Post-trial provisions in the Declaration of Helsinki: a watered-down principle that needs to be strengthened

The Declaration of Helsinki (DoH) states that the ethical principles that the World Medical Association (WMA) considers should guide all clinical research involving human subjects. ¹ The moral authority of the DoH has been recognised internationally, including in low- and middle-income countries (LMICs), and it has been incorporated in the laws and regulations that guide the implementation of clinical trials in most Latin American countries. One of its ethical principles, Post-Trial Provisions refers to research participants' right to continue to access the potentially beneficial interventions after the completion of the clinical trial. The most recent DoH version (2013) has only one paragraph devoted to post-trial provisions:

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. ¹

We shall demonstrate that this wording is weaker than that adopted in the previous DoH versions (2000 and 2008) and it might render such provisions useless because it is too vague and too cumbersome to implement.

Even though the 2013 version is the first one to mention that ‘sponsors, researchers and host country governments should make provisions’, it does not specifically designate who is responsible for ensuring post-trial access, making it very difficult for these stakeholders to reach an agreement ‘in advance of a clinical trial’. In LMICs, research sites compete for patient enrolment, and it is unlikely that there will be interest in delaying the implementation of a clinical trial until the abovementioned parties decide who will provide the intervention, to whom and for how long.

Furthermore, even if those negotiations were to take place, given the secrecy surrounding talks between governments and health industries, not all clinical trial participants and their respective communities would be guaranteed the same benefits. The outcomes would depend on the negotiation capacity of governments and researchers, generating inequities. Due to power imbalances, negotiations between sponsors, researchers and host country governments are especially problematic for LMICs, as illustrated by the recent COVID-19 vaccine contracts with Pfizer that forced countries to gamble state assets. ²

The concept of post-trial provisions was first introduced as post-trial access in the DoH version of 2000, ³ and while not perfect, was more concrete. The 2000 ³ and 2013 ¹ versions differ in the following aspects: (1) which patient-participants should be given post-trial access and (2) what these participants should have access to. Neither version specifies who is responsible for guaranteeing access or discusses how to operationalise this requirement. It could be argued that governments should include the mechanisms to ensure post-trial access in their regulations, and Research Ethics Committees could reject protocols that do not guarantee post-trial access on the basis that they do not comply with the DoH.

The 2000 edition says the following: ‘At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study’. ³ The inclusion of this article, along with that limiting the use of placebos, was highly contentious and continues to trigger discussions until today.^4–6 In an effort to avert the crisis brought about by the article on post-trial access, the WMA organised a conference (Pretoria, March 2021) on how to interpret and implement the DoH. ⁵ The conference was widely attended by representatives from the pharmaceutical industry and the United States Food and Drug Administration (FDA), with sparse representation from LMICs. ⁵ No agreement was reached but arguments in favour of revision were proposed, several of which are still being used in current discussions. For example, patient-participants from LMICs would not have access to the new interventions anyway; therefore, their situation is not worsened by not having post-trial access; post-trial access arrangements are not the moral obligation of sponsors since the latter are not philanthropic organisations; post-trial access can be a real financial strain on these sponsors. ⁵ Along with these arguments came threats of dropping the DoH as a research ethics guide (the U.S. FDA, for other reasons, stopped requiring compliance with the DoH for protocols implemented overseas). ⁷ This eventually led the WMA to add a note of clarification to this article in 2004, reaffirming the need to guarantee post-trial access. ⁸

The 2008 version of DoH, in spite of the WMA’s intent to ‘preserve the substance of the previous version while clarifying the wording’ ⁴ and the expressed lack of consensus on the issue, ² used different language:

At the conclusion of the study, patients entered into the study are entitled to be informed about the outcome of the study and to share any benefits that result from it, for example, access to interventions identified as beneficial in the study or to other appropriate care or benefits. ⁹

Like the earlier version, the principle requires that all patient-participants benefit from the results of the trial, but what they should receive as a ‘benefit’ is less concrete. In the 2008 version, patient-participants are entitled to information and to share in other research benefits. That is, access to the product used in the intervention is only one of several possible benefits. Loopholes were opened allowing study sponsors to make less costly arrangements without the need to guarantee access to the beneficial intervention at the end of the trial. ¹⁰ For example, services such as ‘diagnostic tests, medications and vaccinations, and emergency evacuation services’ ¹¹ are usually part of the trial protocol, but offering a service included in the protocol without including the therapeutic intervention proven to be beneficial for the participants cannot be considered true post-trial access.

John R. Williams, WMA’s Ethics Advisor, Professor in the Medicine Department at Ottawa University, in his account and commentary on the 2008 revision process, affirms that the post-trial access issue continues to generate conflict and concludes that the 2008 version of the DoH is probably a ‘good enough’ improvement, ⁴ at least until the next revision. However, the lack of consensus persisted. During the Stakeholder Meeting that resulted in the 2013 version, there was an expressed desire to draft ‘more precise post-study arrangements’, ideally something that would provide ‘clarification and consistency’. ¹² As we have seen, the statement remains vague.

The working group that revised the 2013 version of the DoH, proposed to resolve the issue through prior agreements between sponsors, researchers and host country governments. As mentioned earlier, the secrecy of these negotiations is likely to benefit the countries with greatest negotiation capacity, and/or those with the largest pharmaceutical markets, to the disadvantage of smaller economies and countries with more stringent protections for research participants, including post-trial access. It is well known that sponsors tend to gravitate towards environments that offer expeditious approval and enrolment processes, and minimal liabilities for sponsors.

It is important to highlight that many LMICs do not have laws addressing patients’ rights and/or who should be responsible for post-trial access. ¹³ Furthermore, the Council for International Organizations and Medical Sciences’ (CIOMS) ethical guidelines on the implementation of the principles outlined in the DoH (originally published in 1982, and updated in 1993, 2002 and 2016) do not clearly define the obligations for post-trial access.

In the absence of clear post-trial provisions, LMIC participants in clinical trials bear the burden of uncertainty about the continuity of their treatments and feelings of abandonment, as demonstrated by an exploratory study conducted in South Africa that ‘highlights voices of participants in their experience of lack of access, loss of support and desertion’. ¹⁴

To ensure access to post-trial provisions the DoH should offer more detailed guidance. It should include how and who will determine that the participant has benefited from the intervention and should continue to have access, the entity responsible for financing the intervention, the process to be used to ensure access, at least until the intervention is registered and commercialised in the host country (for example, through compassionate use or a continuation trial) and the period of time the intervention should be provided to the participants.

The rights of the host communities

Another aspect needing further discussion is the benefits to the communities that host clinical trials. The clinical trials enterprise continues to expand to more disadvantaged countries with vulnerable populations, who may never benefit from the interventions they helped develop. Homedes et al. ¹⁵ checked the affordability of the drugs approved by the FDA in 2011 and 2012 in the Latin America countries where the pivotal clinical trials had been conducted. Due to the business decisions of the sponsoring industries, about 30% (10/33) of drugs marketed in the United States had not been registered or sold in any of the Latin American countries where they were tested. Only one drug was priced below one minimum monthly wage in all the corresponding Latin American countries, and six cost between 100 and 896 minimum monthly salaries. ¹⁵ So, 97% (32/33) of these clinical trials were unethical because they fell short in terms of social value. This is in accord with the 2021 findings of the Access to Medicines Index, which demonstrated that the ‘majority of late-stage (pharmaceutical) R&D projects are not supported by access plans’. ¹⁶ If the price of a new drug is unaffordable to the citizens and public and private insurers of the host country, it cannot be said that this product leads to the improved health and wellbeing of the host population.

Moreover, the health authorities of the LMICs where pivotal clinical trials are conducted are often unable to offer the treatment, either because the company decides not to commercialise it ¹⁵ or because it is unaffordable. ¹² It has become increasingly common for patients to sue the health authorities to secure access to expensive treatments, and because most Latin American Constitutions and/or health laws include the right to health and pharmaceuticals, trial judges tend to rule in favour of the plaintiff, often at the expense of other more pressing public health priorities. ¹⁷

While governments incur costs they can hardly afford, the pharmaceutical industry makes exorbitant profits. Between the year 2000, when post-trial provisions were introduced in the DoH, and 2018, the profitability of large pharmaceutical companies was significantly greater than that of comparable large, public companies. ¹⁸ For this reason, the DoH needs to address benefit sharing, a principle already described in UNESCO's 2005 Universal Declaration on Bioethics and Human Rights. ¹⁹

It is worth mentioning that Guideline 2 of the 2016 CIOMS affirms that sponsors, researchers, governments and other stakeholders, should: ‘make every effort … to make available as soon as possible any intervention or product developed, and knowledge generated, for the population or community in which the research is carried out’. ²⁰ However, this wording implies that an effort should be made but does not guarantee post-trial access.

Conclusion

The primary objective of the DoH is to protect the rights, safety and wellbeing of trial participants. In this context, we advocate in favour of two important policies. The first is to ensure post-trial access to the interventions proven to be effective and not inferior to the best available treatment. We propose guaranteed access for all research participants who benefited from the intervention as determined by their treating physicians, for as long as necessary or for as long the intervention is sold under monopolistic conditions. Sponsors should be held financially responsible, and countries should decide the process to be followed (e.g. Continuation Trial). Second, the DoH should address benefit sharing with host communities, especially in the case of LMICs. A process should be developed by which research sponsors commit to commercialise all products deemed to be successful in the countries where the clinical trials were conducted at an affordable price. National governments should have a leading role in determining what constitutes an affordable price. Ideally, the recommended price should be included in the research protocol and be subject to local ethics review and/or health-technology assessment.

The 2013 version of the DoH does not offer enough guarantees that research participants will be entitled to post-trial access and does not ensure benefits for the host communities, especially for those that are vulnerable populations. Experiments that lead to scientific progress must be conducted in an environment that respects the rights of research participants and their communities and should contribute to social justice.

Declarations

Competing Interests

None declared.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001.

Ethics approval

Not applicable.

Guarantor

FH.

Contributorship

FH and RB wrote the first versions of the article. NH revised and wrote the final version. All authors approved the final version. All authors had access to data and analysis. This version of the article has been approved by all authors.

Provenance

Not commissioned; editorial review.

ORCID iD

Fernando Hellmann https://orcid.org/0000-0002-4692-0545