Regulations pose a challenge for CROs
Both the EU's new Clinical Trials Directive, which was published in May, and recent comments by the US Consumer Product and Safety Commission will affect how pharmaceutical companies carry out future clinical trials in the European Union
Both the EU's new Clinical Trials Directive, which was published in May, and recent comments by the US Consumer Product and Safety Commission will affect how pharmaceutical companies carry out future clinical trials in the European Union
Because of its large, diverse population and strong research and pharmaceutical infrastructure, Europe has long been a preferred site for large-scale multinational clinical trials.
Quintiles Regulatory Affairs Europe has established a highly specialised Clinical Trials Unit, based at the the company's offices in Edinburgh, UK. The main aim of the unit is to provide customers with a centre of excellence for all clinical trial activities within Quintiles Europe, thereby expediting regulatory approvals across Europe.
Discussing the new Clinical Trials Directive its director, Kim Mills, commented, 'The introduction of Good Clinical Practice [GCP] in the early 1990s and developments within the International Conference on Harmonisation [ICH] have facilitated increased transparency of technical data. Such measures have contributed towards reduced development times and expediency in the EC approval process.
'Europe has become very focused on achieving ICH compliance in all respects. It is evident that there is general recognition between member states, even though there are currently national differences prevailing across each one with regard to regulatory requirements for clinical trials.'
There are many factors to consider when planning multinational trials in Europe. Some countries have formal approval procedures, while others have notification procedures; therefore, the amount and type of data required for each country can vary.
This can range from dossiers including full details of chemistry/pharmacy/preclinical and clinical data (similar to a UK clinical trial application) to a simpler notification process that is highly dependent on Ethics Committee approval. The timelines for clinical trial approvals in Europe also can vary considerably.
'Other major variances among European countries include the feasibility and sourcing of active comparators, clinical trials insurance, labelling, import and export licences, and the way in which research drugs are classified,' Mills said.
'Furthermore, each country may have supplementary requirements for adverse drug reporting that are in addition to those of the ICH guidelines.
'The European Agency for the Evaluation of Medicinal Products (EMEA) has established a framework for obtaining marketing authorisations within the EC through a centralised procedure.'
Having waited some 10 years from its initial conception, the Clinical Trials Directive, 2001/20/EU, was published in the EU official journal on May 1, 2001.
The implementation timetable is to create national legislation in each Member State by May 1, 2003 and to fully implement the contents of national legislation by May 1, 2004.
multicentre studies
'The directive is geared primarily toward multicentre studies, although its extension to bioavailability and bioequivalence studies (Phase I) is posing many controversial issues for both industry and authorities alike,' she commented.
'The definitions of terminology used in the directive differ from those under existing law and draw heavily from the ICH. Consequently, the new definitions may alter significantly the legal framework for clinical research in some member states.'
Implications of the directive include:
Europe has a lot to offer pharmaceutical companies wishing to conduct large multinational clinical trials. In spite of the many challenges, Europe's focused attitude on ICH compliance and general recognition of technical data between member states has attracted major international pharmaceutical companies.
regulatory operations
Mills said, 'As national and European regulations have evolved, so have regulatory operations with companies such as Quintiles Europe providing a comprehensive service for all regulatory trial activities.
'Having such a unit will continue to ensure consistent, high-quality trials that are quick to start up and compliant with well-established and new regulations.'
The second piece of legislation to affect contract research organisations (CRO) involves child-resistant packaging. Peter Mayberry, executive director of the Falls Church, VA, US-based, Healthcare Compliance Packaging Council (HCPC), spoke about its implications to clinical trials.
'Blister packaging is nowhere near as widely used in the US as it is in Europe. The percentages are reversed in terms of markets, in the US about 80% of otcs are available in a blister pack, while about 20% of the pharma prescription drugs are available in blister pack form. Usually, prescription drugs are shipped in bulk and the pharmacist is responsible for counting them out as per the individual prescription.
'In the US there is legislation on child-resistant packaging, which is implemented through a broad congress law and then via finite regulations from two regulatory bodies, the FDA and the Consumer Product and Safety Commission [CPSC]. It is the change in the CPSC policy on clinical trials that will concern CROs,' he said.
'The child-resistant packaging requirements are governed by a law passed by Congress in 1970, the poison prevention packaging act [PPPA]. 'The PPPA said that household substances that are potentially harmful for small children must be in a child-resistant format, if the packaging is technically feasible, practicable and appropriate.'
“Non-child resistant packaging may be used if the amount of drug dispensed into the household will not cause serious injury or illness to a young child |
He continued, 'It is important to realise that, in 1970, child-resistant packaging was not widely available, so Congress did not have a good idea of what it was. At that time they left it up to the FDA who determined that prescription drugs were a hazardous substance for which there was packaging that met all the criteria.'
In 1973, the FDA issued regulations which stated that all drugs had to be in a child-resistant format. They also established a test protocol, now overseen by the CPSC, which is still used.
'The protocols were used and everything was fine for 25 years until 1998 when Suzanne Barone, a CPSC project manager in charge of implementing the PPPA, read an article in which there was discussion about ensuring adherence to the act during clinical trials and whether it was critical,'said Mayberry.
child-resistant requirements
'In this article, someone had the misfortune of noting that child-resistant features were not of particular importance in clinical trials. Barone wrote to the editor of the journal in which she asserted that investigational new drugs (INDs) do need to meet the regulatory definition of the PPPA and are, therefore, subject to child-resistant requirements.
'This was a complete bombshell in the US. Clinical trials are not overseen by the CPSC, but by the FDA, who have to approve the protocol for trials. All drugs are dispensed by physicians, every dosage is counted and accounted for and to the best of the HCPC's knowledge no small child had ever been poisoned by an IND that had been dispensed into the house.
'The PPPA specifies child-resistant caps are for household items and many people wondered how the CPSC could say an IND was a household item.' he added. 'Nevertheless, they did if the drug was dispensed into a household on a out-patient basis.
'Naturally the companies and people who ran the clinical trials asked for clarification and the CPSC issued a letter in 1999, which stated that in Phase II and Phase III clinical trials "non-child-resistant packaging may be used if the amount of drug that is dispensed into the household will not cause serious injury or illness to a young child." '
However, they did not state the meaning of "serious injury or illness". They also said it would be OK for INDs to be used if for example, the drug is of low toxicity or the amount of drug sent home is restricted to a level that is of low toxicity.
'But, if child-resistant packaging is required, what happens, for example, if with placebos, i.e. it is a blinded study, wouldn't this compromise the blinding unless everything was put into child-resistant packs?' Mayberry asked.
Another question he raised was, what about Phase IV trials? Do CROs have to put their competitors' products into special packages as well? And what about the international implications of the CPSC statement? If this is done in the US, what about the ripple effects overseas? The CPSC's response was "we don't care", it has to be done.
packaging protocols
Another important question, which the CPSC did answer, was whether this makes all clinical trials subject to protocol testing before the trial begins? 'In other words, if a CRO is running a clinical trial is it going to have to run a protocol on the packaging it is going to use? The CPSC said no to this,' he said.
'The CPSC said that because these INDs are being overseen by a physician and because it is a more controlled environment within the household, protocol testing was not needed.
'Thus, according to CPSC understanding of the PPPA regulations, drugs with sufficient toxicity to cause serious injury or illness to a young child must be packaged with a child-resistant feature,' he said.
This can be achieved in two ways:
The types of blister packs recommended are peel/push, with Mylar backing, peel back, notch and others, such as those requiring a tool to open the blister.
In response to the concerns that were raised in 1999 on the impact of this ruling on international studies for Phase IV trials, the CPSC backtracked and issued an additional statement pointing out that child-resistant requirements do not cover those drugs dispensed for use in hospitals or similar institutions.
Mayberry continued, 'They also gave some room for manoeuvre on Phase IV saying that ASTM D-3475 or outer packaging should be used in Phase IV trials only if "it is not possible to use a commercially available child-resistant package or when the use of such a commercial package configuration would be detrimental to the study." However, they do not define what "detrimental to the study" construes.
'There were also queries about the trials in progress. Did, for instance, the pronouncement mean that trials in progress had to be abandoned and restarted with new packaging?'
The CPSC said that all drugs in Phase II, III or IV clinical trials initiated after November 23, 2000 must be packaged in accordance with ASTM D-3475 standard or in an outer shell. They also said that the concept of an outer package would be abandoned after May 2002 by stating that 'the immediate packaging of all toxic oral drugs intended for human use that are dispensed for household use in Phase II, III or IV clinical trials initiated after May 23, 2002 must be child-resistant'.
Mayberry also stated that there are some get-out clauses companies may investigate. These include:
In conclusion, Mayberry gave a warning. 'Although not tested in law, the belief is that if the CRO fairly shows this statement to the patient, who freely signs it, then, if anything should go wrong, i.e. a child is "seriously injured" by the drugs, the clinical trials company would not be liable. However, it must be pointed out that is has never been tested in court.
'Now, in the US, there are companies who make child-resistant packages for clinical trials, which CROs can buy off the shelf and implement into their trials.
acceptable for trials
'These packages have passed the protocol set by the CPSC, both the child and old age persons sections, so for clinical trials these should be acceptable.'
The impact of this legislation on EU trials is unclear. US pharma companies say they do not want two types of packaging, one for the US and one for the EU. But what does that mean?
'It probably means that they [the US companies] want the EU to comply with the US requirements!' he quipped.
It may also lead to the reduction in use of unit dose formats for clinical trials. It would be easier to use the child-resistant bottles than unit dose formats, if it were simply to meet the CPSC requirements.
However, it is far easier for the triallist to ensure that the medication has been taken using unit dose than using bottles.
Thus, on the US side, there is a firm belief that the off-the-shelf child-resistant products will become the product to use because they get the clinical trial company off the hook with regards to compliance to CPSC.
With economics, the feeling is that the companies are not poor and so there is probably room to increase the costs of packaging if it means compliance with CPSC and other regulations.