PHASE IV STUDIES

-D.SAIKRISHNA

Introduction
Also known as Post Marketing Surveillance Trial. Phase IV trials involve the safety surveillance

(pharmacovigilance) and ongoing technical support of a drug after it receive permission to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is designed to defect any rare or longterm adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials.

Introduction
Harmful effects discovered by Phase IV trials may result

in a drug being no longer sold, or restricted to certain uses: recent examples involve cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx). Companies also may evaluate different formulations of a drug (like sustained release).

Driving Forces.
Commercial: comparison with existing market

leader, trying new dosage forms and formulations Regulatory: fulfillment of post-approval regulatory commitment Academic: developing correlations with new diagnostic techniques or biomarkers, studying drugdrug interactions, experiences with the population that is unlikely to participate in clinical trials Safety: identifying new side effects, contraindications Efficacy: identifying new indications

Information gathered from Phase 4 Clinical Trials

Overall morbidity and mortality in very large sample of the patient population The place for the product in complex treatment algorithms where many alternative therapies may be possible in countless combinations Overall cost-effectiveness in routine medical practice, without the intensive interventions of a preauthorization study The incidence of rare suspected adverse reactions or specific benefits in patient subgroups Compliance in routine medical practice

Seeding Studies
Seeding studies are planned more for marketing

advantage than for a specific scientific reason. Their prime aim is to alter physician prescribing, and since this objective is nowhere mentioned in the protocol, such studies are held in very low esteem Regulatory authorities do not support the conduct of seeding studies that masquerade as Phase IV studies Such studies lack in control group, statistical power, safety and efficacy aim Such studies involve marketing representatives that clinical researchers

Quality of Life and Pharmacoeconomic Studies

QOL studies have been made mandatory by FDA Drug abuse and drug dependencies are

studied extensively in post-approval phase of research Cost of therapy can be studied widely in the post- approval phase since the product becomes commercially available Cost of therapy can be compared with the cost of the existing therapy

Study Design
Generally open label randomized studies
Market leader is used as comparator instead

of placebo Study population is very less restricted to reach close to the routine clinical practice They may involve 300 to 3000 patients They are long term studies to study long term safety profile of the drug

Periodic Safety Update Reports

Subsequent to approval of the product, new drugs should be closely monitored for their clinical safety once they are marketed. The applicant shall furnish periodic safety update reports (PSURs) in order to: Report all the relevant new information from appropriate sources Relate these data to patient exposure Summarize the market authorization status in different countries and any significant variation related to safety Indicate whether changes should be made to product information in order to optimize the use of the product

Periodic Safety Update Reports

Ordinarily all dosage forms and formulations as well

as indications for new drugs be covered in one PSUR. Within the single PSUR separate presentation of data for different dosage forms, indications or separate population need to be given. All relevant clinical and non-clinical safety data should cover only the period of the report. The PSURs shall be submitted every six months for the first two years after approval. For subsequent two years the PSURs need to be submitted annually

Classical phase IV research

Different chemical entities offering similar efficacy

and safety profiles: research work for differentiation Medicines within the same pharmaceutical class: research work to identify the best amongst the lot Demonstration of efficacy in different patient groups: different patient groups get exposed to the new drugs in post marketing surveillance New indication: Aspirin, and sildenafil are classical examples New dosage regimen: optimization of dosage regimen is possible with greater exposure

Categories of phase IV studies

Descriptive Studies: Provide information on pattern of disease occurrence in populations according to demographic and prognostic characteristics. Data used are routinely collected epidemiologic intelligence with is analyzed to identify the occurrence of rare adverse reaction or to generate a hypothesis. Passive monitoring of events and reports is an important method for collecting data included in descriptive studies.

Categories of Phase IV Studies

Cross- sectional Studies: They are also called as surveys or prevalence studies that involve a statistically based random sampling of a target population. Data are classified according to reported exposure to medicines and observed outcomes. Results pertain to a single point in time, and this type of study is therefore like a snapshot in time. If conducted retrospectively, it may be unclear whether exposure truly preceded the outcome.

Categories of Phase IV Studies

Case- control studies: They are always retrospective studies where cases have the disease and controls do not. Data are collected by looking backward in time to determine differences between the two groups in the past. Cases matched for confounding factors (e.g., age, sex) with one or more controls. Such studies may involve bias because of their nature yet generate important data especially incidence.

Categories of Phase IV Studies

Cohort Studies: A Cohort is a group that is exposed, and followed forward to a point in time when its members are evaluated retrospectively to look for differences in the frequency of one or more outcomes from a control unexposed group. If the case and controls both come from the same study population, the results of the study are more easily validated. It is imperative to ensue that both cases and controls are free from disease at the start of the observation period.

Categories of Phase IV Studies

Controlled clinical trials Comparison made with controlled Mostly carried out by Pharmaceutical companies Purpose is regulatory, commercial and safety in the post approval phase of drug development. Most validated hence more reliable Statically very sound

Categories of Phase IV Studies

Observational studies Records specific events that are occurring in a defined population without any intervention by the researcher

Phase IV studies are conducted to

Address unanswered questions arose during

Phases I,II,III Continue clinical trial initiated but not completed during Phase III Investigate interactions of new drugs Expose more patients to the new drug to confirm its efficacy and better understand its safety

 Determine if results obtained at tertiary care and excellent hospitals during Phase I-III can be confirmed in other hospitals as well as

when medicine is used by larger number of new physicians. Evaluate whether any rare but serious adverse reaction occur, or if the drug is a candidate for being abused

 Evaluate the pattern of a medicines utilization in a specific or general populations.

Study the clinical characteristics of over-

dosage and the means of counteracting this problem Assess the costs of adverse reactions to various sectors of society and develop the means to meet theses costs.

THE END