Studies in Support of Special Populations

1. Studies in Support of Special Populations

(This section is organised in the form of a book, please follow the blue arrows to navigate through the book or by following the navigation panel on the right side of the page.)

Some groups in the general population may require special study. This may be because they have unique risk-benefit considerations that need to be taken into account during medicines development, or because it can be anticipated their use of the dose or schedule will need to be modified.

Medicines should be studied in all age groups for which they will have significant use. Patients who participate in clinical trials should be reasonably representative of the population that will be later treated by the medicine.

In these studies, it also should be considered to obtain pharmacokinetic information (i.e. what the body does to the medicine (ADME) in the following sub-populations:

• patients with impaired excretion – i.e. those who may have difficulty removing the medicine from their body due to kidney or liver problems
• the elderly
• children
• women
• ethnic sub-groups.

Non-clinical safety studies should support human clinical trials in special populations – i.e. the special populations should be replicated in animal studies before human studies are carried out.

2. Pharmacokinetic Studies

Most of the recognised important differences between younger and older patients have been pharmacokinetic differences. This is often related to impaired excretion (due to kidney or liver problems) or interactions between medicines.

The information regarding age-related differences in the pharmacokinetics of the medicine can come either from a pharmacokinetic screen or from formal pharmacokinetic studies in the elderly and in patients who have problems with eliminating waste products from the body. It is important to find out whether or not the pharmacokinetic behaviour of the compound in elderly patients is different from that in younger adults. The effects of influences which are more common in the elderly, such as abnormal kidney or liver function should be characterised.

Pharmacokinetic studies in patients with kidney problems:

Kidney impairment is associated with aging but can also occur in younger patients. Therefore, it is a general principle, that medicines excreted mainly through the kidneys should be studied to define the effects of altered kidney function on their pharmacokinetics. To get this information, studies should include elderly participants. Alternatively, the information can be obtained in younger participants with kidney impairment.

Pharmacokinetic studies in patients with liver problems:

Medicines that are broken down and/or excreted in the liver, or that have active metabolites, may pose special problems of liver impairment in the elderly. Pharmacokinetic studies should also be carried out in elderly participants or alternatively, in younger people with liver impairment.

3. Pharmacodynamic or 'Dose Response' Studies

The number of age-related pharmacodynamic differences (i.e. increased or decreased therapeutic response, or side effects) discovered to date is small. Therefore, there is no need to complete dose response or other pharmacodynamic studies in elderly participants as a routine requirement.

Separate studies are, however, recommended in the following situations:

• Sedative/hypnotic agents and other psychoactive medicines or medicines with important central nervous system (CNS) effects
• Where sub-group comparisons (elderly versus younger) in the Phase II/III clinical trials database show potentially medically significant age-associated differences in the medicine’s effectiveness or adverse reaction profile, not explainable by pharmacokinetic differences.

4. Interaction between Medicine Studies (Medicines Interaction)

Interactions are of particular importance to elderly patients, who are more likely to be using more than one medicine at the same time (called ‘concomitant’ medicines). The use of concomitant medicines is not limited to the elderly age group.

Specific studies for the interaction between medicines should be considered when:

• The therapeutic range of the medicine or likely concomitant medicines is ‘narrow’ – i.e. there is not much of a gap between a potentially ‘safe and effective’ dose and a ‘toxic’ dose, and;
• The likelihood of the patient taking the two medicines together is high.

5. Stratified and Personalised Medicine

Stratified medicine is the use of a medicine that is targeted at a patient sub-population (a group or a proportion of patients), instead of using one medicine to treat all patients with a particular disease. The pharmaceutical industry is using this approach more and more in the development of new medicines.

Personalised medicine, on the other hand, aims to use targeted medicines and to take into account other information about the individual in order to tailor the treatment and management of the patient to their particular situation.

Both stratified and personalised medicine can also identify people at risk of developing diseases in the future.  

As these targeted medicines are by definition likely to be used by smaller patient groups the following challenges emerge:

• new trial designs, appropriate statistical methods
• new findings from molecular research and new technologies must be translated (adapted) for use in clinical trials
• proper design and development of companion diagnostics
• new techniques to discover and validate suitable biomarkers
• new reliable ways to collect and manage large amounts of data, e.g. from biobanks.

Further information about personalised medicine will be covered in other courses.

6. Studies in Elderly People

The elderly population will increase significantly over coming years. This means that the management of medicines for geriatric populations is an important issue. The use of medicines in this population requires special consideration due to the frequent occurrence of underlying diseases, use of concomitant medicines and the consequent risk of medicines interaction.

Not all potential differences that can occur in the geriatric population can be predicted from non-geriatric populations. This might include differences in:

• pharmacokinetics  - what the body does to the medicine
• pharmacodynamics - what the medicine does to the body
• disease-medicine interactions - interactions between the medicine and existing diseases
• medicine interactions - interactions between the tested medicine and other medicines the patient takes
• clinical response - the effect of the medicine on the disease.

The elderly patients are far more likely to have multiple illnesses and to be receiving multiple medicines.  Therefore, to assess the benefit-risk balance of a medicine that will be used in the geriatric population, elderly patients should be represented in clinical trials.

7. Studies in Pregnant Women

In general, pregnant women should be excluded from clinical trials where the medicine is not intended for use in pregnancy. If a woman becomes pregnant whilst receiving the medicine, treatment should generally be stopped (if this can be done safely).

For clinical trials that include pregnant women because the medicine is intended for use during pregnancy, it is very important to follow-up of the pregnancy, fetus, and child. In addition, safety data from previous human exposure should be evaluated.

• Toxicity studies must be included as well before pregnant women are included in clinical trials. The studies include female reproduction toxicity studies - studies that look at the risk of damage to reproductive organs.
• The standard range of genotoxicity tests - studies that look at the effect on genes.

8. Studies in Breast-Feeding Women

Excretion of the medicine or its metabolites into human milk should be examined where applicable. When nursing mothers are taking part in clinical trials, their babies should be monitored for the effects of the medicine.

9. Studies in Children

There is a need for clinical trials involving children to improve the treatment available to them. Children represent a vulnerable population - they have developmental, physiological and psychological differences from adults. Age and development related research is therefore important for their benefit.

Medicines for children need to be tested scientifically before widespread use. This can only be achieved by ensuring that medicines which are likely to be of significant clinical value for children are fully studied. The clinical trials required for this purpose should be carried out under conditions affording the best possible protection for the children who take part.

The extent of the studies needed depends on the current knowledge of the medicine. It also depends on whether data from studies in adults and children of other age groups can be extrapolated to the new age group. Some medicines may be used in children from the early stages of medicines development, however, for a medicine expected to be used in children, it should be studied in the appropriate age group. When clinical development is to include studies in children, it is usually appropriate to begin with older children before extending the trial to younger children and then infants.

In this case, investigators need to follow the EMA guidance (CPMP/ICH/2711/99) on clinical investigation of medicinal products in the paediatric population (infants, children and adolescents up to the age of 18 years). This guide is the primary guideline for paediatric medicines development in Europe and stablishes the age classification of paediatric patients. There is, however, considerable overlap in developmental (e.g., physical, cognitive, and psychosocial) issues across the age categories. Ages are defined in completed days, months, or years:

• Preterm newborn infants.
• Term newborn infants (0 to 27 days).
• Infants and toddlers (28 days to 23 months).
• Children (2 to 11 years).
• Adolescents (12 to 16/18 years, depending on region).

When paediatric patients are included in clinical trials, safety data from previous adult human experience would usually represent the most relevant information. This should generally be available before paediatric clinical trials begin. The appropriateness and extent of adult human data should be decided on a case-by-case basis. Extensive adult experience might not be available before paediatric exposures, e.g. for medicines that are for children only.

Before children are included in clinical trials, the following must be completed:

• Repeated-dose toxicity studies of appropriate duration in adult animals.
• The standard safety pharmacology information must be determined, and;
• The standard range of genotoxicity tests – studies that look at the effect on genes.

In line with the EU paediatric regulation (EC) No 1901/2006, as amended, a paediatric investigation plan (PIP) should be submitted early in the development of new medicines to make sure that the appropriate development in children is included.

The design of efficacy studies in the paediatric population is essentially similar to that required in adults. Depending on the type of medicinal product, a deferral (postponement) of the studies in children until efficacy and safety data are obtained in adults might be envisaged by the Paediatric Committee (PDCO), part of the European Medicines Agency (EMA).

For products not likely to be used in children (e.g. medicines for Alzheimer patients) the PDCO may grant a waiver so paediatric studies need not be performed.

10. Ethnic Differences

Although ethnic differences among populations may cause differences in a medicine’s safety, efficacy, dosage or dose regimen, many medicines do have comparable characteristics and effects across regions. Extensive duplication of clinical evaluation for every compound can delay the availability of new therapies and unnecessarily waste medicines development resources.

Once a clinical data package fulfils the regulatory requirements of a new region, the only remaining issue with respect to the acceptance of the foreign clinical data is its ability to be extrapolated (projected) to the population of the new region.

The Regulatory Authority or the sponsor may be concerned that differences in ethnic factors could alter the efficacy or safety of the medicine in the population in the new region.  If this is the case, the sponsor may need to generate a limited amount of clinical data in the new region in order to extrapolate or ‘bridge’ the clinical data between the two regions.

Characterisation of a medicine according to the potential impact of ethnic factors upon its pharmacokinetics, pharmacodynamics and therapeutic effects may be useful in deciding what sort of bridging study is needed in the new region.

No single property of the medicine can be used to predict sensitivity to ethnic factors.  Furthermore, the impact of ethnic factors upon a medicine’s effect will vary depending upon:

• Its pharmacologic class, e.g. the group of medicines it belongs to
• Its indication, and
• The age and gender of the patient.

The following properties of a compound make it more likely to be sensitive to ethnic factors:

• Differences in time or dose can arise from factors associated with absorption, metabolism, binding, and excretion.
• A steep pharmacodynamic curve for both efficacy and safety in the range of the recommended dose and dose regimen – i.e. a small change in dose results in a large change in effect.
• A narrow therapeutic dose range i.e. there is not much of a gap between a potentially ‘safe and effective’ dose and a ‘toxic’ dose.
• High metabolism, especially through a single pathway, thereby increasing the chance of interactions between medicines.
• Genetic modifications causing slightly different versions of an enzyme, can affect this enzyme’s metabolism.
• Administration as a pro-medicine (inactive medicine that is activated by metabolism), with the potential for differences in how it is converted across ethnic groups.
• High variation between participants in ‘bioavailability’, i.e. the amount of  the dose of medicine that reaches the bloodstream.
• Low bioavailability, so more prone to dietary absorption effects.
• High likelihood of being used alongside multiple other medicines.
• High likelihood for inappropriate use, e.g. analgesics and tranquilisers. 

11. Examples of Other Special Populations (Specific Patient Groups)

• Asthma patients (specific types of asthma).
• Patients with cardiovascular (heart) disease.
• Patients with chronic obstructive pulmonary disease (COPD) – lung disease.
• Patients with type 2 diabetes.
• People who are ‘poor metabolisers’ – who do not break down. substances well within the body.
• Healthy pre-menopausal women with regular menstrual cycles, with and without oral contraceptives.
• Hyperlipidemic patients (patients with abnormally high levels of lipids)
• Patients with high blood pressure.
• Hypogonadal men (men with an inadequate function of the testes).
• Obese people.
• Patients with peptic ulcer disease (PUD) or gastro-oesophageal reflux disease (GORD).
• Post-menopausal or surgically ‘sterile’ women (i.e. women who have had their uterus removed).
• Patients with certain types of cancer.