Integrated Drug Safety


Applied Clinical Trials

Applied Clinical TrialsApplied Clinical Trials-06-01-2011
Volume 20
Issue 6

Creating a drug's safety profile through the use of benefit-risk assessments during development.

1. Cardiac Safety Supplement

2. Is it Safe to Outsource Safety?

Biopharmaceutical drug development and therapeutic use are two components of integrated pharmaceutical medicine; drugs are developed to provide safe, therapeutic benefit to patients.1 Patient safety is of considerable current interest among multiple stakeholders in many countries, including the United States. The Food and Drug Administration (FDA), patients, and their prescribing physicians all have a vested interest in drug safety. The topic has attracted attention from Congress, the Supreme Court, the Institute of Medicine (IOM), pharmaceutical companies, patient advocacy groups, and the media.

Given that patient safety is of overriding importance, safety considerations are addressed throughout lifecycle drug development.2 Extensive safety evaluations occur throughout the range and diversity of preapproval clinical trials, postmarketing trials, and postmarketing surveillance. Similarly motivated investigations occur beforehand in two other phases of lifecycle development: drug discovery/drug design and nonclinical development programs. While attention in this article focuses on safety assessments in preapproval clinical development and therapeutic use, references are provided for readers who wish to learn more about nonclinical safety evaluations.3-6

Benefit-risk assessment

No drug can be guaranteed immune from side effects in all individuals, including those who are particularly susceptible for genetic and/or environmental reasons (e.g., slower-than-usual drug metabolism, race, food-drug interactions, drug-drug interactions). Accordingly, a drug's safety profile is assessed throughout drug development. The definition of "drug safety," however, is not as straightforward as one might initially think. One simple way to operationally define drug safety is to measure adverse events and adverse drug reactions (i.e., harm) and define safety as its inverse: the less the harm, the greater the safety.7 While useful conceptually, the FDA's Sentinel Initiative8 provides a more sophisticated definition:

Although marketed medical products are required by federal law to be safe for their intended use, safety does not mean zero risk. A safe product is one that has acceptable risks, given the magnitude of benefit expected in a specific population and within the context of alternatives available.

When considering a marketing application, regulators make a benefit-risk determination at the public health level. On the basis of all of the evidence in front of them at that point in time, and considering the target population in general, is it likely that the drug will have a favorable benefit-risk profile in the postmarketing setting? If an agency decides that the drug is indeed likely to have such a profile, it will be approved for prescribing in the agency's country of jurisdiction. At that point, prescribing physicians make a therapeutically-oriented benefit-risk decision in partnership with each patient who may benefit from the drug on a patient-by-patient basis. It is certainly the case that the benefit-risk profile may be favorable for one patient and not for another—the province of clinical decision making.9

Regulators also consider the continuing benefit-risk profile of marketed drugs. Accumulating evidence of therapeutic effectiveness (or lack thereof) and adverse drug reactions can lead to meaningful reassessments of a drug's benefit-risk profile. A profile that was deemed favorable by a regulatory agency at marketing approval can become less favorable in their eyes, potentially leading to regulatory action. Additionally, as noted in the quote from the Sentinel Initiative, approval of other drugs with more attractive benefit-risk profiles can influence the favorability of an already marketed drug's benefit-risk balance. Benefit-risk decisions are therefore pervasive throughout integrated drug safety.

Preapproval clinical development

As highlighted by the term lifecycle drug development, the transition from nonclinical to preapproval clinical development is best reflected as moving along a continuum, not as crossing a dichotomous chasm. As Amacher observed, translational biomarkers that have "in vitro, in vivo, and clinical transferability" are of particular value.10

Human pharmacology studies, typically conducted in healthy adults, are pharmacologically-oriented trials focusing on safety, understanding the drug's pharmacokinetic profile, estimating pharmacodynamic activity, and determining the best range of doses to employ in later trials. Examples include FIH trials, single- and multiple-ascending dose studies, drug-drug interaction studies, and maximum tolerated dose trials.

Specific safety biomarkers are also examined. One cardiac safety biomarker of regulatory interest is drug-induced QT interval prolongation as seen on the surface electrocardiogram (ECG). QT interval prolongation is considered a surrogate (albeit an imperfect one) for the clinical endpoint of ultimate interest, a rare but potentially fatal polymorphic ventricular tachycardia called torsades de pointes. The 2005 ICH Guideline E14 and a related 2008 "Questions & Answers" document address the thorough QT/QTc study, a rigorous trial dedicated to the evaluation of torsadogenic liability.11,12 This trial adopts a three-component risk exclusion model, utilizing clinical, regulatory, and statistical sciences to identify unacceptable risk.13 An increase in QT/QTc prolongation below the limit of regulatory concern is demonstrated if the upper limits of two-sided, 90% confidence intervals (CIs), placed around the point estimates of the treatment effect (i.e., drug-induced QT prolongation) at all time points assessed lie below 10 milliseconds (msec).

The literal operational definition of unacceptable risk is therefore an observation of QT/QTc prolongation of 10 msec or greater. However, regulatory concern is influenced by additional factors: the expected therapeutic benefit of the drug; the severity of the indication for which it is being developed; and the availability (or not) of other drugs for this indication and their benefit-risk profiles. Should regulatory concern arise, more extensive and intensive ECG monitoring than usual for a drug in that class may be required in subsequent therapeutic confirmatory clinical trials.

Both therapeutic exploratory and therapeutic confirmatory studies are comparative in nature, looking for clinically and statistically significant evidence of efficacy. Importantly, the overall preapproval safety database continues to build during these trials. Additionally, as just discussed, additional specific safety data may be collected as appropriate.

Postmarketing safety evaluations

There is no doubt that information gained during preapproval clinical trials is an extremely important component of compiling a drug's safety profile and in providing the evidence that prescribing physicians use in conjunction with their patients when making pharmacotherapeutic decisions when a drug first becomes available; it is some considerable time until more comprehensive safety data are collected, collated, and disseminated following postmarketing collection. Nonetheless, data obtained during therapeutic use is of critical importance. As the IOM has noted, "The approval decision does not represent a singular moment of clarity about the risks and benefits associated with a drug—preapproval clinical trials do not obviate continuing formal evaluations after approval."14 Postmarketing clinical trials and postmarketing surveillance (passive and active) are components of such continuing formal evaluation.

Postmarketing trials. Postmarketing trials can be relatively small compared with therapeutic confirmatory trials, perhaps investigating the drug's safety in alternate patient populations. They can also be much larger, such as those fulfilling postmarketing commitments when a safety signal has been noted by a regulatory agency during its review of a marketing application, but the overall benefit-risk judgment was sufficiently favorable to market the drug while the postmarketing trial is conducted.

One example is the cardiovascular safety outcomes trial discussed in the 2008 FDA guidance addressing the development of new antidiabetic drugs for type 2 diabetes mellitus.15,16 Upon completion of such drugs' preapproval clinical development program, cardiovascular safety data from therapeutic exploratory and confirmatory trials must be used in a meta-analysis evaluating any degree of increased cardiovascular risk associated with the drug compared with the control treatment. A relative risk point estimate is calculated and a two-sided, 95% CI placed around it. Primary interest falls on the upper limit of the CI. Three scenarios are discussed:

  • If the upper limit of the CI is equal to or greater than 1.3 but also less than 1.8, and the overall benefit-risk analysis presented at submission supports marketing approval, a subsequent step will generally be necessary. A postmarketing cardiovascular outcomes trial is required to definitively show that the upper limit of the CI is actually less than 1.3.

  • If the upper limit is less than 1.3 and the overall benefit-risk analysis presented at submission supports marketing approval, "a postmarketing cardiovascular trial generally may not be necessary."15

  • If the upper limit of this CI is equal to or greater than 1.8, the drug is deemed to have an unacceptable risk on the basis of the data collected to that point. In this case, a cardiovascular outcomes study "should be conducted that alone, or added to other trials, would be able to satisfy this upper [limit of the CI] before [New Drug Application/Biologic License Application] NDA/BLA submission."15 In this scenario, therefore, the cardiovascular outcomes study is actually a premarketing study.

The European Medicines Agency (EMA) has released similar guidance involving the same type of cardiovascular outcomes study.17,18 In that case, the study, if required, is to be conducted before requesting marketing approval.

In addition to postapproval randomized (experimental) trials, postmarketing epidemiological (nonexperimental) studies can be informative. As Avorn commented, both are needed "to understand everything we should know about a drug."19

Postmarketing surveillance. While perhaps initially surprising for those not familiar with drug development, it is (very) unlikely that (very) rare side effects will be observed in preapproval clinical trials, given the relatively small numbers of subjects for whom drug-related safety data are available. While preapproval clinical development programs are certainly complex, lengthy, and expensive, only around 3,000 (or less) participants receive the investigational drug. The "rule of threes"20 indicates that the sample size that would be needed in a clinical trial to be 95% confident that a single case of an adverse event of interest would be observed is roughly three times the reciprocal of the event's frequency in the general population. Accordingly, if 3,000 subjects are exposed to an investigational drug, we can be 95% certain of detecting any adverse events that occur in at least 1/1,000 individuals. Any events occurring less commonly, however, are unlikely to be detected. Many adverse events of interest occur much less frequently than 1/1000. For example, the incidence of drug-induced torsades de pointes is typically estimated to fall within a wide range of 1/10,000 to 1/1,000,000 recipients.21

Postmarketing surveillance involves monitoring very large numbers of patients receiving a drug, with the goal of identifying and quantifying associated adverse drug reactions. The FDA's Sentinel Initiative discussed "an emerging science of safety, which combines a growing understanding of disease and its origins with new methods of safety signal detection," and addressed active surveillance as well as traditional "passive" surveillance.8

Perceptions of safety signals and their consequences. It is a common misperception in the general public that the "identification" of a safety concern for a marketed drug reflects a failure on the part of the sponsor developing the drug and any regulatory agency that granted marketing approval. Identification of a serious risk (e.g., cardiac and cardiovascular concerns, aplastic anemia, and rhabdomyolysis) often leads to a "torrent of recriminations."22 Such recriminations are almost always directed at the biopharmaceutical sponsor, and the costs are considerable, ranging from loss of reputation to a decrease of billions of dollars in market capitalization. However, and perhaps increasingly so, they are also targeted at regulatory agencies.23

The perception of a risk—whether or not the risk is real—attracts enormous media attention. As Turner et al. observed, "In the era of sensationalist, sound-bite coverage, clinical science sadly falls very low on the list of points to be covered in the allotted 30 seconds of television coverage (it can do somewhat better in print coverage)."23

FDA Amendments Act of 2007

The Food and Drug Administration Amendments Act of 2007 (FDAAA),24 which was signed by President Bush on September 27, 2007 and became effective on October 1, 2007, is the third five-year renewal of the Prescription Drug User Fee Act of 1992 (PDUFA). Under PDUFA, sponsors pay a fee to the FDA every time an NDA or BLA is submitted. Of relevance to the topic of this article is that, while PDUFA and PDUFA II prohibited the use of fees for any postmarketing drug safety activities and PDUFA III allowed only around 5% of funds to be used in this manner (the focus was on getting effective drugs to market), this situation changed dramatically with the advent of the FDAAA (sometimes referred to as PDUFA IV). As reflected in Title IX, "Enhanced authorities regarding postmarket safety of drugs," drug safety is a key component of this act. This section provided the FDA with sweeping new safety authorities and significantly increased funding with which to pursue safety activities.

Risk evaluation and mitigation strategies. Section 901, Subtitle A, Title IX, entitled "Postmarket Studies and Surveillance," introduced the risk evaluation and mitigation strategy (REMS). Prior to approving a drug for marketing, the FDA can now require a sponsor to provide a REMS that addresses how risk will be mitigated (hence safety optimized) once the drug is marketed. Additionally, if the FDA becomes aware of "new safety information" concerning a drug that is already marketed, new safety information being defined as information tied to a (perceived) serious risk associated with the drug, the agency can require a REMS to be submitted at that stage in the drug's lifecycle.

Table 1 lists the components of a REMS. The timetable for submission of assessments will always be required, while others are required on a case-by-case basis. Details of the fifth component listed in Table 1, Elements to Assure Safe Use, are provided in Table 2.

One example of the use of a REMS is provided by the FDA's requirement in September 2010 for the submission of a postmarketing REMS for rosiglitazone following a July 2010 joint meeting of its Endocrinologic and Metabolic Drugs Advisory Committee and its Drug Safety and Risk Management Advisory Committee.25 Required elements include:26

  • Provision of complete risk information to each patient, and documentation in his/her medical record that this information has been received and understood.

  • Documentation from healthcare providers that each patient taking rosiglitazone falls into one of two groups: patients currently taking rosiglitazone and other individuals who are not able to achieve glycemic control on other medications, and who decide in consultation with their healthcare professional not to take pioglitazone (the other thiazolidinedione on the market) for medical reasons.

  • Documentation from healthcare providers that the risk information has been shared with each patient.

  • Physician, patient, and pharmacist enrollment.

While this restricted access will likely reduce the number of individuals who will take rosiglitazone, the drug will stay on the US market and hence be available to patients for whom alternative treatment options are considered by them and their physicians to be less suitable.

It is noteworthy that, based on the same data and announced on the same day as the FDA's decision, the EMA's Committee for Medicinal Products for Human Use voted to remove the drug from the European markets: the European Commission will make the final decision that will be legally binding for the 27 member countries in the European Union. This difference in regulatory action, however, is not the result of widely-diverging assessments of the available data.26 Rather, it reflects that the FDA has a useful tool, the REMS, at its disposal that can be used to facilitate the continued availability and use of rosiglitazone by a select group of patients for whom its benefit-risk balance is favorable: the EMA has no equivalent tool.


Drug safety is assessed in all phases of lifecycle drug development. This article has focused on clinical trials and postmarketing surveillance, and illustrated various individual components that come together in the field of integrated drug safety. These include safety assessments in preapproval human pharmacology, therapeutic exploratory and confirmatory clinical trials, specialized safety studies, postmarketing clinical trials and postmarketing surveillance, and epidemiological studies. Benefit-risk estimations are also central components of safety assessment, regulatory decisions, and therapeutic decisions. As Turner and Durham observed, "Many professionals bring diverse sets of skills to the domain of drug safety. The more integrated the efforts of everyone concerned, the better all patients will be served."21

J. Rick Turner, PhD, Senior Scientific Director, Cardiac Safety Services, Quintiles, e-mail: [email protected].


1. J. R. Turner, "Drug Safety, Medication Safety, Patient Safety: An Overview of Recent FDA Guidances and Initiatives," Regulatory Rapporteur, 6 (4) 4-8 (2009).

2. J. Rick Turner, New Drug Development: An Introduction to Clinical Trials, 2nd Ed. (Springer, New York, 2010).

3. Peter Greaves, Histopathology of Preclinical Toxicity Studies, 3rd Ed. (Academic Press/Elsevier, New York, 2007).

4. Joy A. Cavagnaro (Ed), Preclinical Evaluation of Biopharmaceuticals: A Science-based Approach to Facilitating Clinical Trials, (John Wiley & Sons, Hoboken, NJ, 2008).

5. Shayne Cox Gad (Ed), Preclinical Development Handbook: ADME and Biopharmaceutical Properties, (John Wiley & Sons, Hoboken, NJ, 2008).

6. P. T. Sager, "Key Clinical Considerations for Demonstrating the Utility of Preclinical Models to Predict Clinical Drug-Induced Torsades de Pointes," British Journal of Pharmacology, 154 (7) 1544-1549 (2008).

7. Todd Durham and J. Rick Turner, Introduction to Statistics in Pharmaceutical Clinical Trials, (Pharmaceutical Press, London, 2008).

8. Food and Drug Administration, The Sentinel Initiative: National Strategy for Monitoring Medical Product Safety, (FDA, Rockville, MD, 2008),

9. David L. Katz, Clinical Epidemiology and Evidence-based Medicine: Fundamental Principles of Clinical Reasoning and Research, (Sage Publications, Thousand Oaks, CA, 2001).

10. D. E. Amacher, "The Discovery and Development of Proteomic Safety Biomarkers for the Detection of Drug-Induced Liver Toxicity," Toxicology and Applied Pharmacology, 245 (1) 134-142 (2010).

11. ICH, 2005, Guideline E14: The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs,

12. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, E14 Implementation Working Group: Questions & Answers, 2008, .

13. J. Rick Turner, "Integrated Cardiovascular Safety: Employing a Three-Component Risk Exclusion Model in the Assessment of Investigational Drugs," Applied Clinical Trials, 19 (6) 76-79 (2010).

14. Alina Baciu, Kathleen Stratton, and Sheila P. Burke (Eds.), Institute of Medicine of the National Academies, The Future of Drug Safety: Promoting and Protecting the Health of the Public. (National Academies Press, Washington, DC, 2007).

15. Food and Drug Administration, Guidance for Industry, "Diabetes Mellitus—Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes," (FDA, Rockville, MD, 2008),

16. European Medicines Agency, "Guideline on Clinical Investigation of Medicinal Products in the Treatment of Diabetes Mellitus," (Draft), 2010,

17. E. Caveney and J. R. Turner, "Regulatory Landscapes for Future Antidiabetic Drug Development (Part I): FDA Guidance on Assessment of Cardiovascular Risks," Journal for Clinical Studies, 34-36, (January 2010).

18. J. R. Turner and E. Caveney, "Regulatory Landscapes for Future Antidiabetic Drug Development (Part II): EMA Guidance on Assessment of Cardiovascular Risks," Journal for Clinical Studies, 38-40, (March 2010).

19. J. Avorn, "In Defense of Epidemiology: Embracing the Yin and Yang of Drug Research, New England Journal of Medicine, 357 (22) 2219-2221 (2007).

20. Brian L. Strom, "Sample Size Considerations for Pharmacoepidemiology Studies," in Pharmacoepidemiology, 4th Edition, Brian L. Strom (Ed), (John Wiley & Sons, Chichester, UK), 29-36.

21. J. Rick Turner and Todd A. Durham, Integrated Cardiac Safety: Assessment Methodologies for Noncardiac Drugs in Discovery, Development, and Postmarketing Surveillance, (John Wiley & Sons, Hoboken, NJ, 2009).

22. Barton Cobert, Manual of Drug Safety and Pharmacovigilance, (Jones and Bartlett Publishers, Sudbury, MA, 2007).

23. J. Rick Turner, Lawrence Z. Satin, Timothy S. Callahan, and Jeffrey S. Litwin, "The Science of Cardiac Safety," Applied Clinical Trials, Cardiac Safety in Clinical Trials, supplement, (November 2010).

24. 110th US Congress, Food and Drug Administration Amendments Act, September 2007, .

25. J. R. Turner, "Cardiovascular Safety Watch," column. Journal for Clinical Studies, 12 (September 2010).

26. S. Sutter and J. Davis, "FDA, EMA decisions on Avandia reflect the power of REMS 'The Pink Sheet: Prescription Pharmaceuticals and Biotechnology,'" 1, 4-6, (September 2010).

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