Contribution of industry funded post-marketing studies to drug safety: survey of notifications submitted to regulatory agencies

Principal findings

Our analysis of previously inaccessible original notification documents on post-marketing studies registered 2008-10 shows the extensive use of human and financial resources. In this three year period more than a million patients and over 126 000 physicians (not necessarily unique) were estimated to have participated in 558 post-marketing studies, sponsored by 148 manufacturers of drugs or medicinal products. These companies spent more than €217m on physicians’ remunerations alone.

The practice of post-marketing studies we describe takes place in many EU countries, such as Italy, France, Spain, and Austria.3 In contrast with these other countries, however, only in Germany do all such studies have to be registered. We therefore think there is good reason to believe that the German data we analysed are representative of post-marketing studies across the EU.

The quality of the documentation was low, and there were substantial deviations from legal requirements specified in the German Medicinal Products Act with respect to the aims and conduct of post-marketing studies. The large range in length of notification documents reflects the considerable heterogeneity of sponsors’ approach to registration requirements. The median of eight pages raises questions about whether studies are being sufficiently described before they start.

Looking at the study plans, which were present in only 158 of 558 notifications, the designs mostly consisted of case series,17 often labelled with ambiguous terms such as single arm cohort studies or prospective studies. In the context of drug safety research, arbitrarily selected case series of patients receiving the study drug without a suitable comparison group are prone to bias and make interpretation of the results difficult, if not impossible.17

Compared with a descriptive study of premarket trials underpinning drug approval,18 we found that post-marketing studies had lower patient enrolment (median 760 enrolled in trials versus 600 planned in studies) but were of considerably longer duration (98 days for pre-market trials versus 480 days for post-marketing studies). For example, according to EMA information,19 lenalidomide (Revlimid) has been investigated with two randomised controlled trials involving a total of 2000 patients, one comparing lenalidomide with placebo, the other against a standard treatment for multiple myeloma. In the post-marketing study on lenalidomide only 100 patients and 18 physicians were involved. Dabigatran etexilate (Pradaxa)20 has been investigated with two main studies comparing the drug with enoxaparin, another anticoagulant, in patients who had undergone a hip or knee replacement. The first study involved 2101 patients who had had a knee replacement operation, and the second involved 3494 patients who had had a hip replacement. In our dataset we found two post-authorisation safety studies (PASS) on dabigatran (PASS 1160.84 and PASS 1160.85). These studies were mandated post-marketing studies because of specific safety concerns raised by regulatory agencies during drug approval. In PASS 1160.84, 300 patients with renal impairment were undergoing knee or hip replacement. PASS 1160.85 included 2036 patients with normal renal function undergoing hip or knee replacement. These few examples illustrate that the median number of patients enrolled in our sample of post-marketing studies (600 patients) tends to be smaller than the respective numbers (760 patients) recently described for pre-marketing randomised controlled trials.18 Less than a third of post-marketing studies, including those on newly authorised drugs, planned to include more than 1000 patients. Given that the probability of discovering one rare adverse drug reaction with an incidence of 1 in 10 000 requires a large sample size of at least 30 000 patients (achieving a power of 95%),6 these enrolment figures seem far too small to meet the specified objectives of post-marketing studies to contribute to pharmacovigilance and drug safety. With respect to the regulators, it is unclear what authorities do with the notifications they receive, considering that many of the notifications we obtained were missing required fields. The GKV and the KBV entered the information into a post-marketing study database, which they use for internal purposes. Until 2015, however, the drug regulator did not systematically file the notifications but instead registered them as a regular postal document in consecutive order of daily mail arrivals.

Our attempts to identify reports on adverse drug reactions from the 2008-10 post-marketing studies in the adverse event database (Unerwünschte Arzneimittelwirkung (UAW)14) were unsuccessful. The drug regulators’ UAW database contains spontaneous reports from individual physicians and solicited reports—that is, adverse drug reaction reports provided by manufacturers from pre-marketing or post-marketing studies or other sources—without linking of these solicited reports to post-marketing study notifications. To our knowledge the drug regulator, KBV, and GKV did not receive individual patient documents from any study. Of the 558 post-marketing studies we were able to find only five journal articles that reported results of these studies in the databases we searched up to 2015. As only less than 10% (53) of studies were planned to finish after the end of 2013 we think there should have been enough time for most to be published. Even in the publicly accessible study registries of the Association of Researching Pharmaceutical Manufacturers (Verband der forschenden Arzneimittelhersteller), or the clinicaltrials.gov registry, final reports or references to publications of the 558 post-marketing studies were sparse with hardly any agreement between the different trial registries. Our findings suggest that it is not only regulators in the automotive sector who “have to ask tougher questions about how their rules are being implemented.”21

Purpose of post-marketing studies

Post-marketing studies have been criticised for their low scientific value.22 The main criticism relates to what Marcia Angell has called “marketing masquerading as research,”23—that is, studies that are carried out for commercial reasons, not scientific ones, raising questions about their ethical basis.2425 In addition, the more expensive drugs used in so called “seeding trials”—sometimes called marketing trials—impose considerable extra costs to the healthcare system without measurable benefit to patients.26 The existence of seeding trials has been verified by confidential documents accessible to medical experts testifying in legal proceedings,2728 but gauging their prevalence has been difficult.29 The low ratio of patients to physicians that other authors have observed in seeding trials2728 was also observed in our study and is conducive to low data quality as the training and monitoring of many physicians, each treating only a few patients, is cumbersome and inefficient.28

Adverse event reporting

Bearing in mind that spontaneous reporting is thought to cover 10% of all serious adverse drug reactions and less than 5% of non-serious ones,30 the current practice of post-marketing studies is likely to aggravate the under-reporting of adverse drug reactions. Our data show that participating in a post-marketing study is acceptable among a considerable proportion of physicians in Germany. In the contracts we reviewed we found confidentiality clauses requiring physicians to report adverse drug reactions exclusively to the sponsor rather than to the spontaneous reporting scheme. This raises the question of whether such contracts represent a conflict of interest with the physicians’ professional code of conduct31 as it would necessarily diminish their individual, direct role in reporting of such events. Furthermore, we were unable to assess whether adverse drug reactions occurring within our sample of studies were also reported by the sponsor to the respective authorities. In the above mentioned study on dabigatran etexilate, for example, we found indications that adverse drug reactions occurring within post-marketing studies might have never or only partially been reported. Shortly after market authorisation of dabigatran, a new anticoagulant licensed in 2008 for prevention of thrombosis in patients after hip and knee replacement, the manufacturer initiated two post-authorisation safety studies, which were among the notifications to the KBV (PASS 1160.84 and PASS 1160.85). Severe side effects of dabigatran, especially bleeding complications and death, have been reported, especially in elderly patients with impaired renal function.32 In addition, previously undisclosed data from pre-marketing trials on dabigatran had shown that the risk of bleeding and the necessity of measuring plasma concentrations in patients taking dabigatran were downplayed by the manufacturer.33 In contrast with PASS 1160.85, comprising 2036 patients with normal renal function, PASS 1160.84 intended to enrol 300 patients with moderate impairment of renal function. While we could find a link to the tabulated final synopsis on PASS 1160.85 published in 2013 in the clinicaltrials.gov database,34 PASS 1160.84 was not finished at the projected date (1 February 2012) nor was any final report or reference to results or side effects retrievable from Pharmacovigilance Risk Assessment Committee (PRAC) reports or other sources before 2015. Instead, by June 2014, more than two years after the scheduled end date, the drug regulator and KBV received a change notification of the termination date to 2014. Based on the documents that were provided it seemed that neither the drug regulator nor other authorities had taken notice of the course of PASS 1160.84. When we attempted to obtain specific information on adverse drug reactions on PASS 1160.84 between 2009 and 2012 from the solicited reports to the DCGMA database it turned out that the 68 severe adverse drug reactions could not be linked to any PASS/post-marketing study on dabigatran.35 It was not until June 2015 that a tabulated result section including adverse drug reactions of PASS 1160.84 was added to the respective clinicaltrials.gov study page.36 No reference to time of occurrence of serious adverse events was provided. Considering the legal obligation of reporting serious adverse events within 15 days after learning about the event,37 it is of concern that PASS 1160.84 was not terminated at the projected date but three years later, without any explanation why the study period was so much prolonged and with no traceable hints to PASS 1160.84 in PRAC reports during 2009-15. It is worth noting that after the initiation of a post-authorisation safety study, oversight by PRAC with periodic reporting is required.4 Our findings, however, highlight the fact that if reporting of adverse drug reactions from a post-authorisation safety study/post-marketing study is delayed or occurs in such a way that does not allow a determination of whether events listed in a pharmacovigilance database occurred under a post-marketing study or not, this is concerning from a transparency and public health perspective. Our research points out that not only in sponsor directed randomised controlled trials38 but also in post-marketing studies, withholding of data on adverse drug reactions or other information by the sponsor is a problem that so far has not been adequately dealt with.

Data from the UK and the US have shown that by the mid-1990s, 5% of hospital admissions and 0.1% of deaths of medical patients and 0.01% of deaths of surgical patients were caused by adverse drug reactions.6 Some 20 years later drug prescribing habits of doctors have skyrocketed,39 with prescription patterns following industry payments.404142 Some authors have documented that the number of reports of adverse drug reactions decreased by 58% in some areas of the UK during the past two decades.43 This study found a strong correlation between high prescription rates and low spontaneous reporting of adverse drug reactions by GPs in the UK.43 Assuming that industry payment for participation in post-marketing studies is one reason for increased prescribing of drugs, as suggested by the literature on seeding trials,252728 the decreases in reporting of adverse drug reactions over time should be of concern as a possible unintended consequence of post-marketing studies. We cannot exclude that signing of post-marketing study confidentiality contracts in combination with the high remunerations could influence physicians’ attitudes and practice of reporting adverse drug reactions, in particular when contracts require physicians to report reactions exclusively to the sponsor, as we found was the case in our study. From the patients’ and public health perspective, such influences on physicians are detrimental as they undermine the prominent and irreplaceable role of GPs/clinicians in detecting, diagnosing, and reporting adverse drug reactions for continued drug safety monitoring.6

Strengths and limitations of study

For the first time we have analysed previously inaccessible original notification documents provided by 148 manufacturers of drugs or medicinal products over a three year period on their post-marketing study activities. In particular, we found contracts with strict confidentiality clauses that had not been available for public scrutiny before. These were obtained after two lawsuits and administrative court rulings granting freedom of information rights on notification data from post-marketing studies.

Our study has limitations. As mentioned before we analysed original notification documents but not real study data. The notification documents provide data on planned studies, but we do not know how these post-marketing studies were carried out in reality. For example, we do not know if the intended numbers of patients or physicians were really achieved in the course of the study. Our calculated number of 126 000 participating physicians is likely to be an overestimate because physicians can participate in several post-marketing studies. Nor do we know anything about data quality and checks of data quality in these studies. We cannot be sure either, whether the physicians received more or less remuneration than envisaged. Our finding that most post-marketing studies were not published by 2015 in the databases we searched cannot exclude publications elsewhere. In light of the scientific purpose of post-marketing studies, however, published results of these studies should be traceable in established medical literature databases. Similarly our inability to connect the notifications with adverse drug reaction reports in the UAW database is because there is no tagging of the respective reaction reports with specific post-marketing studies. Therefore we cannot know whether the adverse drug reactions database contains reports from our sample of post-marketing studies.

Being aware that we looked only at original notifications rather than the real study documents and that the completeness of the given information was far from satisfactory, our results should be seen as a first estimate of the magnitude and potential risks incurred with current post-marketing study activities.

Conclusions and policy implications

Our findings do not support the aspiration of the German Medicinal Products Act that post-marketing studies serve to improve long term drug safety surveillance. In contrast, we found evidence that drug safety could be jeopardised by the current practice, as post-marketing studies are expected to contribute to pharmacovigilance, but in reality their data and results are treated as business secrets. Our data support the view that the high remunerations paid by the sponsor to the participating physician could be serving commercial purposes rather than transparent and effective pharmacovigilance. In our opinion the major problem with post-marketing studies is the confidentiality clauses in the contracts between physicians and sponsors. These contracts impose a major obstacle to scientific evaluation and discussion of post-marketing studies. In the interest of drug safety and public health, post-marketing surveillance should become more transparent. Data about and from such studies should no longer be considered confidential business information but should be made available to independent scientific evaluation and public scrutiny. Such increased transparency would allow future researchers to evaluate whether the changes in 2012 to EU pharmacovigilance legislation44 have been associated with any material improvements in the situation.

The importance of advising GPs and clinicians on their indispensable role in detecting, diagnosing, and reporting adverse drug reactions cannot be overestimated.