Developing pharmacogenomics guidance in Cuba

Diadelis Remirez, Deybis Orta, Yamira Pérez and Rafael Pérez Cristi� from Cuba's drug regulatory agency discuss their efforts to create the country’s first guidance on pharmacogenomics.

Drug regulators in Cuba have initiated efforts to develop the country's first guidance on using pharmacogenomics to improve and streamline the development of pharmaceutical agents and enhance clinical decisions.

The guidance is still in the concept phase but could be ready in around 18 months. It will focus on the application of pharmacogenomics to pre-clinical and clinical studies to facilitate drug development and ensure the safety and efficacy of medicines. It will also address the use of pharmacogenomic data by physicians in clinical care.

Pharmacogenomics, which involves using genetic information to predict how a patient will react to a specific drug, could also be useful in "rescuing" drugs that might become unavailable due to adverse reactions, by promoting genotype-based prescribing¹. More than 5,000 adverse reaction notifications are reported in Cuba every year².

The pharmaceutical and biotechnology industries have embraced pharmacogenomics in recent years. By guiding and streamlining the drug development process, it promises substantive savings in costs, time and personnel. Published articles have noted that pharmacogenomics is likely to impact the drug approval process and regulatory environment; there are two such articles authored by the US Food and Drug Administration, for example^3,4.

However, few attempts in the literature consider the possible scenarios that might confront regulatory agencies as they increasingly incorporate pharmacogenomic-based drug development into regulatory decision-making processes. The guidance we are developing at CECMED, Cuba's National Centre for State Quality Control of Drugs, will aim to do this.

Regulatory agencies in the US and the EU have already developed guidelines on pharmacogenomics, as has the International Conference on Harmonisation. The World Health Organization is also following developments in the area. CECMED will take into account the experience of these agencies as it prepares its own guidance on pharmacogenomics, as well as various factors specific to Cuba. We will prepare the guidance according real conditions, taking into account the guidance and experience of other agencies.

The need for a guidance in Cuba

Cuba has one of the most proactive primary healthcare systems in the world. Vaccination rates in the country are among the highest globally, as is the percentage of births attended by skilled health workers⁵.

Pharmaceutical companies in Cuba manufacture prophylactic and therapeutic vaccines, interferon, cytokines and other biological products. In addition, Cuba produces more than 60 % of the generic drugs used in the country⁶.

The Cuban population has various genomic influences, from China, Spain and Africa. The country's main population phenotypes are white, black and mulato (ie of mixed black and white ancestry)⁷.

Cuba has been a pioneer in pharmacogenetic studies in Latin America; pharmacogenetics concerns variations in DNA sequences related to drug response. Projects currently in progress include investigating the characterisation of activities of the main cytochrome (CYP) enzymes in the Cuban population. Another study is assessing the characterisation of response by individuals to antiplatelet agents. In addition, a group of pharmacogenomicists is investigating new biological products using pharmacogenomic techniques. They are using pharmacogenomic markers for anticancer drugs, for example, and they are also looking at pharmacogenomic markers for specific diseases.

Studies already completed in Cuba include an analysis of the CYP2D6 genotype and phenotype (debrisoquine and dextromethorphan) relationship in the Cuban and Iberoamerican populations⁸. There have also been studies into the CYP2D6 genotype and phenotype (diclofenac) relationship in Cuban and Iberoamerican populations and into personality and pharmacogenetics in Cuban and Iberoamerican population (both studies are by Llerena et al, unpublished results). In addition, a study has been published on the relation between CYP2D6 phenotype, genotype and personality in healthy volunteers⁹.

Under consideration

In preparing the Cuban guidance, regulators are considering a number of points. These include the following:

• whether genomic data from animal studies are sufficient to be predictive of clinical (human) toxicity;
• whether applying toxicogenomics to the final candidate selection criteria just before commencing clinical trials might improve the risk management of clinical side effects;
• technical validations of the assays (variability and reproducibility) and approaches to data analysis;
• using pharmacogenetic attributes as inclusion/exclusion criteria;
• how to apply pharmacogenetic information in phase I/II for optimising phase II/III design;
• what proportions of study populations with defined genetic variants would be required for credible analysis and interpretation in clinical trials; and
• how the pharmacogenomic information should appear on the product label.

With regard to informed consent for collecting DNA for pharmacogenomic testing, the regulators are considering the following points:

• the information patients need to make informed decisions;
• the information concerning expected benefits or expected harm that should be disclosed to patients;
• the need for an individual participant's right to anonymity, privacy and confidentiality of DNA analysis to be addressed in a research agreement; and
• the need for particular attention to be paid to special populations, such as children and geriatrics patients, and to the influence of pharmacogenomics in these special populations.

The regulators are also discussing: how to balance risk-benefit optimally using pharmacogenomics; age range, race, and sex as co-variates in pharmacogenomic studies; and the need to provide and support training for researchers, doctors and others involved in pharmacogenomics.

With regard to this last point, there is a growing need to alert and prepare clinicians and healthcare providers for the arrival of pharmacogenomic diagnostic tools in the clinic. Without appropriate education, the lack of technical knowledge and awareness could obstruct the implementation of personalised medicine into medical practice for the Cuban population. Incorporating pharmacogenomics into clinical practice has the potential to improve efficacy and reduce toxicity, by allowing healthcare providers to choose the right drug for the right patient for the right disease at the right dose.

Pharmacogenomics in drug development holds great promise. Our regulatory agency should continue work on its proposed pharmacogenomics guideline according to the advances of this science in Cuba.

The authors gratefully acknowledged the support of Dr Lawrence J Lesko for his critical revision of this article.

References

1. R Shah Rashmi, Can pharmacogenetics help rescue drugs withdrawn from the market?, Pharmacogenomics, 2006, 7(6), 889-908

2. National register of adverse reactions, Cuba 2009, www.cdf.sld.cu

3. Goodsaid F and Frueh WF, Implementing the US FDA guidance on Pharmacogenomic data submissions, Environmental and Molecular Mutagenesis, 2007, 48: 354-358,

4. Lesko LJ and Woodcock J, Pharmacogenomic-guided Drug Development: Regulatory Perspective, The Pharmacogenomics Journal, 2002 2, 20-4

5. Policy Forum. Global Health. Fifty years of US Embargo: Cuba’s Health outcomes and Lessons, Science Magazine, 30 April 2010, www.sciencemag.org/content/328/5978/572.summary

6. World Health Organization, Statistical information System (WHO, Geneva, Switzerland, 2006), www.who.int/whosis/en/

7. National Census of Cuba, 2009

8. Gonz�lez I, Pérez B, Alvarez, Dorado P, Llerena A, Estudio farmacogenético del polimorfismo metab�lico de la debrisoquina (CYP 2D6) en la poblaci�n cubana en relaci�n con la española, Med Clin (Barc), 2007, 128, 20, 772-4

9. Gonz�lez I, Peñas-Lled� EM, Pérez B, Dorado P, Alvarez M, LLerena A, Relation between CYP2D6 phenotype and genotype and personality in healthy volunteers, Pharmacogenomics, July 2008, 9(7):833-40

Diadelis Remirez, PhD, and Deybis Orta, MD, are clinical reviewers at CECMED, Cuba's National Centre for State Quality Control of Drugs, where Yamira Pérez is a quality reviewer and Rafael Pérez Cristi�, MD, PhD, is director. Contact email: [email protected].