NATIONAL HEALTH COUNCIL


RESOLUTION Nº 251, DATED 7 AUGUST 1997



Plenary  of  the  National  Health  Council  in  its  15th  Special  Meeting,  held  on  5  August  1997,  in  the 
exercise  of  its  competencies,  as  set  forth  in  its  by-laws,  and  the  attributions  in  Law  8.080  and  Law  
8.142, respectively dated 19 September 1990 and 28 December 1990, Resolves:

To approve the following norms of research involving human beings in the thematic area of research with new 
pharmaceutical products, medicines, vaccines, and diagnostic tests:

I - PREAMBLE

I.1 – This Resolution incorporates all provisions contained in Resolution 196/96 of the National Health Council on 
Guidelines and Norms Regulating Research Involving Human Beings, which this Resolution complements  in  the  specific  
thematic  area  of  research  with  new  pharmaceutical  products,  medicines, vaccines, and diagnostic tests.

I.2 – It also refers to the Resolution on the Common Market Group (GMC) Nº 129/96, signed by Brazil, which establishes 
the technical regulations for ascertaining [the implementation of] good practices in clinical research.

I.3 – The norms, resolutions and regulations issued by the Health Surveillance Secretariat of the Ministry of Health 
(SVS/MS) should be fully complied with, and SVS/MS authorization is required to execute and subsequently follow up and 
control the technical development of research projects in [the area of] Clinical Pharmacology (Phases I, II, III, and 
IV of products not yet registered in the country) and Bioavailability and Bioequivalence. Research projects in this 
area should comply with the provisions of Law 6.360 (23 September 1976), regulated by Decree Nº 79.094 (5 January 
1977).

I.4 – In any clinical essay and particularly when there are conflicts of interests associated with new products, the 
dignity and well-being of the research subject must prevail over any other interests, whether economic, scientific, or 
of the community.

I.5  –  It  is  essential  that  all  research  in  this  thematic  area  be founded on recognized scientific norms and 
on knowledge based on in vitro laboratory experiments and pertinent literature.

I.6  –  It  is  necessary that the investigation of new products be justified and that such products actually result in 
significant progress when compared with existing products.


II - TERMS AND DEFINITIONS

II.1  –  Research  of  new  pharmaceutical  products,  medicines,  vaccines  or  diagnostic  tests.  It refers  to  
Phase  I,  II  or  III  research  with  these  types  of  products  or  with  products  not  yet  registered  in  the 
country, even in Phase IV, when the research focuses on their use with modalities, indications, dosages, or paths of 
administration different from those established at the time registration was authorized, including their use in 
combinations, as well as bioavailability and bioequivalence studies.

II.2 – The terms listed below, which are part of the Common Market Group Resolution (GMC Nº 129/96), are hereby 
incorporated into this Resolution.

a – Phase I
It is the first study with human beings, in small groups of usually healthy volunteers, of a new active  principle  or  
a  new  formulation,  usually  investigated  using  human  volunteers.  The  purpose  of  such research is to establish 
a preliminary notion of the safety and pharmacokinetic profile, and, if possible, the phamacodynamics profile [of the 
product].
b – Phase II
(Pilot-Scale Therapeutic Study)
The  objectives  of  the  Pilot-Scale  Therapeutic  Study  are  to  demonstrate  the  activity  [of  the product] and 
to ascertain the short-term safety of the active principle in patients affected by a given disease or pathological 
condition. The research is carried out on a limited (small) number of individuals and is frequently followed by an 
administration study.  It  should  also  be possible  to establish  the dose/response ratio for the purpose of 
obtaining sound background for the description of the extended therapeutic studies (Phase III).
c – Phase III
Extended Therapeutic Study
These  studies  are  performed  on  a  large  and  varied  number  of  patients,  for  the  purpose  of

determining:

•    the result of short-term and long-term risks/benefits of the active principle formulations and
•    in a global (general) manner, the relative therapeutic value.
In this phase, the type and profile of the most frequent adverse reactions are studied, as well as
the  especial  characteristics  of  the  medication  and/or  therapeutic  specialty,  for  example,  clinically  
relevant interactions, main factors that modify the effect, such as age, etc.
d – Phase IV
This  is  research  performed  when  the  product  and/or  therapeutic  specialty  is  commercially
available.
This  research  is  based  on  the  characteristics  under  which  the  medicine  and/or  therapeutic
specialty   was   authorized.   These   are   usually   post-commercialization   surveillance   studies   that   aim   
at establishing the therapeutic value, [verifying] the emergence of new adverse reactions and/or confirming the 
frequency of known adverse reactions, as well as the treatment strategies.
The same ethical and scientific norms applied in the research in the previous phases should be used in Phase IV 
research.
Once  a  medicine  and/or  therapeutic  specialty  is  already  commercially  available,  the  clinical research  
performed  to  explore  new  indications,  new  methods  of  administration,  or  new  combinations (associations), 
etc. shall be considered research of a new medicine and/or therapeutic specialty.
e – Pharmacokinetics
As a rule, it is all the modifications a biological system causes on an active principle.
In  operational  terms,  it  is  the  study  of  kinetics  (quantitative  relation  between  the  independent variable  
„time‟ and  the dependent variable „concentration‟) of the absorption, distribution, biotransformation, and excretion 
of medicines (active principle and/or its metabolites).
f – Pharmacodynamics
It  is  all  the  modifications  an  active  principle  causes  in  a  biological  system.  From  a  practical 
standpoint,  it  is  the  study  of  the  biochemical  and  physiological  effects  of  medicines  and  their  action 
mechanisms.
g – Margin of Safety
It is the pharmacodynamics indicator that expresses the difference between the toxic dose (for example, the DL 50) and 
the effective dose (for example, the DE 50).
h – Therapeutic Margin
It  is  the  ratio  of  the  maximum  tolerated  dose,  also  toxic  dose,  to  the  therapeutic  dose  (toxic 
dose/therapeutic  dose).  In  clinical  pharmacology,  the  therapeutic  margin  is  used  as  equivalent  of  the 
Therapeutic Indicator.


III – RESPONSIBILITY OF THE RESEARCHER

III.1  –  The  unremittable  and  untrasferable  responsibility of  the researcher  to [comply with] the terms  of  
Resolution 196/96  is  hereby reaffirmed.  All obligations provided for in said Resolution are equally reaffirmed, 
particularly the guarantee of conditions [required] to care for research subjects.

III.2 – The researcher shall be responsible for:
a  –  submitting  a  complete  research  project  to  the  Research  Ethics  Committee  (CEP),  in  the terms of 
Resolution 196/96 and this Resolution;
b – maintaining a file for each research subject, for a period of five years, after the end of the research, due 
compliance being given to the confidentiality and secrecy of the records;

c – submitting a detailed report as requested or established by the CEP, the National Research Ethics Committee 
(CONEP), or the Health Surveillance Secretariat (SVS/MS);
d  –  informing  the  CEP  of  any  occurrence  of  collateral  effects  and/or  unexpected  adverse
reactions;
e – communicating also any proposed changes in the project and/or justification of interruptions,
keeping  in  abeyance  until  the  matter  is  appreciated  by the  CEP,  except  in  urgent  cases  to  safeguard  the 
safety of research subjects; in the latter case, the CEP should be notified immediately afterwards;
f – making available to CEP, CONEP and the SVS/MS all duly required information;
g – continuously analyzing the findings, throughout the research, for the purpose of detecting, as soon as possible, 
the advantages of one treatment over another or preventing adverse effects on research subjects;
h – submitting regular reports within the time periods established by the CEP, with at least one report every six 
months and one final report;
i – providing the patient‟s physician and the patient him/herself access to the results of tests and treatment whenever 
requested and/or indicated; and
j – recommending that no individual be selected as research subject before a year has passed from his/her participation 
in another research, unless that individual were to directly benefit from it.


IV – RESEARCH PROTOCOL

IV.1  –  The  protocol  must  include  all  items  stipulated  in  Chapter  VI  of  Resolution  196/96,  in addition  
to  the  basic  pharmacological  information  appropriate  to  the  phase  of  the  research  project,  in compliance 
with Res. GMC 129/96 - Mercosul – including the following.
a – Specifications and rationale of the clinical research phase in which the study is to be carried out, demonstrating 
that prior phases have been concluded.
b  –  Description  of  the  pharmacological  substance  or  product  being  investigated,  including  its chemical  
formula  and/or  structure,  in  addition  to  a  brief  summary  of  relevant  physical,  chemical  and pharmaceutical 
 properties.  Any  structural  similarity  to  other  known  chemical  compounds  should  also  be mentioned.
c  –  Detailed  preclinical  information  is  required  to  justify  the  phase  of  the  project,  including  a report 
   on    the    experimental    studies    (materials    and    methods,    animals    used,    laboratory    tests, 
pharmacodynamics data, margin of safety, therapeutic margin, pharmacokinetics, and toxicology, in the case of  drugs,  
medicines,  or  vaccines).  The  preclinical  results  must  be  accompanied  by  a  discussion  of  the relevance of 
the findings in connection with the expected therapeutic effects and possible undesirable effects in human beings.
d  –  The  preclinical  toxicology  data  should  include  the  study  of  acute  toxicology,  subacute toxicology with 
repeated doses and chronic toxicity (repeated doses).
e – The toxicology studies should be performed in at least three animal species, one of which must be a non-rodent 
mammal; both sexes must be included in the studies.
f – In studying acute toxicity, two paths of administration must be used, one of which must be related to that 
recommended for the therapeutic use being proposed and the other must be a path that will ensure the absorption of the 
pharmaceutical product.
g  -  In  subacute  toxicity,  repeated  dose  and  chronic  toxicity studies  the  path  of  administration should be 
related to the proposed therapeutic use and the experiment should last at least 24 weeks.
h – In the preclinical phase, the toxicity studies should also include an analysis of the effects on fertility, 
embryo-toxicity, mutagenicity, oncogenic (carcinogenic) potential, and other studies, according to the nature of the 
pharmaceutical product and the therapeutic proposal.
i – Depending on the importance of the project, in view of the lack of time and in the absence of other  therapeutic  
methods,  the  CEP  may  approve  projects  that  have  not  fulfilled  all  clinical  pharmacology phases; in this 
case, approval must also be obtained from CONEP and the SVS/MS.
j – Information about the status of the research and product registration in the country of origin.
k  –  The  detailed  clinical  information  obtained  during  the  prior  phases,  as  regards  safety, 
pharmacodynamics,  effectiveness,  and  dose-response  observed  in  studies  using  human  beings,  whether healthy  
volunteers  or  patients.  If  possible,  there  should  be  a  separate  summary  of  each  essay,  with  a 
description of the objectives, design, method, results (safety and effectiveness), and conclusions. In the case of  a  
large  number  of  studies,  the  summary  must  encompass  groups  by  phase,  in  order  to  facilitate  a discussion 
of the results and their implications.
l – Justification for the use of a placebo and possible suspension of treatment (washout).
m – Access to the medicine being tested must be assured by the sponsor or by the institution, researcher,  or  
promoter,  if  there is no sponsor, in the event its superiority to the conventional treatment is proven.

n  –  In  multiple  center  studies  the  researcher  must,  to  the  extent  possible,  participate  in  the design of 
the project. If this is not possible, the researcher must formally state that he/she agrees with the existing design 
and that he/she will follow it.
o – The sponsor must provide the researcher all data about the pharmaceutical product.
p – Funding must not be tied to the per capita payment of the subjects effectively recruited.
q – The protocol must be accompanied by the terms of consent. In the case of subjects not fully capable  of  
self-determination,  in  addition  to  the  consent  from  the  individual  legally  responsible  for  the proposed  
research  subject,  it  is  necessary  to  take  into  account  the  expressed  wishes  of  the  proposed research 
subject, even when not fully capable (for example, the elderly) or not fully developed (for example, children).
r  –  In  the  case  of  research  on  psychiatric  patients,  whenever  possible  consent  should  be obtained from 
the patient him/herself. It is mandatory that the level of capability to express free and informed consent of each 
psychiatric patient be established by a psychiatrist other than the researcher involved in the project.
In the case of drugs with psychopharmacological action, a critical analysis must be made of the possible risks of 
causing dependency.

IV.2 – Including healthy subjects in research.
a – Justifying the need to include healthy subject in the research project. Critical analysis of the risks involved.
b – Description of how the recruitment will take place; no dependency situation should exist.
c  –  In  the  case  of  drugs  with  psychopharmacological  action,  a  critical  analysis  of  the  risk  of causing 
dependency is necessary.


V – ATTRIBUTIONS OF THE CEP

V.1  –  The  CEP  and  the  researcher  will  be  jointly responsible  for  maintaining  ethically correct conducts 
throughout the project and during the implementation of the research. In addition, they should take the following 
actions.
a  –  Issue  a  consolidated  report  explaining  the  scientific  basis  of  the  research  project  and  its relation 
 with  the  studies  in  prior  phases,  including  the  preclinical  phase,  with  emphasis  on  safety,  toxicity, 
adverse reactions or effects, effectiveness, and results.
b – Approve the justification of the use of a placebo and washout.
c – Request partial and final reports from the main researcher establishing the schedule (on a six-monthly basis  at  
least)  according  to  the  characteristics  of  the  research.  Copies  of  the reports  must  be forwarded to the 
SVS/MS.
d – If announcements in the media are to be used to recruit research subjects, such advertising must be authorized by 
the CEP. No indication may be given, whether implicitly or explicitly, that the product being investigated is effective 
and/or safe, or that it is equivalent to or better than other existing products.
e – Convene the research subjects for follow up and evaluation.
f – Require that the top management of the institution start an inquiry, suspend or interrupt the research and 
communicate the fact to CONEP and the SVS/MS.
g – Any infringement of ethical principles or evidence of fraud of any nature should lead the CEP to request the 
creation of an Inquiry Committee and to communicate the results[of such inquiry] to CONEP, SVS/MS and other agencies 
(top management of the Institution, pertinent Regional Councils).
h – Communicate the occurrence of serious adverse events to CONEP and the SVS/MS.
i  –  Communicate  to  the  Institution  the  occurrence  or  existence  of  administrative  responsibility problems 
that may interfere with the ethical conduction of the research; report to CONEP and the SVS/MS immediately and, as the 
case may be, to the Regional Councils.

V.2 – The National Health Council hereby delegates to the CEP authority to approve, from the point of view of ethics, 
research projects involving new pharmaceutical products, medicines and diagnostic tests, with the provision that the 
following documents be submitted to CONEP and the SVS/MS:
a – a copy of the consolidated report approving the research project, together with a completed header page,
b – official conclusion on the partial and final reports on the research and
c – other documents required by CEP, CONEP or the SVS.
V.3 – In research that includes patients submitted to emergency or urgency situations, the CEP must  previously  
approve  the  conditions  or  limits  for  obtaining  free  and  informed  consent;  in  addition,  the researcher must 
inform the research subject, on a timely basis, about his/her participation in the project.

V.4 – Assess whether all adequate measures are being implemented in the case of research with human beings whose 
capability for self-determination is impaired or limited.


VI - OPERATIONALIZATION

VI.1 - CONEP will exercise its competencies in the terms of Resolution 196/96, with emphasis on the following 
activities:
a – organizing an information and follow up system (item VIII.9.g of Resolution 196/96) on the basis of the data 
supplied by the CEPs (consolidated approval report, duly completed header page, partial and final reports, etc.);
b – organizing a system to evaluate and follow up the activities of the CEPs. The system should enable  peers,  i.e.  
members  of  the  various  CEPs,  to exchange  information and  experience, with reports  to CONEP. It should also 
comply with the specific regulations issued by CONEP;
c – informing the appropriate authorities, particularly the Health Surveillance Secretariat of the Ministry of Health, 
with a view to appropriate action, proven violations of the ethical standards in the execution of research projects; 
and
d  –  supplying  the  various  bodies  of  the Ministry of  Health, particularly the Health Surveillance Secretariat, 
the information required to fully exercise their respective competencies as regards the research covered in this 
Resolution.

VI.2  –  The  Health  Surveillance  Secretariat/MS  shall  exercise  its  attributions  in  the  terms  of Resolution 
196/96, with especial emphasis on the following activities.
a  –  Reporting,  in  writing,  to  CONEP  any indication of  violation of  ethics  observed or  detected during the 
execution of the research projects covered in this Resolution.
b – Supply, upon request or when pertinent, the information required for the full exercise of the competencies of 
CONEP.
c  –  In  the  case  of  research  involving  situations  for  which  there  is  no  recognized  treatment 
(“humanitarian use” or “compassionately”), the release of the product may be authorized as an emergency measure, after 
CEP approval and ratification by CONEP and the SVS/MS.
d  –  Standardizing  its  internal  operational  procedures  with  a  view  to  exerting  effective  health control of 
the products object of clinical research.




CARLOS CÉSAR S. DE ALBUQUERQUE
President of the National Health Council



I  hereby  ratify  CNS  Resolution  Nº  251,  dated  7  August  1997,  in  the  terms  of  the  Decree  on  the 
Delegation of Competency dated 12 November 1991.




CARLOS CÉSAR S. DE ALBUQUERQUE
Minister of Health of Brazil