ETHICAL, LEGAL AND SCIENTIFIC ASPECTS OF DRUG DEVELOPMENT

DRUG DEVELOPMENT

• Refers to the process of taking a compound that has been identified from the drug discovery process described above through the subsequent steps necessary to bring it to market

PHASES OF DRUG DEVELOPMENT

• Discovery Phase

• Preclinical Development

• Clinical Development

• Regulatory approval

PRECLINICAL DEVELOPMENT PHASE

• includes the in vitro and in vivo assay

• Carried out in laboratories and in animals

PRECLINICAL DEVELOPMENT PHASE

• provide __

 preliminary evidence of safety and efficacy

PRECLINICAL DEVELOPMENT PHASE

• Information is used to

• support a request to begin testing among humans

PRECLINICAL DEVELOPMENT PHASE

• takes __ years 

3 to 6 years 

PRECLINICAL DEVELOPMENT PHASE

• only _ of cmpds are tested in humans

2%

PRECLINICAL DEVELOPMENT PHASE (SYNOPSIS)

• Out of 5000 new drug development projects that make it through initial computer modelling and in-vitro testing,

• only 5 will ever successfully pass prior to clinical testing in humans.

PRECLINICAL DEVELOPMENT PHASE (SYNOPSIS)

• Out of 5000 new drug development projects that make it through initial computer modelling and in-vitro testing, only 5 will ever successfully pass prior to clinical testing in humans.

• In the drug development, we identify the hit-to-lead, the target applicable for the potential lead compound

PRECLINICAL DEVELOPMENT PHASE (SYNOPSIS)

• There is less than a 0.1 % chance of a _

• Successful drug product being developed from inception to market.

PRECLINICAL DEVELOPMENT PHASE (SYNOPSIS)

• There is less than a 0.1 % chance of a successful drug product being developed from inception to market.

Must develop the compound in such a way that the ADME has been tested

PRECLINICAL DEVELOPMENT PHASE (SYNOPSIS)

• To reduce failure rate,

• additional safeguards must be placed on the drugs do make it to the animal testing phase to ensure that the percentage of drugs successfully passing preclinical trials is much higher than the current 0.1 %

PRECLINICAL DEVELOPMENT PHASE (SYNOPSIS)

• To reduce failure rate, additional safeguards must be placed on the drugs do make it to the animal testing phase to ensure that the percentage of drugs successfully passing preclinical trials is much higher than the current 0.1 %

• Must be safe for test animals because if not, we will not proceed with the drug development

PRECLINICAL DEVELOPMENT

Stage of research between drug discovery and clinical development.

PRECLINICAL DEVELOPMENT

Stage of research between drug discovery and clinical development. It involves the following:

1. Development of synthetic processes that will enable the compound to be manufactured in reproducible purity on large (multikilogram) scale.

2. Development of a formulation, in most cases a solution or suspension of the drug that can be administered to animals in toxicity tests and a solution or suspension or pill that can be administered to humans in clinical trials.

   • The dosage form must be safe for test animals and eventually safer for humans

   • Take note that the laboratory scale is different from the manufacturing scale

3. Toxicity testing in animals under conditions prescribed by the regulatory authorities in the region where the clinical trials will occur (the FDA in the US; the European Medicines Agency in Europe; the Japanese Ministry of Health and Welfare in Japan).

4. Following toxicity studies, gaining permission from the regulatory authorities to administer the drug to humans through Investigational New Drug (IND) application, which summarizes the discovery and preclinical development research done to date.

   • The document should contain the discovery and preclinical research and its results

PRECLINICAL DEVELOPMENT

Stage of research between drug discovery and clinical development. It involves the following:

• Development of synthetic processes that will enable the compound to be manufactured in

• reproducible purity on large (multikilogram) scale.

PRECLINICAL DEVELOPMENT

Stage of research between drug discovery and clinical development. It involves the following:

• Development of a formulation,

• in most cases a solution or suspension of the drug that can be administered to animals in toxicity tests and a solution or suspension or pill that can be administered to humans in clinical trials.

PRECLINICAL DEVELOPMENT

Stage of research between drug discovery and clinical development. It involves the following:

• Toxicity testing in animals under conditions prescribed by the

• regulatory authorities in the region where the clinical trials will occur (the FDA in the US; the European Medicines Agency in Europe; the Japanese Ministry of Health and Welfare in Japan).

PRECLINICAL DEVELOPMENT

Stage of research between drug discovery and clinical development. It involves the following:

• Following toxicity studies,

• gaining permission from the regulatory authorities to administer the drug to humans through Investigational New Drug (IND) application, which summarizes the discovery and preclinical development research done to date.

WHEN ARE ANIMALS THE MOST APPROPRIATE SAMPLES TO BE USED IN RESEARCH?

• When the mechanism is too complex for in vitro testing or use of lower form of animals to give conclusive results and is unethical to conduct the study on human beings (e.g. preliminary testing of drug safety and efficacy)

WHEN ARE ANIMALS THE MOST APPROPRIATE SAMPLES TO BE USED IN RESEARCH?

The animals used for the research objective should be appropriate

• Ex. Antitussive property - an animal that can produce a cough, such as a rat, as long as there is a machine and software that can measure the frequency. The machine and software should both be validated and backed up by studies.

ETHICAL CONSIDERATIONS IN ANIMAL STUDIES

• Avoidance or minimization of the use of animals by resorting to alternative methods, or if not possible, at least the number of animals that will be used in the study

• Avoidance or minimization of discomfort, distress, or pain as ethical imperatives

• Observance of humane way of anesthesia, surgery and euthanasia 

  • Sacrifice and properly dispose the animals

• Provision of best possible living conditions (same for OECD-451)

ETHICAL CONSIDERATIONS IN ANIMAL STUDIES

Avoidance or minimization of the use of animals by

resorting to alternative methods, or if not possible, at least the number of animals that will be used in the study

ETHICAL CONSIDERATIONS IN ANIMAL STUDIES

Avoidance or minimization of _ as ethical imperatives

discomfort, distress, or pain

ETHICAL CONSIDERATIONS IN ANIMAL STUDIES

Observance of __ of anesthesia, surgery and euthanasia

humane way

ETHICAL CONSIDERATIONS IN ANIMAL STUDIES

• Provision of

• best possible living conditions (same for OECD-451)

EXISTING GUIDELINES/LAWS/PROTOCOLS IN PROTECTING WELFARE OF ANIMALS

• INTERNATIONAL 

• CIOMS (Council for International Organizations for Medical Sciences) International Guiding Principles for Biomedical Research Involving Animals

• Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources, National Research Council, USA

CIOMS (Council for International Organizations for Medical Sciences) International Guiding Principles for Biomedical Research Involving Animals

Guidelines for human and animal research

Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources, National Research Council, USA

focuses on ethical justification, minimizing animal pain, ensuring necessity, and guiding researchers in proper animal handling.

EXISTING GUIDELINES/LAWS/PROTOCOLS IN PROTECTING WELFARE OF ANIMALS

• NATIONAL 

• Animal Welfare Act of 1998 (RA 8485)

• Department of Agriculture AO No. 40

• Philippine Association of Laboratory Animal Sciences (PALAS)

Animal Welfare Act of 1998

(RA 8485)

Department of Agriculture AO No. 40

– Rules and Regulations on the Conduct of Scientific Procedures Using Animals

Philippine Association of Laboratory Animal Sciences (PALAS)

• Code of Practice for the Care and Use of Laboratory Animals in the Philippines

• Drafted the code of ethics for the test animal and facility involved

REPUBLIC ACT 8485: ANIMAL WELFARE ACT OF 1998

• SECTION 6 

 It shall be unlawful for any person to torture any animal, to neglect to provide adequate care, sustenance or shelter, or maltreat any animals or to subject any dog or horse to dogfights or horse fights, kill or cause or procure to be tortured or deprived of adequate care sustenance or shelter, or maltreat or use the same in research or experiments not expressly authorized by the Committee on Animal Welfare.

UST‑IACUC

provides guidelines for the proper care, handling, and use of animals in research, ensuring that animal welfare is maintained and experiments follow ethical standards.

MAJOR CHALLENGES IN PRE-CLINICAL STUDY

• It centers on dosage. 

  • Human dosages are not equivalent to animal dosages; animal dosages are generally lower, and there is no standardized dose for animals; trial and error

• When examining the weight ratio of a mouse at 25 g versus the average human at 60 kg, then the ratio of 1:2400 would suggest that we must administer to the mouse 1/2400 of the anticipated human dose on a dose/kg basis.

• May be exorbitant in the number of animals sacrificed in order to find the dosage level (mg/Kg).

  • Many animals may be sacrificed to establish the proper dosage.

• Will this threshold really correlate to the quantity that must be administered to humans?

  • Very challenging because animal physiology can differ from one animal to another.

• Sensitivity to particular drugs and treatments will vary between species.

• Animal model itself was incapable of manifesting the adverse response evident in humans (ex. animal models for DM Type 1 and Type 2). 

  • It can take weeks or months to induce a disease in animals.

  • An alternative is using genetically modified animal models, which can be more cost-effective, but time-saving

MAJOR CHALLENGES IN PRE-CLINICAL STUDY

• It centers on dosage. 

• Human dosages are not equivalent to animal dosages; animal dosages are generally lower, and there is no standardized dose for animals; trial and error

MAJOR CHALLENGES IN PRE-CLINICAL STUDY

• When examining the weight ratio of a mouse at 25 g versus the average human at 60 kg,

then the ratio of 1:2400 would suggest that we must administer to the mouse 1/2400 of the anticipated human dose on a dose/kg basis.

MAJOR CHALLENGES IN PRE-CLINICAL STUDY

• May be exorbitant in the number of animals sacrificed in order to find the dosage level (mg/Kg).

• Many animals may be sacrificed to establish the proper dosage.

MAJOR CHALLENGES IN PRE-CLINICAL STUDY

• Will this threshold really correlate to the quantity that must be administered to humans?

• Very challenging because animal physiology can differ from one animal to another.

MAJOR CHALLENGES IN PRE-CLINICAL STUDY

• Sensitivity to particular drugs and treatments will

• vary between species.

MAJOR CHALLENGES IN PRE-CLINICAL STUDY

• Animal model itself was

incapable of manifesting the adverse response evident in humans (ex. animal models for DM Type 1 and Type 2).

• It can take weeks or months to induce a disease in animals.

• An alternative is using genetically modified animal models, which can be more cost-effective, but time-saving

PRE-TEST REQUIREMENTS AND RESOLUTIONS

• The model we will use has been proven or shown to be a reflection of the human counterpart and therefore there is a higher value to any data generated from the study.

  • Ensure the model is validated and reliable for the specific endpoints being studied.

• This requires that we have both in-vitro and computational studies to verify the evidence and increase the probability of a successful outcome.

• Previous information on the drug being tested or similar drug especially where it concerns previous animal models tested. 

  • We should gather prior evidence on the animal model, especially from previous studies using the same or similar drug

PRE-TEST REQUIREMENTS AND RESOLUTIONS

• The model we will use has been

• proven or shown to be a reflection of the human counterpart and therefore there is a higher value to any data generated from the study.

  • Ensure the model is validated and reliable for the specific endpoints being studied.

PRE-TEST REQUIREMENTS AND RESOLUTIONS

• This requires that we have both

• in-vitro and computational studies to verify the evidence and increase the probability of a successful outcome.

PRE-TEST REQUIREMENTS AND RESOLUTIONS

• Previous information on the drug being tested or similar drug especially where it

• concerns previous animal models tested. 

  • We should gather prior evidence on the animal model, especially from previous studies using the same or similar drug

PRE-CLINICAL STUDY

• Must be aware of the Good Laboratory Practice (GLP).

• Obtained results animal testing must undergo several checks for reliability before presuming there will be a correlating beneficial effect in humans.

• We should verify animal results before predicting human effects

PRE-CLINICAL STUDY

• Must be aware of the .

• Good Laboratory Practice (GLP)

PRE-CLINICAL STUDY

Obtained results animal testing must undergo

several checks for reliability before presuming there will be a correlating beneficial effect in humans.

GLP PRINCIPLES

• Apparatus, materials, reagents

• Test systems

• Test and reference substances

• Standard Operating Procedures

• Facilities

• Performance of studies

• Reporting of study results

• Storage and retention of records and materials

• Testing facility organizations and personnel

• Quality assurance program

PHARMACEUTICAL DEVELOPMENT OF MEDICINE FOR USE

• Selecting appropriate routes of administration and dosage forms

• dosing frequency excipients

• container closure systems

• devices and technologies

• user instructions in the product information

• Drug developers are encouraged to take a patient-centric approach to pharmaceutical development, i.e. to design medicines that take into account the disease, disease setting and the needs of patients, including older people with co-morbidities and polypharmacy

PHARMACEUTICAL DEVELOPMENT OF MEDICINE FOR USE

• Selecting appropriate routes of administration and dosage forms -

• according to the results generated from the test animals, and consider the applicable route and dosage form (e.g. tablets or injectables), depending on the type of medicine (e.g., diabetes or hypertension)

PHARMACEUTICAL DEVELOPMENT OF MEDICINE FOR USE

• Dosing frequency

• – (e.g. once a day or three times a day)

PHARMACEUTICAL DEVELOPMENT OF MEDICINE FOR USE

• Excipients

• - ensure they are safe and acceptable for all populations (e.g., gelatin  not allowed for Muslims)

  • must be compatible with the extract 

  • in FTIR, the peaks of the API and other important components must still be present, 

  • you can also use HPLC to check the contents

PHARMACEUTICAL DEVELOPMENT OF MEDICINE FOR USE

• Container closure systems

• - Ensure containers prevent dosage degradation; product must be stable

PHARMACEUTICAL DEVELOPMENT OF MEDICINE FOR USE

• User instructions in the product information

• - should be in layman’s terms so every patient can understand

PHARMACEUTICAL DEVELOPMENT OF MEDICINE FOR USE

• Drug developers are encouraged to 

Take a patient-centric approach to pharmaceutical development,

• i.e. to design medicines that take into account the disease, disease setting and the needs of patients, including older people with co-morbidities and polypharmacy

ETHICAL BEHAVIOR

• Integrity

• Information sharing

• Accurate prescription

• Transparency

• Objectivity

• Fairness

• Care for and about people

UNETHICAL BEHAVIOR

• Misleading advertisement (claims should have evidences)

• Personal interest - benefit majority

• Misguiding prescription - not similar to competitor product

• Subjectivity

• Partiality

• Selling of samples to public

• Uncontrolled testing - should have IRB approval

PHARMACEUTICAL DEVELOPMENT STRATEGIES

• Laws in pharmaceutical industry

• Patent - to secure the individuality of the drug

• Generics

• Good Manufacturing Practices 

• Industrial pharmacists (research and development, regulatory affairs)

• Drug information - Information regarding the product should be available for the consumer and the healthcare professional

• Sales marketing

GENERAL ETHICAL PRINCIPLES IN CONDUCTING TRIALS

• Respect for persons

• Beneficence (do good, no harm)

• Justice (no bias)

ELEMENTS OF A CLINICAL TRIAL

All elements must be included and properly executed in the company or during the project

• Aim or objective

• Protocol : study design

• Ethics committee clearance

• Regulatory approval whenever required

• Informed consent

• Implementation of protocol

• Collection of data

• Compilation of data, analysis and interpretation

• Report writing

PARTICIPATING PARTIES IN CLINICAL TRIAL AND FUCNTIONS

• Patient/Healthy Volunteer

• Clinical Pharmacologist, Clinical Investigator & team

• Institution where trials are held

• Ethical Review Board or Institutional Ethical Committee

• Sponsor

• Regulatory Authorities

Patient/Healthy Volunteer

Subject of the trial

Clinical Pharmacologist, Clinical Investigator & team

• Conducts the clinical trials; reports all adverse events

• Qualified and competent

Institution where trials are held

Provides all facilities [Approval required]

Ethical Review Board or Institutional Ethical Committee

• Supervises and monitors every step

• Safeguard of welfare and the rights of the participants

Sponsor

• Pays for all expenses;

• Appoints competent investigators,

• Ships all drugs for the trial,

• Files all papers to legal / regulatory authorities

Regulatory Authorities

Legal authority on the outcomes of the trial

CLINICAL TRIAL PROTOCOL

• A document that is submitted prior to the approval of a clinical trial

TITLE AND ABSTRACT

• introduction

• goals

• study design

• data analysis 

INTRODUCTION

• General statement of purpose

• Complete Preclinical results on animal study

• Time frame

GOALS

Primary and secondary Objectives

STUDY DESIGN

• Type of study

• Recruitment criteria: Exclusion and Inclusion criteria

• Randomization criteria and Sample Size

• Duration of study

introduction: time frame

• Include statement or purpose, animal studies (required by regulatory agencies like the IRB, REC, FDA), clinical data, timeframe of clinical trials, objectives of the study, exclusion and inclusion criteria

Recruitment criteria: Exclusion and Inclusion criteria

• An exclusion criterion is not just the opposite of the inclusion criteria

• Sometimes we include a withdrawal criteria

Randomization criteria and Sample Size

Usually around thousands

Duration of study

Depending on the sponsor’s budget, but much better if it requires a long period of time for the clinician, or the regulatory authorities to further assess the results of the clinical trial

DATA ANALYSIS

• Case report forms

• Statistical Analysis

• bibliography 

Statistical Analysis

Data analysis should be in coordination with a statistician or an expert in analysis should be present or a member of the research team

INFORMED CONSENT /  FORM

• Voluntary

• Explained in simple nontechnical language

• Translated in the native language of the subject

• Comprehensive information regarding the trials

• All possible adverse reactions

• Freedom to withdraw from the trial

  • at any time,

  • without giving any reason

INFORMED CONSENT /  FORM

• Translated in the native language of the subject

• Explain in a simple and layman language especially with the use of placebo. 

• We explain why we add placebo in the study

INFORMED CONSENT /  FORM

• Comprehensive information regarding the trials

• Benefit of new therapy over existing ones

• Alternative treatments available

INFORMED CONSENT /  FORM

• All possible adverse reactions

Declare all the possible risks such as a change in urine

INFORMED CONSENT /  FORM

• Freedom to withdraw from the trial

  • at any time,

  • without giving any reason

The patient has the right to withdraw or terminate his/her participation without any monetary fee

SCIENTIFIC AND SOCIAL VALIDITY

• Governed by clinical equipoise

• Should be performed using the proper study design

• Methodologic issues addressed

• Use of placebo

• Relevant outcomes

SCIENTIFIC AND SOCIAL VALIDITY

• governed by 

clinical equipoise 

SCIENTIFIC AND SOCIAL VALIDITY

• should be performed using 

proper study design 

CLINICAL EQUIPOISE

• Patient may be assigned to

• different subgroupings and these circumstances must be explained to the patient

Wash out period

- is a time wherein the administered drug is being eliminated from the body to prevent drug interference from the previous administered drug because, they are trying to induce a new metabolite

CLINICAL EQUIPOISE

• Based on available data

• – there is genuine uncertainty within the expert medical community about the preferred treatment (Freedman, 1987)

CLINICAL EQUIPOISE

“The point at which a rational, informed person would

have no preference between two (or more) available treatments (Lilford and Jackson 1995)

CLINICAL EQUIPOISE

Thus they would be content to have their patients/client __

pursue any of the treatment strategies being tested since none of them has been clearly established as preferable.

• Especially if the IND is a new molecule 

• Some trials may give the participants payment

CLINICAL TRIAL DESIGN

• Use of treatment and control groups

• Let the investigators know what would have happened had they not received the test intervention

• Randomized, controlled clinical trial as “gold standard” for testing a new medication or therapeutic device

CLINICAL TRIAL DESIGN

Control group :

(permits investigators to determine whether an observed effect is caused by the experimental intervention or due to other factors)

Control group (permits investigators to determine whether an observed effect is caused by the experimental intervention or due to other factors):

• Natural progression of the disease

  • Induce the disease (in animal model, won’t be treated, for observation only

• Participant of observer expectations

• Differences in treatment (or follow-up)

• Differences in baseline characteristics

  • Usually untreated but can be altered depending on the research

Parallel Group -

• divide subjects into equal groups and without bias and simplest design.

• Usually done in patients with INFECTIOUS diseases

Cross-Over

• - one group of subjects takes one drug first, then switches to another after a washout period for comparison.

  • Can only be done in CHRONIC illnesses

  • NOT POSSIBLE for INFECTIOUS diseases

Factorial

- test multiple treatments/factors at the same time to see individual and combined effects and most complex design

METHODOLOGIC ISSUES

• Randomization/ Randomization concealment

• control

• binding

• intention to treat

• baseline characteristics