Dr. Roberto Llanos Zuloaga, (Medical Doctor), Av. Javier Prado Este 1038, Lima 27 Perú

Introduction:
The main purpose of this monograph is to develop a critical research and compare  the criterion to obtain the ecthical validation in the  investigation of human beings, according to the contribution of EZEQUIEL EMANUEL (1) and DIEGO GRACIA (2) in five protocols  presented to the Investigation Ehical Committee of the Peruvian Bioethical Association (ASPEBIO).

Material and Methods:
The material consists of five different protocols of investigation:
1. Comparison between two medicines.
2. Genetic study of patients’ relatives with Down Syndrome.
3. Uterine Cancer discard.
4. Diagnoses and treatment of uterine neck cancer.
5. National reality study regarding the knowledge of Bioethics in the medical group.
 

1. In the diagnosis and treatment of the uterine neck cancer investigation in a native Peruvian population, the protocol answers the following questions:
a) Does it justify to prepare an investigation?
b) Are the participating women  in a lessening situation than the ones that do not participate? Or  in maintaining  their actual situation?
c) Is there any direct benefit for the participating women?
d) Which are the risks for each stage?  Could the risks surpass the benefits? (Diffusion and Treatment).
e) Will the patients have the autonomy of deciding their participation?
f) Training and Human Resources aspects of the project.
g) Responsibility of the participants (central level, national level, international level).
h) Schedule?
i) The informed consent explains:
1. The possible risks of the visual inspection.
2. The inconvenience of other similar exams.
3. The benefits of  participating in the exam.
4. Names of the researchers.
5. Decision of leaving the investigation.
6. The gratuitous posterior treatment.
7. Signatures.
 

2. The second investigation is a search of information and evaluation, during one year is planning to investigate our national reality in terms of Bioethics.  The research expects to know about the grade of knowledge of Bioethics in Medical Institutions of our three regions and in samples of our large population, so it could be used in benefit of the whole population and not only in a stratum.

The informed consent will be requested to the thirty thousand doctors with professional practices in Perú.  The document specifies  that the interview is made by qualified personnel.  The responsibility of the professionals to express their real knowledge about Bioethics.  The existence of other similar international investigations made on a small scale.  The possible risks in case the information could be not accurate or false. The benefits of participating in the exam.  The names of the responsible researchers.  The decision of leaving the investigation.  The right to know about the final results of the investigation.  Signatures.
The results of the Research will shape in one year with the level of knowledge that people related to Medicine has about Bioethics. After one year research it will give us information about the improvement on the theoretic information, the application of Bioethics in the practice, changes in medical diagnosis and treatment, use of technology and new concepts and also improvement within the human relationships that the sample and their enviroment obtained. In addition the research will have intense practical consequences.

Due to the factor that the efforts were concentrated on people with influence on others the researchers wait that it would have an increasing effect. On the other hand with the support of partners which will colaborate in the diffussion of Bioethics and the dissemination of the results of the project.

The researchers will take care to communicate about the project to a wide variety of audiences, many of which do not understand scientific methodology. Scientists concentrated around this project, the main comitte and the partners will be sure to establish appropiate mechanisms to maintain the research withing ethical limits and humanitarian goals. The head interest concern information about informed consent, confidentiality and justice principles. All the participants would be treated in a educational framework and with
respect of individual rights and freedom.

1er. In the first protocol, the investigation has a social and scientific value, the clinic significance consists in using an immediate and simple diagnosis method.

2do. In the second protocol: the investigation has a social and scientific value, its implementation is completely possible, the identification and selection of the persons are suitable, the benefits are bigger than the risks, the checking will be done by experts in the matter, the informed consent is in relationship with the interests of the persons and assures the confidentiality.

3cro. protocol tehe reserch a Prospective, double blind randomized,  comparative study to reviewuate the genetic testing for breast and ovarian cancer.

The objectives are to create molecular patterns for the early diagnosis.To develop strategies to revert the early steps of the tumor that could be the most effective way to control ovarian and breast cancer, and to idenrify the genes responsible for the inherited ovarian and breast cancer.
The participants will be chosen upon their family history. They can join the study referred from their physicians or genetic counselors. After the first contact with the participants is made, they will receive a letter in which they can find the details of the project. If they are interested it will be explained to each of them that we need a detailed story of his or her study. They will be asked for their names, addresses of the relatives alive and we will send a letter to each of them explaining the purpose of the study. If it is necessary we wil expain to them over the telephone all the details they want to know and if they have any doubts, we will invite each member of the family to participate.
The first pedigree will be made with the probands and will include information about parents, grandparents, uncles, aunts, cousins, nieces and grandchildren.
Confidentiality: Clinical histories will be mainteined undisclosed, only the members of the staff will have access to them. The information will be in the computer and the laboratory data will be identified by numbers.
The relationship between data of identification and codes will be kept until the pedigree has been completed, no later than five years. Each participant wil be sure than any answer to the questions will not be informed to the other members of the family.
Risks: The risks and discomfort associated wiyh the procedures are due to the anxiety that could provoque the discussion of the family’s medical history and the discomfort could be present when the blood sample must be taken. Efforts will be done to avoid risks and discomfort.
Benefits: A genetic counselor will answer all the questions about breast cancer to the participants and their relatives, without any cost. Clinic Colaborators will help to refer the patients all over the country. If any member of the family is at risk of developing cancer, she will receive the specific genetic counseling.
The participants of the study will contribute to a better knowledge of the ovarian and breast cancer.
No adverse effects exist in the study, however if one should appear the staff will take care of it and the medical insurance will pay the fees to the participants..

4. to. protocol the reserch: CONTRIBUTION TO THE ETHIOLOGY OF AUTISM. Their objectives are: a) General: To identify the etiologic factors that determinme the diagnostic of autism in the sample being studied. b) Secondary: To investigate in the patients chromosome alterations. To investigate specific genetic tables in the studied sample. To investigate psychopathologic behavior in relatives. To investigate cerebral structural and/or functional alterations with neurological statements. (SPECT).
ETHIC FACTORS: Patients will be enrolled only after having signed a written informed consent. The patients will benefit from the analysis and appropriate studies for free. Moreover they will collaborate with science. Absolute confidentiality of data will be maintained and upon publishing the analysis, the patient’s anomyty will be maintained.
Those patients that happened to be harmed by procedures related to the study will be handled by investigatorss until they are stabilized. Any financial exposes will be covered by the sponsoring entity or the investigator.
The present protocol will be sumitted to the Ethic Commitee in investigation of the institution. The patients will be able to make any type of questions related with the protocol to the investigators during the course of studies as well as to the Ethic Commitee regarding their rights.
SIZE OF THE SAMPLE AND POWER, INCLUSION CRITERIA AND PROCEDURES: All subjects referred with an autism diagnostic will first be examined. The observation and tests have the purpose of establishing which of the subjects referred with a diagnostic of autism show an etiologic diagnostic that correspond to other pathologics. Then the sample conformed by parents and siblings (15 years old and up) will be defined from the patients diagnosed with autism. In third place will begin a recollection of data from the relatives of people with TA, to whom will be applied the Mini-Mult 82.
At the same time there will be a collection of data given by subjects of the control group (normal and with other diagnostics) to whom the Mini-Mult 82 will be applied.

CRITERIA OF EXCLUSION: 1) To be people with other genetic conditions that do not show an autistic behavior.
2. To be non-biological relatives of people with autistic behavior.
MESUREMENTS OF EFFICIENCY AND CERTAINTY: A careful history and clinical analysis as well as the reviewuation of a genetist doctor and other specialists in the advising bureau mentioned above.
The citogenetic andd biochemical studies will be processed in the Citogenetic Laboratory of the Child Health Institute (Instituto de Salud del Niño), in the Laboratory of the Genetic Institute of the University Cayetano Heredia and in the Medical Center Specialized in Genetics.

5to. Protocolo study XYZ:
Tile: Prospective, double blind, randomized, comparative study to reviewuate security and efficacy from drug A versus drug B in the treatment of urinary infections.

Hypothesis: Drug A has the same effectiveness as Drug B, both produce the microbiologic and clinic healing in about 95% from the subjects. The adverse events from A (Drug in study) are less than those produced by Drug B (standard Drug).
Objectives: The main objective of this study is to compare the efficacy and security from Drug A to Drug B in the urinary infection.
Study Design: Prospective study, double blind, random, comparative of two groups for Drugs A and B respectively. The patients assigned to the first group, will receive Drug A, 400 mg. one daily dose during 10 days, while the patients assigned to the second group will receive Drug B 400mg. Bid for 10 days, while the patients assigned to the second group
INFORMED CONSENT: You have been diagnosed as urinary infection. So, you’re invited to participate on this screening. Up next, you’ll be provided of information concerning the study and your participation on it. It’s necessary for you to choose to participate or not. Take the time you need in order to take a determination. The physician in charge of it or any person previously authorized by the ivestigator’s staff will answer any question linked to study as well as any question concerning your rights as a participant will be regarded by the Ethics on Investigation Committee at Hospital ABC.
WHICH IS THE PURPOSE OF THE STUDY?
The scope of the current study is to comare effectiveness ans dafety in drug A versus drug B on urinary infections treatment you are afflicted of. Drug A is a medicine of investigation being screened by Laboratory A while drug B is a medicine used nowadays for urinary infections treatment and is traded in our system.
WHO CANNOT PARTICIPATE ON THE CURRENT STUDY?
The following patients cannot participate on the current study:
If individual is less than 20 years old, or is more than 50 years old.
If individual presents nauseas and vomit.
If individual presents alterations on hepatic or renal function.
History involving Allergy to medicines A or B.
If individual has already been supplied medication for his urinary infection.
If individual is pregnant or is in suckling stage.
If individual presents any final disease, fastly progressive or serious.
If there is need to supply antibiotics different from those relating to the current study. Hemoglobine less than 9 gr/dl. And Neutropenia with neutrophile.

EZEKIEL EMANUEL (1999), believe that there are seven ethical requirements that to provide a systematic and rational framework for determining wether clinical research is ethical. These requirements are meant to guide the development and implementation of protocols and their review, not for reviewuating the ethics of an individual investigator’s actions much less the clinical research enterprise as a whole. This requirements are:
1- Value: To be ethical, clinical research must be valuable, which is a judgement about the social, scientific, or clinical significance of the research. The research must be either reviewuating an intervention that can lead to improvements in the health or well-being of he population, or be conducting a preliminary study to developing an intervention , or be testing a hypothesis that can generate important knowledge about structure or function of human biologic systems if that knowledge does not have inmediate practical ramifications.
2- Scientific validity: the principal idea is that bad science is unethical. In essence the scientific validity of a syudy on human beings is in itself an ethical principle (RUTSTEIN 1969). The research must have a clear scientific objective, be designed using accepted principles, methods, and reliable practices, have sufficient power to definitively test the objective, plausible data analysis plan, and it must be able to be implemented.
3- Fair subject selection: The identification and selection of potential subjects for a research trial must be fair. There are four facets to this requirement: a) specific groups of subjects are selected for reasons related to scientific questions involved in the research. b) fair subject selection requires that all groups should be offered the opportunity to participate in research unless there are good reasons of science or risk to restrict their eligibility.
4- favorable risk-to-benefit ratio: Clinical research can be justified only when: a) The potential risks to individual subjects are minimized. 2) The potential benefits to individual subjects or to society are maximized, and c) the potential benefits are proportionate to or outweigh the risks being assumed.
5- Independent review: An independent review has: a) is reviewed by individuals with appropiate expertise unaffiliated with the study who have the authority to approve, amend or, in the extreme, terminate it. b) has social accountability.
6- Informed consent: The propose of informed consent is to ensure that individuals participate in the proposed clinical research only when it is consistent with their values, interests, and preferences.
7- Respect for enrolled subjects: Subjects must continue to be treated with respect throughout the time they are participating in clinical research: a) permitting subjects to change their mind. and b) confidentiality in information.

DIEGO GRACIA (1999), distinguish two parts in the basic issues in the ethical analysis of a research protocol:
I Scientific analysis of the protocol and
II Ethical analysis of the protocol.
The scientific analysis of the protocol has five parts:
1. Critical analysis of the objectives: a) Objective of the study. b) Reasons for conducting the study. c) Essential information about the problem, and background from relevant literature.
2. Critical analysis of the experimental design: a) Type of study ( controlled study, pilot study, etc.) and prefearably what phase it represents. b) Randomization method, including the procedure and practical means of implementation. c) experimental design (parallel groups etc.). d) Measures taken to reduce biases.
3. Critical analysis of the reviewuation process: a) How will the findings be reviewuated?. b) Methods for computing and calculating the effects. c) Descriptionof how to deal with and report drop-outs and withdrawals from the study.
4. Critical analysis of the methodology: a) Statistical methods to be used. b) Statistical justification of the sample size. c) Significance level used.
5. Critical analysis of the research team: a) Principal investigator. b) Research team. c) Institutional afiliation. d) Institution in which the study will be carried out.
The Ethical analysis of the protocol has three parts:
1. Critical analysis of the informed consent: a) How will healthy patients/volunteers be informed and how will their consent be obtained?. b) Posible reasons for failure to obtain informed consent. C) Analysis and review of the form utilized.
2. Critical analysis of the risk-to-benefit ratio: a) Drugs used and dose. b) Treatment of the control group or during the control period (placebo, etc.) c) Route of administration, dose, dosage schedule, period of treatment for the study drug and the reference drug. d) Rules for the use of concomitant drugs. e) Measures to ensure safe management of drugs. f) Measures to compliance monitoring. g) Analysis of effects. h) collection of reviewuation parameters. i) special techniques. j) Adverse reactions. k) managing complications. l) study code and emergency. m) report of adverse reactions.
3. Critical analysis of equitable sample selection: a) Specification of the subjects. b) diagnostic criteria. c) Exhaustive criteria for the inclusion and primary and secondary exclusion of patients. d) Analysis of special groups fetuses, children, mentally ill persons, prisoners, pregnant women. etc.

RESULTS:

In the first protocol, the investigation has a social and scientific value, the clinic significance consists in using an immediate and simple diagnosis method.  This avoids the patients from coming back to find out about his or her results, the treatment would  also be immediate.  It is simple to implement it, we need to follow a two step requirement, the benefits surpass the risks, the checking is done by qualified people, the informed consent is consistent and assures the persons the continuity of the treatment.  The goals of the investigation are exact, the experimental design appropriate, it has a good checking criterion  an adequate methodology and selection of participants.

In the second protocol: the investigation has a social and scientific value, its implementation is completely possible, the identification and selection of the persons are suitable, the benefits are bigger than the risks, the checking will be done by experts in the matter, the informed consent is in relationship with the interests of the persons and assures the confidentiality.  The goals are clear, the reasons complement with the social value of the protocol, it is a pilot study, the checking methods are appropriate, it has not been defined yet which statistical method is going to be used, the researchers team is leaned in the institutional structure of the medical union.  The informed consent is adequate, and also the critical analysis of the risk-benefit and the selection of the doctors that will take part in the investigation.

In the third protocol: (breast and ovarian cancer) we cannot find clear goals, it lacks of the list of the researchers’ names with data sheet, the protocol does not meet the requirements of the Investigation and Ethical Committee (List of CIOMS), the biomedical techniques should improve.  It lacks of certainty in the goal of the investigation of the sample, the information is not sufficient, the recruitment of the persons is arguable, there are not enough statistical data, the way and the processing is insufficient, the introduction is not easy to understand, there is a lack of definition in the way the study is going to be made, the questionnaire is not being known, we can find an excessive use of medical slang and the panoramic view of the protocol does not adjust to the scheme.  For these reasons, and after following the above mentioned items the protocol must be rejected.

The fourth protocol (Autism) shows an investigation with social and scientific value, the clinic significances consists in the search of etiologic factors determinant in the autism diagnosis.  The implementation is adequate and it assures the continuity of  the procedure. The benefits surpass the risks. The checking is made by qualified people, the informed consent is understandable and adequate and assures the persons the continuity of the medical attention.  The goals of the investigation are precise, the experimental design appropriate, it posses a good checking criterion, appropriate methodology and selection of participants.

In the fifth protocol (medicines)  the signature of the informed consent is missing, the extension of the investigation is adequate, it indicates the fountain of subvention costs for difficult cases, the title of the investigation is appropriate, it indicates the previews steps of the study, the names of the people of the work team, it explains in the consent the subvention of the costs of transportation for the people involved in the investigation, it lay the foundation in the random sample, it meets the requirements of the amplification of the study profile, the incentives to the researchers.  Being solved all the above mentioned items, the project was approved.

DISCUSSION, CONCLUSIONS AND RECOMMENDATIONS

1. The correlation is adequate between the seven items that the author EZEKIEL EMANUEL and the two parts that meet the ethical requirements for the investigation by DIEGO GRACIA.
2. It is obvious that, in the actual state of the  investigation of Ethics in Perú, it does not exist agreement in the structure of the protocol of investigation of the various projects, mainly in the way the informed consent should be redacted.
3. We suggest the need to prepare a universal model of protocol of investigation, ethical qualification, and uniformity in  the way the informed consent should be redacted.
4. The model that meets the items of EMANUEL y GRACIA seems to us the most adequate for the ethical qualification of the future protocols of investigation.
5. It is evident the need of giving the researchers information about the existence of the informed consent, unspoken consent, implicit consent, etc.
6. In the current year it has been appearing new guides for the ethical committees of the investigation (for ex. CIOMS) that could modify in any way the assent we have today.

RESUME
We have been preparing a comparative critic of five protocols of Peruvian investigations. Their qualification  has been made by the Peruvian ethical committees and also supported by EZEKIEL EMANUEL y DIEGO GRACIA.  We  arrive to the conclusion that it is needed to apply the model of both authors for the  ethical qualification of the protocols of investigation of the corresponding committees, the need of information regarding the guides of qualification approved in the current year and the existence of various consents in relationship with the persons that participate in the investigations.

REFERENCES:

1. EMANUEL,E.: “What makes clinical research ethical? Seven ethical requirements”, en: Research on human subjects: international experience, 1999, 33-44, Regional Program on Bioethics, Santiago, Chile.
2. GRACIA,D: “Research on human subjects: Logical, historical, and ethical implications”, en: Research on human subjects: international experience, 1999, 59-78, Regional Program on Bioethics, Santiago, Chile.
3. RUTSTEIN: (citado por EMANUEL, 1999).

We recommend the reading of the following bibliography:
 
1. UNAIDS: “Ethical considerations in HIV preventive vaccine research”, May 2000, Ginebra, Suiza.
2. GARRAFA, V. et al.: “Bioethical language and its dialects and idiolects”, en: Cad. Saúde Pública, 1999, 15, (Sup. 1): 35-42, Rio de Janeiro.
3. OMS: Guías Operacionales Para Comités de Ëtica que revisarán Investigación Biomédica, 2000, Ginebra, (en prensa).