Читать книгу Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition) - William Gregory - Страница 37

Before a drug comes to market, it is studied in patients in clinical trials that aim to show the efficacy of the product for a particular selected disease in a highly selected sample of the population. The clinical trials may be large, covering up to 10,000 patients, or very small, covering dozens to hundreds * patients (e.g., for orphan drugs or rare diseases). The clinical trials also aim to define the safety profile of the drug, at least in this selected population with this selected disease.

These studies, which are (usually) carried out with rigorous and highly regulated methodology are statistically powered to demonstrate efficacy, but have significant limitations in defining the safety profile. They generally only find frequently occurring adverse events (AEs). For example, if in studying 10,000 patients not a single patient has a particular AE, such as a heart attack, we can be only 95% confident that the chance of having a heart attack based on the data from this trial is less than 1 in 3,333. If we raise the safety threshold to be 99% confident that a heart attack has an incidence of only 1 in 10,000 with this drug, we would need to have no heart attacks in 46,000 patients studied. In other words, studying even 5,000 or 10,000 patients does not give a warm enough or fuzzy enough feeling that the major or rare safety issues have been identified before the drug goes on the market for large-scale use.

This means that the uncommon AEs and even the fairly common AEs (e.g., an incidence of 1 in 500) will not be picked up until the drug is extensively used in the general population after marketing. When, say, a million people start using a new drug in the months after a product launch, a “rare” AE with a 1 in 10,000 incidence rate could be expected in about 100 patients. Should the AE in question be dramatic and rapidly discovered, such as torsades de pointes, aplastic anemia, or rhabdomyolysis (a severe skeletal muscle injury), there will be a torrent of recriminations about why this was not discovered earlier during the clinical testing. The correct response is that the testing of only 5,000 to 10,000 patients could not pick up such a rare event because this is the way the drug approval system is designed. This response is usually lost in the clamor. There are now attempts under way to get a better handle on the safety profile before marketing and to follow the safety (and benefit) profile after marketing in a much more rigorous manner.

Also of note is that the clinical trials are often done in a narrow group of patients. For example, an antihistamine may be tested in otherwise healthy adults between 18 and 60 years of age with allergies. Even if the drug is only approved for use in this population, physicians in most jurisdictions have the right (which they freely exercise) to prescribe the drug for anyone and for any disease. Thus, many people with other diseases and at the extremes of the age range (the very old and young) receive the drug and may have AEs that the healthy 18- to 60-year-old study population did not experience in the clinical trials. The elderly, for example, are particularly sensitive to certain AEs (e.g., swallowing disorders) or to certain classes of psychotropic drugs.

Polypharmacy and drug interactions, among other things, cannot be adequately studied in the preapproval setting. Although food interaction studies and some drug interaction studies are done before approval, it is not possible to study “real world” patients (often elderly) who take many drugs and have peculiar or irregular eating and drinking habits. Even after marketing, it is difficult or even impossible to predict or know how the use of three, four, or more drugs given at the same time will act or interact.

Hence, particular attention must be paid to the time just after a product is first marketed to fully understand the drug’s safety profile and minimize risks. In a sense, the first 500,000 to 1,000,000 patients who are prescribed the drug after launch are doing the large-scale safety testing. And, outside of clinical trials, the reporting of safety information by healthcare practitioners and other members of the public to manufacturers and drug regulators is nearly always voluntary.

What this means then is that the entire edifice of the drug safety system as it now stands, depends on the good will and energy of nurses, pharmacists, physicians, and consumers to report AEs. Without them, no one would know of the AEs that are appearing as individual cases in isolated areas around the country or the world. These people must take time out of their day to report such events. The report will inevitably lead to a request for supplementary data (laboratory reports, cardiograms, hospital records, etc.) that are time- and effort-consuming. There is no evident or immediate gain to the reporter. The gain rather is to society at large, which is largely unaware of this noble effort.

Health authorities and regulators well understand the weakness of this system. Major efforts are now under way to look at how the spontaneous reporting system has worked in the past. That is, although we think it is useful and appropriate to rely on this system, did it, in fact, lead to early pick-up of serious problems, leading to a change in the product labeling and its use in clinical practice?

Various health agencies, particularly in North America and Europe, are looking at this question.

There is a lot more digital data, sitting in the cloud, on drug safety that are not being looked at in a systematic manner. Obtaining these data on an ongoing basis and using them for safety analysis is an obvious way to identify a drug’s safety profile. However, the devil is in the details. The databases around the world must be identified and the data extracted in a valid and consistent way. This is a very difficult task since data collection is not yet standardized and there is little true interoperability across IT systems. It is also important to remember that safety generally represents a secondary use of these datasets. Multiple efforts (both nationally and globally) are under way to standardize and normalize data so that they are easily collected, databased, retrieved, and analyzed in a useful, valid, and rapid manner. If every encounter a patient has with the healthcare system is digitalized, we should be able to retrieve excellent safety data rapidly. This, however, will take years to achieve on a national level, let alone a global level. When this does occur, the spontaneous reporting system may then decrease in importance. The fundamental system now in place to discover AEs with marketed products remains the spontaneous reporting system. This system is used, in one form or another, in many countries around the world; examples include the US, Canada, China, the EU, Japan, South Korea, Australia, New Zealand, South Africa, and many other countries around the world. The WHO and the Uppsala Monitoring Centre actively work with more than 150 countries to set up pharmacovigilance (PV) systems and increase capacity.

Another potential issue slowing down new mechanisms of data analysis is the increased data protection requirements being put in place around the world (particularly in the EU). We may need patient consent in one form or another to obtain their data.

The principles of the system are simple. All healthcare professionals (and consumers in most countries, including the US, the EU, and Canada) are encouraged to spontaneously report AEs to either the manufacturer or the governmental healthcare agency or a third party. Standardized forms have been developed (the MedWatch form in the United States, the CIOMS I form elsewhere) specifically for this purpose and are available online, in publications (e.g., the Physicians’ Desk Reference in the United States), as apps on the iPhone and other smartphones, and elsewhere. The form can be folded up and mailed (postage-free), faxed, or filled in online and uploaded to the healthcare agencies. Phone, on-line reports and faxes to the manufacturer and most health agencies are also possible.

The forms are one or two pages in length and include the expected information requests: patient demographics; the AEs that occurred; medical history; drugs taken, including the one or more drugs suspected of causing the AE in question (and the indication for which prescribed); comedications; comorbidities; dose, timing, and route of administration; a narrative summary of the case; and reporter information. In most cases, confidentiality is guaranteed by law, regulation, or policy regarding the patient’s identity and the reporter’s identity. In online systems, the “forms” may be intelligent in the sense that the context determines which questions are asked. For example, if the patient is a male, the pregnancy questions will be eliminated from the online form.

In the US, the United Kingdom, and other countries, information submitted spontaneously to the health authority is available for free or for a small fee to anyone in the public under Freedom of Information Acts. The cases are redacted before being released by the health agency to avoid identifying the patient or reporter. In the US, in 2017 over 60,500 individual reports were sent directly to FDA (3% of the total 1,815,000 reports received) with the remaining approximately 1,754,500 (97%) to the manufacturers, who then forward them to the FDA. Most reporters tend to be pharmacists. Redacted case report data held by FDA in the FAERS database are publically available over the Internet by using an FDA-supplied public dashboard.

In 2017, the FDA’s Office of Surveillance and Epidemiology noted the breakdown of the sources of reports was as follows:

Healthcare Professionals, 53%;

Consumers, 47%.

The requirements for AE reporting have largely been standardized through the International Council for Harmonization (ICH). Reporting for healthcare professionals (and consumers in most places) is usually voluntary and is highly encouraged by agencies, although there is some skepticism about the utility and value of consumer reports, particularly those for OTC products and those not validated by a healthcare professional.

There is no time frame for reporting by a consumer or healthcare professional after the occurrence of the AE, but obviously rapid reporting is preferred for public health reasons; in some cases, it may save lives. For manufacturers, reporting is obligatory in almost all jurisdictions. Any AE that comes into a company, whether through sales representatives, phone calls, Internet and e-mail, literature reports (which must be actively searched for by the company), patient support programs, or other media must be rapidly forwarded to the Drug Safety Unit and reviewed by qualified medical personnel.

For marketed drugs in most countries, all serious AEs that are unexpected (i.e., that do not appear in the regulator-approved product labeling) must be reported to the health authority by the company within 15 calendar days. In the US, most of the remaining serious and non-serious cases must be reported to the FDA in NDA periodic reports (PADERs) or PSURs/PBRERs (quarterly for newer drugs and yearly for older drugs). In some countries aggregate periodic reporting is done as PSURs/ PBRERs, which are prepared according to a schedule, depending on the age of the drug and the country receiving the report. In the EU, PSURs (in PBRER format) no longer have a standard time interval for submission. Periodicity is established by regulators. A regulator may also request a periodic report at any time.

These reports contain line listings of various cuts of the data as well as medical analyses prepared by the company’s medical team, usually headed by a physician. They look at AEs that are expected and unexpected and indicate which need to be added to the drug labeling as new ADRs, warnings, precautions, and so forth, and which AEs/ADRs need to be watched with heightened vigilance. These reports are then scrutinized by the regulatory agencies who may agree or disagree with the company analysis and who decide on changes to the drug labeling, conditions of marketing of the drug, and so forth. There is usually dialogue between the health agency and the company before an action is taken, though health authorities are empowered to act immediately and unilaterally if the public health is at risk. At the health agency, the data are then entered into a database and reviewed. Analysis of individual AE cases and of aggregates of AE cases is done.

Many countries send extracts from their spontaneous databases of local AE reports to the Uppsala Monitoring Centre (UMC) in Sweden. At the end of 2017, there were 127 full and 29 associate member countries most of whom supply AE reports to the Center, which had more than 20,000,000 cases in December 2017. About half are from the United States, 10% from Canada, and 5% each from Germany, France, and Australia. Further information is available from the UMC describing the details of the database and the international monitoring system on its website (www.who-umc.org).

Extracts of the database are available for a fee from the UMC or from private vendors who have access to the database. Specifically regarding spontaneous reports, a company must set up a failure-proof system to receive, process, report, and analyze AEs. Time is of the essence, because some of the reports must be sent to the health authorities within 15 days. The clock for reporting starts counting down from the moment the first person anywhere in the company (or a partner, co-marketer, etc.) learns about a “valid” AE.

For phone reports, this means that any phone number in the company is a potential source of AE reports, and anyone who answers the phone in the company must be instructed what to do if an AE report comes into a place where it is not normally expected. A rapid and painless (to the caller) transfer system must be set up if the information is not immediately written down by the company employee first answering the call. No one wants to be kept on hold or to repeat the same story for the third or fourth time. No AE may be lost, so all efforts must be directed to the proper handling of the call. Because some AEs may need to be reported to one or more healthcare agencies within 15 days, time cannot be lost. The company must be ready to accept calls 24 hours a day, 7 days a week and in multiple languages if that is the normal custom in the country. Many companies do not maintain 24-hour coverage in their company, preferring to outsource this function to private companies (sometimes abroad, often in India). Many companies, even those maintaining a call center during business hours, outsource after-hours calls to poison control centers or private companies. Many companies also use this number (e.g., a toll-free number) for other functions, including product information, queries, and marketing.

Similarly, any e-mail or website or social media site in which an outsider can send a message or key in free text is a potential source of AEs. Many companies, much to their chagrin, receive complaints and AEs on job-posting websites, free sample websites, survey websites, smartphone apps, customer engagement programs, and so forth.

Sales representatives must also be aware that a physician, pharmacist, or other healthcare worker they call on may be the source of an AE. Even innocuous off-the-cuff remarks about a possible AE (“Oh, by the way one of my patients took your other drug XXXX and had a heart attack the next day”) made to a company representative constitute a report to the company that must be acted on. Even offhand remarks over the barbecue on a Sunday afternoon in which a neighbor casually relates an AE to a company employee must be reported to the drug safety department! Some pharma companies include a specific sentence in the employees contract which specifies that, should he/she be informed of an ADR with a company’s drug, he/she must report this information to the drug safety department. Most companies also have this noted in their SOPs and training materials.

Many companies have media services that review transcripts of newspapers, television shows, websites, blogs, and so forth, looking for anything about their products. Should AEs be noted, they must be sent to the safety department. There is no obligation to scan the web trawling for AEs, but anything found on a company-sponsored website or merely discovered in the course of surfing is a reportable AE.

Lawsuits often represent the point of entry of AEs. The legal department must be aware that they must also report the AE noted in the suit to the safety department usually within 48 hours.

Some people still write “snail mail” letters, and the company mail room or mail screeners must be aware that AEs received in the mail are to be sent to the drug safety group immediately (usually by PDF/e-mail or fax and not interoffice mail).

One of the more complex problems companies face is the phone call or letter that notes a product complaint (“the pill was the wrong color”), an AE (“and then I took it and had violent stomach pains”), and then requests restitution (“I want my money back now!”). These cases must be handled by three or more departments in the company: (1) the drug safety group to get details and report the AE, (2) the manufacturing or quality group to see why the pill was the wrong color, and (3) the marketing/sales group to refund (or not refund) the money. Companies must set up systems to handle this.