Placing a study under another country's rules
Where a clinical study runs shapes its protocol and the documents around it. Running a study in another country brings factors to weigh before the study is placed there and consequences for the documents once it runs. A national law can require or prohibit a study, set design requirements that differ from those of other regulators, or leave a writer to borrow guidance where it is silent, and a national study category can turn the protocol's ordinary vocabulary into a regulatory commitment.
Why sponsors place studies abroad
Running clinical studies outside the United States adds complexity that may have a significant impact on the documents a medical writer writes, although writers often do not think about the difficulties involved. Domestic markets in Latin America, China and India had grown, and placing clinical studies in one of these large, potentially global markets can reach a diverse population of untreated patients with a spectrum of diseases and medical conditions. Placing studies there is also often considerably less expensive than placing them in North America or western Europe.
One assessment holds that the advantages of conducting clinical trials abroad, which include rapid enrolment and access to large patient populations at relatively low cost, generally outweigh the disadvantages. In the same assessment, sponsors who are willing to take the time to understand and adapt to country and regional differences can successfully conduct clinical trials globally, and either avoid the pitfalls or develop strategies to deal with them when they arise.
Factors to weigh before placing a study abroad
The factors a company should consider before it places a study in another country include:
- Civil and political stability.
- Culture: social norms and taboos, how laws are interpreted, and what is understood to be a concomitant medication; patients who may not want to disappoint the investigator or study personnel; and close family units in which everyone in the family has to agree to the terms of the study.
- Time: for regulatory and ethical approvals, letters of delegation, import and export licence approval, and the development and finalisation of contracts.
- Ethical considerations: whether the patients, the investigator or the institution are being exploited in any way, how patient safety will be ensured, who will ultimately benefit from the study, whether the medicinal product will be available in the country, and whether some patients will receive placebo.
- Religious considerations: requirements for birth control and routine pregnancy testing; the collection of blood, bone, tissue and other specimens; and requirements for obtaining blood, or for travel, that conflict with dietary changes such as fasting during religious holidays.
- Standards of care, which may not be well established from region to region or well documented in the medical record: which drugs and treatments are available, and how the patients' ability to receive the standard of care might affect their willingness to take part in the study.
- Economic conditions and access to basic necessities.
- Language: dialects that vary within a country or region despite a common language; differences in interpretation where no literal translation exists; translating study documents such as informed consent forms, assessments and dosing instructions; and validating the translated assessments.
- Confounding habits, such as a patient who does not consider an herbal product a medication and so does not list it as a concomitant medication.
- The availability of physicians, hospitals and trained health care workers, such as investigators, study coordinators and site staff trained in Good Clinical Practice.
- Logistics: transport from rural areas may be inconsistent or unavailable; a site may have no dedicated study coordinator or other person to facilitate study management; longer visits may take more than a day away from home or work and require accommodation; facilities may lack equipment required for testing or screening, so that patients travel to ancillary facilities; and contract and budget negotiations, regulatory review and submissions, study drug management, and study conduct and oversight require the sponsor to have someone on the ground in the region.
- Cost: insurance, country-specific equipment, labour, operating overhead, liabilities and risks; the reliability of equipment, which may have to be bought and then serviced, calibrated or replaced; patient transport; and the fluctuating value of the US dollar and the conversion of invoices into US dollars.
- Regulations: the drug and device application and approval process, Boards of Health and clinical study regulations, controls on study site selection, and the shipment of samples and equipment across borders.
- Intellectual property and patent protection, or the lack of it.
What placing a study abroad does to the documents
The impact these factors might have on the medical writer includes:
- country- and site-specific protocol amendments
- potentially more protocol deviations
- free-text or comment fields on case report forms that may have no literal translation
- potentially more analyses and statistical interaction
- the logistical difficulty of obtaining investigator signatures
- questions from the US Food and Drug Administration about whether foreign data apply to the US population
- responses to site audits conducted by regulatory authorities
In Spain the law no longer requires the research protocol to be translated into Spanish, but many ethics committees still request a copy in Spanish.
Designing to a national requirement
Studies a national law requires or prohibits
In the Russian Federation, Federal Law #61 on the Circulation of Medicines, in force from 12 April 2010, stipulated that when the clinical part of a drug's development had been completed in a study population omitting Russian patients, a controlled, evidence-based confirmatory study had to be performed in Russia as part of the registration process. To justify the requirement, Russian lawmakers pointed to differences in the characteristics of the country's population and to imperfections in the legislation for accepting foreign studies. A phase III study therefore had to be conducted in Russia, and this was not considered a violation of good clinical practice.
No national guidelines had been developed on the minimum acceptable number of patients or on the choice of primary endpoints. So medical writers had to study all available ICH general guidelines on study design and the specific guidelines of regulatory agencies such as the FDA, the EMA and Health Canada, and make a scientific judgement on which guideline applied to the particular study. The writer then had to work closely with statisticians to create a design that met the study objectives within the study's budget, and the sample size had to take into account validated sample-size software and publicly available study results. In one experienced writer's account, which verbal communication with experts from the Russian regulatory authorities supported, objective clinical criteria were generally accepted as preferable to pharmacodynamic parameters as primary endpoints, although no official guidance had been issued on the matter.
Federal Law #61 also prohibited phase I studies in healthy volunteers with medicinal products manufactured outside the Russian Federation. Medical writers therefore had to think about alternative designs that enrol patients instead of healthy volunteers, as phase I studies of certain types of drugs, such as antipsychotics and anti-tumour agents, do.
Bioequivalence studies
Russian requirements for bioequivalence studies differed from those of other regulatory agencies, such as the EMA, the FDA and Health Canada, in these aspects:
- Bioequivalence studies could only be performed in people aged 18–45 years, and the minimum number of volunteers should be at least 18.
- Medicines administered by the parenteral route, by inhalation, or by the enteral route as solutions needed to undergo prior therapeutic equivalence studies.
- The washout period between treatment periods had to be at least six half-lives of the drug substance, and the acceptable interval between blood samplings at least four half-lives. The WHO's minimum washout period is five half-lives of the drug substance or at least 7 days, and Health Canada requires 10 half-lives but not more than 4 weeks.
When a foreign sponsor wanted to conduct a bioequivalence study in Russia with a protocol written to the European or American guidelines, local medical writers had to adapt the protocol to the national legislation and requirements. Attention should also be given to the non-clinical comparative toxicity studies of the generic and the original drug, which the regulatory agency generally demanded and which should be described in the investigator's brochure and the protocol.
Biosimilar studies without national guidance
Writing protocols for biosimilar drugs was a problematic area in Russia, and study design and medical writing for such studies were challenging because there was no national guidance on pre-clinical or clinical development programmes for biologicals, and Russian legislation gave no definition of a biosimilar drug. Medical writing on biosimilars is complicated and requires multiparty knowledge.
Medical writers therefore referred to the EMA's general and product-specific guidelines, such as the Guideline on similar biological medicinal products containing monoclonal antibodies, to develop clinical and pre-clinical programmes. The EMA's guidelines are quite precise and stringent, so compliance with them gave a better chance of a drug's approval in Russia.
A clinical study planned to show that a biosimilar and the original drug have comparable pharmacodynamics and pharmacokinetics must consider:
- the choice of study population, healthy volunteers or patients
- the choice of pharmacokinetic parameters of interest
- the availability of relevant pharmacodynamic markers of efficacy
- the determination of the required sample size
- the study cost, including the cost of the original drug
The design of a pivotal study to show that a biosimilar is similar to the original drug needs to consider the availability of relevant pharmacodynamic markers of efficacy, as the EMA's guideline states.
Orphan drug studies
Orphan disease and orphan status were first defined in Russian legislation in 2011. Developing an orphan drug in Russia was challenging because the number of trial participants could not be lowered: statistically there were no exceptions for an orphan drug study, and it had to enrol as many patients as a regular study.
Protocol vocabulary under a national study category
In Switzerland, the Ordinance on Clinical Trials (VKlin) drew no distinction between interventional and non-interventional or observational studies. So every study had to go through notification of, approval by and reporting to Swissmedic and an independent ethics committee, except the Praxiserfahrungsbericht (PEB). A PEB is a clinical research project that is as observational as it can get but cannot be called an observational study, and it documents data on therapeutic efficacy or safety within the framework of clinical practice. Swissmedic translates the term as monitoring of use report, and it has also been translated as field report or clinical survey.
For a PEB only ethics notification was required, and informed consent was usually optional. A study protocol was still needed, but a very short and abbreviated one. Sponsors were very careful about the terms used in a PEB protocol, lest the project be elevated to observational-study status. Terms such as study, treatments, visits, schedule and follow-up could be deemed inappropriate for a PEB because they may connote intervention, although they are words a protocol ordinarily uses.