Patient Voice © Nicolò Assirelli

Improving pharmacovigilance through direct patient reporting

With increasing numbers of cancer drugs being approved on shorter trials that involve fewer patients, getting accurate reports of adverse events and side effects after approval is increasingly important. Maria Delaney reports on efforts to encourage us all to be alert for – and report – possible side effects from the medications we take.

ave you ever suffered a side Side effects are a common reality for melanoma advocate from Melanome- effect while taking medication? patients on cancer therapies and they france, says that getting patients to HRanging from mild to severe, can often be very severe. Despite this, report side effects during a clinical trial the majority of us have experienced new studies show that they are under- is quite hard, as they are terrified they some type of side effect. If so, what did reported by physicians in clinical trials, will lose their place on the trial. She says you do about it? Hope that it would pass, by as much as 74% for some toxicities. this “is bad for pharmacovigilance after shrug it off, notify your doctor, stop your And it isn’t only physicians who the trial, when the drugs go out into medication... under-report. Gilliosa Spurrier-Bernard, normal practice.” 28 March / April 2017 Patient Voice

As more innovative targeted therapies says Chandler, though she adds that, in study found that patients’ reports are move from trials to the general market, Europe, the option to report to either the more focused on the subjective impact continued reporting of side effects is company or national pharmacovigilance of the adverse event, whereas reports something that some members of the centres is there for both patients and from health professionals include a lot oncology community are striving to physicians. The Uppsala Monitoring of clinical information, but less on the improve. One way they are doing this Centre does not collect reports directly experience of the patient. is by putting power in the hands of from patients, but it would like to see patients: side effects can now be directly more patient reporting done at a local “Doctors will dismiss reported to pharmacovigilance centres level. in each country across the EU. Direct reporting by patients to local fatigue, because they But is this direct reporting actually pharmacovigilance authorities was happening, what are the benefits, and first introduced by Denmark and the don’t know what to do how can it be improved? Netherlands in 2003. Today it should be possible for patients in all EU countries, with it, whereas for as EU Pharmacovigilance legislation Progress in pharmacovigilance passed in 2012 requires all national the patient it’s very centres in Europe to have a system Pharmacovigilance has developed that can receive reports directly from important” substantially since the initial WHO patients, says Chandler. In spite of this pilot Program for International Drug new requirement, it is still difficult for Francesco Perrone, director of the Monitoring was set up in the early 1960s, patients to report side effects in some clinical trials unit at the National Cancer following the thalidomide disaster, countries due, for instance, to forms not Institute of Naples, has studied the according to Rebecca Chandler, from the being set up for online completion, or difference between doctor and patient Uppsala Monitoring Centre – the WHO being simply too complex. reporting in a clinical trial setting, Collaborating Centre for International Outside the EU, there are many and has found that under-reporting of Drug Monitoring, based in Sweden. “We countries that have no option for patients toxicities in anticancer treatments by thought it was very important to set up to directly report side effects. A recent physicians ranged from 40.7% to 74.4%. a network of countries so that [events] study found that patients were not He thinks the reasons for this include that might be occurring on a rather small allowed to report in 34 countries, or 24% not having the time to talk to patients level in individual countries might be of the National Competent Authorities about side effects, patients being afraid seen better from a global perspective.” surveyed. to lose treatment, and not noticing side The initial 10 pilot countries has effects such as hair loss in male patients. now expanded to 125 participants, with This leads to a problem for drugs over 14 million adverse event reports Patient vs doctor reporting now on the market, as there is a lack of collected. These reports are entered clear knowledge of the side effects of a into the Monitoring Centre’s VigiBase Patient reporting without the new drug or treatment strategy. Perrone database. As Chandler explains, there is influence of a healthcare professional feels “there is a high probability that the much overlap with the data gathered by is important, as “we know doctors patient will be misinformed” in clinical the US regulatory body, the FDA, with underestimate certain side effects practice, as all the side effects will not be their reports making up approximately and overestimate others in terms of mentioned in studies of the drug. 50% of the entire database. This is due importance or relevance to a patient,” Spurrier-Bernard says this happens a in part to a large number of reports says patient advocate Spurrier-Bernard. lot from her experience in the melanoma collected by drug companies with “Doctors will categorically dismiss patient group. Doctors tell patients that headquarters in the US. fatigue because they don’t really know certain side effects are ‘nothing to do with “In the United States, people often what to do with it, whereas for the this drug’, but “we know that these drugs report to the drug company first, but patient it’s very important.” are new and the doctors themselves Europe is different, with patients in Even when side effects are reported, don’t know all the side effects.” individual countries reporting directly to there are differences in how doctors Chandler agrees, and says that this the national pharmacovigilance centres,” and patients report them. A 2014 is often due to the nature of precision March / April 2017 29 Patient Voice

Patient reporting in the Netherlands

9000 “One of the most important things is working with patient

8000 Sources organisations,” says van Hunsel. 7000 Patients Most recently Lareb produced a series of radio commercials 6000 Pharmacists as part of an EU-wide drive to increase patient reporting. 5000 General practitioners Social medicine The centre also takes part in TV programmes on 4000 Hospital pharmacists No. of reports 3000 Specialist doctors pharmacovigilance topics. Their efforts led to an impressive 2000 Nurses increase in patient reports, with more than 8,000 being Other healthcare 1000 professionals collected in 2015. 0 Online forms were always the preferred option for Lareb, says 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 van Hunsel, because it enables them to receive information in a more structured manner, and is more manageable. The Netherlands Pharmacovigilance Centre, Lareb, began They recently developed a reporting app, which has been accepting patient reports in 2003. Fourteen years on, online for a number of months. The hope is that this will patients are now filing more reports than all other sources further increase reporting levels – 135 reports have already put together, with direct reporting having quadrupled over been submitted via the app by patients and healthcare four years (see figure above). Florence van Hunsel, head professionals. of signal detection at Lareb, told Cancer World why they As well as direct reporting, Lareb are exploring other initiated patient reporting, and how it has developed. ways to improve pharmacovigilance. They are part of the An initial pilot was completed in 2003. The patient reports Web-Recognizing Adverse Drug Reactions (WEB-RADR) submitted during the pilot were analysed, and were found to consortium, which is a large group looking at innovative be very useful. “After the pilot,” says van Hunsel, “we had a ways to get pharmacovigilance information. This includes culture change in our organisation, as we wanted to be more exploring the possibility of data mining of social media, such patient oriented.” as Facebook and Twitter, for adverse events, and researching More than 170 patient reports were submitted in the first frameworks that need to be in place for this. year, but Lareb wanted to increase that number. They Though patient reports are now an important part of started to advertise the reporting site, and publish their pharmacovigilance, van Hunsel stresses that they also need experience. They promoted adverse event reporting in information from healthcare professionals. “I don’t think we patient magazines, and on patient organisation websites. would do a great job without them. The mix is ideal.”

medicine dividing patients into specific on the Uppsala reporting database is practice of pharmacovigilance,” says genetic mutations for new treatments now publicly accessible through a portal, Chandler, who adds “hopefully in the for rare diseases, and other sub- VigiAccess. “It’s been shown that the future it could be adapted to make it populations when it comes to cancer. best way to encourage people to report easier for patients to use directly.” “Drugs are getting licensed based on is to give something back,” explains A certain amount of medical a relatively small number of patients, Chandler, who adds that there is also a knowledge is also required when so it is incredibly important that move in many organisations – including searching the database. A familiarity pharmacovigilance systems are ready.” the FDA and its European counterpart with the system used to code adverse the EMA – to be more transparent. events or side effects is also a plus. It took several years to finalise Patient groups are already using Changing systems VigiAccess, and it gives the public very VigiAccess to help patients with their basic access to this global database. side effects. Spurrier-Bernard helps One area that has improved greatly in The first release of VigiAccess has people with melanoma search for side the past two years is that data on reports a structure which is recognisable effects they are experiencing so that of adverse events and side effects held to those who are familiar with the they are better equipped for their next 30 March / April 2017 Patient Voice doctor’s visit. “It’s extremely useful, as you can go back to your doctor and tell Side effects reports: flow of information them to think again about side effects they dismissed, and deal with them. It gives patients extra confidence.”

Reporting apps

New tools are also being rolled out to the public in some countries to help patients report side effects. Apps are being developed on a pilot basis in the UK, the Netherlands and Croatia. One example is the Yellow Card in the UK, which was a paper-based form and is now available as an app developed by the Medicines Individual case safety reports (ICSRs) are submitted to national pharmacovigilance and Healthcare Product Regulatory (PV centres), which feed them into VigiBase, the WHO international database at the Agency. Its main advantage, according Uppsala Monitoring Centre (UMC) in Sweden. The data can be searched and analysed to Chandler, is that “it eliminates the using the Uppsala centre’s VigiLyze software, to make it easy for national centres need to track down a paper form.” to pull out and analyse relevant data. The Uppsala centre conducts its own analysis, looking for patterns and signals, and reports its findings back to national centres. Though patients have been able to Since 2015, members of the public have been able to search for side effect reports by report in some countries for a number drug via the VigiAccess portal. of years, requiring them to find and return paper forms or navigate Getting the message out in their pharmacovigilance programme multiple links online has acted as a have limited resources, says Chandler, significant deterrent, she argues. The Improving public awareness about so the campaign was designed to development of apps, she says, shows the importance of reporting side effects, aid those countries in particular. “It “a lot of progress is being attempted to and how that can be done without going encourages patients to report and is make it as easy as possible for patients.” through a doctor or pharmaceutical also a general message to everyone In a similar way to VigiAccess, these company, remains a big challenge. One to increase awareness that drugs can apps also offer patients access to data way the Uppsala Monitoring Centre has have adverse events and you can do on adverse events and side effects. tried to address this issue is through their something about it.” Spurrier-Bernard was asked for some ‘Take & Tell’ campaign, which aims to input about the type of feedback “make pharmacovigilance – monitoring, patients would like to receive during assessing and understanding adverse Adapting reporting tools the development of the Yellow Card effects, or other drug-related problems app. “It was really quite cool, as they – into an easily understood, household Apps and adverts may improve asked: ‘Would you like data on all the name… and change the way people patient understanding of side effect drugs related to melanoma or just your view the process of taking medicines reporting and make it easier to report drug?’ It gave people flexibility in what and to facilitate dialogue between the them, but tools are also needed to type of feedback they wanted.” health care provider and patient.” ensure the correct data is recorded on She feels that this feedback is really The campaign consisted of posters these systems. important, as patients want to know and other advertising material, such as Oncologist Perrone feels that more that, if they take the trouble to fill out a the ‘Take & Tell’ song, which can still be research is needed into the tools used in report, then something will happen with watched on YouTube, including a reggae side effect reporting by physicians and the data. “Why would people do it if version and a version in Chinese. patients. He helped develop the Italian they thought it wasn’t going anywhere?” Some of the countries that participate version of PRO-CTCAE, a patient- March / April 2017 31 Patient Voice

There is a caveat though, as Perrone management of side effects with the What does the public feels that more research is needed into oncologist or patient, she would like get out of it? their use outside of a clinical trial setting. to see regulators having a greater role “There is some evidence that patients in providing advice or encouraging People who report side effects staying in touch with the clinical team research on management of adverse contribute to a system designed with this kind of instrument may reduce events. to improve patient safety, which the impact of side effects, and increase Using her previous role as an benefits everybody. quality of life. It may also reduce infectious disease physician as an And since 2015, members of dependence on the emergency room,” example, Chandler says, “the HIV story the public have also been given he says. is remarkable, and they have a lot of direct access to the WHO Uppsala adverse events that people have learned to manage.” As people with HIV lived Monitoring Centre database, via From reporting to managing – VigiAccess, where they can search longer and the disease became more the HIV example for adverse event reports on any treatable, management of side effects medication. This can be important became more important. Drugs to treat in helping make sense of their own Side effects can be fatal – more it can lead to bad rashes, fever, and liver experiences and also give them often they blight lives. Photosensitivity failure, but research into adverse events confidence to press the point if induced by the B-RAF inhibitor with HIV medicines uncovered that their doctor is reluctant to give vemurafenib, for instance, turns patients certain genetic predispositions were a fair hearing to their side effects into ‘vempires’, keeping them inside found to make people more susceptible. complaints. when the sun is out. Poorly controlled Now patients can be tested to minimise Some national pharmacovigilance diarrhoea keeps people from straying far their risk of adverse events. agencies take on a public from a toilet. Sensitive nerve endings can affect mobility and fiddly tasks. information role, publishing the While improving results of their analyses of the Unsightly rashes can also deter people side-effect data they receive and from leaving home. Disturbed sleep reporting is a good providing an information service patterns can make it hard to function. to respond to specific questions. All of these and more can impact on start, Chandler argues The Dutch Lareb pharmacovigilance adherence to potentially life-saving or centre, for instance, claims in its life-extending drugs. While improving that more needs to be 2015 report to have contributed to reporting is a good start, Chandler 10 television and radio broadcasts argues that more needs to be done to done to help patients and 40 articles in the lay press, and help patients manage them. responded to almost 2000 queries. “One area that is currently not being manage side effects The impact of side effect and fully addressed in the drug regulatory adverse event reporting would be all process, in my opinion, is providing Many cancers have now reached the greater if information gathered advice to patients and their physicians a similar stage, with prognoses being on side effects and adverse events on how to manage adverse events,” she improved on a regular basis by new was used in a concerted way to says. Having met with many patient innovations. Many people with improve our ability to manage them. groups around Europe, cancer patient stage 4 melanoma are now living long groups in particular, she feels that as a enough for side effects to have a real next step, they need to figure out how impact, according to Spurrier-Bernard. reported outcome measure developed to deal with adverse events, so they can “Unfortunately, up until three years ago to evaluate symptomatic toxicity in advise patients. patients with this diagnosis only lived patients on cancer clinical trials. He Chandler talks about how shocked from three to six months, so they had suggests that, while it is clear that these she was to hear people say that they no time to develop a decent reporting sorts of instruments need to be used in won’t take their drug that is saving their system.” New therapies changed clinical trials, maybe they should also be life, “if they can’t sleep at night, or have that and direct reporting is now vital. used in clinical practice. a very itchy rash”. Rather than leaving “There’s no messing around anymore!” 32 March / April 2017