Clinical Trial for Infant Formula: Feasibility Exploration

Clinical Trial for Infant Formula: Feasibility Exploration
Colombia

The below version control table serves to document all updates made to the report. The purpose is to ensure the information is always accurate and up-to-date.

1. Assessment

1.1 Background

Infant formula plays a crucial role in providing essential nutrition to infants when breastfeeding is not possible. In recent years, regulators in some markets have introduced requirements for clinical trials to be conducted on infant formula, in order to assure the safety, nutritional adequacy, and efficacy of these products. 

This document outlines the requirements for conducting a clinical trial on infant formula in Colombia and the potential advantages and disadvantages of conducting such a trial.

1.2 Regulation of Infant Formula in Colombia

The primary regulatory authority governing infant formula in Colombia is the National Food and Drug Surveillance Institute (INVIMA), a body under the Ministry of Health and Social Protection. 

https://www.invima.gov.co/

INVIMA is responsible for ensuring the safety, efficacy, and quality of food products including infant formula. Colombia adheres to international standards and guidelines in regulating infant formula, particularly those set by the Codex Alimentarius Commission. 

Codex Alimentarius Codex Stan 71-1981

Infant formula is also governed by INVIMA Resolution 11488 (1984) which reflects Colombia’s adoption of the international standards. 

Resolution 11488. (1984)

For the purposes of conducting a clinical trial on an unapproved infant formula, these regulations do not strictly apply but sponsors should take into consideration any requirements which may be relevant to the product and its stage of development. These regulations outline the permissible ingredients, nutritional requirements, and quality control measures that must be met by the manufacturer to ensure the safety and nutritional adequacy of the infant formula. 

Whilst infant formula is considered a food product, the proposed trial would be considered an interventional study and would be subject to the requirements for clinical trials in humans as described below.

1.3 Regulation of Clinical Trials in Colombia

The National Food and Drug Surveillance Institute (INVIMA) is responsible for approving, monitoring, and regulating clinical research conducted in Colombia. The regulatory framework for the conduct of clinical trials is outlined in Resolution 2378 (2008). 

Resolution 2378 (2008)

This resolution establishes the guidelines, requirements, and procedures for conducting clinical trials and ensures compliance with Good Clinical Practices (GCP), as defined by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

A link to the INVIMA website regarding clinical trials is presented below:

Authorisation and Monitoring of Clinical Trials INVIMA

This website provides detailed information on clinical trials conducted in Colombia since 2014, including protocols, import permits, and other information. The website also contains links to regulatory guidances issued by INVIMA in 2015 in support of the conduct of clinical trials in Colombia. Links to these guidances are presented below. 

Guide for the Evaluation and Monitoring of Research Protocols

Guide to Clinical Research Medications and Supplies

Guide for the Presentation of Research Protocols

All interventional clinical trials must be approved by INVIMA. The timeline for gaining INVIMA approval is 60 days. 

The documents to be provided to INVIMA for a clinical trial application are dependent on the type of product and study but at a minimum should include the following documents:

1. The protocol
2. CV of the Principal Investigator
3. Letter of commitment confirming the study meets the requirements of the Declaration of Helsinki
4. A copy of the Informed Consent Form
5. Quality Information on the pharmaceutical product
6. Information on any known or expected AEs

All documents must be provided in Spanish. 

Once a trial has been approved by INVIMA an application to import the investigational product into Colombia must be submitted. A link to the form for an import permit application is presented below. 

Link to Procedural Forms

(See Form - ASS-RSA-FM052-FORMAT FOR SUBMISSION AND EVALUATION OF REQUESTS FOR IMPORTATION OF SUPPLIES FOR CLINICAL STUDIES)

The investigational product must be provided to patients at no cost. 

All clinical trial sites in Colombia must be registered with INVIMA and must hold GCP certification. Sites conducting clinical trials should have their own ethics committee which must review the trial documentation and issue approval for the trial to proceed. There is no nationally defined procedure, and this may differ from institution to institution. 

Full details of the requirements for the conduct of a clinical trial by clinical sites are described in Resolution 8430 of 1993. A translation of this document is provided in Appendix 1 below. 

Documents relating to the trial should be submitted to the ethics committee prior to their meeting for review. Most committees meet at least monthly. 

The sponsor of the clinical trial does not need to be located in Colombia and may be represented by a local agent. A local Principal Investigator must be assigned to oversee the trial. 

The sponsor of the study must hold insurance to guarantee the protection and safety of trial participants. 

Once a trial has gained both RA and Ethics approval, it may commence. After the commencement of the trial, there are ongoing obligations to INVIMA and the ethics committee. Serious adverse events must be reported to INVIMA within 24 hours and all adverse events must be reported annually. INVIMA must also be advised if the trial is terminated.

The results of the trial, irrespective of the outcome, must be reported to INVIMA.

1.4 Specific Considerations for a Trial Involving Infant Formula

The following points should be considered specific in relation to the conduct of a trial involving the use of infant formula: 

• The age of the children to be involved in the trial
• What will be used as the comparator – typically breastfeeding is considered to be the gold standard in terms of infant nutrition
• The trial design should allow for an assessment of the growth, cognitive development, immune function, and overall health of the child
• The trial must have a suitable adverse event reporting procedure for allergic reactions

Given that the study will be conducted on children who are considered to be a vulnerable population, the procedure for gaining informed consent should be suitably robust.

1.5 Advantages & Disadvantages of Conducting Trial in Colombia

Advantages

• Colombia is known to have high levels of formula feeding compared to other countries. Therefore, the acceptability of the study and the ease of recruitment may be improved as compared to other countries where formula feeding may be less accepted. 
• The regulatory approval timeline for a clinical trial in Colombia is short (quick) compared to other countries. 
• The timeline for regulatory approval is mandated at 60 days and therefore can be relied upon. 
• All sites in Colombia need to have INVIMA GCP approval and must have undergone INVIMA inspection. 
• There is currently significant government investment in clinical trials in Colombia in order to attract companies to conduct studies there. 
• Lower cost to conduct trial. 

Disadvantages

• Despite Colombia having made advances in the regulation of clinical trials it still may not be viewed favorably by other major markets when it comes to acceptance of the data to support product licensing. 
• In conducting a study involving a food product, potential differences in diet need to be considered. 
• Colombia itself does not require clinical data to support the registration of an infant formula and therefore limited trials of this product type may have been conducted there. 
• It may be difficult to find sites with experience of this product type. 

The BMJ reported that between 2015 and 2020, 125 trials were conducted on infant formula. Of these 42% were conducted in Europe, 28% in Asia, and 18% in North America. These locations are therefore likely to have the most experience in conducting this type of trial. Europe and the US are also likely to be seen favorably in terms of the levels of GCP compliance which may lead to greater acceptability of the data.

2. References

1. INVIMA Website

https://www.invima.gov.co/

2. Codex Alimentarius

Codex Alimentarius Codex Stan 71-1981 

3. INVIMA Resolution on Infant Formula

Resolution 11488. (1984)

4. INVIMA Resolution on Clinical Trials

Resolution 2378 (2008)

5. INVIMA Website on Clinical Trials

Authorisation and Monitoring of Clinical Trials INVIMA

6. INVIMA Clinical Trial Guidance

Guide for the Evaluation and Monitoring of Research Protocols

7. INVIMA Clinical Trial Guidance

Guide to Clinical Research Medications and Supplies

8. INVIMA Clinical Trial Guidance

Guide for the Presentation of Research Protocols 

9. INVIMA Procedural Forms

Link to Procedural Forms

10. Conduct and reporting of formula milk trials: systematic review BMJ 2021; 375 doi: https://doi.org/10.1136/bmj.n2202 (Published 14 October 2021)

https://www.bmj.com/content/375/bmj.n2202

3. Appendix 1 - Resolution 8430 of 1993 (English Translation)

MINISTRY OF HEALTH

RESOLUTION NUMBER 8430 OF 1993

(October 4)

By which the scientific, technical, and administrative standards for health research are established.

THE MINISTER OF HEALTH

In the exercise of its legal powers, especially those conferred by Decree 2164 OF 1992 and Law 10 of 1990

CONSIDERING

RESOLVES:

TITLE 1.

GENERAL DISPOSITION.

ARTICLE 1. The provisions of these scientific standards are intended to establish the requirements for the development of health research activity.

ARTICLE 2. Institutions that are going to carry out research on humans must have a Research Ethics Committee, in charge of resolving all matters related to the subject.

ARTICLE 3. The institutions referred to in the previous article, due to their regulations and internal policies, will prepare their internal procedures manual in order to support the application of these standards.

ARTICLE 4. Health research includes the development of actions that contribute

a.       To the knowledge of biological and psychological processes in human beings.

b.       To knowledge of the links between the causes of disease, medical practice and social structure.

c.       To the prevention and control of health problems.

d.       To the knowledge and evaluation of the harmful effects of the environment on health.

and. To the study of the techniques and methods that are recommended or used for the provision of health services.

f.       To the production of health supplies.

TITLE II.

OF RESEARCH IN HUMAN BEINGS.

CHAPTER 1.

ON THE ETHICAL ASPECTS OF RESEARCH IN HUMAN BEINGS.

ARTICLE 5. In all research in which human beings are the subject of study, the criterion of respect for their dignity and the protection of their rights and well-being must prevail.

ARTICLE 6. Research carried out on human beings must be carried out in accordance with the following criteria:

a.        It will comply with the scientific and ethical principles that justify it.

b.         It will be based on previous experimentation carried out on animals, in laboratories or on other scientific facts.

c.         It will be carried out only when the knowledge that is intended to be produced cannot be obtained by another suitable means.

d.         The safety of the beneficiaries must prevail and the (minimum) risks must be clearly expressed, which must not, at any time, contradict Article 11 of this resolution.

and. It will have the Informed and written Consent of the research subject or his legal representative with the exceptions provided in this resolution.

f.         It must be carried out by professionals with knowledge and experience to care for the integrity of the human being under the responsibility of a health entity, supervised by the health authorities, as long as they have the necessary human and material resources to guarantee the well-being of the subject. research.

g.         It will be carried out when authorization is obtained: from the legal representative of the research institution and the institution where the research is carried out; the Informed Consent of the participants; and the approval of the project by the institution's Research Ethics Committee.

ARTICLE 7. When the experimental design of a research carried out on human beings includes several groups, random selection methods will be used to obtain an impartial assignment of participants in each group, and other technical standards determined for this type of research. and the pertinent measures will be taken to avoid any risk or harm to the research subjects.

ARTICLE 8. In research involving human beings, the privacy of the individual, subject of research, will be protected, identifying him or her only when the results require it and he or she authorizes it.

ARTICLE 9. Research risk is considered to be the probability that the research subject will suffer some harm as an immediate or delayed consequence of the study.

ARTICLE 10. The group of researchers or the main researcher must identify the type or types of risk to which the research subjects will be exposed.

ARTICLE 11. For the purposes of this regulation, investigations are classified into the following categories:

a.        Risk-free research: These are studies that use retrospective documentary research techniques and methods and those in which no intervention or intentional modification of the biological, physiological, psychological or social variables of the individuals participating in the study is carried out, among which The following are considered: review of medical records, interviews, questionnaires and others in which they are not identified or sensitive aspects of their behavior are treated.

b.         Minimal risk research: These are prospective studies that use data recording through common procedures consisting of: physical or psychological diagnostic examinations or routine treatments, among which are considered: weighing the subject, electrocardiograms, hearing acuity tests, thermography. , collection of excreta and external secretions, collection of placenta during childbirth, collection of amniotic fluid when the membranes rupture, collection of saliva, deciduous teeth and permanent teeth extracted for therapeutic indication, dental plaque and stones removed by non-invasive prophylactic procedures, cutting of hair and nails without causing disfigurement, blood collection by venipuncture in adults in good health, with a maximum frequency of twice a week and a maximum volume of 450 ml in two months except during pregnancy, moderate exercise in healthy volunteers , psychological tests on groups or individuals in which the subject's behavior will not be manipulated, research with commonly used medications, wide therapeutic scope and registered with this Ministry or its delegated authority, using the indications, doses and routes of administration established and that other than the medications defined in article 55 of this resolution.

c.          Investigations with greater than minimal risk: These are those in which the probabilities of affecting the subject are significant, among which are considered: radiological and microwave studies, studies with medications and modalities defined in titles III and IV of this resolution, trials with new devices, studies that include surgical procedures, blood collection greater than 2% of the circulating volume in neonates, amniocentesis and other invasive techniques or major procedures, those that use random methods of assignment to therapeutic regimens and those that have control with placebos, among others.

ARTICLE 12. The main researcher will suspend the research immediately, upon noticing any risk or damage to the health of the subject on whom the research is carried out. Likewise, it will be immediately suspended for those research subjects who so declare.

ARTICLE 13. It is the responsibility of the research or sponsoring institution to provide medical care to the subject who suffers any damage, if it is directly related to the research, without prejudice to the compensation that legally corresponds to it.

ARTICLE 14. Informed Consent is understood to be the written agreement, through which the research subject or, where applicable, his or her legal representative, authorizes his or her participation in the research, with full knowledge of the nature of the procedures, benefits and risks involved. who will submit, with the capacity of free choice and without any coercion.

ARTICLE 15. The Informed Consent must present the following information, which will be explained completely and clearly to the subject of investigation or, failing that, to their legal representative, in such a way that they can understand it.

a.        The justification and objectives of the research.

b.         The procedures to be used and their purpose, including the identification of those that are experimental.

c.          The expected inconveniences or risks.

d.         The benefits that can be obtained.

and. Alternative procedures that could be advantageous for the subject.

f.         The guarantee of receiving an answer to any question and clarification of any doubt about the procedures, risks, benefits and other matters related to the research and treatment of the subject.

g.         The freedom to withdraw your consent at any time and stop participating in the study without prejudice to continuing your care and treatment.

h.         The assurance that the subject will not be identified and that the confidentiality of the information related to their privacy will be maintained.

i.       The commitment to provide updated information obtained during the study, even if this could affect the subject's willingness to continue participating.

j.          The availability of medical treatment and the compensation to which you would legally be entitled, from the institution responsible for the research, in the case of damages that directly affect you, caused by the research.

k.         If there are additional expenses, these will be covered by the budget of the research or the institution responsible for it.

ARTICLE 16. The Informed Consent of the passive subject of the research, to be valid, must meet the following requirements:

a)         It will be prepared by the main researcher, with the information indicated in article 15 of this resolution.

b)         It will be reviewed by the Research Ethics Committee of the institution where the research will be carried out.

c)         It will indicate the names and addresses of two witnesses and the relationship they have with the subject of investigation.

d)         It must be signed by two witnesses and by the subject of the investigation or his legal representative, failing that. If the research subject does not know how to sign, he or she will print his or her fingerprint and another person designated by him or her will sign in his or her name.

e)         It will be prepared in duplicate, leaving one copy in the possession of the research subject and his legal representative.

FIRST PARAGRAPH. In the case of research with minimal risk, the Research Ethics Committee of the research institution, for justified reasons, may authorize the Informed Consent to be obtained without being formulated in writing and in the case of risk-free investigations, the researcher may be exempt from obtaining risk.

SECOND PARAGRAPH. If there is any type of dependency, ancestry or subordination of the research subject towards the researcher that prevents them from freely granting their consent, this must be obtained by another member of the research team, or of the institution where the research will be carried out, completely independent of the researcher-subject relationship.

THIRD PARAGRAPH. When it is necessary to determine the mental capacity of an individual to grant consent, the principal investigator must consult a neurologist, psychiatrist or psychologist to evaluate the subject's capacity for understanding, reasoning and logic, in accordance with the parameters approved by the Committee. of Research Ethics of the research institution.

FOURTH PARAGRAPH. When it is presumed that the mental capacity of a subject has changed over time, the Informed Consent of the subject or, failing that, of his or her legal representative, must be endorsed by a professional (neurologist, psychiatrist, psychologist) of recognized scientific and technical capacity. morality in the specific field, as well as an observer who is not related to the research, to ensure the appropriateness of the consent obtaining mechanism, as well as its validity during the course of the research.

FIFTH PARAGRAPH. When the research subject is a psychiatric patient admitted to an institution, in addition to complying with what is stated in the previous articles, it will be necessary to obtain prior approval from the authority that is aware of the case.

CHAPTER II.

OF RESEARCH IN COMMUNITIES.

ARTICLE 17. Research, referring to human health, in communities, will be admissible when the expected benefit for them is reasonably assured and when previous studies carried out on a small scale determine the absence of risks.

ARTICLE 18. In research in communities, the main researcher must obtain approval from the health authorities and other civil authorities of the community to be studied, in addition to obtaining the Informed Consent letter from the individuals included in the study. making them aware of the information referred to in articles 14, 15 and 16 of this resolution.

ARTICLE 19. When the individuals that make up the community do not have the capacity to understand the implications of participating in research, the Research Ethics Committee of the entity to which the main researcher belongs, or of the Entity where the research will be carried out. investigation, may or may not authorize the Informed Consent of the subjects to be obtained through a trusted person with moral authority over the community. If authorization is not obtained from the Research Ethics Committee, the Research will not be carried out. On the other hand, the participation of individuals will be entirely voluntary.

ARTICLE 20. Experimental research in communities may only be carried out by establishments that have Research Ethics Committees and prior authorization from this Ministry to carry it out, without prejudice to the powers that correspond to other State agencies, and have in any case complied with the previous toxicity studies and other tests in accordance with the characteristics of the products and the risk they imply for human health.

ARTICLE 21. In all community research, research designs must offer practical measures to protect individuals and ensure the obtaining of valid results in accordance with the guidelines established for the development of said models.

ARTICLE 22. In any community research, the ethical considerations applicable to research on humans must be extrapolated to the community context in the pertinent aspects.

CHAPTER III.

OF RESEARCH ON MINORS OR THE DISABLED.

ARTICLE 23. In addition to the general ethical provisions that must be met in all research on human beings, research carried out on minors or physically and mentally disabled people must fully satisfy all the requirements established in this chapter.

ARTICLE 24. When research is intended to be carried out on minors, it must be ensured that similar studies have previously been carried out on people of legal age and on immature animals; except when it comes to studies of conditions that are typical of the neonatal stage or specific conditions of certain ages.

ARTICLE 25. To carry out research on minors or physically and mentally disabled people, in all cases, in addition to the Informed Consent of those who exercise parental authority or legal representation of the minor or disabled person in question, certification of a neurologist, psychiatrist or psychologist, on the subject's capacity for understanding, reasoning and logic.

ARTICLE 26. When the mental capacity and psychological state of the minor or disabled person allow it, their acceptance to be a subject of research must also be obtained after explaining what is intended to be done. The Research Ethics Committee of the respective health entity must ensure compliance with these requirements.

ARTICLE 27. Research classified as risky and likely to directly benefit the minor or disabled person will be admissible when:

a)         The risk is justified by the importance of the benefit that the minor or disabled person will receive.

b)         The benefit is equal to or greater than other alternatives already established for diagnosis and treatment.

ARTICLE 28. Research classified as risky and without direct benefit to the minor or the disabled, will be admissible in accordance with the following considerations:

FIRST PARAGRAPH. WHEN THE RISK IS MINIMAL

a) The intervention or procedure must represent for the minor or disabled person a reasonable experience comparable to those inherent to their current medical, psychological, social or educational situation.

b) The intervention or procedure must have a high probability of obtaining positive results or generalizable knowledge about the condition or illness of the minor or disabled person that is of great importance to understand the disorder or to achieve its improvement in other subjects.

SECOND PARAGRAPH. WHEN THE RISK IS GREATER THAN MINIMUM

a)         The research must have a high probability of addressing, preventing or alleviating a serious problem that affects the health and well-being of children or the physically or mentally disabled.

b)         The Research Ethics Committee of the research institution will establish strict supervision to determine if the magnitude of the anticipated risks increases or others arise and will suspend the research at the moment in which the risk could affect the biological, psychological or social well-being. of the minor or the disabled.

CHAPTER IV.

RESEARCH IN WOMEN OF FERTILE AGE, PREGNANT, DURING LABOR, PUERPERIUM, BREASTFEEDING AND NEWBORN; OF THE USE OF EMBRYOS, OBITES AND FETUS AND ARTIFICIAL FERTILIZATION.

ARTICLE 29. In investigations classified as having greater than minimal risk, which are carried out in women of childbearing age, they must comply with the following requirements

a)         Certify that women are not pregnant prior to their acceptance as research subjects.

b)         Reduce the chances of pregnancy as much as possible during the development of the research.

ARTICLE 30. To carry out research on pregnant women, during labor, puerperium and breastfeeding; in live or still births; of the use of embryos, deaths or fetuses; and for artificial fertilization, it is required to obtain the Informed Consent of the woman and her spouse or partner in accordance with the provisions of articles 15 and 16 of these regulations, prior information of the possible risks for the embryo, fetus or newborn. in your case. The Informed Consent of the spouse or partner may only be dispensed in the event of incapacity or reliable or manifest impossibility to provide it; because the partner does not take care of the woman or, when there is an imminent risk to the health or life of the woman, embryo, fetus or newborn.

ARTICLE 31. Research carried out on pregnant women must be preceded by studies carried out on non-pregnant women that demonstrate safety, with the exception of specific studies that require said condition.

ARTICLE 32. Research without therapeutic benefit in pregnant women whose objective is to obtain generalizable knowledge about pregnancy must not represent a risk greater than the minimum for the woman, the embryo or the fetus.

ARTICLE 33. Research in pregnant women that involves an experimental intervention or procedure not related to pregnancy, but with therapeutic benefit for the woman, such as in cases of pregnancy toxemia, diabetes, hypertension and neoplasms, among others, must not expose the embryo or fetus at greater than minimal risk, except when the use of the intervention or procedure is justify to save the woman's life.

ARTICLE 34. Research in pregnant women, with therapeutic benefit related to pregnancy, will be allowed when:

a)         Aim to improve the health of the pregnant woman with minimal risk to the embryo or fetus.

b)         Are aimed at increasing the viability of the fetus, with minimal risk for the pregnant woman. 

ARTICLE 35. During the execution of research on pregnant women: 

a)         The researchers will not have authority to decide on the time, method or procedure used to terminate the pregnancy, nor participation in decisions about the viability of the fetus.

b)         It is strictly prohibited to grant incentives, monetary or otherwise, to terminate pregnancy, in the interest of research or for other reasons.

ARTICLE 36. Informed Consent for investigations during labor must be obtained in accordance with the provisions of articles 14, 15 and 16 of these regulations, before it begins and expressly stating that it can be withdrawn at any time during labor. labor labor.

ARTICLE 37. Research on women during the puerperium will be allowed when they do not interfere with the health of the mother or the newborn.

ARTICLE 38. Research on women during breastfeeding will be authorized when there is no risk for the infant or when the mother decides not to breastfeed; Their feeding is ensured by another method and Informed Consent is obtained in accordance with the provisions of articles 14, 15 and 16 of this resolution.

ARTICLE 39. Fetuses will be subjects of research only if the techniques and means used provide maximum safety for them and the pregnant woman.

ARTICLE 40. Newborns will be subjects of research only if the techniques and means used provide maximum safety for them and the mother.

ARTICLE 41. Newborns will not be subjects of research, except when the purpose of this research is: to increase their probability of survival until the viability phase; The procedures do not cause the cessation of vital functions, or when, without adding any risk, the aim is to obtain important generalizable knowledge that cannot be obtained in any other way.

ARTICLE 42. Live births may be subjects of investigation if the provisions on investigation in minors, indicated in this resolution, are complied with.

ARTICLE 43. Research with embryos, deaths, fetuses, stillbirths, macerated fecal matter, cells, tissues and organs extracted from them, will be carried out in accordance with the provisions of this regulation.

ARTICLE 44. Research on artificial fertilization will only be admissible when it is applied to the solution of sterility problems that cannot be resolved in any other way, respecting the moral, cultural and social point of view of the couple.

CHAPTER V.

OF INVESTIGATIONS IN SUBORDINATED GROUPS.

ARTICLE 45. The following are understood as subordinate groups: students, workers in laboratories and hospitals, employees and members of the armed forces, inmates in prisons or social rehabilitation centers and other special groups of the population, in which Informed Consent can be influenced by any authority.

ARTICLE 46. When research is carried out in subordinate groups, one or more members of the study population must participate in the Research Ethics Committee, capable of representing the moral, cultural and social values of the group in question and monitoring:

a)         That the participation, the refusal of the subjects to intervene or withdrawal of their consent during the study, does not affect their school, work, military situation or that related to the judicial process to which they were subject and the conditions of compliance with the sentence of the case.

b)         That the results of the research are not used to the detriment of the participating individuals.

c)         That the research institution and the sponsors are responsible for the medical treatment of the damages caused and, where appropriate, for the compensation that is legally applicable for the harmful consequences of the research.

CHAPTER VI.

OF RESEARCH IN ORGANS, TISSUES AND THEIR DERIVATIVES, PRODUCTS AND CORPSES OF HUMAN BEINGS.

ARTICLE 47. The research referred to in this chapter includes that which includes the use of organs, tissues and their derivatives, products and corpses of human beings, as well as the set of activities related to their obtaining, conservation, use, preparation and destination. final.

ARTICLE 48. This investigation must observe, in addition to due respect for the human corpse, the applicable provisions of this regulation and other regulations related to the disposal of organs, tissues and corpses of human beings.

TITLE III.

OF RESEARCH INTO NEW PROPHYLACTIC, DIAGNOSTIC, THERAPEUTIC AND REHABILITATION RESOURCES.

CHAPTER I.

GENERAL DISPOSITION.

ARTICLE 49. When research is carried out on human beings, on new prophylactic, diagnostic, therapeutic and rehabilitation resources, or it is intended to modify those already known, the provisions of the previous articles must be observed as applicable and satisfy what is contemplated in this qualification.

ARTICLE 50. The Research Ethics Committee of the health entity will be in charge of studying and approving the research projects and will request the following documents:

a)         Research project that must contain an objective and complete analysis of the risks involved, compared with the risks of the established diagnostic and treatment methods and the expectation of living conditions with and without the proposed procedure or treatment and other information pertinent to a research proposal.

b)         Letter from the legal representative of the research and executing institution, when applicable, authorizing the conduct of the investigation.

c)         Description of the available resources, including areas, equipment, and auxiliary laboratory services that will be used for the development of the research.

d)         Description of the resources available for the management of medical emergencies.

e)         Resume of the researchers that includes their academic preparation, their experience and their scientific production in the area of the proposed research.

f)          The requirements indicated in articles 57 and 61 of this resolution, as the case may be.

ARTICLE 51. When there is sponsorship or other forms of remuneration, the necessary measures must be established to prevent these from giving rise to conflicts of interest to the researcher in the protection of the rights of the research subjects, even if they have given their consent to the preservation of truthfulness. of results and in the allocation of resources.

ARTICLE 52. In the development of the investigations contemplated in this title, the following obligations must be met:

a)         The principal investigator will inform the Research Ethics Committee of the research institution or the executing institution of any probable adverse effect or directly related to the research.

b)         The director of the research institution will notify the Research Ethics Committee, when required, of the presence of any adverse effect, within a maximum period of 15 business days following its presentation.

c)         The Research Ethics Committee must suspend or cancel the research in the presence of any adverse effect that is an impediment from an ethical or technical point of view to continue with the study.

d)         The research institution will submit to the Research Ethics Committee and the Ministry of Health, when required, a report within fifteen (15) business days following the suspension of the research, which specifies the observed effect, the measures adopted and the consequences produced.

CHAPTER II.

OF PHARMACOLOGICAL RESEARCH.

ARTICLE 53. For the purposes of this regulation, pharmacological research is understood as scientific activities aimed at the study of medicines and biological products for human use with which there is no previous experience in the country, which are not contemplated in the Pharmacological Standards in this Ministry and therefore, are not distributed commercially, as well as medicines registered and approved for sale, when their use is investigated with modalities, indications, doses or routes of administration different from those established, including their use in combinations.

ARTICLE 54. Drug research in clinical pharmacology includes the sequence of studies that are carried out from when it is first administered to humans, until data are obtained on its therapeutic efficacy and safety in large population groups. For this purpose, the following phases are considered:

a.        PHASE I: It is the administration for the first time of an investigational drug to a healthy human being, in single or multiple doses, in small hospitalized groups, to establish initial pharmacological parameters in man.

b.         PHASE II: It is the administration, to the sick human being, of an investigational medication, in single or multiple doses, in small hospitalized groups, to establish pharmacological parameters in the sick organism.

c.          PHASE III. It is the administration, to large groups of patients, of an investigational medication, generally external, to define its therapeutic usefulness and identify adverse reactions, interactions and external factors that may alter the pharmacological effect.

d.         PHASE IV: These are studies that are carried out after the medicine is granted health registration for sale and are intended to generate new information on the safety of the medicine during its widespread and prolonged use.

ARTICLE 55. All clinical pharmacology research carried out must be preceded by complete preclinical studies that include physicochemical characteristics, pharmacological activity, toxicity, pharmacokinetics, absorption, distribution, metabolism and excretion of the drug in different animal species; frequencies, routes of administration and duration of the doses studied that can serve as a basis for the safety of its administration in humans; Studies on mutagenesis, teratogenesis and carcinogenesis are also required.

ARTICLE 56. The preclinical toxicology studies required for each drug will be a function of this particular drug, the known potential toxicology of others with a similar chemical structure and the route and time of administration intended to be used in humans.

ARTICLE 57. The use of research medications in human beings during their evaluation through Phases I to IV of clinical pharmacological research will be done with the authorization of the Research Ethics Committee, to which the documentation indicating the article 50 of this regulation, in addition to the following:

a)         The basic and preclinical pharmacological information of the medicine.

b)         The information previously obtained on clinical pharmacology in cases of phases II, III and IV and bioavailability tests when required.

ARTICLE 58. Phase I clinical pharmacology studies of new antineoplastic medications and others with a very reduced therapeutic index will be permitted when

a)         They are based on preclinical studies that demonstrate the pharmacological activity of the medication and clearly indicate the characteristics of its toxicity.

b)         They are carried out only in volunteer subjects with the specific disease, confirmed by additional diagnostic means, who have not presented a therapeutic response to any other available treatment and in whom the new medication could offer a therapeutic benefit.

c)         Does not cause expenses to the patient.

ARTICLE 59. In the treatment of emergencies, in conditions that threaten the life of a person when it is considered necessary to use an investigational medication or a known medication using indications, doses and routes of administration different from those established, the doctor must obtain the opinion favorable approval from the Research Ethics Committee of the research institutions and the Informed Consent of the research subject or his or her legal representative, as circumstances permit in accordance with the following bases:

b) Informed Consent will be obtained from the research subject, or failing that, from the legal representative or the closest relative, except when: the condition of the subject incapacitates or prevents granting it, the legal representative or relative is not available. or when stopping use of the investigational medication poses an absolute risk of death.

CHAPTER III.

OF THE RESEARCH OF OTHER NEW RESOURCES.

ARTICLE 60. For the purposes of this regulation, research into other new resources or modalities different from those established is understood to mean scientific activities aimed at the study of materials, grafts, transplants, prostheses, physical, chemical and surgical procedures, instruments, devices. , artificial organs and other methods of prevention, diagnosis, treatment and rehabilitation carried out on human beings or their biological products, except pharmacological ones.

ARTICLE 61. All research referred to in this chapter must have the authorization of the Research Ethics Committee. To this end, the research institutions must present the documentation indicated in article 50 of this resolution, in addition to the following:

a)         The scientific foundations, information on previous experimentation carried out on animals or in the laboratory.

b)         Previous clinical research studies when any.

ARTICLE 62. All research on grafts and transplants must observe, in addition to the applicable provisions of this regulation, what is stipulated regarding sanitary control of the disposal of organs, tissues and corpses of human beings.

TITLE IV.

OF THE BIOSECURITY OF RESEARCH.

CHAPTER I.

OF RESEARCH WITH PATHOGENIC MICROORGANISMS OR BIOLOGICAL MATERIAL THAT MAY CONTAIN THEM.

ARTICLE 63. Research institutions in which research is carried out with pathogenic microorganisms or biological material that may contain them must:

a)         Have laboratory facilities and equipment in accordance with the technical standards issued by this Ministry for this purpose, which guarantee the safe handling of such germs.

b)         Prepare a procedures manual for microbiology laboratories and make it available to professional, technical, service and maintenance personnel.

c)         Train personnel on the handling, transportation, use, decontamination and disposal of waste.

d)         Determine the need for medical surveillance of the personnel participating in the investigations and, if applicable, implement it.

e)         Establish a safety supervision and monitoring program in microbiology laboratories.

f)          Have updated bibliography and a file on the safety of the equipment, the availability of containment systems, rules and regulations, risks involved and other related aspects.

g)         Comply with the other provisions determined by this Ministry.

ARTICLE 64. In the research institutions mentioned in the previous article, microbiology laboratories will comply with the requirements established by the technical standards issued by this Ministry and will be classified into three types as follows:

a)         Basic microbiology laboratory.

b)         Microbiological safety laboratory.

c)         Laboratory of maximum microbiological security.

ARTICLE 65. The procedures manual referred to in literal b of article 63 of these regulations will describe the following aspects:

a)         Laboratory practices.

b)         Personal safety of employees.

c)         Management and maintenance of facilities and equipment.

d)         Emergency situations.

e)         Entry and transit restrictions.

f)          Reception and transportation of biological materials.

g)         Waste disposal.

h)         Decontamination.

i)          Others that are considered necessary to achieve microbiological safety.

ARTICLE 66. The principal investigator, in accordance with the Hospital Ethics Committee, or the Research Ethics Committee, and the legal representative of the research institution, will determine in accordance with existing technical standards, the type of laboratory in which the tests will be carried out. proposed investigations; as well as the respective procedures taking into account the degree of risk of infection presented by the microorganisms to be used.

ARTICLE 67. To evaluate the degree of risk referred to in the previous article, this Ministry will issue the corresponding technical standard and classify the microorganisms within four groups, according to the following criteria:

a)         RISK GROUP I: Microorganisms that represent little risk to the individual and the community.

b)         RISK GROUP II: Microorganisms that represent moderate risk for the individual and limited risk for the community.

c)         RISK GROUP III: Microorganisms that represent a high risk for the individual and little risk for the community.

d)         RISK GROUP IV: Microorganisms that represent a high risk for the individual and the community.

ARTICLE 68. Microorganisms that are classified in risk groups I and II must be managed in basic microbiology laboratories, using safety cabinets when considered necessary.

ARTICLE 69. Microorganisms that are classified in risk group III must be managed in microbiological safety laboratories.

ARTICLE 70. Microorganisms that are classified in risk group IV must be handled in laboratories of maximum microbiological security, under the authorization and control of the corresponding health authorities.

ARTICLE 71. During the development of the investigations referred to in this chapter, the main investigator will be in charge of:

a)         Determine the real and potential risks of the proposed investigations and, if they are approved by the Committees of the research institution, make them known to the other researchers who make up the group and to the technical and auxiliary personnel who participate in the investigation.

b)         Determine the appropriate level of physical containment, select the ideal microbiological practices and design procedures to address possible accidents during the investigation and instruct participating personnel on these aspects.

c)         Monitor that participating personnel comply with the requirements for medical prophylaxis, vaccines or serological tests.

d)         Supervise that the transportation of infectious materials is done quickly, in accordance with the technical standards issued by this Ministry.

e)         Inform the Biosafety Commission about the occurrence of illness among personnel participating in the research that could be attributed to transcutaneous inoculation, ingestion or inhalation of infectious materials, as well as accidents that cause contamination that may affect personnel or the environment.

f)          Report to the Biosafety Commission the difficulties or failures in the implementation of safety procedures, correct work errors that could cause the release of infectious material and ensure the integrity of the physical containment measures.

ARTICLE 72. The Research Ethics Committee of the research institution must carry out periodic visits to evaluate compliance with the measures and recommend modifications to laboratory practices, including the temporary or permanent suspension of research that represents an uncontrolled risk of infection. or contamination to laboratory workers, the community or the environment.

CHAPTER II.

OF RESEARCH INVOLVING CONSTRUCTION AND HANDLING OF RECOMBINANT NUCLEIC ACIDS.

ARTICLE 73. For the purposes of this regulation, recombinant nucleic acids will be understood as new combinations of genetic material obtained outside a living cell, through the insertion of natural or synthetic segments of deoxyribonucleic acid into a virus, bacterial plasmid or other deoxyribonucleic acid molecules that serve as a vector system to allow their incorporation into a host cell, in which they are not found naturally, but in which they will be capable of replicating. The deoxyribonucleic acid molecules that result from said replication are also included.

ARTICLE 74. Research with recombinant nucleic acids must be designed in such a way that the maximum level of biological containment is achieved, selecting the ideal host and vector systems, which reduce the probability of dissemination of the recombinant molecules outside the laboratory, taking into account the origin of the genetic material and the technical standards issued by this Ministry.

ARTICLE 75. The main researcher, in agreement with: his hierarchical superior, the Research Ethics Committee, the Biosafety Commission and the legal representative of the research institution, will determine in accordance with the technical standards issued by this Ministry, the type of laboratory. microbiology in which the experiments referred to in this chapter will be carried out, taking into account the genetic material that is intended to be replicated.

ARTICLE 76. Authorization from this Ministry is required to begin the following types of experimentation:

a)         Formation of recombinant deoxyribonucleic acid derived from pathogenic microorganisms that are classified in risk groups III and IV referred to in article 71 of this resolution, as well as the formation of recombinant genetic material derived from cells that are infected by such agents, regardless of the host and vector system used.

b)         Intentional construction of recombinant nucleic acids to induce the biosynthesis of potent toxins for vertebrates.

c)         Intentional release into the environment of any microorganism that carries recombinant nucleic acids.

d)         Transfer of resistance to antibiotics from microorganisms that do not acquire it in nature, if such transfer could negatively affect the use of the antibiotic in human medicine.

e)         Experiment with microorganisms or with recombinant nucleic acids in cultures larger than ten (10) liters because their physical and biological containment is more difficult unless the recombinant molecules have been rigorously characterized and the absence of dangerous genes in them is demonstrated. . Those processes of an industrial and agricultural nature not directly and specifically related to the activities established in article 1 of this resolution are excluded.

CHAPTER III.

ON RESEARCH WITH RADIOACTIVE ISOTOPES AND DEVICES AND GENERATORS OF IONIZING AND ELECTROMAGNETIC RADIATION.

ARTICLE 77. Medical research that involves the use in human beings of radioactive isotopes and devices that generate ionizing and electromagnetic radiation must be carried out in accordance with the laws, regulations and standards on radiological safety that govern the national territory.

ARTICLE 78. In the institutions where these investigations are carried out, the Biosafety Commission will ensure that for each study, the person responsible for the radiological and physical safety of said institutions is identified before the respective National Organization, for compliance with the requirements and obligations, as in charge of radiation safety.

ARTICLE 79. The responsible person referred to in the previous article must:

a)         Have the training, qualification and certification legally required for said function.

b)         Prepare a procedures manual in accordance with current laws, rules and regulations and with the characteristics of the facility or equipment, which must be available to all personnel, which describes: the identification and control of sources of radiation, controlled and monitored areas, dosimetric monitoring of personnel, emergency plan, waste management plan and training of personnel involved in procedures and radiological safety.

c)         Define, implement and monitor compliance with radiological and physical safety measures.

d)         Inform the personnel involved in the research about these standards and train them on the work procedures and characteristics of the laboratory and equipment.

ARTICLE 80. Taking into account that each exposure involves a risk, improper exposure to ionizing radiation is strictly prohibited. The legally established Equivalent Dose limits should be considered upper limits and not design or control limits. Protective measures against ionizing radiation should be optimized so that the number of people exposed and the Equivalent Doses received by the researcher or the patient undergoing research are as low as reasonably possible, taking into account socio-economic factors. economics of the environment in which one works.

ARTICLE 81. In the examination or treatment that is part of a medical research program and that entails a net benefit for the patient, the justification of the procedure will be carried out with the same justification criteria as for a routine medical exposure. However, given the experimental nature, said justification will be subjected to careful scrutiny on an individual basis, ruling out other diagnostic or therapeutic methods that may be evaluated comparatively.

ARTICLE 82. The deliberate irradiation of personnel during procedures for research purposes that does not seek a direct benefit to the irradiated people, will be carried out only by adequately qualified and trained people, and with the respective permission of the institution where the irradiation is going to be carried out. irradiation, under the advice of the National Entity responsible for radiological protection in harmony with current standards for radiological surveillance and control.

ARTICLE 83. Occupationally exposed personnel must be over 18 years of age, and the occupational exposure limits determined by the authorized national entity will be taken into account, with special consideration in the case of women of childbearing age and pregnant women.

PARAGRAPH. Pregnant or breastfeeding women should not work in places with a high risk of incorporating radioactive materials.

ARTICLE 84. The people included in the procedure must be informed about the risk of irradiation to which they will be subjected, so that their participation is under their free will and with knowledge of the facts. Informed Consent from family members or the legal person responsible is necessary when the subject of the research is not in a position to decide on acceptance.

ARTICLE 85. These investigations must be subject to individual evaluation, followed by a procedural plan and a final protocol approved by the competent authority in the matter, which exhaustively analyzes them from the point of view of radioprotection and the condition of true volunteers. people who will not receive a net benefit from the procedure, since no special dose limits can be set in these cases.

ARTICLE 86. The use of ionizing radiation for research purposes in pregnant women and minors is prohibited, and is restricted to specific studies prior to research in women of reproductive age.

PARAGRAPH. In the above cases, reconsideration may be made as they are therapeutic procedures in pathological processes considered special due to their prognosis or their characteristics, with the prior written authorization of the person involved, or the family member, or legally responsible person.

TITLE V.

BIOMEDICAL RESEARCH WITH ANIMALS.

ARTICLE 87. In all research in which animals are the subject of study, the following must be taken into account, in addition to the provisions determined in Law 84 of 1989: 

a)         Whenever appropriate, methods such as mathematical modeling, computer simulation, and in vitro biological systems should be used.

b)         Experimentation on animals should only be carried out after studying its importance for human or animal health and for the advancement of biological knowledge.

c)         The animals selected for experimentation must be of an appropriate species and quality, and use the minimum number required to obtain scientifically valid results.

d)         Only legally acquired animals will be used and they will be kept in adequate conditions that comply with current health regulations.

e)         Researchers and other personnel must never fail to treat animals as sentient beings and must consider appropriate care and use and avoiding or minimizing discomfort, distress and pain as an ethical imperative.

f)          Researchers must presume that procedures that would cause pain in humans also cause pain in other vertebrate species, even if they are still missing much to know about pain perception in animals.

g)          Any procedure, which may cause animals more than momentary or minimal pain or distress, must be performed with appropriate sedation, analgesia or anesthesia and in accordance with accepted veterinary practice. Surgical or painful procedures should not be performed on unanesthetized animals paralyzed by chemical agents. The euthanasia of animals will be carried out with appropriate anesthetics, approved by the veterinary association.

h)         When it is required to deviate from what is established in the previous section, the decision must not be made only by the researcher directly involved, but must be made by the Ethics Committee, established by Law 84 of 1989. These exceptions must not be be made solely for demonstration or teaching purposes.

i)          At the end of the experiment, or when appropriate during the experiment, animals that may suffer chronic or severe pain, distress, discomfort or disability that cannot be mitigated, must be painlessly euthanized.

j)          Animals kept for biomedical purposes should be kept in the best living conditions, if possible under the supervision of veterinarians with experience in laboratory animals. In any case, veterinary care must be available when required.

k)         The director of the institute, department or unit where animals are used is responsible for ensuring that researchers and other personnel have appropriate qualifications or experience to perform procedures on animals. You must provide adequate in-service training opportunities that include concern for the humane and appropriate treatment of animals in your care. 

ARTICLE 88. The use of animals in research, teaching and testing is accepted only when it promises to contribute to the understanding and advancement of knowledge of fundamental biological principles or to the development of better means for the protection of the health and well-being of both man and man. like the animal.

ARTICLE 89. The animals must be used, in case the researcher has ruled out other alternatives, for this purpose the Russell Burch "3R" principle, replacement, reduction and refinement, is followed.

ARTICLE 90. The vivariums must be in accordance with the species, body conformation, habits, postural preferences and locomotor characteristics of the animals, to provide them with comfort, except when the experimental variables justify other situations.

ARTICLE 91. The production or chronic maintenance vivariums will be supervised by qualified and competent professional personnel in the matter and must allow the growth, maturation, reproduction and normal behavior of the animals, in accordance with the standards issued by the institution itself.

ARTICLE 92. The director of the institution where animal research is carried out must establish and monitor compliance with safety measures for the care and handling of animals, as well as the prophylaxis and vaccination measures necessary for the protection of occupational personnel. exposed.

ARTICLE 93. The director of the institution where animal research is carried out must monitor, order or execute, taking into account the following security measures, as the case may be:

a)         Isolation.

b)         Quarantine.

c)         Personal observation.

d)         Vaccination of people.

e)         Vaccination of animals, as far as it relates to human health.

f)          The destruction or control of insects and other transmitting and harmful fauna, as far as it relates to human health.

g)         The suspension of work or services.

h)         The securing and destruction of objects or products or substances.

i)          Eviction of houses, buildings, establishments and in general of any property.

j)          The prohibition of the use of certain species, and

k)         Other health matters determined by this Ministry or competent entity at its level, which may prevent risks or damage to health from being caused or continuing to be caused. 

ARTICLE 94. This resolution takes effect from the date of its publication.

PUBLISH AND FULFILL

Given in Santafé de Bogotá DC on the fourth day of October, one thousand nine hundred and ninety-three.