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Research Article | DOI: https://doi.org/10.31579/2693-4779/204
1Riggs Pharmaceuticals, Karachi. Department of Pharmacy, University of Karachi-Pakistan
2Head, Department of Pharmacology, Fazaia Ruth Pfau Medical College Air University Karachi, Pakistan
3Assistant Professor,Department of Microbiology University of Karachi, Pakistan
4GD Pharmaceutical Inc OPJS University Rajasthan India
5Assistant Professor, Dow University of Health Sciences Karachi Pakistan
*Corresponding Author: Rehan Haider, Riggs Pharmaceuticals, Karachi. Department of Pharmacy, University of Karachi-Pakistan.
Citation: Rehan Haider, Asghar Mehdi, Anjum Zehra, Geetha Kumari Das, Zameer Ahmed, Sambreen Zameer, (2024), Phase IV Drug Development:Post-Marketing Studies, Clinical Research and Clinical Trials, 10(2); DOI:10.31579/2693-4779/204
Copyright: © 2024, Rehan Haider. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 18 April 2024 | Accepted: 15 May 2024 | Published: 27 June 2024
Keywords: phase IV; post-marketing studies; drug safety; real world effectiveness; pharmacovigilance; risk-benefit profile
Phase IV drug incidents surround post-marketing studies, and subsequently, a drug has been approved and made feasible for all. These studies aim to judge a drug's real-life influence, security characterization, and long-term effects in a better and more varied community than those studied in the former chapters. Unlike pre-shopping points, Phase IV studies are observational or exploratory, depending on the dossier collected from routine dispassionate practice.
Key aims of Phase IV studies involve recognizing rare or unending unfavorable belongings, determining drug interactions, surveying off-label uses, and equating the drug's acting against contestants or standard treatments. These studies frequently include big epidemiological research, patient registries, backward-looking analyses of photoelectric energy records, and following wholes like pharmacovigilance databases.
Phase IV studies play a critical role in apprising healthcare conclusions, leading regulatory conduct, and forming dispassionate directions. They provide valuable judgments into a drug's overall risk-benefit description. Of course, healthcare providers create informed situational resolutions and guarantee patient security. Moreover, these studies contribute to constant improvement in pharmacotherapy by simplifying the continuous refinement of drug menus, prescribing directions, and risk administration strategies.
In summary, Phase IV drug incidents show a critical stage in the lifecycle of drug products, contributing to an inclusive understanding of a drug's evident-realm performance and providing the growth of patient care. Keywords: Phase IV, post-shopping studies, drug security, real-experience influence, pharmacovigilance, risk-benefit sketch.
Objectives of the phase IV Clinical development Program Phase IV studies (in some guests subdivided into aspects IV and V) are generally administered afterward initial output authorization (even though, seldom, few may start superior to merchandise, accompanying the risk that the product is illegal on schedule, but accompanying the potential to gain an aggressive benefit) [1]. The range of purposes of phase IV studies is broader than the former stages of drug incidents. There is customarily no need to support pivotal evidence of productiveness (upon any less condition than new, second evidence). for the drug is wanted). Table 10.1 epitomizes the typical aims and strategies of step IV studies [2]. The Aspect IV studies in a few companies are completed activity apiece original happening crew that again did points II and III. Some parties view this is attractive cause these are the people accompanying that warehouse of facts, for the whole past of the drug, who can spot or get narrow occurrences that power merit review course in phases IV and V.[3] Some of the public will love following the drug through the allure of the complete biological clock, and will be glad for that time.[4] However, possible choices are either unwilling or impotent to develop from a usual-oriented to a concerning business-familiarize approach to dispassionate tests, and when these are nearly all, Some parties will, before starting a different abandonment, gradually become familiar with the administrative structure. Types of development IV studies the conventional traits of step IV studies, in contrasting with chapters I, II, and III, so are that they are best, less technically difficult, have lean inclusion/expulsion tests and are more inclined to involve emotional or qualitative endpoints (for instance, characteristics of existence or patient satisfaction) [5]. Rigorous, placebo-regulated, parallel-group studies still find a place; however, when a bendable insane license is used for a new clue, being examined {6{. As a particular forum enhances busier, the contest for places in formularies and for reimbursement increases, and few phase IV studies are planned specifically: Cally to support facts for services and healthcare transmission organizations either finalized a suggestion of correction; fake pill-reserved studies are usually incompetent for this purpose (unless the (The brand is singular.). Table 10.2 summarize as
Table 10.1 Typical goals and tactics of phase IV clinical trials
The draft ICH Guidance on pharmacovigilance (ICH E2E, 11 November 2003) is likely to cause greater emphasis on the penultimate item of the shadings and challenges of attending phase IV troubles. The type of agent the one inquires during the time IV incident must correspond to the type of study. Usually, the best numbers of investigators the one each donate fewer cases than the time II and III investigators are wanted. If such things are local or civil ideas, pasture deeds, who will ultimately advocate for the device, so much the better. But even at the local level, it is these investigators who may establish ward formulary bureaus, expand local situation algorithms, see extreme books of patients, and are alive in local medical organizations. Comparative superioty trials Well-designed, very close, and evenly contested, alive comparator studies are still continually to be favorites over the.
meta-analytical comparisons of placebo-controlled studies of different drugs, which were conducted at different times and in different places. The general aim is to compare the new drug with a widely recognized ‘gold standard’ [7]. This ‘gold standard’ might be the prototypical drug in the same pharmacological class (e.g., a clinical trial comparing a new cephalosporin with an old one), or it could be a hitherto dominant therapy or procedure (e.g., comparing a proton pump inhibitor with an H2 antagonist, or conservative management with a new drug versus surgery). Sometimes, a change in pharmaceutical formulation may have occurred, and, even after approval, there may be questions over its superiority, patient preference, or economic advantage compared with the formulation that was initially approved Makuch and Johnson, 1986,1989) [8,9]. Open-label studies Conducting open-label studies can be liberating and fascinating experience. When both patients and the prescriber know the treatment being administered, many of the complexities of early-phase studies go away. Furthermore, when it is appreciated that double-blind clinical trials are always an abstraction from the ordinary clinical situation, to observe how one’s new drug actually works in that latter environment is often eye-opening; one a common and pleasant experience to see with one’s own eyes, how conservative was the estimate? of product efficacy prior to its approval.
This ‘real-world’ environment can be studied at length and relatively economical, too. Longitudinal study designs (e.g. the Framingham Study or the UK Physicians Cohort Study can assess multiple effects of treatment: pathological, economical, quality of life and even epidemiological impacts can be assessed. One can also find out what sort of patient one’s drug will be prescribed to, which may or may not resemble the patient population pre-PLA/NDA, and which may suggest unknown benefits and hazards of the new therapy. The open-label trial approach is, however, not without its critics. Friedman et al. (1985)[ 10] drew attention to the need to observe whether the cohort being followed represents the larger population for whom the drug is being prescribed; the treatment groups are truly comparable, as patients are often matched on only one or at most a small number of clinical characteristics. the need to check that randomization, or at At least patient allocation has not become unbalanced or biased as a result of some unspecified factor. Another difficult aspect in the design of open-label studies is how one assesses those patients who withdraw from the study. The reasons for withdrawal can be at least as varied as in double-blind studies (intolerability, administrative difficulties, coincidental emergent disease or concomitant therapies, etc.). However, in addition, in an open-label design, patients may develop an opinion on the superiority of one or other treatment for reasons that may or may not be explicit. If completion of a course of therapy is one endpoint of the study, then All withdrawals can be accounted for for treatment failures, and the statistical handling is fairly straightforward. However, if there is another endpoint, and If withdrawals are imbalanced between the treatment groups and unrelated to product intolerance, then the situation becomes a lot more clouded. Under these latter conditions, the entire trial may have to be abandoned when it becomes apparent that the trial design cannot answer the hypothesis under test one way or the other. On the positive side, open-label trials are usually easy to administer, and patient recruitment and longevity within each treatment group can easily be monitored as the study progresses. Investigators have greater freedom in entering and allocating patients, and this is often more comfortable than a placebo-controlled situation in the ordinary clinical setting Equivalence trials Sometimes, the demonstration of equivalency is satisfactory. efficient, especially when the competing product cannot be expected to be inferior or when a successor the product can be marketed at a lower price than the innovator. In the special case of generic products, at the very end of a drug’s life cycle when patent coverage has expired, equivalence needs only be demonstrated pharmacokinetically (usually involving only a small number of normal volunteers and the relevant, specific types of regulatory applications). However, when the new product challenges the position of an older one, then equivalency trials usually require very large numbers of patients (often hundreds per treatment group). The overall tactic is to show that with a well-powered study (e.g. b ¼ 0:925) There is no clinical or statistical difference between the two treatments. The size of the clinical difference that is worth detecting is the sine qua non-defined prospectively and forms the basis for the power calculations, and hence study size. Mega-trials When it is suspected that there may only be a small difference between active treatments, and when placebo controls are unavailable for clinical or ethical reasons, then it is often necessary to resort to large-scale studies (‘mega-trials’). A good, famous example was the clinical trial known by the acronym GUSTO, where streptokinase and recombinant tissue plasminogen activator (t-PA) were compared for acute coronary thrombosis (for a commentary Hampton, 1996) [11].
Unlike more orthodox studies, mega-trials do not attempt to control for large numbers of confounding variables. Instead, huge numbers of patients (tens of thousands) are randomized, ‘the cards are allowed to fall where they may, and faith is placed in the notion that a large n will automatically lead to well-balanced treatment groups. This is not always the case, and imbalance can often be demonstrated between treatment groups of even several thousand when enough concomitant confounding factors are analyzed (Charlton, 1966)
Safety surveillance The draft ICH Guidance E2E issued on 11 November2003 provides a framework for the pharmacovigilance of new drug products.[12] Each new product should have a pharmacovigilance specification, which describes the clinical hazard landscape for the new product, as far as it can be known at the time of approval. The specification is essentially a problem statement. Each specification should then be accompanied by a pharmacovigilance plan. The plan might include routine adverse event reporting and periodic safety updates are to be provided to regulators, and/or recommendations for clarifications to product labeling. In special cases, however, a post-marketing surveillance the study might be recommended, and these forms another type of phase IV study. It is typical before conducting a post-marketing surveillance study to obtain the view of the regulatory authorities on its design. The study may have been a condition of product approval, and it is both reasonable and wise to ensure that the study design can be expected to provide the information that is needed both by the sponsor and the regulators. Unblinded designs that imitate the ordinary clinical situation are the norm. New indications As in the early phases of drug development, the identification of new indications for old drugs can be both rational and serendipitous. Rarely, even adverse events can be exploited as new indications, and the hair-growing properties of the antihypertensive drug called minoxidil are a famous example.
Finding a new indication is an obvious opportunity to increase market size by enlarging the potential pool of patients who can benefit from the product. In this case, two pivotal, well-controlled phase IV studies demonstrating efficacy will usually be required, at a minimum. If there is the potential for a new type of clinical hazard to be associated with a new disease being studied, then a safety database, of a size that regulators will find acceptable, will be needed for the supplemental application, too. Whenever such a project is contemplated, then a financial assessment is needed of the balance between the cost of the program, the probability of success and the size of the eventual revenue increment that may or may not justify it.
The finding of a new, non-obvious use for an old drug can also be patented. This type of patent is known as a ‘Method of Use’ patent, and its eventual enforcement is probably easier in the United States than in other jurisdictions. Nonetheless, the view of the corporate patent attorney on any proposed phase IV exploration for a new indication should always be sought.
Stimulation of the process of finding new uses for old drugs is often done when companies offer investigator research grants. It is fairly common that individual prescriber will have bright ideas about the use of medical products, and indeed some specialties use most drugs ‘off-label’ (e.g. intensive care physicians, anesthesiologists, and pediatricians). Small grants to such individuals, in order to observe such niche uses under organized circumstances can lead to new indications. At the very At least, such programs encourage the disclosure of new ideas to the company and allow for some review of the safety aspects of what these inventive individuals are getting up to!
New dosage forms Initial dosage forms are usually those that are the most easily developed, most stable, and at least reasonably acceptable to adult patients. Such formulations can often be improved upon, whether for matters of convenience (e.g. a bioequivalent melt-in-the-mouth wafer that, unlike a tablet, does not require access to water for its administration) or to enlarge the patient population that might use the product (e.g. a linctus instead of a tablet for use in children or to permit smaller increments in dose adjustment). Again, when there are serious physicochemical constraints on formulations, the discovery of a new one can itself be patentable.
A variety of regulatory approaches are needed when adding to the range of formulations, and each, in turn, dictates a different phase IV clinical trial design. When the route of administration does not change (e.g. the wafer vs. tablet example above), then orthodox bioequivalence and absence of formulation-dependent intolerability might be all that is needed. A pseudo-phase I the approach during phase IV might then be all that is required. On the contrary, the new formulation might be deliberately designed not to be bioequivalent. Slow-release formulations are, by definition, not bioequivalent but often associated with therapeutic superiority due to reduced probability of Cmax-related adverse events and better compliance because of reduced dosage frequency. In this case, efficacy data will normally be required of the scale and rigor of the earlier phase III program. It should be noted that the company might be wise to consider, when developing new formulations, that the minimum database acceptable to regulators might be insufficient for their purposes. The decision to launch a new formulation has to be based not only on its technical success but also, according to a financial analysis of the type referred to above for new indications. Crucial information on that question can usually only be obtained by studying the new formulation using one of the other authentic phase IV approaches described in this study Special populations In the United States, many product approvals now come with a condition that future studies in children are mandatory. This is probably the most common special the population that phase IV development units now routinely deal with. Other, newly identified special populations result from pharmacovigilance signals, unexpected use of the product in an unanticipated population, requirements for regulatory filings in non-ICH nations, or even the spread of disease into new geographical areas. Traditional pharmacokinetic approaches are usually the first step in assessing whether these events will alter product efficacy or safety.
Drug interactions
These are essentially another form of special population, and almost all drugs can exhibit at least some interactions. Many PLA/NDAs will contain studies of particular drug interactions that seem relevant at the time, especially when the combination therapy is the norm, or when there are biochemical predictions that a new drug will interact with older therapies (e.g., cytochrome P450 isoenzymes findings in vitro). Pharmacokinetic studies are typically done on a small scale. But, in addition, the phase IV team might be asked to do a retrospective case-controlled analysis of the existing clinical trials database trawling for differences between patients who were and were not on a particular concomitant therapy.
The clinical-marketing interface as mentioned, one purpose of a phase IV clinical the trial program is to gather new indications or information that can lead to a competitive advantage.
Optimization of the clinical–legal interface is critical to ensure success. It is the marketing team that is the keeper of the strategy, aware of the competitive environment (both current and future tutors; within and outside of the class of the drug under development) and closest to the commercial environment that the drug will have to compete in (e.g., Formulary issues; pricing concerns). In order to ensure that the product is commercially successful, the clinical team needs to embrace this information when developing a phase IV clinical trial program. It is especially important when entering a very competitive, highly developed marketplace (e.g., Diabetes or hypertension) where there are multiple treatment options or a lack of perceived differences between members of a particular drug class. It is also important for new classes when there will be a within-class competition launching within a short timeframe. In these cases, the label may be similar, especially in the
United States where there has been a trend in recent years to have drugs within the same class have similar labeling verbiage (i.e., ‘class labeling’). In the absence of ‘current’ labeling differences between competitors, it is sometimes the robustness of the phase IV clinical trial program that will differentiate competitors, as it is seen as a harbinger of future indications or positive data. These programs also highlight to the scientific and community the ‘commitment’ that the company has to the drug and the disease state. For these reasons, it is critical that the clinical and marketing teams collaborate extensively on the phase IV development program, usually via a standing commercialization team with representatives from other functional areas that will provide sound input into the program to increase its chance of success (e.g., Regulatory and legal).
The marketing team should provide the commercialization team with a clear understanding of the market environment, including past promotional behavior of key competitors, so that a robust need assessment can be formulated. Once the commercial case has been made, the clinical teams should provide a scientific risk assessment that includes the likelihood of success in achieving the desired outcome. If the ultimate goal of a given study is for promotional purposes, it is helpful for the marketing team to provide examples of how that data are intended to be promoted to ensure that the the trial is designed to ultimately allow for those promotional messages. With the financial stakes so high, it is no longer acceptable for clinical teams to view their roles as purely scientific. Success for a product is no longer dependent solely on the approval of indications. In our information-driven society, consumers of scientific information are always looking for new information to continue to support their use of a product. Effective collaboration between clinical development and marketing teams in the context of phase IV trials can go a long way toward optimizing sales of an effective drug. The clinical–legal interface Concern about product liability can decline and increase as phase IV proceeds. If, on the one hand, the sudden exposure to large numbers of patients to a new drug (i.e., large in comparison to those in the PLA/NDA) does not result in a flurry of serious adverse events, nor any signal of a qualitatively new type of adverse event, then there is reassurance that the label is probably doing its job properly However, when anything new is discovered about a drug in phase IV, then, by definition, it will not be on the product label. Furthermore, sometimes, when such a signal is observed, a retrospective trawl through the preclinical and clinical databases can often uncover consistently information whose significance had not been earlier realized. In this case, a ‘gap’ exists between what is known about a drug and what information has been provided to prescribers.
The gap may exist for a very short period of time because of a prompt change in product labeling and the company will have done everything appropriate as fast as possibly could. In some cases, the ‘gap’ might exist due to a very rarely occurring adverse event of questionable direct association with the product, which does not warrant inclusion into the label. However, on other occasions, the ‘gap’ will need to be urgently addressed. The range of actions that might be needed, in increasingly alarming order, are design/implement purpose-built phase IV study change in the label at the next routine printing more urgent change in labeling assuance of ‘Dear Prescriber/Doctor/healthcare professional’ letter institution of restrictive access program product withdrawal.
The phase IV development program will almost always generate information that is relevant in choosing from among these alternative actions. The corporate lawyers will always be depending on the phase IV clinicians to determine the appropriate course of action due to their knowledge of the post-marketing trial program, results, and how that information has been communicated to the medical community.
Research Methodology:
Phase IV post-marketing studies utilize a variety of research methodologies to investigate the real-world effectiveness and safety of drugs following regulatory approval. These studies often employ observational designs, including cohort studies, case-control studies, and cross-sectional studies. Observational studies allow researchers to collect data from large populations over an extended period, capturing real-world treatment patterns and outcomes. Additionally, Phase IV studies may incorporate randomized controlled trials (RCTs) in specific subpopulation or for specific research questions.
Data collection in Phase IV studies typically involves accessing electronic health records, administrative databases, patient registries, and pharmacovigilance databases. These sources provide comprehensive information on drug exposure, clinical outcomes, and potential confounding variables such as comorbidities and concomitant medications. Patient-reported outcomes and surveys may also be used to gather subjective data on treatment satisfaction and quality of life.
The results of Phase IV post-marketing studies offer insights into the long-term safety, effectiveness, and utilization patterns of drugs in real-world clinical practice. These studies may uncover rare or unexpected adverse effects that were not evident in pre-marketing trials due to the limited sample size or duration of follow-up. Additionally, Phase IV studies provide data on the comparative effectiveness of a drug against standard treatments or competitors, helping clinicians make informed treatment decisions.
The discussion of Phase IV study results involves interpreting the findings within the context of existing knowledge and clinical practice. Researchers often assess the implications of their results for patient care, regulatory decision-making, and healthcare policy. They may explore potential mechanisms underlying observed associations, consider the impact of study design and methodology on the validity of findings, and discuss limitations such as selection bias, confounding, and loss to follow-up.
Phase IV clinical trials, in all their many forms, are the natural extension of the constrained environment of phase II and III drug development, as well as a pivotal, interfacing position between the marketing, research, regulatory, and legal departments. Indeed, such distinctions can be seamless, especially when there is no change in the development team post-approval, or when phase IV is begun before approval. The variety of questions that phase IV teams must answer are many and varied. This can be liberating, stimulating, and educational assignment for those who have hitherto worked only in early-phase product development.
We offer our deepest appreciation to all things and arrangings whose offerings and counseling were necessary to the favorable accomplishment concerning this research endeavor. Special on account of Dr. Naweed Imam Syed, Professor in the Department of Cell Biology at the University of Calgary, and Dr. Sadaf Ahmed from the Psychophysiology Lab at the University of Karachi, for their priceless recommendation and support during the whole of this project. Their acumens and knowledge have considerably affected the course of our work.
I herewith acknowledge that I have no monetary or different private interests, either direct or unintended, in some system that concedes the possibility present a contradiction of my trustworthiness as the head of my area.
The authors insist that they have no conflicts of interest.
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No extrinsic capital was taken to support the readiness concerning this script.
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