Summary of the 34th annual meeting of the Drug Information Association

A variety of issues relating to clinical aspects of drug development were discussed at the 34(th) annual meeting of the Drug Information Association. Among the topics covered at this conference were the following: 1, development of CNS compounds; 2, the Common Technical Document (CTD); and 3, labelling of drugs for use in pregnancy. Issues surrounding the development of CNS compounds were discussed by regulatory authorities from the USA and Europe. In almost all aspects covered, the regulatory requirements for approval in Europe appear to be consistent with those in the USA. Efforts aimed at developing a CTD are ongoing under the auspices of the ICH. The goal of this effort is to develop a common technical information package that can be submitted to regulatory authorities in the USA, the EU and Japan. It is recognised, however, that a number of sections of regulatory submissions will remain outside of the CTD. New initiatives in the labelling of drugs for use in pregnancy in the USA were reviewed. These efforts are being led by the Pregnancy Labeling Task Force of the USA FDA. The overall goal of this effort is to more clearly define by labelling, the relative risks of pharmaceutical agents that must be administered to pregnant women.     

Does the European Clinical Trials Directive really improve clinical trial approval time?

AIMS

To facilitate and improve clinical research within Europe, the European Union (EU) adopted in 2001 the Clinical Trials Directive (EUCTD). The aim of this study was to compare duration between submission of a clinical drug trial application and approval by regulatory authorities in EU countries regulated by EUCTD vs. EU countries regulated by local legislation and, second, to compare the duration of regulatory approval in Europe vs. the USA and Australia.

METHODS

Application for clinical drug trial initiation was submitted to the regulatory authorities of 14 European countries, to the USA and to Australia. In Europe, 10 countries were regulated by EUCTD and four by local legislation.

RESULTS

In Europe, the median duration of regulatory procedures was longer in EUCTD countries compared with countries following local legislation (75 vs. 59 days; P < 0.001). Five EUCTD countries had a time to approval of >60 days (maximum within EUCTD rules). The long duration of regulatory procedures was the consequence of (i) sequential instead of simultaneous submission of trial application to regulatory authorities, and (ii) involvement of local ethics committees in procedures that should be followed only by central ethics committees. The duration of regulatory procedures was similar in Australia (67 vs. 68 days, P = 0.388), but significantly shorter in the USA (67 vs. 15 days, P < 0.001).

CONCLUSIONS

In this early stage of implementation, EUCTD appears not to shorten the duration of regulatory procedures for clinical trial initiation. Furthermore, Europe lags behind the USA in speed of regulatory procedures.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The European Union adopted the European Union Clinical Trials Directive in 2001 to facilitate clinical drug research within Europe.
• The European Clinical Trials Directive has raised concerns over increased costs and complex administrative procedures, but the impact on duration between submission of a clinical trial application and approval by regulatory authorities is unknown.

WHAT THIS STUDY ADDS

• The introduction of the European Union Clinical Trials Directive appears not to shorten the duration of regulatory procedures within Europe.
• Duration of regulatory approval procedures is shorter in the USA compared with Europe.

     

Pixantrone for the treatment of aggressive non-Hodgkin lymphoma

Importance of the field: At present there is no standard treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma who progress following second-line therapy. Anthracyclines are highly active drugs, but their use in this setting is limited by cumulative cardiac toxicity. Pixantrone is a new aza-anthracenedione structurally similar to mitoxantrone and anthracyclines. This compound has been developed to minimize cardiac toxicity without reducing efficacy.

Areas covered in this review: This review summarizes the preclinical and clinical trial data for the use of pixantrone for the treatment of aggressive non-Hodgkin lymphoma.

What the reader will gain: An overview of the mechanism of action of pixantrone, preclinical data, clinical efficacy, safety data and future developments for this compound.

Take home message: Pixantrone has been shown to be superior to other single-agent therapies for the salvage treatment of relapsed/refractory aggressive non-Hodgkin lymphoma. The pixantrone application will be submitted to the regulatory authorities in the USA and in Europe.     

Regulatory aspects of oncology drug safety evaluation: Past practice, current issues, and the challenge of new drugs

The drug development of new anti-cancer agents is streamlined in response to the urgency of bringing effective drugs to market for patients with limited life expectancy. FDA's regulation of oncology drugs has evolved from the practices set forth in Arnold Lehman's seminal work published in the 1950s through the current drafting of a new International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) safety guidance for anti-cancer drug nonclinical evaluations. The ICH combines the efforts of the regulatory authorities of Europe, Japan, and the United States and the pharmaceutical industry from these three regions to streamline the scientific and technical aspects of drug development. The recent development of new oncology drug classes with novel mechanisms of action has improved survival rates for some cancers but also brings new challenges for safety evaluation. Here we present the legacy of Lehman and colleagues in the context of past and present oncology drug development practices and focus on some of the current issues at the center of an evolving harmonization process that will generate a new safety guidance for oncology drugs, ICH S9. The purpose of this new guidance will be to facilitate oncology drug development on a global scale by standardizing regional safety requirements.     

Natural-product-library-based screening for discovery of capsid C-terminal domain targeted HIV-1 inhibitors

Antiretroviral therapy (ART) can effectively suppress replication of human immunodeficiency virus type 1 (HIV-1) and limit disease progression. However, ART is unable to eradicate the virus, and the requirement for lifelong treatment may have side effects and may lead to the development of resistance. New approaches to prevent and treat HIV-1 infection should therefore be developed. HIV-1 capsid (CA) protein is an unexploited but attractive target for antiviral drug development. The hydrophobic cavity of the C-terminal domain of CA (CA CTD) has been validated as a potential target for antiviral drugs. Binding of compounds to this conserved non-polar groove in CA CTD allosterically disrupts the CA assembly. This study screened 2080 natural products to identify potential antiviral agents for further development to combat HIV-1 infection. From the primary screen at a fixed concentration of 50 µM, 16 compounds were found to be effective against this target. Six compounds observed in the primary screen were confirmed in dose–response experiments, and were tested against HIV-1-induced cytopathic effects. Two compounds were found to inhibit HIV-1 replication, and the most active compound – rubranol – inhibited viral replication at a moderate micromolar concentration (EC₅₀ = 15.85 μM). The binding modes of rubranol and hirsutanonol to CA CTD were analysed by molecular docking, providing insight for the design of drugs targeting HIV-1 CA. This study reports, for the first time, identification of natural products that showed potential as anti-HIV-1 agents by targeting the conserved hydrophobic cavity of HIV-1 CA CTD.     

Current and developing therapies for the treatment of non-small cell lung cancer with ALK abnormalities: update and perspectives for clinical practice

Introduction: The treatment of patients with ALK-rearranged non-small-cell lung cancer was completely revolutionized by the introduction of Crizotinib, a small molecule inhibiting ALK, MET and ROS1. Given that resistance occurs within approximately 12 months, in order to develop more potent inhibitors and to increase drug penetration to CNS, innovative ALK-inhibitors were developed. Second-generation ALK inhibitors Ceritinib (LDK378), Alectinib (CH5424802/RO5424802) and Brigatinib (AP26113) have shown significant clinical activity, and were rapidly approved by regulatory agencies. In addition, early clinical data demonstrated that 3^rd generation ALK-inhibitors Lorlatinib (PF-06463922), Entrectinib (RxDx-101) and Ensartinib (X-398) provided promising advantages in terms of both clinical activity and safety.

Areas covered: In this review, the efficacy and tolerability of Crizotinib for 1^st and 2^nd-line treatment, and the clinical and preclinical data that led to the development of innovative second and third generation ALK-inhibitors are described.

Expert opinion: The better characterization of the mechanisms of resistance to Crizotinib led to the development of newest drugs, which are active both after Crizotinib failure and in patients naïve from ALK-inhibitors. Tumor characterization at disease progression will allow to further personalize the treatment by establishing optimal sequences, which represent tough challenges for the future research in this field of cancer treatment.     

Workplace drug testing (WDT) likely to increase in Europe

Will it take a series of drug-related accidents that have already occurred in the USA before workplace drug testing (WDT) becomes accepted in Europe as a preventive measure? Currently, the development of WDT in most European countries lags some 10–15?years behind that in the USA. – Labour authorities in Europe now ought to take initiatives to demand a mandatory programme for accrediting drug analytical laboratories for WDT. – Companies should realise that illicit drug use is no longer only a problem at street corners, and that having a testing system in place is important, not just for public health, but also for their reputations as responsible societal actors. – Improved networking among police and regulatory authorities is required to keep pace with the rapid appearance and dissemination of new substances of abuse. – European research collaboration, including the newly formed European Workplace Drug Testing Group, is needed to assess the impact of drug-testing policies on accidents and other outcome variables, and thereby to convince the general public and politicians that drug testing is beneficial and necessary. – A 1993–1994 survey of quality analysis in some 200 European laboratories reported from Institut Municipal d'Investigació Mèdica (IMIM), Spain, showed good agreement between nominal and found concentrations but that only 10% of the laboratories could both screen, identify and quantify samples. – Experiences from Italy show that proficiency testing schemes lead to improved accuracy of results. These were some major conclusions of the First European Symposium on Drug Testing held at Huddinge University Hospital in Stockholm, Sweden, 30 March to 1 April 1998, organised by Karolinska Institute, with participants from 22 countries.     

国内外皮肤局部外用仿制药等效性评价对比

皮肤局部外用制剂的给药部位为皮肤表面,药物通过皮肤吸收发挥疗效,剂型繁多,其仿制药等效性评价方法也与口服制剂不同.通常,体内药代动力学研究是各监管机构最为认可的等效性评价方法,但大部分外用制剂难以通过此方法证明其等效性;以临床终点为指标的等效性研究是应用最广泛的等效性评价方法,然而此类研究成本高,周期长,且准确性、灵敏度和重现性均较差;针对特定的外用制剂品种,研究人员开发了血管收缩试验、体外BE研究等方法进行等效性评价,被各国监管机构广泛接受;对于外用水溶液制剂,通过理化性质等药学研究方法即可证明生物等效性.本文总结了中国、美国、日本、欧洲关于皮肤局部外用制剂仿制药生物等效性研究的相关法规及指导原则,对比四个国家或地区等效性评价的常规方法,为国内外用制剂仿制药的开发提供参考.     

Different Pharmaceutical Products Need Similar Terminology

In the last decade, discussions on the development of the regulatory framework of generic versions of complex drugs such as biologicals and non-biological complex drugs have attracted broad attention. The terminology used is far from harmonized and can lead to multiple interpretations of legal texts, reflection papers, and guidance documents regarding market introduction as well as reimbursement. This article describes the meaning of relevant terms in different global regions (Europe, USA, WHO) and offers a proposal for a globally accepted terminology regarding (non-) biological complex drugs.     

Models and screening assays for drug discovery in osteoporosis

Importance of the field: Osteoporosis affects nearly 100 million people in Europe, Japan and the US, and the number is increasing due to aging of the population. Preclinical efficacy studies performed according to regulatory guidelines are large, long and expensive, and there is a need for guidance and recommendations on how to perform preliminary studies prior to the regulatory studies. Areas covered in this review: We review research models that can be used for preclinical efficacy testing of new drug candidates for osteoporosis. Our focus is on testing compounds targeted to directly decrease osteoclastic bone resorption or increase osteoblastic bone formation. What the reader will gain: We provide an overview of in vitro bone cell culture systems and osteoporosis animal models useful for preclinical efficacy studies and a step-by-step approach on how the most interesting compound can be selected from thousands of drug candidates. Different approaches for testing anti-catabolic and anabolic compounds are provided. Take home message: Efficacy of new osteoporosis drug candidates can be first proven conveniently using in vitro bone cell cultures and then confirmed in short-term animal studies, followed by more extensive animal studies, and finally a regulatory study performed according to the guidelines of regulatory authorities.     

Dose individualisation in patients with renal insufficiency: does drug labelling support optimal management?

Objective An important information source for pharmacotherapy in populations at risk is drug labelling. We compared the recommendations for patients with renal insufficiency included in German drug labellings with evidence from the literature.Methods From the 120 drugs with the highest turnover in a large university hospital, all drugs with pharmacokinetics independent of renal function (n=48) and those with substantial accumulation in renal failure (n=28) were identified. For both groups of compounds, pharmacokinetic and pharmacodynamic aspects relevant for dose individualisation in those with renal insufficiency were extracted from the literature and compared with the information given in the German drug labelling.Results Over half of the labellings (15 of 26) of non-accumulating drugs without renal adverse drug reactions contained no dose recommendation for patients with renal insufficiency. The labelling of nephrotoxic compounds that do not accumulate included more frequently a recommendation to adapt the dose or to monitor than the labelling of drugs without nephrotoxic potential (15 of 22 versus 5 of 26, P=0.002). For over half of accumulating drugs (16 of 28), the dose given in the labelling depends primarily on creatinine clearance. The ratio between the labelling dose and the dose based on the pharmacokinetic concept to achieve identical plasma concentrations (Q ₀ concept) differed widely (0.4–2).Conclusions When renal failure had no impact on dosing, information was often missing. Such information is however important to differentiate, whether no dose adaptation is necessary or no information is available. If dose adjustment is required, application of a uniform concept is desirable.     

Designing drugs with multi-target activity: the next step in the treatment of neurodegenerative disorders

Introduction: Neurodegenerative diseases have had devastating effects on patients' quality of life. These complex diseases have several pathways that are affected to initiate cell death. Current therapies, designed to address only a single target, fall short in mitigating or preventing disease progression, and disease-modifying drugs are desperately needed. Over the past several years, a new paradigm has emerged which has as a goal the targeting of multiple disease etiological pathways. Such “multi-targeted designed drugs” (MTDD) have shown great promise in preclinical studies as neuroprotective agents, as well as being able to afford symptomatic relief to blunt the day-to-day burden of these illnesses.

Areas covered: In this review, the authors evaluate the use of chemical scaffolds that led themselves exquisitely to the development of MTDDs in central nervous system disorders. Some of the examples discussed have also transitioned into the clinic, which underscores the importance of pursuing drug discovery programs within the multifunctional arena.

Expert opinion: Currently, very little can be done to slow the progress of neurodegeneration. The multifaceted profile of neurodegeneration necessitates a change in paradigm toward the design of compounds that address several drug targets simultaneously. With successful compounds in clinical trials as well as compounds moving into the clinic, support is growing and the feasibility of this approach is now becoming recognized. This review shows that several small molecule scaffolds can be successfully utilized to design MTDD compounds with good CNS pharmacokinetics.     

Meeting Highlights: Central & Peripheral Nervous Systems: Summary of the 97th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics

The 97th annual meeting of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) was held on March 20 – 22, 1996. Lectures, symposia, and poster/slide presentations focused on both new compounds in early clinical development and novel findings with older marketed compounds. Attendees had the opportunity to listen to state-of-the-art lectures on four topics: 1) apoptosis as a mechanism of action of anticancer drugs; 2) structure-based drug design; 3) molecular biology of neurotransmitter uptake systems; and 4) present and future prospects for human gene therapy. In the evenings, workshops and meetings of scientific sections were held that focused on specific topics of interest to the members of ASCPT. The following is a summary of some of the poster and slide presentations made at the ASCPT meeting. Four broad general topics are covered in this summary: 1) studies performed with cytochrome p450 isozymes; 2) studies with new antimigraine compounds; and 3) studies with alpha-1 adrenergic blockers; and 4) general regulatory and drug development issues.     

A population-based case control study of congenital abnormalities and medication use during pregnancy using the Czech National Register of congenital abnormalities

The aim was to identify and quantify the association between the use of particular medications during the first trimester of pregnancy and selected congenital abnormalities (CAs) of newborns. Data were from the Czech National Registry of CAs. We used a case-control design, and collected total of 7285 cases and 9143 controls. Thiethylperazine and iron compounds had no effect on development of CAs. Lower odds ratio and potentially protective associations were found between CAs and bioflavonoids, folic acid, progesterone, levothyroxine, and iodine therapy. Since the protective effect of bioflavonoids was not described before, analysis of interaction with other drugs was performed. However, their protective effect was not confirmed and the strongest significant protective effect was detected in combination of bioflavonoids and progesterone. Increased odds ratio were identified for hydroxyprogesterone, phenoxymethylpenicillin, aspirin, paracetamol and valproic acid. The association between paracetamol and congenital foot deformities was not significant, while the same association for the whole group of CAs and deformities of musculoskeletal system had significantly increased odds ratio. Except newly described effect of bioflavonoids, our results are in agreement with risk categories defined by health authorities in USA and Australia, and with results of other studies. According to our results, paracetamol does not influence development of congenital foot deformities.     

Regulatory framework on bioequivalence criteria for locally acting gastrointestinal drugs: the case for oral modified release mesalamine formulations

Introduction: Bioequivalence testing for locally acting gastrointestinal drugs is a challenging issue for both regulatory authorities and pharmaceutical industries. The international regulatory framework has been characterized by the lack of specific bioequivalence tests that has generated a negative impact on the market competition and drug use in clinical practice.

Areas covered: This review article provides an overview of the European Union and United States regulatory frameworks on bioequivalence criteria for locally acting gastrointestinal drugs, also discussing the most prominent scientific issues and advances that has been made in this field. A focus on oral modified release mesalamine formulations will be also provided, with practical examples of the regulatory pathways followed by pharmaceutical companies to determine bioequivalence.

Expert commentary: The development of a scientific rationale to demonstrate bioequivalence in this field has been complex and often associated with uncertainties related to scientific and regulatory aspects. Only in recent years, thanks to advanced knowledge in this field, the criteria for bioequivalence assessment are undergoing substantial changes. This new scenario will likely result in a significant impact on pharmaceutical companies, promoting more competition through a clearer regulatory approach, conceived for streamlining the demonstration of therapeutic equivalence for locally acting gastrointestinal drugs.     

Learning the effects of psychotropic drugs during pregnancy using real-world safety data: a paradigm shift toward modern pharmacovigilance

The growing evidence on psychotropic drug safety in pregnancy has been possible thanks to the increasing availability of real-world data, i.e. data not collected in conventional randomised controlled trials. Use of these data is a key to establish psychotropic drug effects on foetal, child, and maternal health. Despite the inherent limitations and pitfalls of observational data, these can still be informative after a critical appraisal of the collective body of evidence has been done. By valuing real-world safety data, and making these a larger part of the regulatory decision-making process, we move toward a modern pregnancy pharmacovigilance. The recent uptake of real-world safety data by health authorities has set the basis for an important paradigm shift, which is integrating such data into drug labelling. The recent safety assessment of sodium valproate in pregnant and childbearing women is probably one of the first examples of modern pregnancy pharmacovigilance.     

Syntheses of novel N‐([18F]fluoroalkyl)‐N‐nitroso‐4‐methyl‐benzenesulfonamides and decomposition studies of corresponding 19F‐ and bromo‐analogues: potential new compounds for the 18F‐labelling of radiopharmaceuticals

N‐([¹⁸F]fluoroalkyl)‐N‐nitroso‐4‐methyl‐benzensulfonamides [n‐alkyl = (?CH₂)[^18,19F]F, n=2–4)] were synthesized in radiochemical yields ranging from 75–90% to provide new secondary labelling precursors for the syntheses of ¹⁸F‐labelled compounds. Preliminary decomposition studies utilizing the corresponding non‐radioactive ¹⁹F‐compounds as well as the bromo containing analogous compounds were performed to evaluate their stability regarding temperature and basicity of the labelling medium. Furthermore, initial difficulties in labelling these compounds led to the development of a modified labelling procedure applying nearly solvent‐free conditions. Extensive decomposition experiments of the new fluoro‐ as well as the bromo‐compounds were conducted under various conditions in order to get experimental data about their stability and reactivity. As a result, different trends for the stability of the bromo as well as the fluoro compounds could be observed. Copyright © 2003 John Wiley & Sons, Ltd.     

Models and screening assays for drug discovery in osteoporosis

Importance of the field: Osteoporosis affects nearly 100 million people in Europe, Japan and the US, and the number is increasing due to aging of the population. Preclinical efficacy studies performed according to regulatory guidelines are large, long and expensive, and there is a need for guidance and recommendations on how to perform preliminary studies prior to the regulatory studies.

Areas covered in this review: We review research models that can be used for preclinical efficacy testing of new drug candidates for osteoporosis. Our focus is on testing compounds targeted to directly decrease osteoclastic bone resorption or increase osteoblastic bone formation.

What the reader will gain: We provide an overview of in vitro bone cell culture systems and osteoporosis animal models useful for preclinical efficacy studies and a step-by-step approach on how the most interesting compound can be selected from thousands of drug candidates. Different approaches for testing anti-catabolic and anabolic compounds are provided.

Take home message: Efficacy of new osteoporosis drug candidates can be first proven conveniently using in vitro bone cell cultures and then confirmed in short-term animal studies, followed by more extensive animal studies, and finally a regulatory study performed according to the guidelines of regulatory authorities.     

Abuse-Deterrent Formulations, an Evolving Technology Against the Abuse and Misuse of Opioid Analgesics

The increased use of opioid pain medication has been mirrored by the increased misuse and abuse of these drugs. As part of a multidisciplinary approach to this epidemic, pharmaceutical companies, with the encouragement of the Food and Drug Administration, have increased the development of abuse-deterrent formulations. While all have the goal of treating pain while mitigating misuse and abuse, there are different technologies utilized to impart the abuse-deterrent properties. The goal of this paper is to review the basis of abuse-deterrent formulations, the different types and approaches of some of the abuse-deterrent products, and their current regulatory status in the USA.     

Risk management strategies in the Physicians' Desk Reference product labels for pregnancy category X drugs.

BACKGROUND: Drugs that carry a concern for teratogenicity are often classified as pregnancy category X in the drug label and contraindicated for use during pregnancy. Many drug labels can be found in the Physicians' Desk Reference (PDR), a widely used source of drug information by American clinicians and patients. OBJECTIVE: To review product labelling in the electronic PDR for the pregnancy category X products for pregnancy prevention risk management components in labelling. METHODS: The electronic version of the 2001 and 2002 PDR was searched for 'pregnancy category X' products using the full text search feature. All product labels identified were retrieved and reviewed for trade name, generic name, manufacturer and indication. Product labels were manually searched for any pregnancy prevention risk management strategies included in labelling. Those labels that had specific pregnancy prevention risk management strategies were further evaluated. RESULTS: One hundred and seventeen pregnancy category X products were obtained from 2249 products searched in the 2001 PDR database and 124 pregnancy category X products were obtained from the 2150 products in the 2002 PDR database. All pregnancy category X products identified were drug products. The label/package insert for each drug was reviewed to identify risk management strategies for pregnancy prevention. The majority of the labels include as the sole risk management strategy either a black box warning and/or a contraindication for use in women who are or may become pregnant. Only 13 drugs contained specific pregnancy prevention risk management strategies in the label directing the clinician and/or patient, e.g. frequency of pregnancy testing, number and type of contraception methods. Two drugs, bexarotene capsules and gel, were only included in the 2001 PDR. Three drugs, isotretinoin, acitretin, and thalidomide, have formal pregnancy prevention risk management programmes. CONCLUSION: This study demonstrates the varied risk management approaches in labelling for pregnancy prevention for pregnancy category X drugs. There is a need for consistency in the classification of pregnancy category X products and the pregnancy prevention risk management strategies utilised in the labelling for them.