Role of the Expert
Evaluation Models for Causality Assessment
Legal Classification of the Medical Assessment
Comment
Drugs produced using human blood or blood plasma(1) are now considered safe, as far as the risk of transmission of viruses such as HIV (human immunodeficiency virus) or hepatitis A, B or C is concerned. These drugs are submitted to modern virus inactivation procedures during production. Base materials and end products are also screened.
However, it has not always been possible to maintain such high safety standards. Standards in science and technology have changed significantly over the years.(2) Thus, there are still numerous disputes about the potential liability of pharmaceutical companies, doctors or hospitals for blood products contaminated with viruses. In many cases - especially in relation to haemophilia patients who need treatment with blood products over many years, or even for life - the events in question took place years or decades ago. A scientifically plausible assessment of suspected cases of virus transmission via blood products is therefore crucial not only for medical assessments, but also for a legal evaluation of the facts.
The decisive question for the legal assessment of a suspected case is usually whether there is a causal link between the infection of the claimant and the administration of a certain blood product. Before the amendments to the German regulations on liability for pharmaceutical products came into effect in August 2002,(3) it was always the injured party who had to state and prove that the drug taken had in fact caused the damage to health in question. It was difficult for the injured party to furnish such evidence, particularly in cases where several medicines from different manufacturers were prescribed successively or simultaneously over a long period of time, and where each of these might have caused the damage.
The Second Act on the Amendment of the Law of Damages(4) made it significantly easier for claimants to furnish proof of liability relating to pharmaceutical products for all cases of damages occurring after August 1 2002. The new provisions now provide for the assumption of a causal link in favour of the injured party in cases where the medication used is capable, taking into account the particular circumstances of the individual case, of causing damage.(5) If this assumption of causality applies, the injured party need no longer state and prove the specific causal process in order to convince the court. The only option available to any pharmaceutical company against which a claim has been asserted is to refute the assumption of causality by making plausible submissions on other specific circumstances which could also have caused the damage. The causality assessment is therefore of crucial importance.
In almost all cases the help of a medical expert is needed in order to determine (i) whether - and if so, which - blood products might have caused a virus, and (ii) whether other causes are possible, and their importance to the assessment. The expert's job is to provide its client, the court or the Public Prosecutor's Office with the expertise which these parties lack for the assessment of issues of proof crucial to the decision of the point of law. The expert must communicate his knowledge of empirical scientific findings in his specialist field of knowledge to the court. He can assess certain facts and these empirical findings applying his particular expertise and draw certain conclusions from these.(6)
Evaluation Models for Causality Assessment
World Health Organization criteria
In 1994 the World Health Organization (WHO)(7) developed methods and categories designed to standardize the assessment of undesired effects of medication on an international basis.(8) In Germany, the assessment of suspected cases using this system of classification is recommended by the Federal Institute for Drugs and Medical Devices and by the Paul Ehrlich Institute (the Federal Agency for Sera and Vaccines). In 1996 these two senior federal authorities jointly issued the "Third announcement on the notification of side effects, interaction with other agents and abuse of medication pursuant to Section 29(1)(2-8) of the Medicines Act".(9) The WHO system of classification distinguishes between five possible ratings in a causality assessment, whereby the causal link between the administration of the medication and the undesired effect can be classified as:
- certain;
- probable/likely;
- possible;
- unlikely; or
- unassessable/unclassifiable.
Algorithm for causality assessment
Although the WHO criteria are suitable for assessment of causality with 'typical' drugs whose effect depends on certain chemical substances, they are not suitable for a causality assessment in the case of transmission of infection by biological drugs.(10) A group of authors - Rudolf Schosser, Brigitte Keller-Stanislawski, C Micha Nübling and Johannes Löwer - have therefore developed an algorithm which takes into account the peculiarities of the causality assessment of virus transmissions by biological drugs. The team is formed of representatives of Baxter Deutschland GmbH and the Paul Ehrlich Institute. The algorithm provides the medical specialist with a means of carrying out the causality assessment using a standardized procedure, making the decision process more comprehensible and transparent by means of a series of simple questions. The algorithm is based on the findings of the latest methods of virus testing using gene technology and the assessment of empirical data.
In order to assess causality, the standardized procedure sets up to 11 questions, to be answered in each individual case by yes/no or positive/negative. As each question is answered, the expert is brought one step closer to a comprehensible assessment.
The standardized procedure for answering the specific medical questions can be outlined as follows:
- Is the data sufficient? Clinical data and product data are required in sufficient volume for the causality assessment. Infection with a specific virus must be verified by a confirmation test. If insufficient data is available, the suspected case can be deemed non-assessable.
- Is the virus transmission clinically plausible? If the temporal connection between administration of the product and occurrence of the symptoms, the serological pattern (acute or chronic infection) and the clinical picture are not plausible to begin with, a causal link between administration of the product and the infection can be excluded. The expert must then simply state in a comprehensible manner why transmission of the virus cannot be shown in a plausible manner.
- Is the lot number known? Current legal requirements stipulate that for every instance of treatment with a blood or blood plasma preparation, the relevant lot number must be recorded. Manufacturers are also obliged to retain samples from each batch to allow products to be traced back at any time. Thus, where lot numbers are known, the relevant sample should be investigated. If this is not possible without lot numbers, the effectiveness and validity of the virus inactivation procedure must be assessed retrospectively.
- Are product samples available? Any available product samples are to be tested for viruses using nucleic acid amplification testing (NAT).
- What is the result of NAT? If NAT produces a negative result, the effectiveness of the virus inactivation procedure must be assessed, since even in the event of negative NAT infectious virus particles cannot be excluded. If the NAT result is positive, the blood of the recipient should be tested.
- Is a recipient's blood sample available? If the recipient's blood is available, the DNA/RNA sequence of the pathogen in the product sample and in the recipient's blood should be compared to establish any sequence identity. If the recipient's blood is not available, the possibility of carrying out an infection test on animals should be considered.
- Is a DNA/RNA sequence identity detectable? If the DNA/RNA sequence of the pathogen genome in the product and the recipient is identical (sequence identity), the causal link is certain. If there is no similarity, the causal link is unlikely.
- Has an infection experiment been performed, and if so with what result? Given their high cost, infection experiments on animals, in particular primates, are rarely carried out. In the event of a positive infection experiment with product samples, the causal link is certain. With a negative infection experiment or in the absence of any such experiment, the effectiveness and validity of the virus inactivation must be taken into account in the assessment.
- Is the virus inactivation method effective and validated? If the virus inactivation procedure is effective and validated pursuant to the corresponding recommendation of the Committee for Proprietary Medicinal Products,(11) the causal link is unlikely. If no effective and validated inactivation procedure has been applied, the safety record of the products is to be taken into account in the assessment.
- Is the safety record high or low? The safety record of a product depends on several factors. For example, the longer a product has been on the market without any reports of virus transmission, the safer it is. A retrospective finding that despite the use of highly infected plasma no instances of virus transmission were known also improves the safety record. The results of the batch-related look-back procedure also contribute to the safety record.
- Are batch-related clusters identified? If there are two or more reports of suspected virus transmission with the same pathogen for the same batch, a cluster is suspected. In this context, a cluster refers to the frequent occurrence of an infection after administration of the same batch. In the event of a batch cluster, the assessment is based on the safety profile.(12) On the basis of the result, causality is assessed as unlikely, possible or probable.
The systematic answering of these questions by the medical expert results in an assessment of the causal link as certain, probable, possible, unlikely, no association or not assessable. This causality assessment is based on the WHO classification system for causality assessment. This system introduces a new category to the WHO's five under which, with regard to a causal link, there can also be deemed to be 'no association' if the assessment justifies this end result.
Legal Classification of the Medical Assessment
The expert opinion is usually the most important basis of evaluation in the legal assessment of the causal link. However, the amendments to legislation on liability with regard to pharmaceutical products have seen a decisive shift of the liability threshold. The previous legislation on liability with regard to pharmaceutical products, valid until August 1 2002, imposed the full burden of proof on the claimant (and still applies to cases that originated before its entry into force). Therefore, a claim often only existed if the expert concluded that the causal link was 'certain' in accordance with the WHO classification system. Even the more cautious classification of 'probable/likely' often meant that the causal link could not be proved beyond any doubt of the court, and that claims for damages were therefore dismissed.
Following the amendment of this legislation, it is likely to be sufficient for the assumption of causality if the expert concludes, in a manner which is comprehensive and plausible to the court, that a causal link between the administration of the product and the damage incurred is 'possible' in the sense of the WHO criteria. In such case, as stated above, it would be up to the defendant to demonstrate specific circumstances which nevertheless exclude causality.
The algorithm will be a valuable aid to any medical expert assessing a possible causal link between the administration of plasma preparations and the occurrence of virus infections. It indicates to any lawyer concerned with such legal questions that a complex medical causality assessment is certainly feasible as evidence and is based on a comprehensible assessment procedure drawing on objective criteria.
For further information on this topic please contact Uwe Froehlich at Lovells by telephone (+49 89 290 120) or by fax (+49 89 290 12 222) or by email ([email protected]).
Endnotes
(1) The most important product groups are the factor concentrates for treatment of blood-clotting disorders.
(2) See also Bender, MedR 2002, 487, 489 and following; Koenig/Engelmann, PharmR 2001, 74 and following.
(3) See Brock, Lovells Pharmaceutical and Biosciences Newsletter, July 2002, p 18 and following; Brock, Lovells European Product Liability Review, June 2002, p 16 and following.
(4) Zweites Gesetz zur Änderung schadensersatzrechtlicher Vorschriften - SchErsRÄndG (BGBl I 2002, p 2674-2680).
(5) Section 84 of the new version of the Medicines Act.
(6) Laufs/Uhlenbruck, Handbuch des Arztrechts, 3rd edition 2002, Section 116 margin no 5 and following.
(7) More precisely, the World Health Organization Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
(8) Edwards/Biriell, Drug Safety 1994, 93 and following.
(9) BfArM/PEI, announcement of May 15 1996, BAnz 1997, 5929-5933.
(10) Schosser/Keller-Stanislawski/Nübling/Löwer, "Causality assessment of suspected virus transmission by human plasma products", Transfusion 41 (2001), 1020-1029.
(11) Committee for Proprietary Medicinal Products/BWP (1995) "Note for Guidance on Virus Validation Studies: The Design, Contribution and Interpretation of Studies Validating the Inactivation and Removal of Viruses", CPMP/BWP/268/95, available at: www.emea.eu.int/pdfs/human/bwp/026895en.pdf.