, Dilip R. Karnad2 and Snehal Kothari3
(1)
Cardiac Safety Services Quintiles, Durham, North Carolina, USA
(2)
Research Team, Cardiac Safety Services Quintiles, Mumbai, India
(3)
Cardiac Safety Services Global Head, Cardiac Safety Center of Excellence Quintiles, Mumbai, India
Generally speaking, the safety evaluation of new drugs is intended to detect quantifiable effects in as many organs and bodily systems as possible, hence the expression “casting a wide net.” However, in the domain of cardiovascular safety, hypothesis-testing approaches are employed to investigate cardiovascular adverse events of special interest.
5.1 Introduction
The previous chapter provided examples of statistical analyses that are used to assess efficacy in clinical trials. In this and the following chapter, the focus moves to assessments of safety. As will be seen in the first part of this chapter, general safety assessments are conducted quite differently from those for efficacy, in that descriptive statistics are used as opposed to hypothesis testing. However, in the domain of cardiovascular safety, hypothesis-testing approaches are employed to investigate the potential occurrence of specific cardiac and cardiovascular adverse events. In the language introduced in this chapter, these can be regarded as adverse events of special interest.
5.2 FDA’s Premarketing Risk Assessment Guidance
The FDA’s premarketing risk assessment Guidance for Industry discussed the generation, acquisition, analysis, and presentation of premarketing safety data (FDA 2005). To maximize the information gained from clinical trials, the FDA recommends that, from the outset of development, sponsors pay careful attention to the overall design of safety evaluation. The agency is fully aware that “Even large clinical development programs cannot reasonably be expected to identify all risks associated with a product,” and it is therefore expected that “some risks will become apparent only after approval, when the product is used in tens of thousands or even millions of patients in the general population” (FDA 2005, p. 6). Nonetheless, the FDA also acknowledges that the larger and more comprehensive the preapproval database, the more likely it is that serious adverse events will be detected during preapproval drug development.
Several factors influence the determination of the appropriate size of a preapproval safety database for a new investigational drug:
Its novelty, i.e., whether it represents a new mechanism of action or one similar to that of another available treatment(s)
The condition being treated and the intended population for whom the treatment will be prescribed if approved
The intended duration of use
The availability of alternative therapies and the relative safety of those alternatives as compared with the new drug’s safety profile
The fact that assessment of both benefit and risk is needed for benefit–risk analysis has a direct impact on the quantity and quality of the safety database. Generally speaking, the greater the drug’s benefits, the greater the degree of uncertainty about its safety that will be acceptable and the smaller the safety database that is warranted. (That said, even “smaller” safety databases are extremely large.) Conversely, the fewer the drug’s benefits, the less the uncertainty that may be acceptable with regard to its safety and the greater the safety database that is warranted. Additionally, a larger safety database may be appropriate if a drug’s nonclinical assessment or human pharmacology studies have identified signals of risk that warrant considerable clinical safety data to define the risk in an adequate manner.
The FDA recommends that sponsors address the potential for serious adverse effects in various categories for all new small-molecule drugs, including the following:
Drug-related QT interval prolongation
Drug-related liver toxicity
Drug-related nephrotoxicity
Drug-related bone marrow toxicity
Drug–drug interactions
Polymorphic metabolism
The meaning of the word “address” in this context varies with circumstance. For example, for a drug that is intended to be applied topically, if it has been demonstrated that the drug has no systemic bioavailability, systemic toxicities would not be of concern, and addressing this issue could therefore be done in relatively less detail.
Temporal relationships between exposure to a drug and the occurrence of an adverse event can be very informative: when preparing individual participant safety reports, the temporal relationship between drug exposure and an adverse event is a critical consideration in the assessment of potential causality (FDA 2005). However, temporal parameters such as time to event and the duration of the event can be overlooked in aggregate inspections of safety data. As noted in the guidance, “Simple comparisons of adverse event frequencies between (or among) treatment groups, which are commonly included in product applications and reproduced in tabular format in labeling, generally do not take into account the time dependency of adverse events” (FDA 2005, p. 20).
Certain adverse events, e.g., those leading to discontinuation, death, and other serious adverse events, require narrative summaries to be written and submitted. These narratives should not simply repeat in sentence format the information that was presented in the body of the clinical study report in numerical format. Rather, the narratives should permit an adequate understanding of the nature of each adverse event by providing “a complete synthesis of all available clinical data and an informed discussion of the case” (FDA 2005, p. 26). Useful components in a narrative include:
The participant’s age, sex, and treatment group
Signs and symptoms related to the adverse event being discussed
An assessment of the relationship of exposure duration to the development of the adverse event
Concomitant medications, with start dates relative to the adverse event
Pertinent medical history, physical examination findings, and test results (e.g., laboratory data, ECG data, biopsy data)
Discussion of the diagnosis as supported by available clinical data (for events without a definite diagnosis a list of possibilities is useful)
Outcomes and follow-up information
5.2.1 The Utility of Safety Data for Prescribing Physicians and Patients
In addition to enabling regulators to assess the safety of a new drug at the time of its marketing application, and hence to assess the drug’s benefit–risk balance in conjunction with efficacy data, a concise summary of the safety data collected during clinical trials is useful to physicians once an approved drug becomes available for prescription. These data provide physicians with the best possible safety data to use when considering, on a case-by-case basis, whether the drug may be a good treatment option for their patients. Similarly, the data also provide patients with information they can consider when discussing treatment options with their physicians.
As Durham and Turner (2008) discussed, when a physician prescribes a new drug for a patient for the first time, both the physician and the patient will be interested in obtaining the best possible answers to several questions, including the following:
How likely is it that the patient will experience an adverse drug reaction? As will be seen in this chapter, the term adverse event is used in clinical trials to refer to an unwanted event. Since we do not actually know at the time of the event which treatment a clinical trial participant was receiving, the term adverse drug reaction is not suitable. However, once we move into the realm of therapeutic use of a drug, the prescribing physician and the patient will know which drug is being taken, and if an unwanted event occurs, it is now appropriate to use the term adverse drug reaction.
Are the typical adverse drug reactions temporary or permanent in nature?
If more than one dose of the drug is available for prescription, how might the risk of an adverse drug reaction vary with each of the doses?
How might the risk of an adverse drug reaction change with the length of time the drug is taken by a patient? Given that many of today’s most prevalent diseases, such as hypertension and diabetes, require long-term pharmacotherapy, this becomes a question of considerable importance.
Are there identified clinical parameters that should be monitored more closely in a patient once he or she starts taking the drug?
Is there a possibility that the patient may experience an adverse drug reaction so severe that it is life-threatening? And, if so, what is the likelihood of such an event occurring? A likelihood of 1 in 100 will be viewed very differently by both the physician and the patient than a likelihood of 1 in 1,000,000.
If approved for marketing, safety information collected during clinical trials conducted before the marketing application is made will be summarized in the drug’s prescribing information, also known as its package insert. The prescribing information thus provides physicians and patients with the best information available at the time of the drug’s marketing approval with which to answer the questions just listed. Generally speaking, the safety evaluation of new drugs is intended to detect quantifiable effects in as many organs and bodily systems as possible, hence the expression “casting a wide net” (Durham and Turner 2008).
5.2.2 Drug Labeling
From a sponsor’s perspective, it can reasonably be argued that the driving purpose of all preapproval research and development is to obtain marketing approval supported by the most favorable labeling possible, i.e., labeling that will allow the most widespread prescription of the drug: to obtain the financing to develop additional drugs, biopharmaceutical companies need to sell approved drugs. The content of a new drug’s labeling is the result of discussions/negotiations between the sponsor and the regulatory agency considering granting marketing approval. Given regulatory agencies’ dual mandate of promoting and protecting public health, regulators wish to allow the drug to be prescribed in all instances where the benefit–risk of doing has a favorable balance while also working to prevent the prescription of the drug to individuals in the target population for whom the benefit–risk balance is not favorable.
Table 5.1 lists the section titles of information presented in a typical label. The “Highlights of Prescribing Information” section comes at the beginning of the label. While it is a useful summary, labels explicitly state that the highlights do not include all of the information needed to use drugs safely and effectively: this more detailed information is provided in the next part of the label, the “Full Prescribing Information.”
Table 5.1
Contents of a typical prescription drug’s label
Highlights of prescribing information | Full prescribing information |
|---|---|
Boxed warning (if any) | Boxed warning (if any) |
Recent major changes | Indications and usage |
Indications and usage | Dosage and administration |
Dosage and administration | Dosage forms and strengths |
Dosage forms and strengths | Contraindications |
Contraindications | Warnings and precautions |
Warnings and precautions | Adverse reactions |
Adverse reactions | Drug interactions |
Drug interactions | Use in specific populations |
Overdosage | |
Description | |
Clinical pharmacology | |
Nonclinical toxicology | |
Clinical studies | |
How supplied/storage and handling | |
Patient counseling information |
5.3 General Safety Descriptions
Safety-related data collected during clinical trials can be considered at three levels: the extent of exposure; common, serious, and other significant adverse events; and common laboratory tests.
5.3.1 Extent of Exposure
The extent of participants’ exposure to a drug during a clinical trial is a determinant of the extent to which safety can be assessed from the data collected. Extent of exposure can be characterized in several ways:
Number of participants exposed
Duration of exposure
Dose(s) to which participants were exposed
Definition of daily dose levels: maximum dose for each participant, dose with the longest exposure for each participant, mean daily dose, and cumulative dose
Numbers of participants exposed to the dose(s) for certain periods of time
Profile of exposure for different participant populations: participants broken down by age, sex, ethnic subgroup, disease severity, and concurrent illnesses
Combined dose–duration: numbers of participants exposed for a given duration to the most common dose or highest recommended dose
5.3.2 Vital Signs
Vital signs typically measured in clinical trials include blood pressure, heart rate, and weight. This is perhaps not surprising since these measures are regarded as general indicators of good health: unwanted increases in blood pressure and heart rate and unwanted increases or decreases in weight can be informative to physicians in clinical practice settings. As well as SBP, diastolic blood pressure (DBP) is typically measured. Heart rate is sometimes legitimately referred to as pulse rate: medical examinations in a physician’s office typically evaluate heart rate by palpating pulses in arteries in the wrist. For continuous data, such as blood pressure, heart rate, and weight, descriptive data providing information about central tendency and dispersion are useful.
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