formula) and the control group (given a commercially available infant formula). Serum concentration of urea nitrogen is another useful indicator of protein adequacy of the infant formula.

4.2.2 Serum indices of iron nutritional status for research studies

A healthy term infant is born with considerable iron stores (ferritin). During the first few months of life, iron is transferred from its stores to the blood compartment, making the normal infant self-sufficient with regard to iron until the infant has doubled his or her weight, which occurs at about 4-6 months of age in a term, normal birth-weight infant (11,12). Therefore, ferritin level could potentially be a confounding factor in assessing iron status in the circulating blood. No single measurement is currently available that will characterize the iron status of a child. A battery of tests that include hemoglobin and serum ferritin, and transferrin saturation can be used (13). Inflammatory processes can elevate serum ferritin, which is an acute phase reactant. The use of C-reactive protein simultaneously with serum ferritin to rule out inflammation can help to eliminate misclassifying iron deficient infants as having normal iron status.

4.3 Record of adverse reactions

Accurate and clear information on adverse events and side effects occurring during the study or during a pre-specified follow-up period must be carefully described and reported whether or not it is immediately associated with the study treatment (10).

5.0 Other studies for infant formula

In addition to clinical studies and laboratory analyses, animal studies may be required to test the initial safety of the infant formula's ingredients. This could include measuring the PER which assesses protein quality and can be used to assess adverse interactions between nutrients.

Before new hypoallergenic formulas are tested in human trials, comprehensive preclinical testing must be conducted in animal models of allergenicity. These trials should assess toxicity, nitrogen balance and predict whether infants allergic to cow's milk proteins will react adversely. Petitioners are encouraged to request a pre-submission consultation as per Section 7 of this document.

6.0 Circumstances that warrant clinical testing and other testing

The recommended testing needed for a new infant formula or a previously approved infant formula, which has undergone a major change is listed below. Note: submission requirements vary on a case-by-case basis.

6.1 New infant formula

A new infant formula may contain a variety of ingredients, and may be subject to different methods of processing, and/or matrix-interaction among different ingredients, all of which could affect nutrient content, absorption, bioavailability, or adequacy. Therefore, it is essential to demonstrate safety and nutritional non-inferiority/equivalency (or superiority) of a new infant formula compared with that of an infant formula whose nutritional adequacy and safety have been well established.

Studies and data required:

6.2 Major changes or modifications of a previously approved formula

The extent of the assessment or clinical testing that is required for a specific modification to an existing infant formula is determined on a case-by-case basis. For example, lowering the protein level, or adding a new ingredient that has never been used in infant formula in Canada to an existing infant formula, are considered cases where clinical testing would be required.

6.2.1 Energy content

Infant formula providing less than 66.4 kcal per 100 ml or more than 68 kcal per 100 ml requires a clinical study designed to assess both growth and tolerance of the infant formula. Infant formula providing a high energy density may lead to increased urinary solute loads, especially under increased stress conditions, for example, fever or infectious diarrhea leading to dehydration. Therefore, the potential renal solute load of the high energy infant formula should be measured and submitted in the premarket notification.

6.2.2 New energy source

Introduction of a new source of protein, fat or carbohydrate in a formula will generally require a growth and tolerance study.

6.2.3 New protein source

A new soy protein isolate or new animal milk protein for example would require the following studies and data:

6.2.4 New fat source

For example, a new source of animal fat, vegetable oil or a new source of long chain polyunsaturated fatty acids.

Studies and data required:

6.2.5 New carbohydrate source

A new source of carbohydrate (e.g. monosaccharides, disaccharides, polysaccharides or dietary fiber) would require a growth and tolerance study.

6.2.6 Protein level less than 2 g/100 kcal

Studies and data required:

6.2.7 Processing of protein

Any change in the processing of protein require the following:

Additional information required for specific protein sources (for example partially, extensively hydrolyzed and amino acid based formulations):

6.2.8 Change in protein, fat or carbohydrate mixture, or source of calcium or phosphorus

Please contact Health Canada to discuss recommended testing. Section 7 contains information on how to arrange a consultation. For approved sources of calcium and phosphorus, please consult Codex Alimentarius for a list of acceptable vitamin and mineral sources for foods for special dietary use.

6.2.9 Iron less than minimum level or greater than maximum level or change in source of iron

A proposed new infant formula should be compared with a currently marketed infant formula, which is adequate in iron. The range of iron levels currently acceptable (minimum to maximum) are as follows, according to Health Canada guidance:

Milk-based term infant formula: 4 to 8 mg iron per litre of infant formula (0.6 mg to 1.2 mg per 100 kcal). The maximum specification is 1.35 mg per 100 kcal.

Milk-based follow-up infant formula for infants aged 6 to 12 months: 6 to 10 mg iron per litre of infant formula (0.9 mg to 1.5 mg per 100 kcal). The maximum specification is 1.65 mg per 100 kcal.

Soy-based infant formula: requires 50% more iron than milk-based infant formula. Soy protein isolates used in infant- and follow on infant formula contain phytic acid (myoinositol hexaphosphate and other inositol phosphates), which is an inhibitor of iron and zinc absorption (14). This is the reason for the EFSA's recommendation of a 50 % higher iron level in infant and follow-on infant formula based on soy protein (8). Therefore, the recommended minimum and maximum fortification levels in soy-protein based infant formula and follow-up infant formula are 1.5 times higher.

Recommended studies: Refer to above assessment of iron nutritional status in Section 4.2.2

6.2.10 New combination of macronutrient sources

New combinations of macronutrient sources that have been used or studied separately in various currently marketed infant formula (made by the same manufacturer or made by other manufacturers) but not together in the same infant formula under review, may require new studies. These may include a new growth and tolerance study, and possibly biochemical testing, depending on the anticipated effect of the new combination, and based on evidence from scientific literature.

6.3 Novel food ingredient or new infant food ingredient (NIFI)

An infant formula containing a novel food which has been approved (for example, docosahexaenoic acid and arachidonic acid ] or a NIFI [2'-fucosyllactose and short-chain fructo-oligosaccharides) which has been cleared for use must undergo clinical and possibly other testing. It requires the same testing as a new infant formula (including a growth and tolerance study), unless such testing has already been conducted and the data has been submitted for the novel food or new infant formula ingredient assessment.

For further information on the approval process for a novel food or NIFI, the manufacturer should refer to Heath Canada's Guide for the Preparation of Infant Formula and Human Milk Fortifier Premarket Submissions.

7.0 Post-marketing surveillance

A post-marketing (also known as in-marketing) surveillance plan may be considered to support long-term safety (7).

Post-marketing surveillance consists of:

8.0 Pre-submission consultations

Manufacturers are encouraged to contact Health Canada's Food Directorate Submission Management Information Unit (smiu-ugdi@hc-sc.gc.ca) to request a pre-submission consultation to better prepare for premarket notifications process and submission requirements to demonstrate nutritional adequacy.

9.0 Abbreviations

FDA
Food and Drugs Act
FDR
Food and Drug Regulations
NIFI
New infant formula ingredient
PER
Protein efficiency ratio

10.0 References

  1. Codex Alimentarius. (revision 2007). Standard for Infant Formula and Formulas for Special Medical Purposes Intended for infants. Codex Stan 72-1981 [Online]. Available: https://www.fao.org/fao-who-codexalimentarius/sh-proxy/en/?lnk=1&url=https%253A%252F%252Fworkspace.fao.org%252Fsites%252Fcodex%252FStandards%252FCXS%2B72-1981%252FCXS_072e.pdf
  2. Codex Alimentarius (revision 2008; amended 2015). Advisory Lists of Nutrient Compounds for Use in Foods for Special Dietary Uses Intended for Infants and Young Children. Codex CAC/GL 10-1979 [Online]. Available: ADVISORY LISTS OF NUTRIENT COMPOUNDS FOR USE IN FOODS FOR SPECIAL DIETARY USES INTENDED FOR INFANTS AND YOUNG CHILDREN (fao.org)
  3. Raiten D, Talbot J, Waters J. (1998). Assessment of nutrient requirements for infant formulas: [LSRO report]. Journal of Nutrition, 28(11).
  4. Koletzko B, Baker S, Cleghorn G, Neto UF, Gopalan S, Hernell O, Seng Hock Q, Jirapinyo P, Lonnerdal B, Pencharz P, Pzyrembel H, Ramirez-Mayans J, Shamir R, Turck D, Yamashiro Y, Zong-Yi D. (2005). Global standard for the composition of infant formula: recommendations of an ESPGHAN coordinated international expert group. Journal of Pediatric Gastroenterology and Nutrition, 41(5), 584-99.
  5. Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, Gøtzsche PC, Lang T for the CONSORT Group. (2001). The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Annals of Internal Medicine, 134(8), 663-694.
  6. Cochrane Collaboration. (2019). Glossary of Cochrane terms. [Online]. Available: https://epoc.cochrane.org/sites/epoc.cochrane.org/files/public/uploads/SURE-Guides-v2.1/Collectedfiles/source/glossary.html
  7. Institute of Medicine (US) Committee on the Evaluation of the Addition of Ingredients New to Infant Formula. (2004). Infant formula: evaluating the safety of new ingredients. Washington (DC). National Academies Pres.
  8. EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies). (2014). Scientific Opinion on the essential composition of infant and follow-on formulae. EFSA Journal 12(7), 3760. [Online]. Available: http://www.efsa.europa.eu/en/efsajournal/doc/3760.pdf
  9. International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use. (2016). ICH harmonised tripartite guideline for good clinical practice E6 (R1). [Online]. Available: https://ich.org/page/efficacy-guidelines
  10. Ioannidis J, Evans SJW, Gøtzsche PC, O'Neill RT, Altman DG, Schulz K, Moher D for the CONSORT group. (2004). Better reporting of harms in randomized trials: an extension of the CONSORT statement, Annals of Internal Medicine, 141, 781-788.
  11. Domellöf M. (2007). Iron requirements, absorption and metabolism in infancy and childhood. Current Opinion in Clinical Nutrition and Metabolic Care, 10(3),329-335.
  12. Jonsdottir OH, Thorsdottir I, Hibberd PL, Fewtrell MS, Wells JC, Palsson GI, Lucas A, Gunnlaugsson G, Kleinman R. (2012). Timing of the introduction of complementary foods in infancy: a randomized controlled trial. Pediatrics, 130(6), 1038-45.
  13. Baker R, Greer FR, and The Committee on Nutrition. (2010). Diagnosis and Prevention of Iron Deficiency and Iron-Deficiency Anemia in Infants and Young Children (0–3 Years of Age). Pediatrics. 126(5), 1040-50.
  14. Hurrell R, Juillerat MA, Reddy MB, Lynch SR, Dassenko SA and Cook JD. (1992). Soy protein, phytate and iron absorption in humans. American Journal of Clinical Nutrition, 56,573-578.

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