INTRODUCTION:

There is a continuous need to monitor and evaluate the effectiveness and safety of medicines when they are used in daily clinical practice after their release for marketing ^{[1, 2]}. Safety is a key issue in the appraisal of drug therapy outcomes ^[3-5]. Drug related problems are probably one of the most frequently occurring and significant health hazards ^[6]. Recently, the withdrawal of five drugs from the US market in a 12-month period has raised concerns about the role of pre- and post marketing regulations with respect to drug safety.

Friedman et al have reviewed these cases and came to the conclusion that the approval dates of these removed drugs were scattered over the last decades, making a time association between the recently established reduction of review time at the FDA and the drug withdrawals not very likely ^[3].

Balancing the risks and benefits of drug treatment is one of the most challenging responsibilities of all stakeholders in pharmacy (Prescribers, Industry, Pharmacists, Regulators, and Academia) ^{[4, 5].}

History and Objectives of Post marketing Surveillance:

In the 1960’s, at least two serious drug reactions were observed in many patients. The drug thalidomide, taken worldwide, led to limb deformities (phocomelia) in the newborns of those mothers who took the drug while pregnant. Less known, and almost exclusively observed in Japan, was the optic nerve damage (subacute myelo-optic-neuropathy) and other adverse effects from the drug clioquinol, over which almost 4,000 civil suits were still pending in 1979. ⁽⁸⁾ And in Great Britain in the early 1970’s, more than 4 years after the drug had been introduced there, the “practolol syndrome” was uncovered. Practolol, a drug used to treat cardiovascular disease, was eventually found to cause skin rashes, eye lesions, hearing impairment, and sclerosing peritonitis ⁽⁹⁾ with deaths occurring in about 2 percent of reported cases.⁽¹⁰⁾ Great Britain, with its National Health System, already had a voluntary reporting system.⁽¹¹⁾ The National Health System had instituted the use of “yellow cards” for reporting suspected adverse drug reactions. As a guide to reporting, certain drugs are marked the first 4 years after they are marketed with an inverted black triangle in a booklet, the Monthly Index of Medical Specialties (MIMS), which is distributed to physicians and used as a source of information for prescribing drugs more frequently than any other publication. In 1976, a slip of yellow paper was inserted into prescription pads to remind physicians to report reactions, leading to a large and consistent increase in the rate of reporting. Many British drug companies now use the yellow card, and the yellow card system and reports from drug companies together yield 90 percent of all reports of suspected adverse drug reactions (ADRs).

Proponents of more rapid drug approval claim that phase III testing (e.g., the chronic trials) adds little to the data collected in phase II, and that, as a consequence, phase III testing could be curtailed or shifted to the post marketing period. On the other hand, those concerned about drug deficiencies discovered after drug approval point out that FDA has limited options once a drug has been released. Since FDA lacks authority to limit drug distribution or use, it can only try to remove a drug from the market, if such action appears appropriate.

The drug approval process:

A drug’s sponsor must provide

1) Adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended or suggested

2) Substantial evidence that the drug will have the effect it purports or is represented to have. “Substantial evidence” means “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and reasonably be concluded by such experts that the drug will have the effect it purports or is represented to have” (21 U. S. C., sec. 355(d)). This statutory language has led the Food and Drug Administration (FDA) in practice to establish a pre marketing phase of drug testing that consists of two parts :1) The investigational new drug (IND) application process 2) The filing of a new drug application (NDA). Once the IND application is approved, additional protocols and investigations can be added. FDA sets no time limit on the IND process as long as annual reports in the form of summaries are submitted and serious adverse reactions are promptly reported. All data on drug effectiveness, including that from clinical studies in patients, as well as chemical and animal data, are considered to be the sponsor’s property and subject to protection as trade secrets. If, at any time during the tests on human subjects, the continuance of those tests is determined to endanger public health, they can be stopped immediately. The clinical investigations of a new drug i.e., studies in humans are divided into three phases that in actual practice are not so distinctly separated. ⁽²⁴⁾

Methods of Drug Evaluation:

The primary objective of post marketing studies is to develop information about drug effects under customary conditions of drug use. The initial clues about a drug’s potential effects come from the experimental studies carried out with both animals and humans in the pre marketing period. Spontaneous or voluntary reporting (e.g., in letters to the editors of medical journals) is the oldest, and to date, the most productive source of new information about a drug’s possible effects once a drug is marketed. Other types of studies are used to examine in more detail the possible effects of a drug. In general, these other types of studies use either cohort or case-control methods. Thus, four types of studies are generally used to identify drug effects

1) Controlled clinical trials

2) Spontaneous or voluntary reporting

3) Cohort studies,

4) Case-control studies

Controlled clinical trials match treatment and control groups as closely as possible, minimize bias through such methods as randomization and “double-blinding,” and directly monitor patients for the duration of the study. For example, patients can be randomly assigned to either the control or treatment group. The control group receives a placebo or an active comparison drug that looks exactly like the drug being tested, and both the investigators and patients do not know who is receiving the real drug. (Personnel not directly involved in the tests would of course know what substance each patient was receiving). In this method, possible drug effects, both therapeutic and adverse, are closely monitored, so that they are discovered as they occur. The controlled clinical trial is considered the most definitive method for evaluating a drug’s efficacy and safety, but the use of rigorous criteria for patient selection usually means that the patients tested represent only a special class of the anticipated users of the drug(s), and the carefully controlled conditions allow for study of fewer patients than in the other methods, Thus, for example, to observe drug effects that are rare or that appear only after long-term use, controlled clinical trials might be impractical or too expensive.

Pharmacovigilance: Ensuring the safe use of Medicines:

Modern medicines have changed the way in which diseases are managed and controlled. However, despite all their benefits, evidence continues to mount that adverse reactions to medicines are a common, yet often preventable, cause of illness, disability and even death. In some countries, adverse drug reactions (ADRs) rank among the top 10 leading causes of mortality. Aside from the intrinsic dangers associated with the products themselves, individual patients may exhibit particular and unpredictable sensitivities to certain medicines. In addition, if more than one medicine is prescribed, there is always a risk of negative interactions. The selection and use of the best and safest medicine(s) for a given individual out of the many choices available thus requires considerable skill on behalf of the prescribing practitioner. In order to prevent or reduce harm to patients and thus improve public health, mechanisms for evaluating and monitoring the safety of medicines in clinical use are vital. In practice this means having in place a well-organized pharmacovigilance system. Pharmacovigilance – an umbrella term used to describe the processes for monitoring and evaluating ADRs – is a key component of effective drug regulation systems, clinical practice and public health programmes.

New FDA Requirements for Post-Marketing Studies and Clinical Trials: Patent Strategy:

Prior to 2007, post-marketing studies and clinical trials were something of a rarity, required only for accelerated approvals, deferred paediatric studies or approvals based on animal efficacy studies. Unlike pre marketing trials, which are strictly regulated by FDA rules, post-approval studies were subject to less rigorous oversight, and information gathered was seldom made public. The Medicare Modernization Act of 2003 gave the FDA greater authority to monitor these trials, but did not expand FDA authority to order them.

In 2007, after several well-publicized drug withdrawals, Congress passed the FDA Administrative Amendments (FDAAA), giving the FDA broad powers to require post-marketing studies or clinical trials for any drug or biologic for which “new safety information” becomes available. The FDAAA defines “new safety information” to include any information derived from a clinical trial, an adverse event report, a post approval study or peer-reviewed biomedical literature; data derived from a risk evaluation and mitigation strategy (REMS); or scientific data deemed relevant by FDA about a “serious risk,” or the effectiveness of a REMS. “Serious risks” are defined as those that could result in death, risk of death, hospitalization, incapacity, substantial disruption of normal life functions, or birth defects, or require medical or surgical intervention. The FDA Guidance indicates that NDA applicants will have input on the design and conduct of all studies, however such input is purely discretionary, as the FDA is given authority to impose post-marketing requirements (PMR’s) unilaterally, and can pursue legal action against non-compliant manufacturers for unapproved marketing or misbranding of drugs.

Post marketing Surveillance and Adverse Drug Reactions: Current Perspectives and Future Needs:

With the use of any medication comes the possibility of unintended consequences. These events, when harmful, often are referred to as adverse drug reactions (ADRs).¹ while the nature of the intended benefit from using the medication is known, ADRs can include both predictable and unpredictable events. Premarketing trials frequently do not have sufficient power to reliably detect important ADRs, which may occur at rates of 1 in 10 000 or fewer drug exposures.^2,3 Premarketing trials also lack the follow-up necessary to detect ADRs widely separated in time from the original use of the drug or delayed consequences associated with long-term drug administration.^3,4 These trials often do not include special populations such as pregnant women or children who may be at risk for unique ADRs or for an increased frequency of ADRs compared with the general population. Taken together, these limitations of premarketing clinical trials mean that, in the United States, the Food and Drug Administration (FDA) approval of a new drug does not exclude the possibility of rare but serious ADRs or common, delayed ADRs. Safety is not an absolute concept. The seriousness of the underlying illness and the availability of alternative effective treatments will alter what are considered tolerable ADRs.⁵ For example; the toxic effects of many available chemotherapeutic agents would be unacceptable in drugs marketed for uncomplicated urinary tract infections. In addition to ADRs, medication use may be associated with unintended consequences that are beneficial as well as detrimental.⁴ Postmarketing studies of hormonal therapy in postmenopausal women have shown a reduction in deaths from cardiovascular disease compared with nonusers, ⁶ and oral contraceptive users have a lower risk of ovarian cancer than nonusers.⁷ In this article, however, we focus on methods used to uncover adverse effects.

RESULTS AND DISCUSSION:

Post marketing evaluation studies can be conducted much more cheaply than clinical trials. As a motivator for industry; it is desirable to have the drug marketed sooner with a return on investment while studies are being conducted. At the same time, much larger observational studies can be done, at the same cost, evaluate drugs in their customary use situation. It is important to recognize that phase III clinical trials and post marketing drug evaluation studies are not alternatives. They address different issues and are complementary. The appropriate question is whether it would not be better to reduce the size and cost of phase III with limited likelihood of losing meaningful information and conduct much larger studies after marketing. Hence, some relationship does exist between proposed changes in the pre marketing approval process and the monitoring activities of the post marketing period. This relationship can be clarified by the answers to two questions. Can the size and cost of phase III clinical trials be reduced with limited likelihood of losing meaningful information. And, should pharmaceutical manufacturers be required to maintain the level of their drug evaluation responsibilities by increasing post marketing surveillance.

SUMMARY AND CONCLUSION:

The Pharmaceutical industry has recently endured intense speculation and negative publicity as a result of high profile product withdrawals caused by inadequate safety profiles. Regulatory bodies have responded swiftly; the FDA now requires mandatory surveillance data submission for drugs under increased scrutiny, and the EMEA is close to implementing similar strategies as part of drug policy harmonization initiatives for phase IV trials. Post marketing clinical research has also become a key feature of product lifecycle management. Phase IIIb/IV trials are increasingly being used in company specific initiatives to provide strategic guidance in areas such as payor approval and reimbursement, indication expansion, franchise development and marketing. Post marketing surveillance is defined broadly as any information gathering activity that is performed after product approval. The present study mainly emphasises the emerging role of post marketing clinical research in new drug development .The ostensible purpose of such researches is to assess the safety and side effects of the new drug, when it is available to the needy general population like physician, patient, wholesalers, stockist, chemist, druggist etc. They are designed to evaluate efficacy and safety relative to other marketed compounds, and to explore new indications for the drug. By the post marketing surveillance research the extent to which the new drug has to be developed is discussed and explained. Drug profile such as dosage, indication, ADR etc can be monitored and confirmed.

REFERENCES:

1. Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs. JAMA 1999; 281:824-9.

2. Strom BE (ed). Pharmacoepidemiology. Chichester: John Wiley & Sons, third edition, 2000.

3. Friedman MA, Woodcock J, Lumpkin MM, Shuren JE, Hass AE, Thompson LJ. The safety of newly approved medicines: do recent market removals mean there is a problem? JAMA 1999; 281:1728-34.

4. Meyboom RHB, Egberts ACG, Gribnau FWJ Hekster YA. Pharmacovigilance in perspective. Drug Saf 1999; 21:429-47.

5. Temple R. Meta-analysis and epidemiologic studies in drug development and postmarketing surveillance. JAMA 1999; 281:841-4.

6. Bemt MLA van den, Egberts TCG, de Jong-van den Berg LTW, Brouwers JRBJ. Drug related problems in hospitalised patiensts. Drug Safe 2000; 22:321-33.

7. Hawker, P, C., et al., “Gastric Cancer After Cimetidine in Patient With Two Negative Pretreatment Biopsies,” Lancet 1:709, 1980.

8. Finkel, M. J., “FDA’s Criteria for Safety and Effectiveness of Drugs” presented at the First Workshop on Drug Control in the Region of the Americas, Pan American Health Organization, Washington, D. C., May 1, 1979.

9. Beta-Blocker Heart Attack Study Group, “The Beta-Blocker Heart Attack Trial,” A.h4. A. 246:2073, 1981.

10. Waller PC, Wood SM, Breckenridge AM, Rawlins MD. Why the Safety Assessment of Marketed Medicines (SAMM) guidelines are needed. Br J Clin Pharmacol 1994; 38:93.

11. Leufkens HG, Urquhart J. Variability in patterns of drug usage. J Pharm Pharmacol 1994; 46 Suppl 1:433-37.

Received on 27.11.2012 Modified on 19.12.2012

Asian J. Management 4(1): Jan.-Mar. 2013 page 12-15