It gives a brief description about Phase IV clinical trial.

1. PHASE IV CLINICAL TRIAL
Dr Abisha T
Department of Pharmacology
AIIMS Jodhpur

2. CLINICAL TRIALS
A systematic study on pharmaceutical products in human subjects (including patients and other
volunteers) in order to
◦ discover or verify the effects
◦ identify any adverse reaction to investigational products
◦ to study the absorption, distribution, metabolism and excretion
of the products with the object of ascertaining their efficacy and safety.
Guidelines for good clinical practice (GCP) for trials on pharmaceutical products

4. PHASE 3 LIMITATIONS
◦ Limited sample size (few thousands).
◦ Short duration (3-5 years).
◦ Strict inclusion/exclusion criteria.
◦ No dose adjustment.
◦ No concomitant medications.
◦ Relatively uncommon side effects are likely to be missed.
◦ Special population are rarely included.

5. PHASE IV
◦ These are referred to as post-marketing surveillance studies.
◦ Phase IV studies comprise the obligatory post-marketing surveillance designed to detect any rare or
long-term adverse events resulting from the use of the approved drug in a clinical setting.
◦ Open label study.
◦ After a product has been placed on the market, clinical trials designed to explore new indications,
new methods of administration or new combinations, etc. are normally considered as trials for new
pharmaceutical products.
◦ No fixed duration.
Goodman and Gilman’s Pharmacological basis of thareapeutics

6. OBJECTIVES
⁕ Comparative long term Risk-Benefit assessment.
⁕ Long term drug usage in the community.
⁕ Quality of Life assessment.
⁕ Dose-refinement.
⁕ Rare ADR’s and long term safety.
⁕ Drug-drug interaction.
⁕ Cost-Benefit assessment.
⁕ Improvement in Primary End-points of disease.

7. Estimated Necessary Sample Size in relation to
incidence of Adverse Events

8. POSTMARKETING STUDY DESIGNS

9. I. Regulatory Authority mandated studies:
1. Drug-drug interactions.
2. Formulation advancement.
3. Special safety.
4. Special populations.
II. Non-Regulatory Authority mandated studies:
A. Randomized controlled trials:
1. Superiority versus equivalence testing.
2. Large simple trials.
3. PROBE designs.
B. Surveillance studies:
1. Pharmacovigilance studies.
2. Effectiveness studies.
3. Drug utilization studies.
4. Observational epidemiology studies.
III. Health services research (HSR).
IV. Health outcomes research (HOR).

10. Regulatory Authority mandated studies
A. Drug-drug interactions:
◦ Unanticipated, unrecognized, or mismanaged DDIs are an important cause of morbidity and mortality
associated with prescription drug use and have occasionally caused the withdrawal of approved drugs from
the market.
◦ Clinically relevant DDIs between an investigational drug and other drugs should therefore be:
(1) defined during drug development as part of assessment of the investigational drug’s benefits and risks.
(2) understood via nonclinical and clinical assessment at the time of the investigational drug’s approval.
(3) monitored after approval.
(4) communicated in the labeling.

11. ◦ For example, Terfenadine, a once-popular antihistamine, was removed from the market
because its metabolism was inhibited by CYP3A4 substrates such as erythromycin and
grapefruit juice.
◦ When DDI information has direct implications for the safe and effective use of the drug, this
information is often included in varying levels of detail in other sections of the labeling (e.g.,
boxed warning, dosage and administration, contraindications and warnings and precautions
sections)

12. B. Formulation advancement:
◦ Ease of drug administration, safety, affordability and efficacy are the major concerns in
pharmacotherapy leading to exploration of better drug delivery systems.
◦ Different carriers used in new drug delivery systems are liposomes, microspheres (intramuscular) and
nanoparticles (intravenous), pegylated proteins, polymeric gels, implants and anti-IgE monoclonal
antibody.
◦ For example, Diclofenac is available in stomach acid-resistant formulations (25 and 50 mg), fast-
disintegrating oral formulations (25 and 50 mg), powder for oral solution (50 mg), slow- and controlled-
release forms (75, 100 or 150 mg), suppositories (50 and 100 mg), trans-dermal patches (100 and
200mg) and injectable forms (50 and 75 mg).

13. C. Special safety:
Meta analysis can be done
-to evaluate a safety endpoint by statistical analysis of data from completed studies or clinical trials.
-to evaluate
◦ occurrence of all-cause mortality.
◦ cardiovascular death.
◦ cancer incidence.
◦ identify potential predictive factors.
in patients treated with the drug compared to control therapies in all completed randomized clinical
trials that include the drug.

14. D. Special population:
◦ Special populations which include women (non-pregnant and pregnant), pediatrics and the
elderly require additional consideration with regard to clinical research.
◦ The definition of ‘‘special population’’ exists to provide enhanced awareness of their
vulnerabilities, thereby allowing the creation of regulatory guidance aimed to decrease injury
or outright harm.
◦ There are very specific regulatory laws, which protect these special populations, that need to be
understood and adhered to in order to perform clinical research.

15. Women and pregnant population:
◦ One of the primary mandates of the regulatory authority was for the investigation of gender differences
related to drug safety and efficacy.
◦ In addition to tracking the rate of women participating in clinical trials and providing education, the office
of women health (OWH) under the regulatory authority funds a wide variety of studies to better
understand the role of gender and health.
◦ The OWH encompasses the mission of advancing the understanding of gender and health to the state of
pregnancy.
◦ Pregnant women very often receive or take medication and therefore, warrant protection from ‘‘off-label’’
experimentation by being included in the process of clinical trials where relevant.
◦ The Regulatory authority hosts a list of Pregnancy Exposure Registries which has information on drugs
and vaccines for pregnant women. Although, the registries are a great resource to find what data exist and
is being actively collected, drug information concerning pregnant women is frequently unavailable.
Therefore, many registries are seeking pregnant women for participation in a clinical study.

16. Paediatric population:
◦ The Code of Federal Regulations (CFR) states that research may include children if
(a) No greater than minimal risk to children is presented.
(b) Adequate provisions are made for soliciting the assent of the children and the permission of their
parents or guardians.
◦ There are two more categories of research as it applies to children:
(1) Research involving interventions or procedures that present a minor increase over minimal risk
without the prospect of direct benefit to the individual participant, but is likely to produce generalizable
knowledge about the child’s disorder or condition.
(2) Research which presents an opportunity to understand, prevent, or alleviate a serious problem
affecting the health or welfare of children. Research in this category must be reviewed and approved by the
regulatory authority.

17. Geriatric population:
◦ Regulatory authority recommends that drug sponsors include elderly people (>65 years) in
clinical trials, as well as requiring that drug sponsors report data by age.
◦ Individuals with Decisional Impairment are those who have diminished capacity for
understanding information or making a reasoned decision due to a cognitive or emotional
disorder.
◦ A legally authorized representative (LAR) may consent for these individuals to participate in
research studies. The LAR may be the spouse of a married person or any adult child.

18. II. Non-Regulatory Authority-mandated studies:
A. Randomized controlled trials:
1. Superiority versus equivalence testing.
2. Large simple trials.
3. PROBE designs.

19. RCTs
1. SUPERIORITY VERSUS EQUIVALENCE TESTING

20. SUPERIORITY TRIAL
o Demonstration of improved efficacy of a new treatment over
placebo/standard treatment meeting statistical significance.
o For serious illnesses, when a therapeutic treatment which has been
shown to be efficacious by superiority trial exists, a placebo-
controlled trial may be considered unethical. In that case the
scientifically sound use of standard treatment as a control should be
considered.

21. ◦ Example, PLATO - To determine whether ticagrelor is superior to clopidogrel for the prevention
of vascular events and death in a broad population of patients presenting with an acute
coronary syndrome. The cardio-vascular death (primary end point) was significantly less with
ticagrelor treatment when compared to clopidogrel treatment.

22. EQUIVALENCE TRIAL
◦ Demonstration of the absolute reduction of events achieved by one
treatment is similar to that achieved by another treatment. A trial
with primary objective of showing that the response to two or more
treatments differs by an amount which is clinically unimportant.
◦ For an equivalence trial, it is necessary to determine a “zone of
clinical equivalence” prior to the trial onset.

23. ◦ For example, consider standard and experimental anti-hypertensive drugs. Suppose that the
standard drug yields a mean reduction of 5 mm Hg in diastolic blood pressure for a certain
patient population. The investigator may decide that the experimental drug is clinically
equivalent to the standard drug if its mean reduction in diastolic blood pressure is 3-7 mm Hg.
This is based on clinical judgment and there may be differences of opinion on this 'arbitrary'
level of equivalence.
◦ Unlike a placebo-controlled trial, equivalence trial does not provide a natural check for internal
validity because equivalence of the experimental and active control therapies does not
necessarily imply that either of them is effective.

24. 2. LARGE SIMPLE TRIALS

25. ◦ Sometimes, an already marketed drug needs to be evaluated for a different condition than
existed for its approval or at a different dose, different release system, and so on.
◦ In that instance, the regulatory authority might mandate a phase IV RCT that has all the
characteristics of a classic phase III design.
◦ The concept of large simple clinical trials is to demonstrate even modest benefits of an
intervention, particularly in common conditions.
◦ The presumption in this trial is that the benefits are similar across participant types, so that the
entry criteria can be broad, and the data entry and management can be simplified, thereby
reducing the cost.

26. ◦ This model further depends on a relatively easily administered intervention and an easily
ascertained outcome.
◦ If these criteria are met, the size of the study also allows for a large enough sample size to
assess less common ADEs.
◦ For example, The Clinical Trial of Reviparin and Metabolic Modulation of Acute Myocardial
Infarction (CREATE). In this trial, more than 20,000 subjects from 21 countries were enrolled
to compare 2 therapies: glucose-insulin-potassium infusion and low molecular weight heparin.

27. 3. PROBE DESIGNS
[Prospective, Randomized, Open-Label, Blinded Endpoint]

28. ◦ A variation of the Large Simple Trial (LST) that also addresses a more “real-world” principle.
◦ By using open-label therapy, the drug intervention and its comparator can be clinically titrated,
as would occur in a doctor’s office, as compared to the fixed dosing of most RCTs.
◦ Blinding is maintained as to the outcome.
◦ To test whether the use of open-label versus double-blind therapy affected outcomes
differentially, a meta-analysis of PROBE trials and double-blind trials in hypertension was
reported by Smith et al. They found that changes in mean ambulatory blood pressure from
double-blind controlled studies and PROBE trials were statistically equivalent.

29. II. Non-Regulatory Authority-mandated studies:
B. Surveillance studies:
1. Pharmacovigilance studies.
2. Effectiveness studies.
3. Drug utilization studies.
4. Observational epidemiology studies.

30. SURVEILLANCE STUDIES
1. PHARMACOVIGILANCE STUDIES

31. ◦ Pharmacovigilance is the science and activities relating to the Detection, Assessment,
Understanding and Prevention of adverse effects or any other possible drug-related problems.
◦ It is known that in the occurrence of adverse drug reactions, other factors are involved, such as
the individual variation in pharmacogenetic profiles, drug metabolic pathways, the immune
system, and drug-drug interactions.
◦ In addition, the dose range established in clinical trials is not always representative of that used
in the post-marketing phase.
◦ Wider variety of dosages and diverse populations needs to be included in the premarketing
phase, and/or additional studies should be requested and enforced in the post-marketing phase.

32. Aim of Pharmacovigilance
• To improve patient care & safety in relation to
medicines & all medical & para-medical interventions
Patient Care
• To improve public health & safety in relation to the use
of medicines
Public Health
• To contribute to the assessment of benefit, harm,
effectiveness and risk of medicines
Risk Benefit Assessment
• To promote understanding, clinical training & effective
communication to health professionals & the public
Communication

33. Pharmacovigilance methods
Passive Surveillance
oSpontaneous reporting
oCase series
Stimulated reporting
Active Surveillance
oSentinel sites
oDrug event monitoring
oRegistries

34. Comparative observational studies
oCross- sectional study
oCase- control study
oCohort study
Targeted Clinical Investigations
Descriptive Studies
oNatural history of disease
oDrug utilization study

35. Periodic safety update reports (PSUR)
◦ The applicant shall furnish periodic safety update reports (PSURs) in order to-
(a) report all relevant new information from appropriate sources;
(b) relate the data to patient exposure;
(c) summarise the market authorisation status in different countries and any significant variations
related to safety;
(d) indicate whether changes shall be made to product information in order to optimise the use of
product.
◦ Usually all dosage forms and formulations as well as indications for new drugs should be covered in one
periodic safety update report.

36. ◦ The periodic safety update reports shall be submitted every six months for the first two years
after approval of the drug is granted to the applicant. For subsequent two years – the periodic
safety update reports need to be submitted annually.
◦ Central Licencing Authority may extend the total duration of submission of periodic safety
update reports if it is considered necessary in the interest of public health. However, all cases
involving serious unexpected adverse reactions must be reported to the licencing authority
within fifteen days of initial receipt of the information by the applicant.
◦ New studies specifically planned or conducted to examine a safety issue should be described in
the periodic safety update reports.

37. 2. EFFECTIVENESS STUDIES

38. ◦ Also called “real-world studies” or “pragmatic trials ”.
◦ It measures the degree of beneficial effect under “real world” clinical settings.
◦ The greater variance caused by the different kinds of confounders as well as problematic design issues,
such as insensitive primary outcome criteria, unblinded treatment conditions, inclusion of chronic
refractory patients, etc, can lead to wrong conclusions.
◦ Due to these methodological problems, effectiveness studies are on a principally lower level of evidence,
adding only a complementary view to the results of phase III trials without falsifying their results.

39. Advantages
◦ Higher external validity.
◦ Arguably greater applicability to “real-world”
practice settings.
◦ Capacity to inform policy process.
◦ Longer duration can be easily achieved.
◦ Can enroll large number of patients more easily.
Disadvantages
◦ Internal validity limited.
◦ Cannot be used to examine effective dose
ranges.
◦ Cannot make as meaningful clinical
comparisons between agents.

40. 3. DRUG UTILIZATION STUDIES

41. ◦ Drug utilization studies aim to evaluate “the marketing, distribution, prescription, and use of
drugs in a society, with special emphasis on the resulting medical, social and economic
consequences”.
◦ DUS are useful to estimate the number of patients exposed to specific drugs within a given
time period.
◦ Their scope is to evaluate the present state and future trends of drug usage, to estimate crudely
disease prevalence, drug expenditures, appropriateness of prescriptions and adherence to
evidence-based recommendations.

43. 4. OBSERVATIONAL EPIDEMIOLOGY STUDIES

44. ◦ Observational studies fall under the category of analytic study designs. The goal is to identify and
evaluate causes or risk factors of diseases or health-related events.
◦ Cohort studies and case-control studies are two primary types of observational studies.
◦ Randomized controlled trial methodology, which was first developed for drug trials, can be difficult to
conduct for surgical investigations. Instead, well-designed observational studies, can play an important
role in deriving evidence.
◦ Results from observational studies are often criticized for being vulnerable to the influence of
unpredictable confounding factors.
◦ However, recent work shows comparable results between observational studies and randomized
controlled trials.
◦ Observational studies can also complement randomized controlled trials in hypothesis generation,
establishing questions for future randomized controlled trials, and defining clinical conditions.

45. HEALTH SERVICES RESEARCH (HSR)

46. ◦ Due to the complexities of health care services and systems, investigating and interpreting the
use, costs, quality, accessibility, delivery, organization, financing, and outcomes of health care
services is key to informing government officials, insurers, providers, consumers, and others
making decisions about health-related issues.
◦ Health services researchers examine the access to care, health care costs and processes, and the
outcomes of health services for individuals and populations.
◦ The goal of HSR is “to provide information that will eventually lead to improvements in the
health of the citizen.”

47. ◦ As new diagnostic and treatment technologies are introduced, HSR examines their impact on
patient outcomes of care and health care costs.
◦ Six critical elements:
◦ Patient Safety.
◦ Effectiveness.
◦ Timeliness.
◦ Patient Centred.
◦ Efficiency.
◦ Equity.

48. HEALTH OUTCOMES RESEARCH (HOR)

49. ◦ It is a research aimed at assessing the quality and effectiveness of health care as measured by
the attainment of a specified end result or outcome. Measures include parameters such as
improved health, lowered morbidity or mortality, and improvement of abnormal states (such as
elevated blood pressure).
◦ It aims to:
(i) provide better information to inform patient decisions.
(ii) guide health providers.
(iii) inform health policy decisions.
◦ The scope of outcome research focus on Quality-of-life measures, Effectiveness, Cost, Quality
of care, Patient preferences, Appropriateness, Access and Health status in areas such as Disease
prevention, Screening, Drug treatment, Medical procedures, Medical practices, Diagnostic
tests, Guidelines and Health-care policy.

50. PHASE 4 OUTCOMES

52. BOX WARNING
◦ Approximately 20% of drugs acquire new black box warnings post-marketing.
◦ A black box warning is issued when reasonable evidence suggests an association of a
serious safety hazard with a drug product. A causal relationship does need to be established
for a black box warning to appear on a drug's labeling.

54. Drugs Withdrawn From the Market
4% of the drugs were ultimately withdrawn for safety reasons.

55. Role of Phase 4 in accelerated approvals
◦ After granting accelerated approval for such drug, the post marketing trials shall be required to
validate the anticipated clinical benefit.
◦ If the remarkable efficacy is observed with a defined dose in the Phase II clinical trial of
investigational new drug for the unmet medical needs of serious and life threatening diseases in
the country, it may be considered for grant of marketing approval by the Central Licensing
Authority based on Phase II clinical trial data.
◦ In such cases, additional post licensure studies may be required to be conducted after approval
to generate the data on larger population to further verify and describe the clinical benefits, as
per the protocol approved by the Central Licensing Authority.

56. SEEDING TRIAL
◦ Seeding trials are clinical studies designed by pharmaceutical companies with primary
intention to promote the use of drugs that were recently approved or are under review by
regulatory authorities.
◦ The purpose is
 To ‘seed’ the habit of prescribing the new drug into the trial investigators.
 To trigger a ‘switch’ of brands from a competitor product to the new drug, thereby
increasing volume of sales.
 To convert the investigators into brand ambassadors.

57. ◦ Adverse impacts:
 Quality is not reliable and the scientific validity and utility are usually limited.
 Physicians are manipulated into prescribing and promoting the drug.
 Lead to general mistrust of healthcare providers by society at large.
◦ Some well-known seeding studies are STEPS (Study of Neurontin: Titration to Effectiveness
and Profile of Safety) and ADVANTAGE trial (Assessment of Differences between Vioxx and
Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness).
◦ Hence these trials should be identified and discouraged by IRB/IEC.

58. REFERENCES
1. Guidelines for good clinical practice (GCP) for trials on pharmaceutical products.
2. Goodman & Gilman’s Pharmacological basis of therapeutics.
3. Glasser SP, Salas M, Delzell E. Importance and Challenges of Studying Marketed Drugs: What Is a Phase IV Study? Common Clinical
Research Designs, Registries, and Self-Reporting Systems. J Clin Pharmacol. 2007 Sep;47(9):1074–86.
4. Song JW, Chung KC. Observational Studies: Cohort and Case-Control Studies: Plast Reconstr Surg. 2010 Dec;126(6):2234–42.
5. Grimsrud KN, Sherwin CMT, Constance JE, Tak C, Zuppa AF, Spigarelli MG, et al. Special population considerations and regulatory
affairs for clinical research. Clin Res Regul Aff. 2015 Apr 3;32(2):45–54.
6. Zhang X, Zhang Y, Ye X, Guo X, Zhang T, He J. Overview of phase IV clinical trials for postmarket drug safety surveillance: a status
report from the ClinicalTrials.gov registry. BMJ Open. 2016 Nov;6(11):e010643.

59. THANK YOU