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Pharmaceutical Transparency under the EU's Clinical Trial Regulation

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About The Author

Ceylan Simsek (Regular Writer)

Ceylan Simsek is a law school graduate whose main area of interest is medical law and international law. Alongside her studies, she has obtained certifications from Stanford University School of Medicine on overprescription of antibiotics and unconscious bias in medicine. She works at Medical Protection Society, the world's leading medical defence organisation for medical, dental and healthcare professionals. Outside of law, she enjoys learning new languages and, in order to combat her fear of heights, rock climbing.

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A lack of transparency results in distrust and a deep sense of insecurity.

Dalai Lama

As the reality of Brexit fast approaches, the pharmaceutical industry has reason for concern. The current EU regulatory framework encompassing pre-clinical and completed clinical trials is to be replaced by new EU legislation: the Clinical Trial Regulation (CTR). The CTR will put in place an EU-wide portal for all clinical trial applications whereby sponsors must give notification not only of when a trial begins but also when a trial is temporarily halted, terminated prematurely, or ends.

This is crucial in order to ensure clinical trial transparency, especially for pharmaceutical companies which could otherwise “cherry-pick” data from drug trials. Such cherry-picking could lead to pharmaceutical companies choosing to omit negative results from a drug trial to avoid bad publicity.

However, under the CTR, these pharmaceutical companies will be bound to disclose every trial and result. This will benefit the research community, patients, pharmacists and doctors, since the appropriate medication can be based on the fully-transparent research pharmaceutical companies undertake.

This article will argue that the CTR ought to be implemented post-Brexit. However, it will also assert that the exemptions included under the CTR should be avoided due to the difficulties such exemptions have caused in the past (as discussed below). In addition, it will consider the recent policy paper published by the House of Commons Science and Technology Committee on 22 February 2019.

What is ‘clinical trial transparency’ and why is it necessary?

Clinical trials are vital for medical innovation and progress within the pharmaceutical industry and medicine. There are usually five phases in clinical trials, namely:

  • Phase 0: the drug is tested on animals;
  • Phase I: the safety of the new treatment is tested, usually by examining the way the treatment reacts to the body and how the body responds. This is typically done by giving a low dose to a few people and then slowly increasing the dose to find a dose with acceptable levels of side effects.
  • Phase II: whether the treatment works is tested. This phase normally involves 25-100 participants taking doses in different ways (i.e. orally or by injection) to test safety and effectiveness;
  • Phase III: tests whether the proposed treatment is better than those in the current market. This phase may involve several thousand people being monitored closely and may include the use of placebos; and
  • Phase IV: post-marketing surveillance. Once the drug application has been approved by the Medicines and Healthcare products Regulatory Agency (MHRA), this phase looks at safety over time focusing on the long-term effects.

Lack of transparency at any phase of the clinical trial may result in patients being harmed and medical progress being slowed due to evidence distortion. The benefit of having  legislation to encourage clinical trial transparency is that it promotes greater accountability and responsibility, avoiding circulation of biased or misleading evidence of clinical effectiveness. This allows healthcare professionals to make informed decisions when prescribing certain drugs.

For example, the Cochrane Collaboration published results that the safety and effectiveness of the flu antiviral drug Tamiflu were marketed incorrectly. They found more than 100,000 pages of unpublished data showing negative or inconclusive trial results which stated that the drug had, as summarised by Michelle Llammas:

little to no benefit in preventing the flu or shortening the duration of flu symptoms. It also had a chance of life-threatening side effects (psychiatric and cardiovascular) linked to the drug.

Prior to this, the British Medical Journal had started a Tamiflu campaign. As Cochrane reviewers were refused trial data, they began to publish letters between Cochrane researches and regulatory bodies, as well as pharmaceutical companies, to promote greater accountability and responsibility in public health decision making.

The CTR

The purpose of the CTR is to regulate all clinical trials undertaken by pharmaceutical companies. This is done by inserting a single assessment model through the introduction of a shared portal, thereby increasing the transparency of negative trial results.

This is of particular importance, since the UK is the headquarters of two major pharmaceutical companies: GlaxoSmithKline and Astrazeneca. Likewise, providing greater access to both the public and healthcare professionals who may benefit from ‘open-data’, as well as allowing these parties to see whether a similar trial has been conducted elsewhere and the results of those trials, will save costs.

Moreover, this presents a solution to previous ethical challenges. Professionals can only make assessments on the effectiveness of a drug based on the available evidence to them. Sponsors of clinical trials can control the data through legally binding contracts with research groups. This often means that any negative results arising out of a clinical trial may be withheld. The sponsor can cherry-pick the data that gets published for academics, researchers, and healthcare professionals to read, which can lead to patients being subjected to potentially harmful drugs.

However, in light of its exemptions outlined below, the CTR may not have any great impact in preventing this problem.

Exemptions under CTR: Legal considerations

The previous guidelines on access to European Medicines Agency (EMA) documents provide that, under Article 3, the EMA can:

… refuse access to a document where disclosure would undermine the protection of: a) commercial interests of a natural or legal person, including intellectual property…

Under the proposed CTR, commercial interests will once again be protected. The CTR will require all those running clinical trials to register all information surrounding such trials in an EU-wide portal, making it publicly available, unless the data fall under one of the following exemptions:

  • personal data;
  • commercially confidential information, in particular the marketing-authorisation status of the medicine, unless there is an overriding public interest;
  • confidential communication between Member States in the preparation of their assessment;
  • supervision of clinical trials by Member States.

This presents difficulties in light of the purpose for which the CTR was created. For example, the EU Trials Tracker (which requires all trials to report results within 12 months) shows that the University of Birmingham reported only 3/16 (18.8%) trials. However, for pharmaceutical companies such as GlaxoSmithKline – though their recent reporting figures are impressive, standing at 568/1084 (52%) – the trials entered into the register have inconsistent data.

Past difficulties with regulators and pharmaceutical companies

The Nordic Cochrane Centre

The exemptions under the CTR seem problematic in light of the previous practice of the EMA. For example, in 2007 the Nordic Cochrane Centre conducted a systematic review of two widely used diet drugs: orlistat and rimonabant. This information was vital as anti-obesity pills have been reported to cause:

...cardiac and pulmonary complications or have experienced psychiatric disturbances, including suicidal events, and most of the drugs have been deregistered for safety reasons…

However, the EMA refused to allow access to the full data regarding the benefits of these two drugs on the basis that they were protecting ‘commercial interests’, which are equally protected under the CTR.

The researchers from the Nordic Cochrane Centre took the EMA to the European Ombudsman. Three years later the trial on rimonabant was concluded: the EMA had been in breach for withholding vital information regarding the clinical trials of rimonabant. However, damage to patients had already been done as during those three years rimonabant had been found to increase the risk of serious psychiatric problems and suicide.

Past difficulties with pharmaceutical companies

Avandia, otherwise known as ‘rosiglitazone’, was a drug developed by GlaxoSmithKline to control Type 2 diabetes. However, in July 2010 the Commission on Human Medicines in Europe (CHM), an independent body, found that the drug increased the risk of heart attack and strokes. In addition, the CHM were:

not able identify any groups, including people without a raised risk of cardiovascular disease, for whom the benefits of rosiglitazone could outweigh the risks.

The MHRA – the UK government agency responsible for safety of medicines – was subsequently informed, leading to Avandia (alongside Avandamet and Avaglim containing Avandia) being banned by the EMA.

Recommendations report & Brexit

In August 2018, the MHRA released information as to what would happen after Brexit. In the event of a soft-Brexit, it stated that from 30 March 2019 to 31 December 2020 – the implementation period – all EU regulations, including CTR, will still apply in the UK. After that period, only certain parts of the CTR will be applied within the UK whilst the entirety of clinical trial guidelines will be applied within the jurisdiction of the EMA. The UK will not be able to enjoy the benefit of the shared central IT portal under the CTR.

Of course, following the withdrawal date, the UK may create variations of the provisions of the CTR. Most recently, the House of Commons Science and Technology Committee (STC) put forward recommendations in relation to improving the implementation of CTR within its tenth report on “Research integrity: clinical trials transparency”. In response, the government published a report in February 2019.

One of the recommendations posed by the STC was that the ‘government should explicitly commit to introducing the transparency requirements’. The government has responded with a paraphrased version of “commercial interests”, which is listed under the CTR, and stated that all results will be publicly accessible unless withholding the information can be justified on the grounds of commercial interests.

The reason for protecting commercial interests is simple: if a product cannot be commercialised, it will not be innovated. This means that pharmaceutical companies need enough resourcing to fund future test trials, otherwise they stand to lose millions in revenue. However, whilst protection of commercial interests encourages innovation for future patients, it should not be done to an extent where such a right is abused in the case of drugs with proven negative side effects.

Pharmaceutical companies withholding negative information for fear of profit reductions is injurious to the public interest (as seen from the case of Tamiflu), which demands respect for the right to adequate health, per Article 25 of the United Nations' Universal Declaration of Human Rights 1948. However, proving a certain medicine is not actually beneficial, or even detrimental, for patients’ health could nevertheless be bad for the pharmaceutical industry, which is a for-profit organisation. Having a group of patients receiving treatment for an illness (i.e. cancer treatments) proves to be a sustainable business model as there is sustained cash flow from an incident pool that remains stable. Thus, for the sustainability of the company, commercial interests are likely to remain an exemption exercised frequently under the CTR as patients may seek alternative treatments or stop receiving treatments all together if they are in the knowledge of withheld negative trial results.

Another recommendation made by the STC was that:

the government should explicitly re-commit to tackling clinical trials transparency, perhaps through a focused ministerial speech on this issue. This should set a clear time limit for institutions to fully comply with clinical trials transparency requirements and make clear what the consequences will be of failing to meet that deadline.

The government has responded that they have taken further action to address the issue by developing ‘Model clinical trial agreements’, which include the requirements with which pharmaceutical companies should comply to promote transparency. These include the Clinical Trial Agreement templates designed for industry-sponsored trials in the NHS, which state that all the results of the clinical trial are to be published on a free, accessible database within one year.

Conclusion

The CTR is both innovative by encouraging a single-assessment model, and archaic by recycling exemptions (such as ‘commercial interests’) under the previous EU regulatory framework.

These exemptions should not be put in place so as to ensure that transparency is encouraged. This way, healthcare professionals can have access to the necessary data which allows them to make informed decisions on patients health, alongside researchers who can use even the negative data on existing research as a learning curve for future research.

However, the CTR is undeniably a greater step towards transparency and collaboration between researchers throughout the EU, who will have access to studies that have previously been conducted in their field. Such information can be used in developing effective medicine by building on previous trials, while simultaneously saving costs by avoiding duplication and going down clinical rabbit-holes.

Reform in the UK is necessary in order to promote clinical transparency. It is yet unclear how the scheme under the CTR will be applied across the EU. But, undeniably, it is likely to promote greater accountability and responsibility.

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Tagged: Drugs, European Union, Medical Law & Ethics, Regulators

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