All together now – harmonising clinical trial regulation

8 December 2016

The impact of international regulation changes in the harmonisation of global requirements is a huge issue in clinical trials. Clinical Trials Insight speaks to Dr Robert Temple, deputy director for clinical science at FDA’s Center for Drug Evaluation and Research, about the challenges encountered in working in an increasingly global manner without harmonised international regulations amid the rise of multiregion clinical studies.

Gout was Horace Walpole’s favourite disease. According to the 18th-century scrivener, it served as an effective firewall against a cocktail of other infections of unknown origin, preventing “other illnesses and [prolonging] life… could I cure that gout, should I not have a fever, a palsy or an apoplexy.” It was a beguiling, if unfortunate, misapprehension.

Walpole wasn’t a typical victim of the condition. He was thin and pallid, keeping to the sort of frugal diet rarely associated with the meaty, boozy lifestyle of archetypal sufferers. In fact, that link – between self-indulgence and punishment of the joints in the ankle and foot – went back as far as Hippocrates, who also helpfully observed that the disease tended to afflict men of a certain age. This conclusion was reached partly through a process of elimination; eunuchs, after all, didn’t develop gout (or become bald), and neither did women nor virginal youths.

It took his distant disciple Galen to recognise a hereditary trait in the condition, and another 2,000 years for doctors to identify the specific role played by uric acid in fostering the disease. Since then, treatments have focused overwhelmingly on accelerating its excretion from the body. One of the latest variations on this theme is the drug lesinurad – marketed as ‘Zurampic’ by AstraZeneca – which, when used in combination xanthine oxidase inhibitor, was endorsed last year by an advisory committee to the US Food and Drug Administration (FDA). The supporting data recommending its use itself derived from three multiregional clinical trials. Zurampic, as it turns out, is one of the latest examples of a drug developed as a result of clinical trials with an increasingly global perspective.

Trial and error

Historically, there has been a consistent disparity between the level of international harmonisation to be found in drugs standards and the acquisition of clinical trials data. In the wake of the thalidomide crisis of the late 1950s, US Congress passed the 1962 Drug Efficacy Amendment, empowering FDA to rule on a drug’s effectiveness and whether it conformed to strict new rules on manufacturing practices. This regime began to be complemented by a movement towards international harmonisation among American, Japanese and European medical regulators in the late 1980s.

By 1990, the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) was established. As Lembit Rago and Budiono Santoso make clear in their history of international drug regulation, additional support for international harmonisation coming from the World Health Organization (WHO) in recent years has allowed an “international consensus on quality, safety and efficacy standards [that] can accelerate the introduction of new medicines and increase [the] availability of generic medicines through fair competition, thereby lowering prices.”

Support for international harmonisation from WHO in recent years has allowed an international consensus on quality, safety and efficacy standards that can accelerate the introduction of new medicines.

This slow advance towards internationally harmonised standards has, however, not been fully matched in the sphere of clinical trials. For the most part, while they have increased in size and complexity, trials have largely remained confined within national borders. Although standards on the quality of pharmaceuticals may in fact remain very similar between one country and the next, for many years drug development was tailored to the needs of specific regulatory regions. That, in turn, could result in a significant delay between experimentation, clinical trials and production of certain pharmaceuticals.

As such, multiregional clinical trials (MRCTs) were mainly conducted when very large numbers of patients needed to be studied, or if the condition a drug was designed to treat was especially rare. However, according to Premnath Shenoy in a review article on MRCTs for the journal Perspectives in Clinical Research, in recent years such studies have “been widely conducted by many discovery-based global pharmaceutical companies with the objective of reducing the time lag of launch in key markets, and improving patient access to innovative treatments.”

Nevertheless, key challenges have emerged for drug regulators in how best to assess the data garnered from these studies.

American action

According to Dr Robert Temple, deputy director for clinical science at FDA’s Center for Drug Evaluation and Research, advances in technology and methods to evaluate clinical data have, in many ways, made the agency’s monitoring role a whole lot easier. “Clinical data submitted in current marketing applications may be from studies conducted at sites outside of the United States,” he explains. “This applies to products manufactured in, as well as those imported into, the US. Imported trial materials that are subject to an Investigational New Drug Application (IND), Investigational Device Exemption (IDE), or Investigational New Animal Drug Application (INAD) typically do not face trouble with the importing process.”

Nevertheless, the current rules surrounding the use of data derived from MRCTs are predicated by longstanding concerns on the part of FDA about the value of clinical data acquired abroad to the US market. “Studies conducted in locations other than the country considering a marketing application are a concern in many countries, and are considered in an ICH document, ‘ICH E-5 Ethnic Factors in the Acceptability of Foreign Clinical Data’, reflecting a concern that populations may differ in response,” explains Temple. “FDA regulations also address this issue in 21 CFR 312.120, 21 CFR 814.15 and 21 CFR 314.106, generally requiring that the studies be well-designed and well-conducted in accordance with good clinical practice, be conducted by qualified investigators, that the foreign data be applicable to the US population and US medical practice, and that rights, safety, and well-being of subjects are protected.”

Additionally, explains Temple, while trial designs in the US are generally similar to those conducted abroad, since they usually correspond with guidelines laid down by ICH, “to serve as the basis for clearance or approval of a medical product, the study and results, and the data submitted must meet standards acceptable to FDA as the basis for clearance or approval, as specified in the FD&C Act, implementing regulations and guidance.”

Ultimately, it comes back to an issue of harmonisation. If a trial is multiregional and uses a common protocol, FDA’s primary concerns revolve around whether the procedures, diagnoses and treatments used throughout the process are similar to those that would be employed in the US. Nevertheless, there are signs that FDA is becoming more open to the possibility of MRCTs playing a greater role in clinical trials. In September, the agency published a new ICH guideline, known as ICH E17, for public consultation concerning the validity of multiregional clinical trials (MRCTs). As per ICH rules, once a guideline is agreed within the organisation, it is submitted to each of its five members for ratification before it can become what is known as an ‘internationally harmonised document’.

Perfect harmony

The intention behind the new guideline is straightforward: harmonisation of the rules that govern MRCTs present a clear opportunity to cut down on the regulatory contradictions that present bureaucratic obstacles to the adoption of workable drug remedies across national borders. Furthermore, according to ICH guidance, “MRCTs can facilitate simultaneous global drug development by reducing the number of clinical trials that need to be conducted separately in each region, thereby avoiding the ethical issue of unnecessary duplication of studies.”

Studies have been widely been conducted by many discovery-based global pharmaceutical companies with the objective of reducing the time lag of launch in key markets, and improving patient access to new and innovative treatments.

There are, of course, challenges associated with conducting MRCTs. In 2009, the European Medicines Agency (EMEA) published its own evaluation of extrinsic and intrinsic factors that could affect the way in which clinical trials data from multiple national jurisdictions is extrapolated. Ultimately, as Shenoy put it, “EMEA opined that… more clinical trials are performed in new regions in which social and cultural aspects may be different in comparison with the EU population.” In 2013, FDA published its assessment of the value of data acquired abroad in support of clinical drug applications within the US.

In essence, the agency recommended considering the heterogeneity of treatment effect across regions when designing MRCTs, concluding that the quality of the trial itself largely depended on an investigational plan with clearly defined objectives that foresaw likely errors in the organisation and execution of the study.

Ultimately, current attitudes have been heavily shaped by the way in which the advantages of MRCTs are compared with the prevalence of specific diseases or conditions across national borders. Neither, after all, are equal-opportunity affairs; certain national populations have a better time in dealing with certain conditions, and that’s usually down to the composition of local diets and environmental factors. Gout is a prime example in this respect: it would be misguided to base a MRCT across European and Asian populations, since incidences of the condition among the latter are relatively low, thanks to the lack of purines found within diets built around rice and vegetables. European diets, meanwhile, contain greater quantities of meat and seafood, both of which are heavily associated with hyperuricemia.

The obvious conclusion to draw from examples like these would be that the full globalisation of clinical trials may be, at the present time, an impossible goal to reach for. Nevertheless, the increasing prevalence and relevance of MRCTs has shown that the old model of restricting studies within single national jurisdictions can, in fact, be one option among many in pharmaceutical research. If – as is likely – designers of clinical trials are circumspect in the placement of MRCTs, it isn’t too much to consider drugs like Zurampic becoming a familiar sight on the shelves of pharmacies worldwide.

Dr Robert Temple received his medical degree from the New York University School of Medicine in 1967. He currently serves as the deputy centre director for clinical science at the FDA Center for Drug Evaluation and Research and as the acting deputy director of the Office of Drug Evaluation.

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