Pharmaceutical sector SOMO Paper SO M O Medicines for the European market are increasingly being tested on clinical trial participants in lowand middle-income countries (LMICs), where most participants are poor and have limited access to health care. Against this backdrop, the entitlement to Post-Trial Access to Treatment (PTA) after the trial has ended becomes increasingly important to avoid the exploitation of vulnerable participants. The problem is that patients are being enrolled onto clinical trials in the full knowledge of the trial sponsors that they will not have access to the continuing treatment they may need once the trial has finished. This practice is unethical. "Because I will get into this trial, I get better, and then afterwards I am going to die. You have promised me life and then you take it back; that's not fair." HIV/AIDS Clinical Trial Participant, Kenya 2006 The Good Clinical Practice Guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH),1 which have been integrated into European legislation,2 comprehensively describe the responsibilities and expecta- tions of those involved in the conduct of clinical trials. However, these guidelines do not describe any responsi- bilities for continuing treatment after the trial. Leading international ethical guidelines such as the Declaration of Helsinki and the Council for International Organizations of Medical Sciences (CIOMS) guidelines include the right to PTA, but they use different wording and still raise many questions. This lack of firm guidance is fuelling a heated academic debate about fundamental ethical questions regarding the treatment of patients after clinical trials. "In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial. This information must also be disclosed to participants during the informed consent process." (Article 34, Declaration of Helsinki 2013) In the midst of this ethical and theoretical debate, what happens in practice? How do pharmaceutical companies deal with this complex issue with little practical guidance and without binding regulations? There is a big gap in our knowledge about how the pharmaceutical industry currently deals with PTA in practice. The objective of this research is to address this gap by offering a collection of PTA practices in low- and middle-income countries, as provided by the pharmaceutical industry. q Post-Trial Access to Treatment Corporate best practices February 2015 2Pharmaceutical sector SOMO Paper The Centre for Research on Multinational Corporations (SOMO) approached a number of the biggest pharmaceutical companies asking for a good example of a real situation in which they arranged and financed the continuation of treatment after the completion of a trial in a low- or middle-income country – in other words, we were looking for examples of best practice. Therefore, this paper does not aim to expose individual unethical company practices. Instead, it offers an insight into current corporate policies and practices relating to PTA based on company sources. The aim of this paper is to identify elements of corporate best practice in relation to PTA. The underlying assumption is that this will help to put a realistic standard in place that may lead to minimum regulatory rules in the longer term. Expert: "There is no consensus on what a PTA best practice should look like. My personal opinion is that if you don't have an alternative treatment, then you should continue with the experimental drug. But if there is an available treatment, then you should go back to that drug until the regulatory authority approves the drug. So there is not one recipe." Problem description While all the phases of a clinical trial are highly regulated, including the stage prior to the actual beginning of the trial (informed consent process), what happens right after the trial is not regulated. In theory, pharmaceutical companies accept a certain degree of responsibility regarding the provision of PTA. However, in practice PTA appears to be rarely provided in LMICs, where the need for PTA is the greatest. National health-care systems in LMICs are often not able to provide the follow-up treatment that is needed after the trial. This can lead to a situation where patients who have received treatment and care through their participation in a trial fall back on the insufficient local standard of care once the trial is completed (if they have access to treatment at all). This can result in the unwanted situation of the cessation of a beneficial treatment. Methodology This research focuses on nine of the 20 pharmaceutical companies that ranked highest by revenue in 2013. The sample of the companies analysed in this paper has been influenced by the degree of difficulty in identifying and gaining access to relevant people within the companies. The selection is therefore linked to the degree of accessi- bility and responsiveness of the companies on the subject of PTA. The findings are not representative for the whole sector. However, since we want to highlight the most advanced company policies on PTA, our assumption is that they are likely to be obtained from the most responsive companies on the subject. Company: "I supervise the department that manages clinical trials, so I don't know anything about the posttrial phase. For this point you need to contact our global headquarters." Nine companies provided answers about their PTA policies and practices by email, and five of them agreed to a phone interview. SOMO asked for examples of PTA solely sponsored by the company provided after a clinical trial in an LMIC.3 The requested examples were supposed to represent a good example of what the company considers to be in line with the international ethical guidelines they endorse. Not all the companies were willing or able to share examples of PTA matching SOMO's request, due to the fact that they do not keep records on PTA, or the information is not for public consumption, or simply because PTA is not provided by the company in an LMIC as far as the contact person was aware. All companies are given the opportunity to review their quotes and the presentation of their PTA examples. Alongside the search for corporate best practice, SOMO analysed the company policies on PTA, the strong and weak points of international guidelines, and reviewed part of the academic debate, without the goal of contributing to this debate. Reading guidance to the briefing paper Although the literature on the subject of PTA is quite extensive, practical examples are poorly documented, both in the literature and on the internet. As previously mentioned, this research aims to fill that gap. Starting from a review of the current international guidelines and of the main streams of academic output on the topic, it will then offer a reflection on the most advanced company policies on PTA. Examples of what companies indicated as their best PTA practice will follow. On the basis of these reviews and practices, this paper will then draw some conclusions and suggest elements for corporate best practice on PTA. Finally, some recommendations for implementation of such standards will also be provided. 3Pharmaceutical sector SOMO Paper PTA in the international ethical guidelines We have indicated that it is a problem that international ethical guidelines are not aligned. However, existing guide - lines do contain strong elements that, together, offer enough grounds for a strong PTA policy. The review on the next page highlights the strongest characteristics of each set of guidelines in order to identify what can be considered essential for PTA best practice. PTA in legislation Brazil and Argentina6 are currently the only countries where there are binding regulations to provide PTA (see Box 1). In a few LMICS, such as Uganda, India, South and Africa7 non-binding national guidelines support the provision of PTA. However, these are not mandatory. Although the wording in the Argentina law is somewhat vague, it is one of the two examples of PTA obligations incorporated in national laws.8 PTA in the European Medicines Agency reflection paper The guidance of the European regulatory authority (the European Medicines Agency – EMA) on how to deal with PTA in LMICs can be found in their reflection paper on ethical and good clinical practice aspects of clinical trials conducted outside Europe. PTA transparency is of paramount importance for the EMA, which requires clinical trial sponsors to describe the situation of trial participants with regard to PTA and medical care with respect to the local situation where the trial is conducted. They must describe what provisions were made for PTA and medical care and what information was given to the patients prior to their consent.9 PTA in the academic debate Issues around PTA range from medical science, bioethics, human rights, law and politics to economics and marketing. As a result of this complexity, a vast array of academic resources is available to deal with the medical needs and ethical, moral, political, legal and practical dilemmas. For this paper, two main streams of debate are particularly relevant. The first stream of academic literature deals with the fundamental question about the general desirability of PTA; arguments in favour and against PTA are widely discussed. In the second stream of debate, academics discuss the ethical implications of what appears to be the most pragmatic way to provide PTA with an unlicensed drug: Open Label Extension Studies.10 A fundamental question: is PTA always desirable? The principle of non-malfeasance (do no harm) is undisputed in medicine, and most arguments in favour of PTA refer to it. A drug that has proven to be beneficial to someone cannot be withdrawn. Moreover, when it comes to LMICs, the principles of justice and global ethical standards are evoked and contribute to an increasing consensus on the desirability of PTA. Rank (by revenue 2013) Companies participating in the research Interview Answers by email Provided examples of good PTA practice in LMIC 1. Novartis No Yes 1 2. Pfizer No Yes 3. Roche No Yes 4. Sanofi Yes Yes 6 6. GlaxoSmithKline (GSK) Yes Yes 1 8. AstraZeneca Yes Yes 1 9. Eli Lilly Yes Yes 13. Bayer No Yes 18. Gilead Yes Yes 14 Source: IMS Health, based on revenue 2013.5 4Pharmaceutical sector SOMO Paper 2013 Declaration of Helsinki,11 article 22: "In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions." 2013 Declaration of Helsinki, article 34:12 "In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial. This information must also be disclosed to participants during the informed consent process." CIOMS/WHO Guidelines, guideline 5:13 "Before requesting an individual's consent to participate in research, the investigator must provide (the research subjects) the following information (...) whether, when and how any products or interven- tions proven by the research to be safe and effective will≈be made available to subjects after they have completed their participation in the research, and whether they will be expected to pay for them." CIOMS/WHO Guidelines, guideline 10:14 "Before undertaking research in a population or community with limited resources, the sponsor and the investigator must make every effort to ensure that: (...) any intervention or product developed, orknowledge generated, will be made reasonably available for the benefit of that population or community." CIOMS/WHO Guidelines, commentary to guideline 10:15 "If an investigational drug has been shown to be beneficial, the sponsor should continue to provide it to the subjects after the conclusion of the study, and pending its approval by a drug regulatory authority." Nuffield Council on Bioethics:16 "We therefore endorse the NBAC recommendation that researchers should endeavour before the initiation of a trial to secure post-trial access for effective interventions for participants in the trial and that the lack of such arrangements should have to be justified to a research ethics committee." Importance of advanced planning of any provisions of PTA (Declaration of Helsinki – DoH, Nuffield Council, CIOMS/World Health Organization – WHO). PTA provisions should be described in advance both in the clinical trial protocol (DoH) as well as in the informed consent forms (DoH, CIOMS/ WHO). Allocation of specific responsibilities to actors involved in the trial and post-trial phase should be clear prior to the trial (DoH, Nuffield, CIOMS/ WHO). Financial responsibilities in particular need to be clearly specified (CIOMS). PTA should be ensured for all participants in the trials (Nuffield, CIOMS/WHO), and undoubtedly for those who still need an intervention identified as beneficial (DoH). The intervention or product developed, or generated knowledge, should be made (reason- ably) available, not only for trial participants, but also for the benefit of that population or community (CIOMS/WHO) Effective interventions: These may include but should not be limited to the investigational drug (Nuffield). It is important to recall here that, although no longer en force, the 2008 version17 of the DoH mentioned that PTA was not limited to access to interventions identified as beneficial in the study, but it was extended to "other appropriate care or benefits". Lack of PTA arrangements should be justified to research ethics. International ethical guidelines – strong elements Recap of the strong elements in the guidelines 5Pharmaceutical sector SOMO Paper "if need be". He says that, "Implementation of mandatory post-trial provision usually encounters many difficulties, but they may be tackled by careful advanced planning".24 Along with this larger stream of debate,25 26 Usharani and Naqvi identify a number of potential points to ponder before considering the provision of PTA: one of them is that giving the drug to trial participants while the rest of the population does not have access to it can create disparity, especially in low-resource settings. Another point is the duration of PTA: the feasibility (or otherwise) for the sponsor to provide PTA for an unlimited period, especially for chronic diseases. Moreover, PTA with an investigational drug should be reconsidered when evidence is preliminary and exposure to that drug may still be hazardous. Usharani and Naqvi highlight the importance of addressing all these issues in the clinical trial protocol before regulatory and institutional approval. They argue that "providing alternative benefits is more feasible for sponsors and can be applied uniformly to all subjects rather than agreeing to post-trial access" (to the investigational drug).27 Alternative benefits may range from strategies to make medical drugs more affordable in developing countries28 to benefits tailored to specific contexts and negotiated with communities when there is no opportunity of direct benefit from a specific intervention.29 However, academic experts argue that PTA may not always be desirable. During a meeting on PTA organised by SOMO and Wemos in June 2012,18 experts voiced some of the common objections against the provision of PTA: PTA may cause undue inducement, since the expectation of follow-up care or any other benefit, especially in LMICs, may persuade people to participate in clinical research.19 20 PTA may delay trials because of procedures and agreements to be made with governments, sponsors, researchers and others involved. PTA may prevent trials from happening, since the financial burden of PTA provision may become a disincentive for sponsors to conduct clinical research, especially in LMICs.21 PTA may be misused as a marketing tool, as in the case of Long Term Extension studies.22 In their 2011 article, Dainesi and Goldbaum stress that decision-making processes about PTA should take into account that PTA may not always be appropriate: "The decision must be submitted to at least two assessments: efficacy and safety of the new experimental drug".23 In his 2008 article, on the other hand, Zong highlights how much PTA is influenced by contextual circumstances. He claims that provision of PTA should be established Box 1: National regulations on PTA – the unique case of Brazil In her interview with SOMO, Dr. Sonia Dainesi, a Brazilian leading expert in the field and author of studies on the topic of PTA, explained why Brazil is an exception in the area of PTA: "The national system is very good, because you have to provide PTA by law and you have to include the PTA provisions before the trial starts, except if the patients don't benefit of the drug or if the doctor thinks it's not necessary to continue with this drug".30 The first regulation that addressed access to unregistered drugs under expanded access programmes was the RDC 26/1999.31 Recently, Brazil's Health Surveillance Agency issued a new regulation, RDC 38/2013,32 which further expands the access to investigational drugs. However, Dr. Dainesi explained the shortcomings: "Who is responsible for providing the drug is the problem. The legislation says that the sponsor is responsible for the provision of PTA, which is usually the industry, but not always. Sometimes it's the institutions, or the government, or the academia that conduct the studies."33 However, the latter often do not have sufficient funds to grant the provision of PTA. The result is that the ethical duty of providing PTA and the legally enforceable right of receiving it are constantly regulated in courts: "Patients who participate in clinical trials can sue, with a high probability of success, either the pharmaceutical company or the State to force them to keep providing the experimental drug. This has triggered, in turn, further lawsuits in which either the state or the pharmaceutical company, when sued by the patient, sue each other trying to transfer the responsibility to provide the experimental treatment".34 The current legal conditions described here contribute to making Brazil a very unique case as far as the provision of PTA is concerned. Participants have the right to PTA as part of their right to health care, but the duty of providing it is often decided through litigation. 6Pharmaceutical sector SOMO Paper In reference to the concept of 'benefits', some scholars critique the formulation of paragraph 34 in the new version of the Declaration of Helsinki. The recent exchange of opinions between Del Re and collaborators35 and Mastroleo36 demonstrate how definitions of 'benefits' or 'other appropriate care', which were lost in the 2013 version of the Declaration of Helsinki, are still being discussed. The matter is not semantic but rather substantive, as it relates to a fair distribution of the benefits of clinical research. The debate on pragmatic choices Whilst the primary goal of clinical research is to contribute to scientific knowledge, the provision of health care is based on the ethical principles of treating patients and possibly saving their lives. The common practice of 'Open Label Extension Studies' as a pragmatic way to provide PTA with unlicensed drugs results in blurring the lines between research and health-care provisions, which are fundamentally and practically regulated by different ethical principles. This has prompted a stream of debate among scholars.37 38 39 40 The issue is concisely expressed by the title Cho has given to her paper: "Open-Label Extension Studies: are they really research?"41 Authors discussing this topic point to the ethical dilemma of using clinical research to provide health care. While research has the ultimate objective of generating scientific knowledge, the goal of health care is to provide health to individuals. This may not coincide with the balance of risks/benefits for a clinical trial where in principle individuals volunteer to serve research purposes. As well as highlighting the ambiguity between care and research, Open Label Extension (OLE) studies also blur the lines between PTA and marketing. Taylor and Wainwright published an article that also summarises the ethical dilemma in its title: "Open Label Extension studies: research or marketing? Who is benefiting the most out of it: the patients or the companies?"42 PTA within the context of an OLE raises the question whether the company is doing this out of compassion or just because it still needs data on the long-term safety and tolerability of the investigational drug for the marketing applications. PTA in the companies' policies and practices Since many aspects of PTA are still being debated and international ethical standards provide little guidance regarding what responsibilities a commercial sponsor must take and how, pharmaceutical companies are adopting a pragmatic approach towards the problem of conducting trials among vulnerable or underprivileged populations. Some common practices emerge from the analysis of the policies published by the companies that collaborated with this research and the statements given by the companies' representatives in their interviews with SOMO. Commitments to PTA There is a definite lack of clear company commitments in reference to the right to PTA. There was one clear statement on Novo Nordisk's website: "Clinical trial participants should have access to best proven and available treatment after a trial has stopped".43 Although not comprehensive, PTA is mentioned in various company policy documents. All nine companies analysed for this research have included the Declaration of Helsinki (DoH) in policy documents on their websites. Either as a reference instrument for human rights (Sanofi44) or as an international ethical guideline the company "follows" (GSK45) or "adheres to" (Gilead,46 Eli Lilly,47 Novartis48) or "complies with" (AstraZeneca,49 Pfizer50), or operates "in accordance with" (Bayer51), or "in full conformance" (Roche52). Including the DoH unreservedly can be seen as a commitment by companies to acknowledge the entitlement to PTA. Disclosure of PTA provisions The addition to article 34 in the 2013 version of the DoH says that PTA provisions must be disclosed to the participants during the informed consent process. This is actually already part of some company policies: Roche: "Before commencing a Roche Sponsored Clinical Trial in a low or middle income developing country, Roche will ensure that a description of posttrial drug supply is written and incorporated into the protocol and patient informed consent forms."53 Sanofi: "The issue of PTA is always addressed in the study protocol and in the patient information documents which are used for soliciting informed consent."54 For Sanofi, addressing PTA also means that if it is clear that no post-trial treatment will be provided, patients will be informed beforehand, and the protocol will indicate the rationale for this.55 The practice of these policy statements cannot be verified by SOMO because original clinical trial protocols and informed consent forms are not made public. Protocol summaries in clinical trial registries such as ClinicalTrials.gov56 do not include a field for the PTA provisions. Also the 'WHO Data Set', which defines the minimum amount of trial information that must appear in a register in order for a given trial to be considered as fully registered, does not include the requirement to give information about PTA provisions.57 SOMO has been informed by Bayer that the company keeps a database of Managed Access Programs (MAP) 7Pharmaceutical sector SOMO Paper (this definition is used as equivalent to PTA programmes by Bayer).58 Bayer is the only company in this research that mentioned collecting this kind of information centrally in a database, but this is not made publicly available.59 In the absence of a standard definition of PTA, is there a standard practice? Only in exceptional circumstances Most of the companies included in this research are very clear that PTA will only be provided in very specific and exceptional circumstances, on a case-by-case basis. They indicate that under certain circumstances they may decide to provide PTA. Sanofi shared a part of an Internal Quality Document on Informed Consent recently validated by the internal Bioethics Committee. The document contains a certain number of principles, which are in the process of being integrated into operating procedures documents. The Internal Quality document's section on Post-Trial Access clarifies Sanofi's position in respect to the issue of post-trial access to investigational products, both in pre-approval studies and in post-marketing studies using locally licensed medicines. It reads: "Post-study access and participant follow-up arrangements can only be made on a disease-by-disease, compound-by-compound or study- by-study basis".60 The way GSK describes these circumstances in its policy summarises the various company positions very well: "There may be circumstances when there is a compelling medical rationale for patients who have derived a measur- able medical benefit from an investigational compound during a clinical trial to continue to receive that compound (e.g. the illness being treated is life threatening or seriously debilitating and there are no other treatments available or there are significant risks in switching patients to alter - native treatments). When this is the case, GSK may extend a study to facilitate appropriate continued access to the investigational product. Alternatively, the availability of an expanded access programme may serve as a means of continued access".61 If we summarise the information that is available in policies and that was obtained through interviews with companies, we see a standard practice emerging. Companies consider providing PTA in case of non-licensed medicines until the medicines are approved and become licensed under the condition that: The disease or condition being studied is serious or life threatening and/or long term. The patient is benefiting and discontinuation of treat- ment might adversely affect the patient's health or well-being. There is no (local) availability of alternative treatment. There is sufficient efficacy and safety data and a positive benefit-risk balance.62 Companies consider providing PTA in case of licensed medicines (i.e. with marketing authorisation in the country) when the four conditions occur and patients still do not have access to the medicines despite the license, as in the situation where national health care does not fund it. However, this is considered even more exceptional. AstraZeneca: "If we decide to continue, then we make sure that it is up to the moment that the drug is authorized and we can bring the product in the market. And if we do a trial with a medicine that is already in the market, normally we will not provide further treatment. But even then, in certain exceptional circumstances, we can decide to provide them to the patients who don't have access to the medicine".63 Merck: "In general, the provision of post-trial care for clinical trial participants continues under the applicable health care system of the host country."64 GSK: "I think that most companies are very sympathetic to find a way to provide access when it's a disease where patients are at acute risk of death or sickness. But I guess the problem is that most drugs are offering a benefit but there are still other treatments available that could be used. So I suspect that in most circumstances, patients fall back on (a) standard of care which may not have the new advantages of the new medicine but nonetheless provides some sort of reasonable cover."65 The described nature of "exceptional circumstances" under which companies "may" (or may not) consider providing continued access to treatment after a clinical trial shows the freedom of the companies to make their own decisions about this because there are no binding regulations, except in Brazil. It also becomes clear that companies only consider PTA when the trial concerns a non-licensed drug. The provision of licensed drugs is seen as the responsibility of the government and national health-care systems. As Sanofi put it: "The company cannot replace the national health-care system".66 8Pharmaceutical sector SOMO Paper The preferred routes for PTA The emerging standard practice for providing an unlicensed investigational drug until marketing approval is: 1 By enrolling the participants into a study extension (an Open Label Extension Study (OLE) or Long-Term Extension Study (LTE). 2 Through one of the forms of Early Access Programmes (EAP), depending on the national regulatory framework in place. Related to point 2, in the US, the Food and Drug Admini- stration (FDA) regulation67 allows access through "Expanded Access Programs", while EU regulation68 allows such access through Compassionate Use Programmes (CUPs). There are Cohort CUPs (CUPs made available for groups of patients or hospitals on the basis of requests from physicians or companies69) and Named Patient CUPs (CUPs made available for individual patients on the basis of the physician's request70). AstraZeneca describe their practice as follows: "If a decision is made to continue to provide a clinical study drug after the original study is completed, we will ensure that appropriate oversight measures are in place, such as dispensing treatment in the context of a clinical study or a compassionate use programme."72 Since Gilead mostly engage in the production of HIV and AIDS drugs, the company confirmed their coherence with the Good Participatory Practice issued by UNAIDS in 2011, where it is stated that post-trial access should be provided in the form of "follow on, open label, or other such studies before product licensure or approval".73 It follows that Gilead's way of allowing access to investigational drugs will be Gilead's sponsored protocol. Novartis: "Where applicable, (...) research participants may, after trial completion, be offered participation in an extension study until marketing authorization."74 Although considering Open Label Studies as their current standard, GSK seem to be in the process of considering a transition to a different practice. A spokesman said that, if an OLE is based only on the ethical need to supply the drug to the trial participants who benefited from the drug, then the drug should be provided with more clinical freedom and without the limitations of clinical trial protocols and the requirements for clinical data collection. Therefore the company's standard may shift from an OLE to an Expanded Access Program. GSK has produced a new protocol on this topic, which is expected to be rolled out soon.75 PTA in LMICs From what has already been discussed above, we can conclude that companies accept responsibility for PTA in principle but only under very specific and exceptional circumstances, on a case-by case basis and only until the investigational drug is licensed. The current shift of clinical trials to LMICs76 means that pharmaceutical companies increasingly have to deal with poor patients with limited access to health care (i.e. vulnerable groups) in their trials. Dealing with groups that are defined as vulnerable by the international ethical guidelines77 78 makes PTA even more relevant for these countries. In their policies and in their interviews, all companies confirm that they apply the same ethical principles globally. When ethical standards cannot be upheld or where the local standard of care is unacceptably low, the common solution seems to be that companies avoid conducting trials in those places altogether. Gilead: "If local care would not be able to provide treatment follow up, then we would stop doing research in that site."79 Some of the companies in this research stated that, before doing research in an LMIC, they will obtain assurance that the local health-care system will be able to provide continued care. Characteristics of the most common PTA practices Open Label Extension Studies (OLE) or Long-Term Extension studies (LTE) Description: An extension of a clinical trial on the basis of a new study protocol in which the participant, health-care professional and others know the drug and dose being given (not blinded). Aim: It is conducted to assess the long-term safety and tolerability of an Investigational New Drug but is also used for continued prescribing of unlicensed medicines after a randomised trial to patients with medical need of the investigational medicine. Compassionate Use Programs (CUP) or Expanded Access Programmes (EAP) Description: An early access programme is a way of making a promising medicine available to patients when it has not yet been authorised (licensed) for their condition.71 Aim: To make available unlicensed medicines on the basis of compassion but also used to provide a PTA. Compassionate Use Programmes and Expanded Access Programs can be considered substantially equivalent on the basis of the following characteristics: a) the compassion-based drug provision; b) the drug is not yet authorised; c) no alternative therapy is available; and d) there is no research objective or study protocol involved. 9Pharmaceutical sector SOMO Paper GSK: "Responsibility for post-trial provision of nationally licensed medicines used during a trial lies with governments as part of national healthcare programmes. For diseases/conditions that continue beyond the end of an interventional study, GSK-sponsored clinical trials will not be carried out unless we have assurance from the investigator that subjects will receive, or be referred for, any necessary continued healthcare and that the healthcare system is able to provide for the continued care of trial participants."80 Talking about unlicensed medicines, Sanofi says: "We ask ourselves whether we are dealing with a population that qualifies as vulnerable. Our position is to exclude vulnerable populations from these clinical trials".81 In relation to trials with licensed medicines in LMICs (but not limited to LMICs), Sanofi says that "participants will be included in a study only if they can indicate that they expect having, within the local healthcare system, access to continued care for their medical condition once they have completed their study (e.g. through public insurance, private insurance, out-ofpocket payment, etc.)". This is a recent decision which we are in the process of rolling out. The question will be directly asked to the patient by the investigator and this will be an inclusion criterion for the study. We discussed at length whether we would require actual documentation that post-trial access will be guaranteed (e.g. insurance contract, social security documents, etc...). This was seen as too complicated, given the variety of situations and countries in which we operate, and too much of a burden for patients."82 Roche write in their policy that their "preferred route is a written agreement obtained by the national health system assuring continuous medication and eligibility of all patients within national treatment systems, post completion of the Roche Sponsored Clinical Trial".83 So we see that the way 'guarantees' are obtained by the companies differ (through the investigator, the patient or the national health system). However, they all ensure beforehand that it is the national health system that will be responsible for PTA in LMICs. Examples of good PTA practice, as provided by the companies The intention of this research was to collect and publish the industry's best practices in securing PTA, since there is to date no general consensus or overview about what best practices should look like. SOMO approached the largest companies in the sector and asked them to report their best practices, with only one condition: that the PTA should be arranged and financed by themselves and should be provided in LMICs (amongst others). This exercise proved very challenging as finding the knowledgeable people within the companies was difficult, and examples of good PTA practices were scarce. Among the companies that participated in this research, only five were able or willing to provide cases of PTA. We collected a total of 13 cases. Gilead offered a large number of examples, but only one is an example of PTA exclusively financed by the company. Sanofi offered six cases (four Long-Term Extension studies and two Compassionate Use Programmes). One of each is presented in the table on page 11 and further. GSK provided SOMO with two cases. However, one falls outside our scope. The one excluded is a case of Post- Approval Commitment study, requested by the EMA prior to final authorisation of the drug, and therefore cannot be counted as PTA. Novartis mentioned a number of roll-over protocols84 and provided two examples, one of which is presented below. The excluded one is an Expanded Access Program for those who are not eligible to participate in clinical trials and also falls outside our scope. 10Pharmaceutical sector SOMO Paper High income countries Low and Middle Income countries Is local standard of care acceptable? Can assurances that local standard of care is able to provide continued treatmement be obtainted? Company may consider PTA provisions Are the following conditions all there? 1 The disease being studied is serious or life threatening 2 Discontinuing the treatment may cause adverse effects on patients' health 3 There is no (local) availability of alternative treatment 4 There are sufficient efficacy and safety data and a positive benefit-risk balance 5 Is the drug unlicenced? NO NO TRIAL TRIAL NO PTA LTE CUP NO NO YES YES YES PTA decision tree based on SOMO's analyses of company policies 11Pharmaceutical sector SOMO Paper ClinicalTrials.gov identifier: NCT0015882185 Company: Gilead Sciences Drug brand name: Viread® Generic name: tenovofir disoproxil fumarate (TDF) Disease: HIV Countries: US, Brazil, Argentina, Dominican Republic Enrolled: 180 Date: Start date March 2000, primary completion date December 2011 Long-Term Extension Studies Related to the provision of PTA, Gilead indicate that: "One of the issues is that you can only administer an investigational drug under protocol. So if you do a study and you finish the study, for those patients to access the drug, you can't just provide it. It has to be administered under a protocol. Authorities usually do not give special authorization; it's a highly regulated industry. It requires creating an open label protocol and collecting data and publishing the results."86 As an example of such situations, Gilead offered the case of Viread®. In 2000, Gilead started a randomised double blind clinical trial to demonstrate the greater efficacy and safety of Viread®, lamivudine and efavirenz, in comparison with a regimen of stavudine, lamivudine and efavirenz. The drug was tested on antiretroviral naïve HIV-1 infected patients in a study that was solely sponsored by Gilead. According to the company, PTA was provided to patients in the Dominican Republic and South America (Brazil and Argentina) for up to roughly 10 years post completion of the study financed by Gilead. "Since Viread® and Truvada®87 were not yet approved in these countries when the original 3 year blinded study was completed, these drugs were provided through an expanded protocol until the drug was marketed, as required by the laws of those countries." The study protocol submitted by Gilead to the clinical- trials.gov database documents what the company stated in their interview and confirms that, after the original 144 weeks, the trial was extended as an open label study multiple times for a total of 480 weeks (about 10 years). In the first 246 weeks of extension, Gilead provided tenofovir DF in combination with lamivudine and efavirenz. In the last 144 weeks, only tenofovir DF was provided. 12Pharmaceutical sector SOMO Paper ClinicalTrials.gov Identifier: NCT0154417988 Company: AstraZeneca Drug: Iressa®89 Generic name: gefitinib Disease: (non small cell) lung cancer Countries: China, France, Germany, Hong Kong, Hungary, Italy, Japan, Korea, Russia, Spain, Taiwan Enrolled: 287 Date: Started March 2012, estimated study completion date January 2016 ClinicalTrials.gov identifier: NCT0071293390 Company: GlaxoSmithKline Drug brand name: Benlysta® Generic name: belimumab Disease: systemic lupus erythematosus Countries: United Kingdom, Slovakia, Germany, US, Austria, Korea, Colombia, Chile, Spain, Netherlands, Taiwan, Italy, Poland, Philippines, Argentina, Hong Kong, India, Brazil, Canada, Romania, Mexico, Israel, Russia, Sweden, Belgium, Peru, Czech Republic Enrolled: 733 Date: Start date June 2008, estimated primary completion date March 2015 Long-Term Extension Studies Iressa® is a drug that is used to treat adults with non small cell lung cancer and was granted marketing authorisation by the EMA on 24 June 2009. AstraZeneca provided a quote from an Iressa® study that is being conducted in China (and other sites) to illustrate how PTA is included in clinical trial protocols, although the protocol published in the clinicaltrial.gov database does not enclose the relevant quote. In their interview with SOMO, AstraZeneca stated that in every clinical trial and in every country where a trial is carried out, there will be a similar quote to the following: "After the study analysis for PES and OS, patients will have their treatment unblinded. Patients receiving gefinitib and still considered to be gaining benefit will be provided an option for continued gefitinib treatment. This will be via the standard commercial and reimburse- ment routes or via open label study supply if the commer- cial supply route is not possible." (Revised Clinical Study protocol, Drug substance: Iressa, Study Code D791LC00001, Edition Number 3, Date: 8 April 2013). GlaxoSmithKline stated that the company is running a "large post approval commitment program with Benlysta".91 They also stated that post-approval extension studies on Benlysta® are also being conducted, indepen- dently of an approval commitment. As an example, the company indicated how Benlysta® has been approved in Argentina since April 2012, but the extension study is still ongoing with the aim of ensuring participants have access to the drug. At the time of the interview, GSK said: "The current study was originally intended to run until approval from the local regulatory authorities. We are still trying to manage that and while that is going on, we haven't stopped the extension study yet. We have kept it going significantly longer than planned because of patient access issues. We are currently looking to close the study and we are considering other options to ensure that the patients without reimbursement to the drug are managed well. Until things become clear, we continue with the extension studies. In these studies, the drug is supplied through the continuation protocol with no charge to the patient."92 Patients are now transitioning off the study and are in the process of seeking reimbursement through local standard of care. 13Pharmaceutical sector SOMO Paper ClinicalTrials.gov Identifier: NCT0093055395 Company: Sanofi Drug: Lemtrada® Generic name: alemtuzumab Disease: Relapsing-Remitting Multiple Sclerosis (RRMS) Countries: Argentina, Austria, Australia, Belgium, Brazil, Canada, Croatia, Czech Republic, Denmark, France, Germany, Israel, Italy, Mexico, Netherlands, Poland, Russia, Serbia and Montenegro, Spain, Sweden, Ukraine, UK and US. Enrolled: 1,322 Date: Start date August 2009, estimated completion date February 2016 ClinicalTrials.gov Identifier: NCT0174229993 Company: Novartis Drug brand name: Glivec® Generic name: Imatinib Disease: cancer Countries: US, Switzerland, Turkey, United Kingdom, Thailand, China, Finland, France, Germany, Hong Kong, Romania, Singapore Enrolled: 149 (30 from China) Date: March 2013 – present In this example, the PTA is provided through an open- label extension study for multiple sclerosis patients who participated in one of three prior Sanofi sponsored studies of alemtuzumab (NCT00050778, NCT00530348 and NCT00548405). As described in the protocol, the main purpose of this study is to examine long-term safety and efficacy of the drug. The alemtuzumab treatment offered will either be on a fixed schedule of two treatment cycles a year, or on an 'as needed' schedule. There is no comparison treatment in this study. All patients will be required to return to their study site every three months for neurologic and other assessments. In addition, safety-related laboratory tests and surveys will be performed at least monthly. Participation in the extension study will last 48 months from enrollment. Study duration may be extended per protocol amendments to allow patients to remain in the study throughout the time of drug approval process or until a long-term follow up study is available in each respective country.96 Novartis conducts roll-over protocols. These protocols allow patients to continue treatment and have access to drug after the parent (and extension trials) have finished. Novartis states that they have ongoing roll-over protocols with drugs such as Tasigna, Afinitor, Glivec, Panobinostat and Signifor, and others. These roll-over protocols are compound-specific and are open to patients that have participated in a clinical trial with that compound, but that clinical trial has ended. One example of such a programme is the Glivec (imatinib) roll-over protocol. Other countries that participate in this ongoing roll-over protocol, and that are not listed in the clinicaltrials.gov database, include Korea, India, Mexico, Peru and Argentina, as well as many other countries.94 Long-Term Extension Studies 14Pharmaceutical sector SOMO Paper ClinicalTrials.gov Identifier: NCT0125427997 Company: Sanofi Drug: Jevtana®98 Generic name: cabazitaxel Disease: Prostate cancer Countries: Argentina, Australia, Austria, Belgium, Bosnia, Bulgaria, Canada, Croatia, Czech Republic, Denmark, Finland, Hungary, India, Ireland, Italy, Kazakhstan, Luxembourg, Malaysia, Mexico, Netherlands, Philippines, Poland, Portugal, Romania, Serbia, Singapore, Slovakia, Sweden, Taiwan and UK Enrolled: 984 Date: Started 17 December 2010, estimated completion date December 2014 Expanded Access Programme Sanofi implemented an Expanded Access Programme study to provide early access to cabazitaxel in patients with metastatic hormone refractory prostate cancer previously treated with a docetaxel-containing regimen. As stated in the protocol submitted to the database clinicaltrial.gov, the primary outcome measure of this programme was to provide early access to cabazitaxel in patients with metastatic hormone refractory prostate cancer. The secondary outcome was to document the safety of cabazitaxel in those patients. In the study protocol, it is clearly stated that, in each country, patient recruitment ends when cabazitaxel becomes commercially available, but considering the timing or delay in getting approval and reimbursement in the participating countries, cabazitaxel was therefore administered through this early access programme. 15Pharmaceutical sector SOMO Paper Conclusions The current corporate practice All the companies included in this research refer in their company policies to the Declaration of Helsinki (DoH), which includes the right to Post-Trial Access to Treatment (PTA). At the same time, the companies are very clear that PTA will only be provided in very specific circumstances on a case-by-case basis. The standard practice followed is that the provision of post-trial care for clinical trial participants continues under the applicable health-care system of the host country. Companies say in general that they only consider providing PTA themselves in case of non-licensed medicines for which no alternative treatments are available. This minimises the commitment to provide PTA enormously, since clinical trials testing new experimental drugs for which no alternative treatments exist are relatively scarce. In combination with the other mentioned conditions (the seriousness of the disease, the serious consequences of discontinuation and a positive benefit-risk balance), it is clear that provision for PTA arranged and paid for by a commercial sponsor is the exception rather than the rule. PTA is even more exceptional in low- and middle-income countries (LMICs), where the need is much greater. Pharma- ceutical companies do not want to become responsible for what they consider to be the responsibility of the national health-care system related to continuing treatment after clinical trials. This is the reason some companies give for avoiding conducting trials altogether in countries where the standard of care is too low to fulfill this responsibility. Other companies claim to exclude vulnerable people with limited access to health care from their trials altogether. An extra step that companies take in LMICs is to obtain an assurance that the national health-care system will be able to provide continued treatment. This assurance may be obtained in different ways; from a written agreement with the national health system to a confirmation given by individual patients that they will have access to continuing treatment. (And therefore no PTA needs to be provided by the company in question.) The reliance on such assurances might be deceptive. In fact, populations in LMICs are considered to be particularly vulnerable on the basis of lack of access to quality health care due to economic factors (e.g. low personal income of the patients and/or no reimbursement possibilities). Reliance on a failing national health-care system can, in fact, result in the cessation of the care that was available during the trial. In LMICs, there is a greater appeal for the company to take responsibility for providing PTA. The focus of the companies on obtaining these assurances, however, seems to shy away from these responsibilities and instead push the problem off to the host countries and the patients themselves. Best practice? The difficulty SOMO experienced in collecting good PTA examples from the companies in question and the absence of examples in the academic literature confirms the highly exceptional nature of PTA. The scarcity of PTA arrangements by commercial sponsors in LMICs is especially worrying. In those exceptional circumstances where a company has decided to arrange post-trial access to an unlicensed drug, it is done through an Open Label Extension Study or a Compassionate Use Programme. Open Label Extension Studies are the most common way to provide PTA in LMICs. However, ethical concerns voiced by academics, and to a certain extent also recognised by some companies, relate to the ambiguity between care and research in these studies. It is not always clear whether extension studies are done out of compassion or in order to gain long-term safety data for marketing reasons. The limited number of PTA arrange- ments collected within this research has not provided enough information to identify elements of best practice. Recommendations for companies Pharmaceutical companies should act with 'due diligence' in relation to the issue of PTA in line with the UN Guiding Principles on Business and Human Rights. 'Due diligence' is understood as a business process through which enter- prises actively identify, prevent, mitigate and account for their potential and actual adverse human rights impacts. Proposed elements of best practice are presented in line with this concept. They are based on the review of the international ethical guidelines, the academic articles and company policies. 16Pharmaceutical sector SOMO Paper Elements for corporate best practice: Adequate policy commitment on PTA (publicly available). Minimal incorporating article 22 and 34 of the Declaration of Helsinki (DoH). No limitation to provide PTA only in cases of non-licensed medicines for which no alternative treatment exists. This is too limited for LMICs as there is often also no affordable access to licensed medicines. Including alternative treatments or other appropriate care and benefits when addressing the issue of PTA in LMICs. Identification and assessment of potential and actual adverse human rights impacts. A realistic assessment of the post-trial situation of trial participants related to PTA, including questions such as: What does the local health-care system have to offer and do the participants have access to it? Will the drug being test be reasonably available for the benefit of the population or community where the research took place? Assessments should include trials that are conducted by third parties on behalf of the company. Prevention and mitigation. Advanced planning: before undertaking a clinical trial in a population or community with limited resources the commercial sponsor must plan whether, when and how provisions for PTA will be made available. In areas with limited resources, commercial sponsors should be willing in principle to take financial (co-) responsibility for PTA arrangements and make these arrangements in cooperation with host country governments and researchers prior to the trial. These arrangements should be described in the clinical trial protocols These arrangements should be described in the informed consent forms. Patients also need to be informed beforehand if PTA will not be provided. The lack of PTA arrangements should be justified to research ethics committees. Tracking performance and evaluation. Evaluation whether PTA has caused undue inducement. Evaluation whether PTA arrangements have delayed or prevented trials from happening. Evaluation if any negative impacts emanate from the situation that research (i.e. open-label extension studies) is used to provide care and treatment post-trial. Transparency and communication about PTA arrangements. Offering access to information about PTA arrange- ments. For instance to give stakeholders/civil society organisations (CSOs) access to clinical trial protocols and informed consent forms on request to check PTA arrangements. Effective grievance mechanism. The establishment of a grievance mechanism for participants who may be negatively impacted, so that grievances can be addressed early and remediated directly. Recommendations for other actors. SOMO considers the following recommendations important for achieving better PTA practice in future: The International Conference on Harmonisation of Technical Requirements for Registration of Pharma- ceuticals for Human Use (ICH) should consider including a section on PTA arrangements in their guidance documents, such as in the E3 guidelines for the clinical study reports and E6 guidelines for good clinical practice. As the ICH guidelines are incorporated into EU legislation, this would be binding in nature. The World Medical Association should consider re-adopting the language applied in the 2008 version of the Declaration of Helsinki and include again the wording "other appropriate care or benefits" as provisions of PTA. The World Health Organization (WHO) should consider including a field for PTA in the 'WHO Data Set' to increase transparency on PTA arrangements. (EU) Regulatory Authorities should ensure that the applicant for a marketing authorisation provides a description of the situation of trial participants with regard to PTA. Also, the applicant should describe the provisions made for post-trial access to treatment and medical care for study participants depending on their location and the treatment and medical care otherwise available. This information can form part of the clinical study report section on ethical considerations in accordance with ICH E3. (EU) Regulatory Authorities should identify those studies that may give rise to special ethical concerns regarding access to post-trial treatment and, where applicable, to seek additional assurance that the solution was appropriate and ethically acceptable. (EU) Regulatory Authorities should summarise this information in public assessment reports.99 17Pharmaceutical sector SOMO Paper End notes 1 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Guidelines for Good Clinical Practice, 1996, <http://www.ich.org/fileadmin/Public_Web_ Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf>, (accessed 4 November 2014). 2 The ICH guidelines are recommended for adoption to the regulatory bodies of the EU, Japan and US but are also integrated in many other national legislations. In the EU, they are implemented through Dir. 2001/20/EC and Dir. 2005/28/EC. 3 The focus of this research is on cases where PTA is paid by the commercial sponsor of the trial. PTA is often funded by government, public or private funds, particularly in the case of HIV and AIDS trials. However, this falls outside our scope of corporate best practice. 4 Gilead provided several cases, but PTA was solely sponsored by Gilead in only one of the cases. 5 Website Imshealth Services, "IMS Consulting, How We help, Strategy & Portfolio Analysis, The Accelerating Growth of Specialty Markets," <http://www.imshealth.com/deployedfiles/consulting/Global/Content/ How%20We%20Help/Strategy%20&%20Portfolio/pharma50_2014.pdf> (accessed 10 November 2014). 6 ANMAT's PTA provisons are in Disposición 6677-10 <http://infoleg.mecon.gov.ar/infolegInternet/anexos/170000- 174999/174557/norma.htm>. Ministry of Health PTA provisions are in Resolución 1480/2011, <http://www.infoleg.gov.ar/infolegInternet/ verNorma.do;jsessionid=650B877AF7D1E6B7C272DE595DF81C5 3?id=187206>, (assessed 12 February 2015). 7 Guidelines for the Conduct of Health Research Involving Human Subjects, issued by National Consensus Conference on Bioethics and Health Research in Uganda; Ethical Guidelines for Biomedical Research on Human Subjects, issued by Indian Council of Medical Research; Guidelines for Good Practice in the Conduct of Clinical trials in Human Participants in South Africa, issued by the Clinical Trials Working Group of the South African Department of Health, quoted in Zhiyong Zong, "Should post-trial provision of beneficial experimental interventions be mandatory in developing countries?" Journal of Medical Ethics, Volume 34, Number 3, 2008, p.188-192. 8 Article 58 of the new Argentinian Civil and Commercial Code includes, as a requisite to biomedical research, the obligation to: "ensure appropriate medical care, the participant during and after the investigation". 9 EMA, "Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities", 16 April, 2012, <http://www.ema.europa.eu/docs/en_GB/ document_library/Regulatory_and_procedural_guideline/2012/04/ WC500125437.pdf>, (accessed 30 December 2014), page 28-29. 10 An extension of a clinical trial on the basis of a new study protocol in which the participant, health-care professional and others know the drug and dose being given (not blinded). 11 World Medical Association website, "Declaration of Helsinki," 2013, <http://www.wma.net/en/30publications/10policies/b3/> (accessed 10 November 2014). 12 World Medical Association website, "Declaration of Helsinki," 2013, <http://www.wma.net/en/30publications/10policies/b3/> (accessed 10 November 2014). 13 Council for International Organizations of Medical Sciences (CIOMS), "International Ethical Guidelines for Biomedical Research Involving Human Subjects," 2003, <http://www.cioms.ch/publications/layout_guide2002.pdf> (accessed 10 November 2014). 14 Ibid. 15 Ibid. 16 Nuffield Council on Bioethics website, "The ethics of research related to healthcare in developing countries," 2002, <http://nuffieldbioethics.org/ wp-content/uploads/2014/07/Ethics-of-research-related-to-healthcare-in- developing-countries-I.pdf> (accessed 10 November 2014). 17 World Medical Association website, "Declaration of Helsinki," 2008, http://www.wma.net/en/30publications/10policies/b3/17c.pdf (accessed 11 November 2014). 18 In June 2012, SOMO and Wemos organised a two-day strategy meeting on PTA with academics, experts and activists from Africa, South America and Europe. The identified knowledge gap on company practices and the idea of approaching companies for best practices was initiated here. 19 E. J. Emanuel at al., "Undue inducement in clinical research in developing countries: is it a worry?", Lancet, Volume 366, 2005, p. 336-340. 20 R. Macklin, "'Due' and 'Undue' Inducements: On passing Money to Research Subjects", Ethics and Human Research, Volume 3, Number. 5, 1981, p. 1-6. 21 B.A. Brody, "Ethical issues in clinical trials in developing countries", Statistics in Medicine, Volume 21, Number 19, 2002, p. 2853-3858. 22 G.J. Taylor, P. Wainwright, "Open label extension studies: research or marketing?", BMJ, Volume 331, 2005, p. 572-574. 23 S.M. Dainesi, M. Goldbaum, "Provision of investigational drug after clinical research – Review of literature, national and international guidelines", Revista da Associacao Medica brasileria (English Edition), Volume 57, Number 6, 2011, p. 696-703. 24 Zhiyong Zong, "Should post-trial provision of beneficial experimental interventions be mandatory in developing countries?" Journal of Medical Ethics, Volume 34, Number 3, 2008, p.188-192. 25 N. Sofaer et al., "Subjects' views of obligations to ensure post-trial access to drugs, care, and information: Qualitative results from the Experiences of Participants in Clinical Trials (EPIC) Study," Journal of Medical Ethics, Volume 35, Number 3, 2009, p. 183-188. 26 N. Sofaer, D. Stretch, "Reasons Why Post-Trial Access to Trial Drugs Should, or Need not be Ensured to Research Participants: A Systematic Review," Public Health Ethics, Volume 4, Number 2, 2011, p.160-184. 27 P. Usharani, S. M. H. Naqvi, "Post Trial Access," Perspectives in Clinical Research, Volume 4, Number 1, 2013, p. 58-60. 28 R. Macklin, Ed., Double standards in medical research in developing countries (Cambridge: Cambridge University Press, 2004). 29 J.V. Lavery et al., "Relief of oppression: An organizing principle for researchers' obligations to participants in observational studies in the developing world," BMC Public Health, Volume 10, Number 384, 2010. 30 S.M. Dainesi, PhD, Brazilian Society of Pharmaceutical Medicine, 2 April 2014, telephone call with the author. 31 Diretoria Colegiada da Agência Nacional de Vigilância Sanitária (Anvisa), Resolução – RDC No. 26, de 17 de dezembro de 1999, <http://www. comissoes.propp.ufu.br/sites/comissoes.propp.ufu.br/files/Anexos/ Bookpage/Resolucao_RDC_n_26_normatizar_a_avaliacao_e_aprovacao_ de_programas_de_acesso_expandido.pdf> (accessed 10 November 2014). 32 Diretoria Colegiada da Agência Nacional de Vigilância Sanitária (Anvisa), Resolução – RDC No. 38, de 12 agosto de 2013, <http://www.sbppc.org. br/site/images/publicacoes/dou%20-%20resolu%E7%E3o%20rdc%20 38_%20de%2012%20de%20agosto%20de%202013.pdf> (accessed 10 November 2014). 33 S.M. Dainesi, PhD, Brazilian Society of Pharmaceutical Medicine, 2 April 2014, telephone call with the author. 34 D.W. L., Wang, O.L.M. Ferraz, "Pharmaceutical Companies vs. the State: Who Is Responsible for Post-Trial Provision of Drugs in Brazil?", Journal of Law, Medicine & Ethics, Volume 40, Issue 2, 2012, p. 188-196. 35 Del Re et al., "Protections for clinical trials in low and middle income countries need strengthening not weakening," BMJ, Volume 349, 2014, p. 1-5. 18Pharmaceutical sector SOMO Paper 36 I. Mastroleo, "Strengthening protections for LMICs is not straight forward: a response to Del Re and collaborators," BMJ, 14 July 2014, <http://www. bmj.com/content/349/bmj.g4254/rapid-responses> (19 September 2014). 37 Cho M.K., "Open Label Extension Studies: are they really research?" The American Journal of Bioethics, Volume 14, Number 4, 2014, p. 60-61. 38 Cassarrett D., Karlawish J., Sankar P., Hirshman K.B. and Asch D.A., "Open label extension studies and the ethical design of clinical trials," IRB: Ethics & Human research, Volume 4, 2001, p. 1-5. 39 Micetich K.C., "The ethical problems of the open label extension study," Cambridge Quarterly of Healthcare Ethics, Volume 5, 1996, p. 410-414. 40 R.O. Day, K.M. Williams, "Open Label Extension Studies: do they provide meaningful information on the safety of new drugs?" Drug Safety, Volume 30, 2007, p.93-105. 41 M.K. Cho, "Open-Label Extension Studies: Are they really research?" The American Journal of Bioethics, Volume 14, Number 4, 2014, p. 60-61. 42 G.J. Taylor, P. Wainwright, "Open label extension studies: research or marketing?" BMJ, Volume 331, 2005, p. 572-574. 43 Website Novo Nordisk, Research and Development, Bioethics, Clinical trials Ethics, Downloads, "A responsible approach to clinical trials," <http://www.novonordisk.com/images/science/Bioethics/Downloads/ Bioethics_Clinical%20trials%20UK_27-10.pdf> (accessed 4 November 2014). 44 Website Sanofi, Our Responsibility, Our Approach, CSR download centre, "Human rights in our activities," <http://csr-humanrights.sanofi.com/> (accessed 4 November 2014). 45 Website GSK, About us, Policies, Codes and Standards, Public Policies, GSK and Research & Development, "GSK Public policy positions: Clinical Trials in the Developing World," <http://www.gsk.com/media/280806/ clinical-trials-in-the-developing-world-policy.pdf> (accessed 4 November 2014). 46 Website Gilead, Responsibility, Policy perspectives, "Gilead sciences policy position: Investing in Research and Development," May 2014, <http://www.gilead.com/~/media/Files/pdfs/Policy-Perspectives/ Investing%20in%20Research%20and%20Development.pdf> (accessed 4 November 2014). 47 Website Eli Lilly, About, Key issues, Research and Development, <http://www.lilly.com/about/key-issues/Pages/research-development.aspx> (4 November 2014). 48 Website Novartis, Corporate Social Responsibility, Novartis Positions, R&D, "Clinical Trials in Developing Countries," <http://www.novartis.com/ downloads/corporate-responsibility/resources/positions/clinical-trials- developing-markets.pdf> (accessed 4 November 2014). 49 Website AstraZeneca, Responsibility, Code, Policies and Standards, Code of Conduct, <http://www.astrazeneca.com/cs/Satellite?blobcol=urldata&b lobheader=application%2Fpdf&blobheadername1=Content-Dispos- ition&blobheadername2=MDT-Type&blobheadervalue1=inline%3B+filena me%3DDowload-the-Code-in-English.pdf&blobheadervalue2=abinary%3 B+charset%3DUTF-8&blobkey=id&blobtable=MungoBlobs&blobwhere= 1285670234849&ssbinary=true> (accessed 4 November 2014). 50 Website Pfizer, Research, Clinical trials, Policies, Positions & Case studies, Positions, Conduct of Clinical Studies, "Statement on the Declaration of Helsinki and the Ethical Conduct of Clinical Studies," <http://www.pfizer.com/files/research/Helsinki_statement_5_08.pdf> (accessed 4 November 2014). 51 Website Bayer, "Research and Development, Ethics in R&D, Worldwide standards," <http://www.bayerpharma.com/en/research-and-develop- ment/ethics_in_r_and_d/worldwide-standards/index.php> (accessed 4 November 2014). 52 Website Roche, "Research and Development, Who we are and how we work, Clinical trials, What is a clinical trial," <http://www.roche.com/ research_and_development/who_we_are_how_we_work/clinical_trials/ what_is_a_clinical_trial.htm> (accessed 4 November 2014). 53 Website Roche, "Research and Development, Who we are and how we work, Ethics in research and Development, Ethical conflicts, Clinical trials Policy in low and middle income countries," <www.roche.com/clinical_ trials_policy_in_low_and_middle_income_developing_countries.pdf> (accessed 4 November 2014). 54 F. Bompart, Vice President, Deputy Head and Medical Director of Access to Medicine, Sanofi, email 19 June 2014. 55 Ibid. 56 Website ClinicalTrials.Gov, <https://clinicaltrials.gov/>. 57 Website WHO, WHO Registry criteria, WHO Data Set, Primary Registries, Partner Registries, "WHO Trial Registration Data Set (Version.2.1)," <http://www.who.int/ictrp/network/trds/en/> (accessed 4 November 2014). 58 SOMO personal communication with Bayer, email 26 September 2014. 59 Bayer did not provide any best practice case of MAP for PTA to medicines. 60 F. Bompart, Vice President, Deputy Head and Medical Director of Access to Medicine, Sanofi, email 7 May 2014. 61 GlaxoSmithKline, About us, Policies, codes and standards, Public policies, "Clinical Trials in the Developing World," January 2014, <http://www.gsk. com/media/280806/clinical-trials-in-the-developing-world-policy.pdf> (accessed 6 October 2014). 62 See also, website Eli Lilly, Research & Development, Approach to R&D, Research Ethics, Bioethics, Lilly's bioethics positions, "Continued access to an Investigational medicine", August 2012, <http://www.lilly.com/ Documents/continued_access.pdf > (accessed 6 October 2014). 63 A. Antonisse, Director of Economic Affairs, AstraZeneca Netherlands, 11 June 2014, telephone call with author. 64 Website Merck, About us, Views and Positions, Public Policy Position Statements, Clinical Trials Ethics, <https://www.merck.com/about/ views-and-positions/clinical_trial_ethics_march2012.pdf> (accessed 5 November 2014). 65 D. Gordon, Director, Clinical Development Department, GlaxoSmithKline, 13 June 2014, telephone call with author. 66 F. Bompart, Vice President, Deputy Head and Medical Director of Access to Medicine, Sanofi, 7 May 2014, telephone call with author. 67 US Food and Drug Administration, 21 CFR part 312, subpart I, 13 October 2009, http://www.fda.gov/downloads/drugs/guidancecompli- anceregulatoryinformation/guidances/ucm351261.pdf (accessed 11 November 2014). 68 European Medicines Authority (EMA), Regulatory and procedural Guideline, http://www.ema.europa.eu/docs/en_GB/document_library/ Regulatory_and_procedural_guideline/2009/10/WC500004075.pdf (accessed 11 November 2014). 69 European Medicines Authority (EMA), Article 83, Regulation (EC) no. 726/2004, 2004, http://www.ema.europa.eu/docs/en_GB/document_ library/Regulatory_and_procedural_guideline/2009/10/WC500004075.pdf (accessed 11 November 2014). 70 European Medicines Authority (EMA), Article 5, Directive 2001/83EC, 2001, http://www.ema.europa.eu/docs/en_GB/document_library/ Regulatory_and_procedural_guideline/2009/10/WC500004481.pdf (accessed 11 November 2014). 71 See also the definition of compassionate use by the European Medicines Authority (EMA), Human Regulatory, Pre-authorisation, Compassionate Use, <http://www.ema.europa.eu/docs/en_GB/document_library/ Other/2010/01/WC500069898.pdf> (accessed 11 November 2014). 19Pharmaceutical sector SOMO Paper 72 Website Astra Zeneca, Responsibility, Research Ethics, Clinical Trials, "Protecting participants," <http://www.astrazeneca.com/Responsibility/ Research-ethics/Clinical-trials/Protecting-participants> (accessed 24 July 2014). 73 UNAIDS, Good Participatory Practice, Guidelines for Biomedical HIV Prevention Trials, 2011, http://www.unaids.org/en/media/unaids/ contentassets/documents/unaidspublication/2011/JC1853_GPP_ Guidelines_2011_en.pdf. 74 Website Novartis, Corporate Social Responsibility, Novartis positions, Research and Development, "Clinical Trials in Developing Markets," August 2011, http://www.novartis.com/downloads/corporate-responsi- bility/resources/positions/clinical-trials-developing-markets.pdf (accessed 24 July 2014). 75 D. Gordon, Director, Clinical Development Department, GlaxoSmithKline, 13 June 2014, telephone call with author. 76 EMA statistics confirm the shift of clinical trials from the traditional testing countries (i.e. the EU and North America) to other parts of the world, including many LMICs. In 2005, 17.5% of patients in pivotal clinical trials for EU marketing applications lived outside the EU and North America. In 2011, this percentage had grown to 37%. As well as this, the number of trial participants is declining in the "old" EU countries (from 28% to 19%) and the number of participants in the new EU countries (joining the EU after 2004: Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Malta, Poland, Slovakia and Slovenia, Bulgaria and Romania) increased from 4.7% to 11.7% in 2011. Source: European Medicines Authority (EMA), Clinical trials submitted in marketing-authorisation applications to the European Medicines Agency: Overview of patient recruitment and the geographical location of investigator sites, containing data from 2005 to 2011, 11 December 2013, <http://www.ema.europa.eu/docs/en_GB/ document_library/Other/2009/12/WC500016819.pdf >. 77 In the WHO/CIOMS guidelines, vulnerability is defined as follows: "Vulnerable persons are those who are relatively (or absolutely) incapable of protecting their own interests," in: Council for International Organizations of Medical Sciences (CIOMS), "International Ethical Guidelines for Biomedical Research Involving Human Subjects", 2003, <http://www.cioms.ch/ publications/layout_guide2002.pdf>, Commentary on Guideline 13 (accessed 11 November 2014). 78 Article 20 of the Declaration of Helsinki states that, "Medical research with a vulnerable group is only justified if the research is responsive to the health needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In addition, this group should stand to benefit from the knowledge, practices or interventions that result from the research", in: World Medical Association, "Declaration of Helsinki: Ethical Principles for medical research involving human subjects", 2013, <http://www.wma.net/en/30publications/10policies/b3/index.html> (last accessed 11 November 2014). 79 J. Rooney, Vice President, Clinical Affairs, Gilead, 21 May 2014, telephone call with author. 80 Website GlaxoSmithKline, About us, Policies, codes and standards, Public policies, "Clinical Trials in the Developing World," January 2014, <http://www.gsk.com/media/280806/clinical-trials-in-the-developing- world-policy.pdf> (accessed 3 October 2014). 81 R. Cariou, Head of Medical Operations, Sanofi, 7 May 2014, telephone call with author. 82 F. Bompart, VP, Deputy Head and Medical Director of Access to Medicine, Sanofi, email 19 June 2014. 83 Website Roche, Research and Development, Who we are and how we work, Clinical trials, Global Standards, "Clinical Trials Policy in Low and Middle Income Developing Countries," November 2008, <www. roche.com/clinical_trials_policy_in_low_and_middle_income_developing_ countries.pdf> (accessed on 3 October 2014). 84 L. Beauregard-Zollinger, Corporate Responsibility Manager, Novartis, email 6 November 2014. 85 For additional details about the study, see website ClinicalTrials.gov, "Study of Treatment of Antiretroviral-naive, HIV-1-Infected Patients Comparing Tenofovir Disoproxil Fumarate Administered in Combination With Lamivudine and Efavirenz vs. Stavudine, Lamivudine and Efavirenz", <https://clinicaltrials.gov/ct2/show/NCT00158821?term=NCT00158821& rank=1> (accessed 16 July 2014). The study is also known as the 903 study. 86 J. Rooney, Vice President, Clinical Affairs, Gilead, 21 May 2014, telephone call with author. 87 Viread® was replaced by Truvada® by Gilead. 88 For additional details about the study, see website ClinicalTrials.gov, "A Study of IRESSA Treatment Beyond Progression in Addition to Chemotherapy Versus Chemotherapy Alone (IMPRESS)", <http://www.clinicaltrials.gov/ct2/show/record/NCT01544179?term=NCT 01544179&rank=1&show_locs=Y > (accessed 23 July 2014). 89 European Medicines Authority (EMA), Summary for the Public, http:// www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_ for_the_public/human/001016/WC500036359.pdf> (accessed 11 November 2014). 90 For additional details about the study, see website ClinicalTrials.gov, "A Continuation Trial for Subjects With Lupus That Completed Protocol HGS1006-C1056 or HGS1006-C1057", <http://clinicaltrials.gov/show/ NCT00712933> (accessed 17 July 2014). 91 D. Gordon, Director, Clinical Development Department, GlaxoSmithKline, 13 June 2014, telephone call with author. 92 Ibid. 93 For additional details about the study, see website ClinicalTrials.gov, "Study to Allow Access to Imatinib for Patients Who Are on Imatinib Treatment in a Novartis-sponsored Study and Are Benefiting From the Treatment as Judged by the Investigator", <http://clinicaltrials.gov/ct2/show/study/ NCT01742299?show_locs=Y#locn> (accessed 7 November 2014). 94 Dr. Lyse Beauregard-Zollinger, Corporate Responsibility Manager, Novartis International AG, email 6 November 2014. 95 Website ClinicalTrials.gov, "An Extension Protocol for Multiple Sclerosis Patients Who Participated in Genzyme-Sponsored Studies of Alemtuzumab", <http://clinicaltrials.gov/ct2/show/record/NCT00930553> (accessed 16 July 2014). 96 Example provided by Dr. Cariou, Head of Medical Operations, Clinical & Sciences Operations Platform, Sanofi Aventis, R&D. 97 For additional details about the study, see website ClinicalTrials.gov, "Early Access to Cabazitaxel in Patients With Metastatic Hormone Refractory Prostate Cancer Previously Treated With a Docetaxel- containing Regimen", <http://www.clinicaltrials.gov/ct2/show/study/NCT0 1254279?term=cabazitaxel&cntry1=SS%3AIN&cntry2=SE%3AMY&cntry3 =ES%3ATW&rank=1&show_locs=Y#locn> (accessed 17 July 2014) 98 Ibid. 99 The recommendations for the (EU) Regulatory Authorities are according to the "Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities", EMA/121340/2011, p. 29-42. 20Pharmaceutical sector SOMO Paper Colophon Authors: Silvia Colona and Irene Schipper Layout: Frans Schupp Photo: iStockphoto ISBN: 978-94-6207-050-9 This paper has been written by SOMO as part of a research programme on corporate responsibility in the pharmaceutical sector and has been made possible through funding from the Dutch Ministry of Foreign Affairs and the Sigrid Rausing Trust. The content of this publication is the sole responsibility of SOMO and can in no way be taken to reflect the views of the Dutch Ministry of Foreign Affairs and the Sigrid Rausing Trust. SO M O Stichting Onderzoek Multinationale Ondernemingen Centre for Research on Multinational Corporations Sarphatistraat 30 1018 GL Amsterdam The Netherlands T: +31 (0)20 639 12 91 info@somo.nl – www.somo.nl The Centre for Research on Multinational Corporations (SOMO) is an independent, not-for-profit research and network organisation working on social, ecological and economic issues related to sustainable development. Since 1973, the organisation investigates multinational corporations and the consequences of their activities for people and the environment around the world.