Public Health Genomics 2013;16:322–335 DOI: 10.1159/000355941

Published online: February 3, 2014

Clinical Trial Transparency and Orphan Drug Development: Recent Trends in Data Sharing by the Pharmaceutical Industry D. So Y. Joly B.M. Knoppers Centre for Genomics and Policy, McGill University, Montreal, Que., Canada

Key Words Clinical trial · Data sharing · European Medicines Agency · GlaxoSmithKline · Medtronic · Orphan drug · Rare disease · Roche · Transparency

Abstract Background: Data sharing from clinical trials can be key to the development and approval of medicines for rare diseases. Many events during the first half of 2013 have contributed to the movement for increased transparency. These include the development of the European Medicines Agency’s new data publication policy, the creation of the AllTrials petition and GlaxoSmithKline’s choice to sign it, the launch of GlaxoSmithKline’s system for access to patient-level clinical trial data and Roche’s commitment to create a similar system, the release of results from the Yale University Open Data Access project’s first medicine analysis for Medtronic, and the creation of the Reg4All website. Aims/Objectives: This paper summarises major developments in clinical trial transparency between January and June 2013 and analyses the composition of datasets released by GlaxoSmithKline. Methods: GlaxoSmithKline’s database of available trials was tabulated and graphs of relevant trial characteristics were produced. Results/Conclusions: Due to current transparency initiatives, it is likely that much more data will be made

© 2013 S. Karger AG, Basel 1662–4246/13/0166–0322$38.00/0 E-Mail [email protected] www.karger.com/phg

available over the next few years through systems similar to GlaxoSmithKline’s. Although some aspects of GlaxoSmithKline’s model could limit its usefulness, the data currently listed is diverse and could be promising for researchers interested in rare disease treatment. © 2013 S. Karger AG, Basel

Introduction

The European Union (EU) defines a rare disease as a life-threatening, debilitating and/or seriously chronic illness affecting fewer than 5 in 10,000 people, while the US defines one as affecting a total of fewer than 200,000 people in the country [1, 2]. Approximately 7,000 diseases fall into these categories, of which 85% are serious or life-threatening and fewer than 5% have known treatments [3–5]. Despite the significant combined burden of these diseases, the limited number of potential purchasers for any one rare disease treatment can make it difficult for a pharmaceutical company to justify spending money on drug development in these areas. Furthermore, it can be difficult to conduct useful clinical trials for these medicines because few participants may be available, and their conditions are often heterogeneous and poorly understood [6, 7]. Derek So Centre of Genomics and Policy, McGill University 740 Avenue du Dr. Penfield, bureau 5101 Montreal, QC H3A 5101 (Canada) E-Mail derek.so @ mail.mcgill.ca

The EU, US, and other countries have adopted policies which grant incentives for the development of rare disease treatments designated as ‘orphan drugs’. These policies have successfully increased interest in rare disease treatment, resulting in the development of thousands of new medicines [1, 2, 7]. However, even these drugs may not be approved or reimbursed for patients unless the available benefit, risk and cost-effectiveness data is rigorous enough. Of over 2,500 medicines designated as orphan drugs since the US’s Orphan Drug Act in 1983, only about 400 have been approved for use by patients [6, 7]. One strategy that can be used to identify viable new rare disease treatments at a reduced cost is that of drug repurposing, in which a previously developed medicine is used for a new indication. This method relies upon the availability of thorough information about the original drug as well as evidence that it can be safely and effectively repurposed. Therefore, the use of pre-existing data is often key for the development of rare disease drugs, partly in order to compensate for the limited number and lifespan of many patients and partly due to the importance of repurposing methods. Data availability from previous clinical trials is a key driver of the increasing interest and investment in rare disease treatment [5–7]. Of course, there are many benefits of clinical trial data sharing other than those which relate directly to rare disease. Data sharing minimises redundant data collection, reducing costs and safety risks; allows results to be verified and pooled for meta-analysis; reveals new trends and enables further research; strengthens collaboration between data users; allows physicians and patients to make informed and evidence-based decisions; honours the contribution of trial participants; and builds trust in clinical research so that more people will be willing to join trials in the future [8–16]. In accordance with these benefits, many journals, funders and countries have adopted data-sharing requirements of some kind. During its 7th revision in 2008, the Declaration of Helsinki was even amended to include a paragraph stating: ‘Authors have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports … Reports of research not in accordance with the principles of this Declaration should not be accepted for publication’ [17]. These principles have been retained in the Declaration’s newest draft, published for public consultation in April 2013 [18].

Yet although pharmaceutical companies must share their clinical trial data with agencies such as the European Medicines Agency (EMA) and US Food and Drug Administration (FDA), they are not currently required to publish comprehensive data in order to receive marketing approval [9]. Furthermore, compliance with the existing clinical trial publication standards is very inconsistent. Almost half of clinical trials are never published (regardless of trial stage, size, location, or conductor), those that are published frequently omit safety findings, and studies with favourable outcomes are twice as likely to be published as those that did not result in the authors’ preferred findings [8, 19]. This lack of unbiased information can make it difficult for peer reviewers and health technology assessment panels to appraise the accuracy of studies and can, therefore, have significant consequences for the decision-making process [8, 13]. Arguments which have been raised by investigators and industry against mandatory data sharing include such potential issues as the additional cost of preparing data for release, use of data by competitors to accelerate their development programmes, legal trouble such as groundless litigation or the inability to obtain patent rights due to prior public disclosure, health scares caused by misinterpretation of data, and the possibility of endangering the confidentiality of patients, particularly those with rare diseases who are easier to re-identify due to their limited numbers [8, 9, 13, 15, 20–24]. Despite significant interests by some stakeholders in keeping clinical trial data confidential, there have been a number of major developments towards increased transparency during the first half of 2013. These developments could impact significantly on the growth and mission of the International Rare Diseases Research Consortium (IRDiRC), which aims to have 200 new therapies for rare diseases by 2020 [25]. They include the publication of the EMA’s proposed policy for proactive publication of clinical trial data [26], the creation of the AllTrials petition and GlaxoSmithKline’s (GSK) choice to sign it [27, 28], the launch of GSK’s system for providing access to patient-level clinical trial data and the development of that of Roche [23, 29], the release of the results from the Yale University Open Data Access (YODA) project’s analysis of open data from Medtronic [30, 31], and the creation of the Registries For All (Reg4All) website [32]. This paper endeavours both to summarise these important events and to analyse the composition of the patient-level datasets listed as available by GSK, in order to suggest whether data of this type may be useful for researchers developing new rare disease treatments.

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Context

Data Sharing and the FDA In 1997, the FDA Modernization Act created clinicaltrials.gov, a website managed by the US National Library of Medicine which grants public access to information about ongoing clinical trials from the US and internationally [8, 14, 33]. This resource did not become prominent until 2005, when the International Committee of Medical Journal Editors (ICMJE) began requiring that investigators register their clinical trials as a prerequisite for publication [8]. However, it was found in 2009 that only half of studies subject to the ICMJE’s requirement had been properly registered and that a quarter had never been registered at all [34]. Although the FDA Amendments Act of 2007 expanded the role of clinicaltrials.gov to include results from all US-based trials within 1 year of trial completion, an independent audit in 2012 revealed that only 22% of studies conducted since then had followed this law [8, 9, 35]. Yet no fines have been issued to these companies for noncompliance, and most of the drugs currently used in health care entered the market before those requirements were put in place [27]. Although researchers with a National Institutes of Health grant of over USD 500,000 are required to share actual clinical data, there is no uniform system for submission, format or oversight [9]. Investigators who register their trials on clinicaltrials.gov are given great flexibility in what to report and are not required to submit raw patientlevel data or full clinical study reports (CSRs) to the website [8, 9]. Patient-level data refers to data containing results from individual participants rather than averages from groups of patients. CSRs include information on clinical trial design, methods and results and are used as the basis of submissions to regulatory agencies such as the FDA and EMA for marketing authorization [28]. Researchers interested in this type of data cannot request it from the FDA either, since current US laws make it impossible for regulators to disclose clinical trial documents from the companies that have submitted them. However, the agency is considering other ways to increase its transparency [36]. Despite the jurisdictions’ differing legal requirements, a spokesperson for the FDA stated that the agency was ‘following with interest’ the current movement towards proactive data publication by the EMA [9]. Document Release by the EMA The EMA, created in 1995, has recently been at the centre of a number of disputes concerning data sharing from clinical trials [9]. Article 2 of EU Regulation 324

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1049/2001/EC allows citizens and residents to request documents held by institutions such as the EMA, except in cases where commercial interests are at stake (although those commercial interests can be overridden if there is an important public interest in disclosure) [37]. In 2007, Peter Gøtzsche of the nonprofit Nordic Cochrane Centre made a request to the EMA under Regulation 1049/2001/ EC for information about trials concerning 2 antiobesity drugs [9, 20]. Although this request was denied, he appealed to the European Ombudsman, which ruled in November 2010 that clinical trial information should no longer be treated as confidential by default [9, 20, 22]. Under its new protocol, the EMA has released over 1.9 million pages of data from various types of documents in response to 613 requests, about one-third of which have come from pharmaceutical companies [9, 20, 38]. According to an analysis of the 457 requests received by the EMA between November 2010 and November 2012, only 38 (8%) came from academia [9, 39], 33% came from the pharmaceutical industry, 18% from the media, and 16% from lawyers. Some documents were also requested by the general public, other institutions, consultants, health care professionals, patients’ organizations, and the financial sector. Furthermore, 27% of these requests were not granted due to inapplicability or time expiration, and 71% of the documents provided contained at least one redaction [39]. The EMA plans to institute a more streamlined new policy in 2014, in order to reduce the time spent responding to requests under the current system [9]. This model will proactively provide public access to patient-level data and CSRs through the EMA website [9, 20]. Discussions with stakeholder advisory groups about topics such as patient confidentiality, data formats, rules of engagement, analysis practices, and legal issues were carried out from November 2012 to April 2013 [9, 40]. The initial draft was published for public consultation on June 24. The final document will be published in November, and the new policy will come into effect in January 2014 [26, 40]. According to the current draft, clinical trial data submitted to the agency will be automatically made accessible to external parties when its European Public Assessment Report is published. The EMA will also require that all secondary analyses of this data be published to the public domain. Documents which may pose concerns for the protection of personal data will be made available only to established requesters who agree to sign a data-sharing agreement, which will prevent them from attempting to re-identify participants or using the data for purposes beyond the boundaries of their initial consent. In addition, So/Joly/Knoppers

documents containing commercially confidential information will not be made available through this system and must still be requested under Regulation 1049/2001/ EC [16]. However, recent events may have presented a setback to this initiative. The first legal challenge to the new protocol came in January 2013, when AbbVie (a North Chicago-based spinoff of Abbott Laboratories) sued the EMA to prevent disclosure of data about its top-selling autoimmune drug Humira (adalimumab) to other pharmaceutical companies including the Belgian firm UCB [9, 20, 21, 41]. InterMune (a much smaller company from Brisbane, Calif.) filed an independent suit in February regarding data about its only product Esbriet® (pirfenidone), which treats a rare lung disease called idiopathic pulmonary fibrosis and has been approved as an orphan drug in the EU since 2011 [20, 22, 42]. These companies claimed that clinical trial information should be exempted from disclosure under Regulation 1049/2001/EC, since the requests were made for private rather than public interests and releasing the documents would endanger the companies commercially [22]. On April 25, the General Court of the European Union granted temporary injunctions preventing the EMA from releasing clinical trial data on either drug until the Court’s final ruling [43, 44]. The agency initially stated that other data requests would continue to be accepted during the case, although documents similar to those contested by AbbVie and Intermune would have to be considered on a case-by-case basis [38]. However, on May 28–29 the EMA sent letters to researchers informing them that it had been forced to suspend access to CSRs from other medicines in order to prevent further legal action from pharmaceutical companies [45, 46]. Although the EMA will continue drafting its new policy for making clinical trial data available online in 2014, these plans must now take into account the General Court’s forthcoming final ruling on data sharing and the concept of commercially confidential information [20, 38, 40]. The Pharmaceutical Research and Manufacturers of America applauded the General Court’s decision in a press release, stating that the EMA’s policies disrespected ‘responsible data sharing that protects patient privacy … the integrity of the regulatory review process, and … incentives for biomedical research’ and that pharmaceutical companies were already committed to data sharing in ways supportive of public health [47]. Guido Rasi [48], the executive director of the EMA, commented that ‘The strategy of keeping data secret that should be open for public scrutiny to benefit public health

AllTrials and GSK The decision of the General Court was also strongly condemned in an April 30 statement released by the AllTrials initiative [49]. This campaign, whose title is short for ‘All Trials Registered, All Trials Reported’, was launched in January 2013 at http://www.alltrials.net/. It circulates a petition for the publication of full CSRs from all past, present and future clinical trials involving drugs currently in use [27]. AllTrials was cofounded by the BMJ (formerly the British Medical Journal), which simultaneously took the steps of encouraging its authors to publish data through a digital repository called Dryad and requiring them to share anonymised patient-level data if requested [50]. ‘Anonymization’ here refers to the removal of all information that could allow a researcher to determine a participant’s identity from their clinical data. The BMJ also launched its own Open Data Campaign to document cases of ‘hidden data’ by pharmaceutical companies and published a special issue addressing the subject [51]. In February 2013, the multinational British pharmaceutical company GSK signed the AllTrials petition, expressing a commitment to publish anonymised CSRs from all phases and types of human research study. GSK submits its results to peer-reviewed scientific journals 18–24 months after study completion, and its CSRs are now posted on GSK’s Clinical Trials Register once those results are published and the medicines in question have been either approved or discontinued [10, 28, 29, 52, 53]. GSK also established a team to retrieve and anonymise CSRs from all of its previously approved medicines since the formation of the company, with priority given to its most commonly prescribed products [28, 52]. No other company or industry representative has signed the petition, despite GSK’s choice to do so. In response to its announcement, the Association of the British Pharmaceutical Industry issued a brief press release stating that AllTrials was not the only initiative addressing transparency, and the decision to sign the petition ‘is one for individual companies to make’ [54]. One reason for GSK’s choice to join the initiative may be its experience with successfully conducting open data projects. GSK has previously released data intended to help other researchers repurpose its drugs for malaria treatment and has more recently shared data on potential

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has not worked’. He cautioned companies that their concerns were unfounded and that fighting against data release would end up costing the pharmaceutical industry due to increased public distrust [21].

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tuberculosis medicines [11, 55]. The company’s initial deposit of over 13,500 drug structures into the European Bioinformatics Institute’s public domain ChEMBL-NTD database marked the first large-scale release of this type of data by a pharmaceutical company. GSK also created an ‘open lab’ in which researchers could apply to use the company’s neglected-diseases research facility in Tres Cantos (near Madrid) [56, 57]. GSK was also the first major pharmaceutical company to develop a system for releasing anonymised patient-level data to researchers through an independent review panel (table 1) [28, 52]. This project was announced in October 2012 and debuted on May 7, 2013 [29]. GSK stated that this system is only a first step, and ‘is likely to evolve’ as the company gains experience in providing data access [10]. Their ultimate goal is to develop a system through which all of industry and academia can make anonymised patient-level clinical trial data available to researchers via an independent public or charitable-sector custodian [10, 29]. Indeed, GSK is already in discussion with other organizations interested in setting up or participating in such a system [29]. Roche Another company which has been in discussions to join this industry-wide initiative is the Swiss firm Hoffmann-La Roche [10]. Roche announced on February 26, 2013 that it would also be working with the same independent review panel to provide access to anonymised patient-level clinical trial data (table  1). Roche also expressed its support for the EMA’s policy of disclosing clinical trial data and announced that it would make its CSRs available more broadly, although some information would be redacted in order to protect patient confidentiality and the company’s commercial interests [10, 23]. Roche and GSK have both been the subjects of controversy relating to clinical trial transparency. GSK’s diabetes drug Avandia (rosiglitazone) and Roche’s antiflu drug Tamiflu® (oseltamivir phosphate) have been investigated as part of the BMJ’s Open Data Campaign [51]. The UK spent £424 million to stockpile Tamiflu between 2006 and 2013. However, in 2009, researchers affiliated with BMJ and the Cochrane Collaboration found that organizations including the EMA, World Health Organization and Centers for Disease Control and Prevention had approved or recommended the purchase of Tamiflu without having been shown the full clinical trial data [58, 59]. Although Roche announced the formation of a Multi-party Group for Advice on Science to analyse the complete data in February 2013, the Cochrane Collaboration declined to join 326

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due to concerns about bias among the group’s members [23, 60, 61]. That April, after over 3 years of correspondence, Roche finally offered the Cochrane Collaboration access to edited CSRs from all 74 Tamiflu trials [62]. Meanwhile in July 2012, GSK paid a record-setting USD 3 billion fraud settlement to the US government over misrepresentation of safety data from its clinical trials of drugs including Avandia and the antidepressant Paxil (paroxetine) [11]. Given these highly publicised concerns over drug safety and effectiveness, it is likely that recent moves towards transparency by GSK and Roche may have been partly motivated by the desire to counter these controversies and address public distrust of the pharmaceutical industry and regulatory authorities [21, 36]. In April 2013, 14 companies including AbbVie, GSK and Roche jointly expressed support for a consensus study planned by the Institute of Medicine. The study will seek input from a wide range of shareholders in order to provide recommendations for a wider clinical trial datasharing model. The companies stated that based on the results, they will seek ‘broad adoption of a unified approach applicable to all groups involved in generating or sponsoring clinical trial data’ in which ‘patient confidentiality is preserved, scientific integrity is maintained, and intellectual property rights and confidential company information are protected’ [12]. Medtronic and YODA The only major company besides GSK which has released full clinical trial data from at least one of its products is Medtronic, a Minneapolis-based firm which is the world’s largest medical technology company. In 2011, Medtronic released safety data, post-marketing data and full patient-level data from 17 studies of its product INFUSE® Bone Graft (recombinant human bone morphogenetic protein-2) [8, 63]. INFUSE has been approved by the FDA since 2002 as an orthobiologic agent used to promote bone growth after certain surgeries [15, 24, 64]. However, in June 2011 the Spine Journal published an entire issue criticising Medtronic for buying the support of surgeons and failing to report numerous side effects of INFUSE, including an increased risk of cancer [65, 66]. Medtronic was simultaneously being investigated by the US Senate’s Finance Committee and the Department of Justice for infractions like omitting safety issues from its clinical trial data and helping to write medical journal articles in favour of the medicine [64, 65]. As a result of this criticism, INFUSE sales dropped from USD 800 to 528 million between the 2011 and 2013 fiscal years [65]. So/Joly/Knoppers

Table 1. Data transparency plans from GSK and Roche

Data

GSK (active)

Roche (prospective)

CSRs

• Posted to http://www.gsk-clinicalstudyregister.com after product approval/termination and result publication • Individual patient data removed • Currently being retrieved from all previously-approved drugs

• Can be requested after health authorities’ assessment • Edited for patient confidentiality and commercial interests

Patient-level data

• Approved/terminated medicines listed on https:// clinicalstudydata.gsk.com within 6 months of publication • Global studies since 2007 and all studies from 2013 onwards included; list updated at least biannually, all major studies since founding of GSK in 2000 to be added by 2015 • Raw and analysis-ready datasets, full protocols with amendments, annotated case report forms, reporting and analysis plans, dataset specifications, and CSRs included • Data-sharing agreement requires researchers to publish results, inform GSK and authorities of safety concerns, allow GSK purchase or nonexclusive use of any new invention • Independent review panel examines rationale, relevance, expertise, publication plan, conflicts of interest, privacy management, ethics approval within 30 working days • Analytic software (R, SAS) and helpline provided • Datasets combinable on the website but cannot be downloaded • No observational studies, meta-analyses, or data on outlicensed medicines or rare diseases listed; requests for unlisted data granted if GSK deems it retrievable, anonymizable and legally sharable • Successful applications listed on website • 12 months of access granted, with potential extension

• Medicine trials submitted for regulatory review in the US and EU available after heath authorities’ assessment • Shared with independent researchers with scientifically robust analysis plan • Independent third party assesses proposals for bias, scientific integrity, etc.

Other data

• Group-level summaries of medicinal product research with human subjects posted to http://www.gskclinicalstudyregister.com 8 – 18 months after completion • Manuscript submitted to peer-reviewed journal within 18–24 months, full protocol posted to register when published • Register currently includes almost 5,000 result summaries, receives 11,000 visitors/month

• Data summaries posted to http://www. rochetrials.com • All trial results published at conferences and in journals, often preceding regulatory review • Summary reports (incl. periodic safety reports) can be requested after health authorities’ assessment

Privacy considerations

• Data anonymised based on privacy laws and regulatory guidance; viability of anonymising rare disease trials considered case-by-case • Password-protected website and secure download system to prevent unauthorised access • Data sharing agreement to protect privacy, restrict use to the medicine or disease studied in the initial patient consent • Participants in trials from 2013 onwards asked to give broader consent

• Data anonymised through redaction from CSRs • Data made available through secure system • Future participants informed that anonymised data may be shared broadly for research

Data retrieved from press releases and public-domain presentations by GSK and Roche as well as GSK’s active data access websites [10, 23, 28, 29, 53, 73].

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In response, Medtronic provided a USD 2.5 million grant to the YODA project for analysing the complete data on INFUSE. Part of the grant supported the dissemination of this data to other scientific researchers through an application process [15, 67]. YODA also commissioned independent teams at Oregon Health and Science University and the University of York to conduct systematic reviews [15, 63, 64, 67]. Both teams’ findings were published in the June 18, 2013 issue of the Annals of Internal Medicine [30, 31]. This journal had previously set a data-sharing precedent in 2007 by requiring all authors to state what data they were willing to make available to readers and under which terms [68]. Medtronic commented that pioneering open access to clinical trial data would benefit all stakeholders by providing slower but more balanced and reliable information about product safety and effectiveness, whether or not the findings fell in line with the company’s own conclusions. Standardised data analysis methods and open discussion of the results were seen as key to this type of project [24]. YODA’s principal investigator, Harlan Krumholz, also suggested that this type of transparent data analysis could become a common way for companies to improve their ‘declining public perception’ [15]. Unfortunately for Medtronic, INFUSE was found to be no more effective than the traditional method of iliac crest bone grafts and to be associated with a small increase in cancer rates. Some sources of bias were identified within the conduct of Medtronic’s clinical trials [30, 31, 63]. Within a day of the announcement of these results, Medtronic’s share prince had begun to slip downwards [64]. Given these outcomes, it remains to be seen how the results of YODA’s first systematic review of clinical trial data will affect the data transparency movement. Registries for All A final recent initiative which should be mentioned is the Reg4All project. On February 28 (Rare Disease Day) 2013, the nonprofit health advocacy organization Genetic Alliance launched Reg4All at https://www.reg4all.org. The website, which was funded by the USD 300,000 first prize from the Sanofi US Collaborate Activate challenge in December 2012, is described as a secure ‘consumerdriven, cross-disease health registry platform’ through which individuals can ‘share the information they specify, with the researchers and research organizations they chose’. One of Reg4All’s goals is to increase enrollment in clinical trials by creating an online community of all types of patients and connecting them to the appropriate researchers [32, 69]. Although it is early to tell how much 328

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Table 2. Listed patient-level datasets from GSK orphan drug trials

[73] Drug

Orphan Orphan designation designation in the EU in the US

GSK trial

Clindamycin

sarcoidosis

acne

Eltrombopag

purpura

AIDS-related pneumonia, sarcoidosis

purpura

Fluticasone

esophagitis, eye disease

asthma, chronic obstructive pulmonary disease, allergic rhinitis

Lamotrigine

Lennox-Gastaut syndrome (epilepsy)

mood disorders, bipolar disorder, epilepsy

Lapanitib

ErbB2-positive gastric and esophageal cancers

breast and lung cancer

Omega-3-acid ethyl esters

prevention of organ graft, pediatric Crohn’s disease, IgA nephropathy

hypertriglyceridemia

Pazopanib

ovarian and soft-tissue cancer

breast and lung cancer, soft-tissue sarcoma, solid tumours

Tazarotene

congenital ichthyosis

Topotecan

glioma

acne glioma

small-cell lung cancer

this project will succeed in its objectives, it is certainly possible that Reg4All will help attract more rare disease patients to trials where larger numbers of participants are desperately needed.

Analysis of GSK Datasets

GSK’s new website for patient-level data access includes an initial list of 211 available trials, of which all but 90 were for vaccines. We wanted to ascertain whether the data released by GSK and other companies joining this initiative would be likely to aid research in rare disease treatment. Therefore, we undertook a review of every dataset included on the website. We visited the database available at https://clinicalstudydata.gsk.com/PostingsBrowseOnly.aspx and noted the medicine, indication, stage, and completion year of each trial. The listed vaccines were not included in our analysis because they are So/Joly/Knoppers

40

Trials Using Drugs with Orphan Designation

50

9

Drugs with Orphan Designation

17

Trials Using Drugs 50 Trials Using with Orphan Designation Drugs without Orphan Designation

Drugs 17 Trials Using with Orphan Designation Drugs without Orphan Designation

Fig. 1. Drugs used in trials available from GSK. This figure indicates the number of trials using orphan and nonor-

phan drugs, along with the total number of distinct drugs tested of each type [73].

Orphan Designation

17

No Orphan Designation

9

6

15

Trials

16

9 Trials

11 Drugs

5

4 Drugs 9

9

6 Trials 5 Drugs

Phase I

Phase II

Phase III

10 Trials

1 Drugs 5

Phase IV

Fig. 2. Phases of trials available from GSK. This figure indicates the number of trials using orphan and nonorphan drugs, along with the total number of distinct drugs of each type, listed from each phase of development [73].

not typically relevant for the development of medicines for rare disease. For each of the remaining drugs, the number of trials at each stage of development, the indications being tested and the completion years of those trials was recorded. Following this, 2 official lists of orphan designations in the EU and in the US were consulted to determine which of those medicines appeared on at least one list [70, 71].

Those 9 products were categorised as ‘drugs with an orphan indication’, and the indications for which they had received one or both orphan designations were also recorded (table  2). Last, the listed medicines were sorted into 6 categories by researching the type of disease or condition into which their indication could best be grouped. Those that could not be grouped with any other indications were simply listed as ‘other’.

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Mental and neurological disorders

Cancer Allergies and autoimmune disease 20 Chronic obstructive pulmonary disease

Phase I

Phase III

25 Phase II

Phase IV

Trials Using Drugs with Orphan Designation

Infectious diseases

Trials Using Drugs without Orphan Designation

Other 0

5

10

15

Fig. 3. Conditions treated in trials released by GSK. This figure indicates the number of trials listed that were be-

ing developed for each general category of indications. Drugs being tested for conditions that could not be grouped with any others are designated ‘Other’. The figure also indicates the number of these trials from each phase of development and using orphan and nonorphan drugs [73].

The resulting data was graphed in order to visually demonstrate the total number of orphan and nonorphan drugs tested as well as the total number of trials using orphan and nonorphan drugs (fig. 1). Next, it was graphed to show the number of trials conducted with orphan and nonorphan drugs at each trial phase as well as the number of orphan and nonorphan drugs used in trials at those stages (fig. 2). It was also graphed to show the number of trials at each phase conducted for the treatment of each general type of disease and the number of trials using orphan and nonorphan drugs conducted for the treatment of each of those types (fig. 3). Finally, the data was graphed to show the number of trials using orphan and nonorphan drugs that were concluded in each year, from the oldest trial in 2007 to the ongoing ones (fig. 4).

Discussion

Advantages To our knowledge, this paper includes the first analysis of the composition of the datasets recently made available by GSK. This is the only large pharmaceutical company (not including Medtronic) to have released patient-level data on its products so far. Since only 90 nonvaccine trials 330

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were included in the initial list and it is not known whether GSK’s pipeline is representative of other pharmaceutical companies, it is difficult to draw any conclusions about the usefulness of the whole industry’s data from the composition of this database. However, many more new and historical trials are forthcoming from GSK over the next 2 years (table 1), and further analysis may be warranted once these are listed. Despite the limited number available at this point, an initial review of the datasets offered suggests that information from the pipelines of large pharmaceutical companies could indeed be useful for the development, approval and reimbursement of orphan drugs. As expected, phase I trials were more commonly represented than any other, with fewer trials available from each successive phase. There were about half as many phase IV trials listed as there were phase I trials. Despite this difference, the presence of a significant amount of data from all 4 phases indicates that these databases could be useful for purposes beyond the basic investigation of safety and toxicology. It is also promising that a broad variety of drugs were included in the listed datasets: although all of the drugs were tested for common diseases, there were indications in many areas and not just the most lucrative ones. CanSo/Joly/Knoppers

Trials with Orphan Designation 16

Trials without Orphan Designation

14 12 10 8 6 4 2 0

2007

2008

2009

2010

2011

2012

Ongoing

n/a

Fig. 4. Number of trials from each year released by GSK. This figure indicates the number of trials listed with completion dates in each year. Some of these trials were still ongoing at the time the database was analysed. Some trials did not have a date of completion indicated, and these are labelled n/a in the graph [73].

cer drugs, for example, are often very toxic and can be inappropriate for repurposing. Furthermore, a significant fraction of the data (40 of 90 drug trials and 9 of 17 drugs) concerned drugs with an orphan designation in the EU and/or US. It is worth noting that although some of the drugs were being tested for the same indication as their orphan designations, just as many were being repurposed to the context of a different medical condition. Based on our analysis of this data, it seems reasonable to assert that GSK’s data release framework and others like it should hold promise for researchers who need additional data on drug safety or effectiveness. In jurisdictions like the EU and US which have established incentives for the development of orphan drugs, researchers could use the information accessed this way to strengthen the scientific rationale supporting their applications for a repurposed drug. This clinical trial data could also be very useful in demonstrating safety during health technology assessment, especially when very limited numbers of rare disease patients are available to participate in trials for the new indication. Challenges In our analysis of GSK’s data access framework and list of trials, we identified a number of factors which could reduce the usefulness of this type of data for the development of rare disease treatments. About half of rare disease patients are children, who often require lifelong treatClinical Trial Transparency and Orphan Drug Development

ment, and data from adults may not provide appropriate evidence for safety in many of these cases [4]. Another significant challenge for orphan drug development could be the fact that although GSK has included data from drugs with orphan designation, it has not listed trials which were actually conducted for the purpose of treating rare diseases. Information about some of these trials can be found on the website (table 3), and researchers also have the ability to make inquiries about those datasets. Yet since the independent review panel will only be consulted if GSK decides that this data is capable of being effectively anonymised, this constitutes a step in the process which could limit access to highly relevant information. GSK’s choice not to provide patient-level data from observational studies and meta-analyses may also pose challenges to some researchers. It is important for any model of clinical trial data release to apply retroactively, since most of the drugs currently in use were approved years ago. The inclusion of all global studies, but only from after the merger of Glaxo Wellcome and SmithKline Beecham in 2000, could allow GSK to avoid releasing data from older products which remain on the market, including controversial drugs such as Avandia and Paxil [11]. Their choice not to disclose patient-level data from drug trials that did not make it to publication and not to post historical CSRs from trials of unapproved drugs will also limit the availability of information that could be useful to researchers.

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A more significant challenge is the contractual clause from GSK’s patient-level data-sharing agreement, which states that the researcher must grant GSK a ‘perpetual, non-exclusive, royalty-free worldwide license’ and ‘an exclusive option … to negotiate in good faith an exclusive, fee-bearing, worldwide license’ [72]. This could limit interest from some researchers, since it would limit their ability to use the data to develop medicines for commercial purposes. However, it remains in line with the spirit of the transparency initiative that is putting data in the public domain. Given this constraint, it will be intriguing to see which types of organizations apply for data and how it is used once information on approved requests is posted on GSK’s website. Finally, an issue which may eventually become problematic is that of data format standardization. Although different GSK datasets can currently be combined with each other, they are not compatible with other sources because for now researchers must analyse them on GSK’s website and are not able to download the data directly. This issue could become more troublesome as pharmaceutical companies using different data collection methodologies begin to make their data available, and it becomes necessary for some researchers to compare different types of data on the same drug or disease. It goes without saying that harmonization, or even better standardization of industry data types and formats will become crucial. An Industry-Wide Initiative Despite the difficulties that may be caused by competing data formats, the fact that multiple pharmaceutical companies are even considering patient-level clinical trial data disclosure must be considered a significant breakthrough for transparency. It has even been speculated that if another large pharmaceutical company (most likely Roche) joined GSK, all other such companies might be forced to do the same in order to preserve their public image [11]. Of course, there will also be significant benefits for companies that follow through with this initiative. The most obvious of these benefits is that data sharing can increase public trust in the drug development process and should be very good publicity for the pharmaceutical industry. The timing of this movement with respect to recent policy changes by the EMA may also indicate that European companies are developing their own data release systems as a way of demonstrating responsibility and preventing less favourable regimes from being legally imposed upon them. 332

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Table 3. Unlisted patient-level datasets from GSK orphan drug tri-

als [73] Drug

Orphan designation in the EU

Tadalafil

Nelarabine

acute lymphoblastic leukemia

Orphan designation in the US

GSK trial

pulmonary arterial hypertension

pulmonary arterial hypertension

T-cell acute acute lymphoblastic lymphoblastic leukemia, chronic leukemia lymphoblastic leukemia, lymphoblastic lymphoma

Botulinum toxin type A

strabismus, blepharospasm, cervical dystonia, cerebral palsy

mood disorders, bipolar disorder, epilepsy

Epoprostenol

pulmonary hypertension, heparin replacement

hemifacial spasm, blepharospasm, cervical dystonia, spasticity, juvenile cerebral palsy

Eptifibatide

purpura fulminans

pulmonary arterial hypertension

Atovaquone

AIDS-related pneumonia and encephalitis

AIDS-related pneumonia

Ambrisentan pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension

pulmonary arterial pulmonary hypertension arterial hypertension, idiopathic pulmonary fibrosis

A third factor which may have contributed to the initiative is pharmaceutical companies’ interest in the contents of each others’ drug development pipelines. This could also explain the Association of the British Pharmaceutical Industry’s resistance to the AllTrials petition, since smaller industry members with fewer products than GSK and Roche could be hurt financially if their only products were discredited or if inefficiencies revealed in their research and development processes reduced the interest of their potential buyers. It will certainly be interesting to see whether other companies follow GSK’s lead, which types of companies do so and how their data access policies differ. Many different access models have been proposed, from data sharing only with legitimate researchers, to a dual system with some data completely open and more sensitive data availSo/Joly/Knoppers

able to researchers, to broad public sharing of all anonymised data [9]. It has yet to be seen which model may prove best at maintaining the balance between the health needs of patients, the privacy needs of the participants in clinical trials and the commercial needs of the pharmaceutical industry. Regardless of how data is made available, caution must be also taken to minimise the risk of data misinterpretation: no stakeholder benefits from inaccurate conclusions being drawn about medicinal products. GSK’s current system, in which applicants require scientific expertise, statistical software is provided to researchers and a helpline is available to help researchers understand the data, is a good example of how some erroneous conclusions might be avoided. One significant benefit which may arise from this movement is the fact that both companies releasing clinical trial data have begun to ask their participants to provide broader consent. The data currently available from GSK must be used to study the same medicine or disease as the initial trial in order to conform to the specific purposes laid out in the original consent forms. As companies such as GSK and Roche adapt their clinical trial practices to include consent for broader types of research, a great deal more data will become available for scientific purposes. If similar policies are chosen for an industrywide initiative, this could set a precedent that would be very useful to both patients and researchers for years to come. The rare disease community may stand to receive the greatest benefit from a unified portal for access to clinical trial data, as advocated by both Roche and GSK. Such a system could greatly facilitate not only the streamlined release of documents, but (especially if the data standardization concerns mentioned earlier are addressed) the combination of data from multiple sources. In cases where there is limited information on a rare disease or orphan drug and researchers need access to as much as possible, the possibility of requesting trials from multiple companies through the same application and monitoring process could save a great deal of time and effort.

Conclusion

The first few months of 2013 presented a surge of activity related to clinical trial transparency, much of it in favour of new data-sharing models but some (most notably the lawsuits by AbbVie and Intermune) as a reaction to evolving paradigms of drug development. Although Clinical Trial Transparency and Orphan Drug Development

their case against the EMA could make access to some types of data significantly more difficult in Europe, the sheer number of recent transparency initiatives by industry, regulators, universities, and patients’ organizations alike suggest that this trend has the support necessary to continue and expand. In fact, it would not be surprising if the industry-wide system initially proposed by GSK was adopted in some form over the next few years. Given the huge amounts of data which could soon be available, it was worthwhile to examine the trials listed on the industry’s first patient-level clinical trial database and to see whether this data holds promise for the development, approval and reimbursement of orphan drugs. Our findings in this initial review indicate a relatively diverse spread of phases and indications and a higher percentage of drugs with orphan designations. Although the number of trials examined was too small to draw definite conclusions and there is no guarantee that other companies will have similar pipelines, the types of data currently being offered show more potential for drug repurposing than initially expected. There is room for improvement in GSK’s and Roche’s current data-sharing model, but there is also a distinct possibility that healthcare for rare disease patients will be improved as a result of its leadership in the transparency movement.

Acknowledgements The authors would like to thank Rob Sladek for his scientific advice in the development of this paper, Gracien Dalpe and Rosel Kim for their help compiling data, and Elena Olvera-Rivera for her work in creating the figures. This paper was funded through the Canadian Institutes for Health Research through the New Emerging Team for Rare Diseases (REF# CIHR TR3-119193/BC).

Disclosure Statement B.M.K. is a member of the single independent review panel which assesses researchers’ applications to access patient-level datasets from GlaxoSmithKline and Hoffmann-La Roche.

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