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Long Term Use: How Are Medications Assessed for Long Term Safety?

General | June 6, 2014 | Author: The Super Pharmacist

safety, drug approval, clinical safety, FDA, animal studies

Long Term Use: How Are Medications Assessed for Long Term Safety?

To better appreciate how the long term safety of drugs is assessed, it is important to understand the drug approval process.The total cost for a drug to go from an idea to the market is an estimated $802 million. It takes roughly 16.5 years of development for a drug to reach the market. Both private pharmaceutical companies and public research institutions (such as the National Institutes of Health) sponsor research that identifies the need for a drug and provides insight into its development. The first step in the drug approval process involves animal testing. The drug is tested on a variety of species to ensure its safety, and its initial effects are documented. An Investigational New Drug (IND) application is submitted to the U.S. Food and Drug Administration (FDA) which reports the animal testing results.

Next, Phase 1 testing is performed on 20 to 80 healthy volunteers. The emphasis in Phase 1 is on safety. The goal here is to determine the most frequent side effects of the drug and, often, how the drug is metabolised and excreted.

In Phase 2, the drug is given to hundreds of people with a particular condition which the drug intends to treat. The emphasis of Phase 2 testing is on effectiveness. This goal here is to obtain preliminary data on whether the drug works in people who have a certain disease or condition. For controlled trials, patients receiving the drug are compared with similar patients receiving a different treatment, either a placebo or a different drug. Safety continues to be evaluated.

In Phase 3, the drug reaches thousands of patients. Safety and effectiveness are evaluated, as are side effects and interactions with other medications. The average size of a Phase 3 trial is 4,000 people. These studies gather more information about safety and effectiveness, study different populations, different dosages, and drug-drug interactions. If the drug successfully passes these stages, the manufacturer now formally requests that the FDA consider the new drug. The FDA reviews the information provided and devises a drug label for the medication, complete with side effects, warnings, and potential interactions. Of every 5,000 drugs that go to animal trials, five make it to human testing, and only one makes it to market.1 The FDA continuously monitors the safety and effectiveness of the new drug, even after approval. The manufacturer is also required to submit periodic updates on safety and effectiveness of the drug.

What Are the Limitations of the Drug Approval Process?

Randomised controlled trials (RCT's) are the principal way of establishing drug efficacy. RCT's have significant limitations:

  1. RCT's usually only last for a period of months (even when the drug is intended for long term use) such that adverse events requiring a long duration of exposure may not be detected
  2. RCT's tend to recruit highly selected patients and do not assess the drug's safety profile in special populations such as those with co-morbidities, the elderly, children, and pregnant women; 3, 4
  3. RCT’s involve relatively small patient populations which limits the detection of adverse event rates to about 1% of subjects per year; rarer events such as those that occur in 0.1% of subjects per year are often not detected at all.4

It is estimated that 51% of approved drugs have serious adverse effects not detected prior to approval. In extreme cases, the FDA may remove a drug from the market. More often, the product label or package insert is revised to reflect newly discovered risks or adverse effects. The most clinically significant new information is added to one of three legally defined sections of the prescribing information5:

  1. A boxed warning (information that is essential to be considered when prescribing the drug);
  2. A contraindication (clinical situations when the risks of a drug clearly outweigh its benefits); and
  3. A warning (adverse reactions with reasonable evidence of a causal association, reactions that may require discontinuation, or reactions that interfere with a laboratory test).

About 7.5% of drugs receive a black box warning after approval.6 Over the last 40 years, more than 130 drugs have been withdrawn from the market for safety concerns.4 Many of these drugs had been used by hundreds of thousands of people prior to their withdrawal. Examples include astemizole and terfenadine (anti-histamines which caused deaths from "torsades de pointes arrhythmias"), valdecoxib (a nonsteroidal inflammatory drug which increased the risk of heart attack and stroke), and most recently, efalizumab (prescribed for psoriasis with potential risk to patients of developing progressive multifocal leukoencephalopathy).6

How Are the Gaps in Drug Safety Regulation Addressed?

shutterstock_95710246 In order to address the gaps in safety information that exist at the time of drug approval, "pharmacovigilance", which is defined by the World Health Organisation as the activities involved in the detection, assessment, understanding, and prevention of adverse effects or any other drug related problems, is a critical aspect of assessing the risk to benefit ratio of medications.6 The science of pharmacovigilance is pharmacoepidemiology.7 The majority of pharmacovigilance is done via spontaneous case reports submitted to the FDA (through the TGA adverse drug reaction program and/or the pharmaceutical companies).4 The FDA receives over 370,000 case reports of suspected adverse drug reactions annually.8 Spontaneous adverse event reporting is relatively inexpensive, potentially captures data from all prescribers and patients and is the mainstay of post-marketing drug safety surveillance.

Are There any Additional Safety Measures in Place?

In order to address the limitations of the spontaneous reporting system, the FDA has increasingly required that companies conduct additional longitudinal studies following drug approval to investigate potential safety risks identified in the pre-approval process.6 Unfortunately, these post-approval studies are often not completed. In 2004, the FDA reported that only about 30% of the 1,300 post-approval studies requested had even been started and only about 15% had been completed.9 In 2007, as a response to the public health crisis associated with Cox-2 inhibitors, Congress passed the FDA Administration Amendments Act which dedicated $225 million to studying drug safety and granted the FDA two important new powers: the authority to change a drug’s label after approval without negotiating with the drug’s manufacturer and the ability to institute civil penalties (e.g. fines) when post-marketing studies are not completed.10


  1. Singh S, Loke YK. Drug safety assessment in clinical trials: methodological challenges and opportunities. Trials 2012, 13:138.
  2. Regal C. The FDA drug approval process. Health Central. Accessed 19 May 2014. http://www.healthcentral.com/chronic-pain/cf/slideshows/the-fda-drug-approval-process#slide=
  3. Khong TK, Singer DR. Adverse drug reactions: current issues and strategies for prevention and management. Expert Opin Pharmacother. 2002;3(9):1289–300.
  4. Gelfand JM. Pharmacovigilance: verifying that drugs remain safe. Comprehensive Dermatologic Drug Therapy. Elsevier B.V.; 2004.
  5. US Food and Drug Administration. Guidance for Industry: US Food and Drug Administration.  Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drugs and Biological Products—Content and Format (Draft Guidance). Silver Spring, MD: US Food and Drug Administration; 2006.
  6. Seminara N, Gelfand JM. Assessing long term drug safety: lessons (Re) learned from Raptiva.Semin Cutan Med Surg. Mar 2010; 29(1): 16–19.
  7. Strom BL. In: Pharmacoepidemiology. Fourth Edition. Strom BL, editor. John Wiley & Sons, Ltd.; West Sussex, England: 2005.
  8. Okie S. Safety in numbers--monitoring risk in approved drugs. N Engl J Med. 2005; 352(12):1173–6.
  9. D.O.H.A.H. SERVICES, editor. Report on the Performance of Drug and Biologics Firms in Conducting Postmarketing Commitment Studies. 2004.
  10. Schultz WB. Bolstering the FDA’s drug-safety authority.  N Engl J Med. 2007; 357(22):2217–9.
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