Clinical trial and error

Caroline Stockwell, an associate at a leading law firm, reviews the legal implications for those involved in clinical trials following the disastrous TGN1412 trials at Northwick Park Hospital in the UK

Shock waves are still travelling through the pharma-ceutical industry following the disastrous clinical trial of TGN1412 at Northwick Park Hospital on 13 March 2006. Many questions relating to why the six volunteers had such an adverse reaction to the drug remain unanswered, despite the fact that Britain's pharmaceutical industry has a robust, well respected regulatory regime enforced by the Medicines and Healthcare products Regulatory Agency (MHRA).

TGN1412, a novel monoclonal antibody manufactured by German company TeGenero showed no adverse effects in previous trials on animals. This has led the scientific community to ask whether there was sufficient understanding about the mode of action of the compound in different biological systems and, therefore, whether the tests which were undertaken before the compound was administered to humans were sufficient and appropriate.

The MHRA's investigation into the now notorious trial suggests that the established regulatory process was indeed robust and that the necessary protocols and procedures were followed, apart from some deficiencies in procedures at Paraxel, the contract research organisation. The MHRA's final report found that the adverse incidents were not a result of any errors made in the manufacture of TGN1412, its formulation, dilution or administration to the trial volunteers. The report concluded that the drug showed an effect in man that had not come to light in pre-clinical tests in animals at higher doses.

Despite the report, much controversy remains and the MHRA has formed an expert group to consider any changes that are necessary to the clinical trial regime to improve safety. The authorities await the findings of the expert group and in the meantime the MHRA will not authorise clinical trial applications for Phase I trials of any monoclonal antibody without additional expert opinion.

failings in GCP

Paraxel and TeGenero should have complied with the requirements of the Clinical Trial Directive (Directive 2001/20/EC), implemented in the UK by the Medicines for Human Use (Clinical Trials) Regulations 2004. In general, there was compliance but Paraxel failed to meet six elements of the Regulations (namely GCP). The failures concern: no written contracts between both the companies and with the physician; not checking the manufacturer's insurance cover; not taking a volunteer's full medical background; lack of 24-hour medical cover, and not adhering to the un-blinding procedure.

In line with the regulations, the volunteers would have given their consent to take part in the trial and would have entered into a contract with the above companies. There is no denying that there are risks and side-effects associated with drug trials but these risks would have been explained and clearly no one would volunteer for a trial knowing that there was a substantial risk of serious injury.

Taking a closer look at the potential liabilities for the companies involved, Paraxel and TeGenero may still face legal proceedings and liabilities, including claims from each other and from the volunteers. Monetary compensation may also have to be paid to settle such claims and/or fines in the event of regulatory non-compliance.

penalties

Paraxel may be subject to enforcement action from the MHRA for non-compliance with GCP. This can range from the issue of a formal infringement notice to prosecution for an offence under the regulations, where penalties could include imprisonment for a period of up to two years, if the conviction is made in a UK Crown Court.

Other criminal liabilities are unlikely to be faced by Paraxel or TeGenero. Such liabilities would have been possible if the companies involved conducted a trial knowing that there was a significant risk that a volunteer could die - for which they could have been prosecuted for manslaughter and faced prosecution for offences under the Health and Safety at Work Act 1974.

In the case of manslaughter, the prosecution would have to show that death had been caused by a reckless or grossly negligent act or omission on the part of a senior individual at the company (where such an individual represents the controlling mind of the company) undertaking a trial and/or the manufacturer of the compound. In a small company this may not be difficult to prove, but in large companies where directors and senior managers may be remote from day-to-day operations this type of prosecution would be difficult. Unsurprisingly, they are also very rare.

The proposed bill on corporate manslaughter, currently before the UK Parliament, is intended to make prosecutions easier. The draft bill aims to allow successful prosecution of companies where there have been management failures at a senior level that have caused a person's death. In the context of a clinical trial a prosecution under the proposed bill might be brought if a death occurred and the company had not complied with the principles of good clinical practice.

It is likely, depending on the specific terms of the contracts in place, that TeGenero may have claims for breach of contract against Paraxel and/or the manufacturer of the compound for the trial and vice versa. The volunteers participating in the trial may also have claims for breach of contract against TeGenero or Paraxel.

In order to be successful in a claim for breach of contract the claimant has to show that the damage they have suffered or incurred has resulted from the breach and that such damage was reasonably foreseeable from the breach. In breach of contract claims the UK court awards damages on the basis of putting the person who has suffered in the position they would have been in had the contract been properly performed.

The volunteers may have a claim in negligence under the law of tort against TeGenero and Paraxel,

provided that they can show that the companies owed the volunteers a duty of care; that there has been a breach of that duty, and that the breach has caused the injury. These requirements should be fairly easy to prove for the volunteers, who have suffered and continue to suffer injury following the clinical trials.

The European Union, through an EC directive on product liability (85/374/EEC), imposes strict liability on producers of products if their product contains a defect that causes damage to a person. The directive is implemented in the UK by the Consumer Protection Act (CPA) 1987. If product liability were an issue in this case, the drug manufacturer and the company that developed the drug would automatically be liable. This right of action is limited to consumers, and there is no statutory definition of a consumer in the UK. However, EC law considers a consumer to be a natural person so it is possible that volunteers for clinical trials would be included in this definition of a consumer. The damages awarded can include an element for pain and suffering.

There are a number of defences available to a producer under the CPA. The most relevant to the pharmaceutical industry is known as the "development risks defence". This defence is based on showing that the state of scientific and technical knowledge at the time the product was supplied or put into circulation, was not advanced enough to detect the defect in question. Under the CPA consideration is given as to whether it was reasonable to expect the producer to discover the defect. This concept of reasonableness is not in the EC directive and makes the defence easier to invoke in the UK, and it may well be used by the companies involved in the Northwick Park trial.

Liabilities can be minimised with insurance policies and indemnities in contracts. These allow, for example, company directors to protect themselves against personal liability through the company's directors and officers policy. Defects in products may also be covered by product liability policies and, for pharmaceutical companies, this may give rise to large premiums that will often be beyond the reach of small start-up research and development companies.

trial delays

Looking at the implications for the future, the disastrous trial at Northwick Park Hospital has thrown up more questions than answers and also reminds us how much we do not know despite scientific advancement. The unforeseen event raises important scientific and medical questions about human trials, which will make it increasingly difficult for companies to obtain approval to conduct future Phase I trials with novel biological compounds.

As a result of the data now required by the regulator, the entire process is likely to take longer. This works against the driver that many pharmaceutical companies have to maximise their competitive advantage in the market by shortening the development time from discovery of a compound until it is put onto the market.

For novel biological compounds targeted to work on particular aspects of the human immune system it may become the norm to undertake more tests on human tissue in the laboratory (in vitro) prior to putting the compounds into people for the first time.

On 19 May 2006, the World Health Organisation announced that companies should register all trials on humans. Until more is known about the risks associated with human trials, the industry and the MHRA will be under increasing pressure to disclose information regarding clinical trials in human volunteers and allow for greater transparency in the authorisation process.