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The Roles and Interactions of Companies, Governments, Nongovernmental Organizations (NGOs), and Others in the World of Pharmacovigilance

There are many players in the world of pharmacovigilance. The interactions are complex. Alliances are formed and severed as issues or interests change. The groups are active in various causes in the medical and pharmaceutical world, touching not just on safety but on healthcare costs, drug prices, and healthcare availability.

Patients who take medicines and suffer from adverse events (AEs) are the first and primary group involved in drug safety. Healthcare professionals make up the next category and include those who prescribe, sell, or dispense medications and those who must also help deal with the AEs. Other participants in the medical world include pharmaceutical companies, pharmacies, pharmacy/formulation committees (in hospitals, insurance companies, and other institutions in the United States and elsewhere), and drug benefit managers (in the United States) and others who decide which medications are made available or reimbursed and which are not.

Patients suffer the consequences of adverse drug reactions directly and personally, sometimes suffering dearly or even dying. Patients and their families are becoming more sophisticated and research drugs and treatments they take or will take on the internet and through social media, websites, and elsewhere. Some sites and sources, of course, are far more accurate and unbiased than others. Yet patient perceptions are quite variable. Sometimes there may be a perception that every AE that occurs is due to the drug, and, at other times, there is not a real awareness or level of suspicion by the patient that a particular problem could be due to one or more drugs. Many patients believe that if the government agency has approved the drug for marketing it is “safe and effective,” using this “buzzword” phrase. This is an unfortunate phrase since it implies absolutes—totally safe and always effective—when in fact its meaning is rather more like: this product has benefits that outweigh the risks (sometimes not by much) when used by the approved patient group, at the approved dosage and route of administration, for the approved length of time; safety is not absolute or guaranteed and is not (ever) fully known, and some patients may have totally unexpected (idiosyncratic) bad side effects. This concept is hard to convey.

It is often presumed (sometimes incorrectly) that a drug cannot produce an adverse reaction if it has been taken safely for months or even years. Drug–drug, drug–food, and drug–alcohol interactions, manufacturing issues, and so on are almost never thought of by patients as explanations of their problem. Patients often do not think of over-the-counter (OTC) products, “health foods,” “nutraceuticals,” or “herbals” (which may contain drugs or interact with drugs), cosmetics, and illicit drugs as culprits in adverse reactions. Physicians too often forget to ask about them when taking the medical history and investigating medical problems. Many patients who are receiving multiple drugs, particularly the elderly, who are often “polypharmacy” patients, cannot recall the drugs or the doses they take. Moreover, when patients take multiple drugs, it is hard to know or predict drug interactions.

In some societies or cultures, there has been a perception that AEs are the fault of the patient and represent a weakness or a shameful act on the patient’s part and that they need to “tough it out.” This attitude is changing as the dissemination of information occurs, but is still seen in some older patients.

Healthcare practitioners prescribe, dispense, and administer drugs. When AEs or reactions occur, it may not be the same prescriber, dispenser, or administrator who has to deal with the drug’s medical consequences. Emergency rooms may not be able to get immediate access to the patient’s medical records or drug history, for example, though it is hoped this will change when and if electronic medical records become widespread.

Pharmaceutical companies play a major role in the world of safety. In the United States, most AEs on marketed drugs are reported to the manufacturers; in other countries, most AEs may be reported to the health agency or other institutions (e.g., medical centers). The companies, through PhRMA and the EFPIA (see below) and the International Conference on Harmonization, have worked with the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and Japanese regulators to harmonize the safety reporting procedures, requirements, formats, documents, and expectations. This effort has been very successful because the requirements for reporting certain serious AEs from clinical trials and postmarketing situations are clear, consistent, and quite rigorous (7 or 15 calendar days). Major efforts are under way, with varying degrees of harmonization and cooperation between the industry and government, in the areas of electronic transmission and standards (e.g., formats for transmission of healthcare documents, laboratory tests, cardiograms), risk management and minimization, clinical trial standardization, and more. These efforts in regard to “mechanics and operations” may well go beyond the pharmaceutical industry as the FDA and the Department of Health and Human Services standardize the transmission of healthcare data among other entities (hospitals, doctors, pharmacies, laboratories, insurance companies, etc.) and produce significant additional benefits for the public. See HL7, CDISC, and other initiatives in Chapter 8. Most dealings between scientific personnel in the industry and the FDA, EMA, and other agencies are cordial and correct, with the goal of protecting the public health and helping each do his or her job more efficiently and more rapidly, given limited resources.

The reverse of this coin, however, is represented by controversies about specific medical products and safety issues. Some people (consumer groups in particular) believe there is too much cordiality and warmth between the regulators and the regulated, allowing the companies to “get away” with many things to increase profit at the expense of public health. They point out that people move from the government to industry (as in other regulated industries) and vice versa, like revolving doors. They claim that this may compromise the safety of the public because regulators will be hesitant to cross or oppose a company they may shortly wish to work for. There are clearly professional and medical differences between and within the companies and the industry. Many of these “battles” occur behind closed doors or through written (e-mail) or telephonic communications. Most of these communications are privileged and not available to the public.

Pharmaceutical companies play a major role by promoting their products to healthcare professionals and the public (direct-to-consumer advertising in the United States in particular). Sometimes the promotion is not balanced in the eyes of the FDA, and Warning Letters are sent to companies by the FDA’s Division of Drug Marketing, Advertising, and Communications. See the Warning Letter section of the FDA’s website at Web Resource 29-1. FDA and other health agencies are now struggling with social media in which drugs are publicized, criticized, and commented upon by users, providers, and companies on blogs, tweets, and Facebook without fair balance and often without attribution.

Physicians and other healthcare workers are also “detailed” by pharmaceutical representatives on products for their patients. The detail should contain balanced information and include the AE profile. The approved prescribing information should also be supplied.

In each country or region, there is, of course, the governmental agency or agencies that regulate medicines (the FDA, the EMA, the Medicines and Healthcare Products Regulatory Agency [MHRA], the Agence Française de Sécurité Sanitaire des Produits de Santé [AFSSAPS], etc.). In addition to the agency, its parent organization may exert significant control and pressure (in the United States the Department of Health and Human Services; in other countries the Ministry of Health or Parliament/National Assembly/Congress), and so forth. In the United States, Congress and other federal departments and agencies work in or provide healthcare and medications (e.g., Veterans Affairs, the armed forces, the Centers for Disease Control and Prevention, Medicare, Medicaid, and new agencies that will be created under the U.S. healthcare reform law passed in 2010 and coming into effect over the next several years), as do state/provincial and local health departments, including boards of health. Some countries separate drug safety from drug approval, and some countries, particularly in the European Union, have an overlay at the European level in addition to national-and local-level agencies. In addition, each country may have local institutions that handle various drug safety issues. In France, for example, more than 30 regional centers (often associated with academic/university medical centers) deal with postmarketing AEs.

Government entities involved directly or indirectly in drug safety are complex. In the United States, at the federal level, the executive cabinet-level (ministry-level) Department of Health and Human Services controls the FDA and other health-related agencies and entities. The U.S. Congress controls the budget for the FDA and has legislative oversight of FDA and other health matters. Other federal-level groups with major interests in healthcare and pharmaceuticals include the Veterans Administration, which maintains hospitals, clinics, and pharmacies; the U.S. armed forces, which also maintain hospitals clinics and pharmacies; and the National Institutes of Health, the National Cancer Institute, and the Centers for Disease Control and Prevention. Similar complexities may be seen in many countries around the world, depending on their level of centralization and federalism. Some countries (France in particular) have tight arrangements with academic medical centers in the world of drug safety.

At the state and local level in the United States, there are state and local health departments, Medicaid offices (the program that supplies healthcare to the indigent and certain others at the state level), and state budget and formulation offices. One of the recent controversies has been the push by state and local governments to aid consumers in importing prescription drugs from outside the United States.

Views on drug safety by all of the players may sometimes be simplistic and polarized, especially if they are conveyed in short sound bites. One may hear that the health authority should approve safe drugs only after careful and thorough study. Side effects, if any, should be mild, reversible, and of limited duration. Some supposedly neutral observers refuse to admit a drug to a formulary for cost reasons rather than for medical reasons and justify this with either lack of efficacy or increased safety concerns. Others believe that there should be no more than two or three products in any particular class of drugs because the me-too drugs add no value to the public health. Others disagree. Consumers often believe that, if any really bad side effects occur, someone (somewhere) should be made to pay. At the extreme end, some groups assume malevolence and ill will on the part of the drug companies, whose goal (they say) is only to make money, and helping the ill is a “side effect” of making profit. There are periodic reports of bribery or various illegal actions to get drugs sold, studied, or put on formularies. The FDA encourages whistle-blowers to come forth with information on bad behavior with the inducement of substantial monetary rewards. As rhetoric heats up, the science and clarity disappear.

The controversy and politics tends to cloud some of the very real areas of controversy and concern:

• How much secrecy should be permitted in the competitive area of drug development and drug safety? How much transparency should there be?
  
• What is the role of the industry in patient and healthcare professional education?
  
• Is direct-to-consumer advertising a good or bad thing for the public and how does it play regarding drug safety?
  
• Is a single-payer system for drugs a good or bad thing for drug safety, and is it too expensive?
  
• Is the current drug safety system in the United States, the European Union, and elsewhere adequate?
  
• Should the universities be more heavily involved? Should there be a single national formulary?
  
• Should me-too drugs be limited? Is the WHO Model List of Essential Drugs (Web Resource 29-2) a good way to handle pharmaceuticals?
  
• Should drug safety be separated from the drug agency that approves drugs, as the approvers would be hesitant to “admit” they might have approved a drug with safety issues that appear after marketing?
  
• As healthcare is finite and demand infinite, how should rationing be done?
  
• Should some level of drug imports by consumers from abroad be tolerated or even encouraged to save money? And how will quality be ensured?
  
• How should OTC drug safety be handled? Are consumer reports without any healthcare professional worth collecting and how much effort should be expended in their analysis?

One positive outcome of the controversies of the last several years in drug safety is more availability and transparency of safety information by companies and governments. Detailed information on most clinical trials is now available online at governmental websites (Web Resource 29-3) as well as pharmaceutical companies’ individual clinical trial sites.

Postmarketing adverse events are now appearing online or are available as files of variable user-friendliness. Health Canada’s safety database is friendly and available for immediate online searching. The United Kingdom’s MHRA makes Drug Analysis Prints available, summarizing a drug’s cumulative safety profile for many years, and is also easy to use. The FDA puts quarterly files online for downloading (though they are not user-friendly). Anonymized line listings and individual MedWatch reports are available from the FDA for nominal fees or from private companies (for higher costs but with anonymity of the requester).

Much of the older and some of the current clinical trial data are largely proprietary and unavailable to the public or medical profession beyond what is in a drug’s labeling, monograph, or record at clintrials.gov. The European Union puts summaries of approvals (EPARs) online, and the FDA has some Summary Bases of Approval (SBOAs) also available online. However, safety data are often limited.

Many countries (United States, United Kingdom) have Freedom of Information laws that allow anyone to obtain nonclassified and nonproprietary data for minimal cost. However, often one must know exactly what one is looking for. “Fishing expeditions” can be hard or not permitted.

Proposals in many countries aim to make far more data available online. The FDA is proposing for marketed products to provide “the public with online access to public information from AE reports about FDA-regulated products submitted to FDA, in a format that is searchable and allows users to generate summary reports of this information, including, if known and as applicable, the trade name and/or established name of the product, dosage, route of administration, description of the adverse event, and the health outcome.”

Interestingly, for drugs still unapproved and in use in clinical trials, the FDA is proposing to “disclose relevant summary safety and effectiveness information from an investigational application, or from a pending marketing application” as well as “non-summary safety and effectiveness data from applications submitted to FDA.” Whether these are “trial balloons” or changes that will actually be put in place remains to be seen (Web Resource 29-4).

The United Kingdom MHRA also has a freedom of information act and some safety information is available. Interestingly, unlike the U.S. government’s published information, which is basically not subject to copyright, there is strict copyright control of information released: “The information below was supplied in response to a Freedom of Information Act request. It is the copyright of MHRA and/or a third party or parties, and is made available for personal use only. You may not sell, resell or otherwise use any information made available via the MHRA FOI Disclosure Log without prior agreement from the copyright holder.” See information about “crown copyright” at Web Resource 29-5.

One public venue where differences are aired, often with full media coverage, is represented by public meetings of the FDA advisory committees and similar groups in other countries. See the FDA’s website at Web Resource 29-6. See in particular the Drug Safety and Risk Management Advisory Committee (Web Resource 29-7). These are standing committees called by the FDA to discuss and recommend courses of action in controversial or unclear areas in which the agency wishes external advice. Members include the FDA and academia (but not industry). They receive, in advance, data from the FDA and the industry and then meet in public (usually) to discuss the issues involved. The companies are usually well represented in the audience and often make presentations. The discussions are usually scientific and technical but can become adversarial and even quite heated. Some sessions may be held behind closed doors and are not open to the public. Transcripts and presentations of the public sessions are often available shortly afterward on the FDA website. These sessions are often attended by media and Wall Street types when public companies’ products are involved. Comments by the committees often influence stock prices of both the company whose drug is discussed and competitors’ drugs whose sales might be threatened by a new drug. This is a good example of transparency in the world of pharmaceuticals.

Broadly speaking, professionals working in the drug safety area of government and industry tend to be more aligned and better able and motivated to share ideas than are professionals in other areas of the industry (research, marketing, legal, etc.), because they are less constrained by legal restrictions and by competitive issues. Sharing ideas about “what works” in drug safety, pharmacovigilance, and risk management is common and is seen particularly with operational issues (e.g., drug coding, conventions for the Medical Dictionary for Regulatory Activities coding of AEs). Proprietary drug-specific safety information is not shared. Such alignment and cooperation is now international and facilitated by the web. Data are now being shared on Facebook and other social media.

It is in everyone’s interest for AEs to be sent to the FDA and other health authorities in a timely, complete, and correct manner. Companies do, in fact, want their competitors to have well-run and efficient safety departments so that the competition’s AEs are sent to the health agencies in a timely and complete manner too!

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