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The European Medicines Agency ("EMA") has released their report giving detailed information regarding numbers of patients, sites and inspections with respect to pivotal clinical trials submitted in marketing authorization applications ("MAA") between January 2005 and December 2011.

As we noted in a previous blog there has been an increase in concern amongst regulators and the public about how well clinical trials are conducted from an ethical and scientific/organizational standpoint, and especially with regard to good clinical practice ("GCP") compliance. An applicant has to provide information in every MAA regarding the location, conduct and ethical standards applied in respect of the clinical trials conducted in third countries.

Written by Howard E. Rosenberg, Ph.D.

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The report relates mainly to new applications (485), line extensions (95), and variations where new clinical trial information was provided (97). Generic applications are included as part of the new applications, but they generally do not add much to the number of patients, because these applications are mainly based on small bioequivalence trials, but they do provide information on the locations where these trials were conducted.

For some time now, there have been strident calls for the publishing of all clinical trial data. The pressure has arisen due to revelations that companies may have hidden crucial clinical data that might have shown that the drug being tested was not as efficacious or even as safe as they appeared from quoted trial results (see, for instance, a previous blog here). The campaign group AllTrials has brought together several people and groups (including for example David Tovey, editor The Cochrane Library; Ben Goldacre (book Bad Pharma); Carl Heneghan, Centre for Evidence-Based Medicine, University of Oxford) because, as they put it:

Around half of all clinical trials have not been published; some trials have not even been registered. If action is not taken urgently, information on what was done and what was found in trials could be lost forever, leading to bad treatment decisions, missed opportunities for good medicine, and trials being repeated unnecessarily.

Key publications like the British Medical Journal and research bodies such as the Medical Research Council and the Wellcome Trust agree, the trust encouraging its grant recipients to release their trial data.

Written by Howard E. Rosenberg, Ph.D.

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The European Medicines Agency ("EMA") has been looking at this for some time, with the same aim in mind and is trying to develop a workable policy to enable the data to be published. Indeed it is thought that in the next few weeks, major players in the United Kingdom's medical community will meet to try and take things further in a more practical manner.

Purchasing of pharmaceuticals through on-line pharmacies is on the rise and gives rise to many potential problems. Crucially the most important issue is whether the medicinal product is genuine, contains the correct ingredients, and is an approved product in the relevant regulatory jurisdiction. Medicines supplied via on-line links can come from anywhere in the world, and this method of distribution is more open to fraudulent activity.

In Europe, the European Parliament passed Directive 2011/62/EU, which relates to medicinal products for human use, and is in regard to the prevention of the entry into the legal supply chain of falsified medicinal products. The European Commission ("EC") has put some thought into how on-line pharmaceutical purchases can be made safe and to comply with the Directive. To that end, they have released a Concept Paper for public consultation on the introduction of a "common logo" for websites of legally-operating
on-line pharmacies/retailers.

Written by Howard E. Rosenberg, Ph.D.

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The requirements are that the logo is recognizable throughout the EU and identifies the Member State in which the on-line pharmacy/retailer is established. There is also an obligation for each Member State to set up a dedicated website providing a national list of all legally-operating on-line pharmacies/retailers. The entries in these lists must have a hyperlink to the respective on-line pharmacies/retailer's website and a reciprocal link from the logo on the on-line pharmacies/retailer's website back to the national list. The point being that a customer can go to either the national list to find approvable pharmacies and vice versa to the on-line pharmacies/retailer's website and link back to the national list via the logo thus assuring authenticity.

Whenever an applicant wishes to register their follow-on medicinal product, be it a generic product or a biosimilar, the applicant has to include in their dossier a comparison between the newly-developed product with a previously-approved and registered medicine. For "standard" generic products evidence, such as the approved product's dosage form, strength, excipient and content can be obtained from published information and further "proof" is generated by such things as dissolution profiling and bioequivalence studies. However, there is always a question as to whether the comparison product (usually the originator's product) is the same internationally. For example, it is possible that the same active ingredient in the same dosage form could have been formulated differently from country to country, either as a result of differing timing of the drug's development and launch or on purpose to create artificial barriers, such that the follow on products will be more complex to develop. Of course, the difficulty of having what outwardly appears to be the same product, but inwardly is significantly different, creates potentially dangerous problems for both doctors and patients. Clearly, if a patient travels across borders and needs to refill their prescription, it could result in real problems, if the apparent same drug and dosage form act differently biologically.

Health authorities around the world now work much more closely together and confidential information about their registered and approved products can be passed between them, such that differences in formulations that affect bioavailability would be available to them and thus will be alert to possible issues. For a company making a follow-on product, however, this information is not available. As a result, companies wishing to make a generic product have to carry out extra studies as outlined above to investigate the differences from country to country and carry out bioequivalence studies against a local reference product.

Written by Howard E. Rosenberg, Ph.D.

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Biological medicines are medicines that are made by or derived from a biological source. They can consist of relatively small molecules, such as human insulin or erythropoietin, or complex molecules, such as monoclonal antibodies. Biosimilar products are, thus, far more complex and need far more studies to show similarity, requiring a large number of clinical trials, as opposed to the bioequivalence studies that generic products undergo. Given the difficulty in developing, testing and registering new biological, it may well be that, unlike non-biological medicines, biological products may well be the same product internationally.

The Pediatric Committee ("PDCO") of the European Medicines Agency ("EMA") is tasked with identifying the needs for children in a variety of therapeutic areas and aims to encourage the research and development of pediatric medicinal products. The first Inventory, which is now open for discussion and public consultation, covers medicines for cardiovascular diseases. The EMA points out that it will be releasing similar lists for other therapeutic areas for public consultation during 2012 and 2013.

According to the EMA, the Inventory aims to enable:

• Companies to identify opportunities for business development;

• The PDCO to judge the need for medicines and studies when assessing draft pediatric investigation plans, waivers and deferrals; and

• Healthcare professionals and patients to have an information source available to support their decisions as to which medicines.

Written by Howard E. Rosenberg, Ph.D.

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The Inventory is based on a report on the survey of all pediatric uses of medicinal products in Europe completed by the PDCO in December 2010.

On August 2, four members of the House of Representatives, led by Congressman Edward Markey, introduced, H.R. 6272, "The Trial and Experimental Studies Transparency (TEST) Act of 2012." The TEST Act will amend Section 402(j) of the Public Health Service Act, tightening the reporting requirements for the Internet site designed to better inform the public about ongoing and completed clinical trials in the United States, ClinicalTrials.gov. The main goal of the TEST Act is to prevent clinical-trial sponsors from withholding negative study data and safety concerns while emphasizing the positive results of their clinical trials.

Prior to the proposed TEST Act, under the Food and Drug Administration Amendments Act of 2007 ("FDAAA"), most United States-conducted interventional clinical trials were registered at ClinicalTrials.gov, and most of the results of those clinical studies were eventually published. However, loopholes in the requirements of the FDAAA resulted in clinical studies that were either not registered, that failed to report results, or both. There are a number of clinical trials, therefore, that are not registered in the publically-accessible database.

Written by Julie E. Kurzrok

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The TEST Act will require all interventional biomedical studies conducted on humans to be registered on ClinicalTrials.gov prior to enrolling any patients. In addition, sponsors of these clinical trials will be required to post the study results and other required information on ClinicalTrials.gov within one year of the completion date of the trial. According to the proposed legislation, interventional studies include all human studies where patients are assigned, via protocol, by an investigator to receive specific intervention where the effects of such intervention on biomedical or health-related outcomes are evaluated. For clinical trials involving drugs or medical devices that have never been approved for any use, the TEST Act permits a delayed results submission of up to two years from the date of completion of the clinical trial.

On July 2, the much heralded new European Pharmacovigilance legislation came into operation. This new piece of legislation is aimed at promoting and protecting public health by strengthening the existing Europe-wide system for monitoring the safety and benefit-risk balance of medicines and provides regulators with a range of new or improved tools to ensure that patients are not exposed to unnecessary risks when taking medicines.

Highlights of the new legislation include:

• The establishment of a new scientific committee, the Pharmacovigilance Risk Assessment Committee ("PRAC").


• A clarification of the roles and responsibilities leading to more robust and rapid European Union ("EU") decision-making.


• The engagement of patients and healthcare professionals in the regulatory process.


• An improved collection of key information on medicines, e.g., through risk-proportionate, mandatory post-authorization safety and efficacy studies.


• More transparency and better communication.

Written by Howard E. Rosenberg, Ph.D.

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The first meeting of the new key committee, PRAC, will be on July 19 and 20, 2012. PRAC's mandate includes, among other things, "All aspects of the risk management of the use of medicinal products including the detection, assessment, minimization and communication relating to the risk of adverse reactions, having due regard to the therapeutic effect of the medicinal product, the design and evaluation of post-authorization safety studies and pharmacovigilance audit".

by Howard E. Rosenberg, Ph.D.

The general public's expectation for transparency in the regulation and assessment of the safety of medicines is characterized by the number of Freedom of Information Act ("FOIA") requests to FDA asking for detailed information regarding this data and the multitude of blog articles covering this subject matter. To some extent, public postings on FDA's website, particularly Drugs@FDA, has quelled the need for some FOIA requests. In Europe there is the same public pressure and an increasing trend for the release of information contained in the Marketing Authorization Applications ("MAAs") after they are granted. For example the release of clinical and safety data is regularly requested.

Feedback from initial European proposals found that in general the pharmaceutical industry had concerns regarding the release of contractual arrangements between companies, personal data of experts, and clinical and non-clinical data. Pharmaceutical companies also raised special concerns with regard to the disclosure of non-clinical data, while the release of clinical data was supported by most stakeholders.

The European Medicines Agency ("EMA") and the Heads of Medicines Agencies ("HMA") have now adopted a joint guidance document, providing, for the first time, a consistent Europe-wide approach to the identification of commercially-confidential information and personal data in a MAA. This "major step for transparency," will apply in the future to identify which parts of an application dossier can or cannot be released in response to requests throughout the regulatory authorities in the European Economic Area ("EEA"). This policy applies regardless of whether the product concerned was authorized using the centralized, mutual recognition or decentralized procedures.

by Howard E. Rosenberg, Ph.D.

Late last year, the European Medicines Agency ("EMA") published a new guideline, "Guideline on the use of pharmacogenetic methodologies in the pharmacokinetic evaluation of medicinal products" to provide a framework for where it is recommended that pharmacogenetics should be implemented in the drug development process. At the same time, the guideline recognizes that pharmacogenetics may not be equally important for every drug.

Patients are not all identical and different individuals may well react to a particular medicine in diverse ways. For example the manner in which a patient absorbs and/or metabolizes a particular drug may well differ form one to another. In recent years there has been a rapid development in the understanding of the influence of genes on interindividual differences in drug action. Hence the pharmacokinetics of many medicinal products is prone to interindividual variability, caused by several factors such as gender, age, weight, impaired renal and hepatic function, and genetics.

In the field of pharmacogenetics, interindividual variability in genes influencing or predicting the outcome of drug treatment (e.g., genes encoding drug transporters, drug metabolizing enzymes, drug targets, biomarker genes) is studied in relation to efficacy of drug treatment and adverse drug reactions. A knowledge of genetic factors influencing absorption, distribution, metabolism and excretion ("ADME") is centered on drug metabolism. Genetic variations in metabolizing enzymes may lead to: (i) increased or decreased clearance of the parent drug or pharmacologically active or toxic metabolites, (ii) increased or decreased production of active metabolites of the respective prodrugs, or (iii) increased or decreased formation of toxic products.

by Howard E. Rosenberg, Ph.D.

The European Medicines Agency ("EMA"), together with the European Member States and the European Commission, is preparing for the introduction of the new pharmacovigilance legislation in July this year. The new legislation (Directive 2010/84/EU and Regulation (EU) No. 1235/2010) amending existing legislation was adopted in the European Union ("EU") in December 2010. The legislation aims to promote and protect public health by strengthening the Europe-wide system for monitoring the safety and benefit-risk balance of medicines.

The new legislation is designed to strengthen the procedures for the submission of risk management plans and periodic safety update reports ("PSURs") to the EMA. Currently companies submit a risk management plan at the time of application for a marketing authorization. The plan includes information on how the medicine will be monitored for safety during its lifetime and describes risk minimization activities. PSURs provide an evaluation of the benefit-risk balance of a medicine and these are submitted at defined periods during the post-authorization phase. This month the EMA will be publishing draft good pharmacovigilance practice ("GVP") modules for both risk management plans and PSURs for consultation.

The legislation provides for a new approach to the use of post-authorization safety and efficacy studies ("PASS" / "PAES") and implementation will also begin in 2012. A PASS is a study of an authorized medicine which identifies, characterizes or quantifies a safety hazard, confirms the safety profile of the medicine, or gauges the effectiveness of risk management measures during its lifetime. A PAES aims to clarify the efficacy for a medicine on the market including efficacy in everyday medical practice. The information obtained in the studies is to support regulators in decision-making on the safety and benefit-risk profile of a medicine. Like the other GVP modules above a PASS module will also be published for public consultation in February 2012. The scientific guideline for public consultation on PAES will be published by the EMA during the year.

by Howard E. Rosenberg, Ph.D.

Three more Supplementary Protection Certificate ("SPC") cases were decided by the Court of Justice of the European Union ("CJEU") recently underlining and further enhancing the decisions in the two cases Georgetown and Medeva, which we previously reported on here.

In Case C 630/10, the University of Queensland owned three patents but had been unable to get any SPCs at the United Kingdom's Patent Office. The UK Patent Office rejected all the SPC applications submitted, either because: (1) the combination of active ingredients in question were not claimed in the patents concerned or (2) the Marketing Authorizations ("MAs") provided in support of the SPC applications related to medicinal products containing other active ingredients that were not claimed in any of those patents, even though the applications related to individual active ingredients that were claimed in the patents concerned. The patents related to methods of production of papillomavirus-like particles ("VLPs") of the Human papillomavirus ("HPV") Type 6 ("HPV 6") and Type 11 ("HPV 11"), the VLPs per se and vaccines produced from or comprising VLPs.

As in Medeva, the first set of questions were answered by first restating that Article 3(a) of the regulation precludes the grant of an SPC relating to active ingredients that are not specified in the wording of the claims of the basic patent (Medeva, paragraph 25). Next, the CJEU stated that Article 3(a) of Regulation No. 469/2009 must be interpreted to preclude the competent industrial property office of a Member State from granting a SPC relating to active ingredients that are not identified in the wording of the claims of the basic patent relied on in support of the SPC application.

by Howard E. Rosenberg, Ph.D.

These cases concerned attempts at obtaining Supplementary Protection Certificates ("SPCs") for multi-component vaccines. Health Authorities prefer to administer several vaccines combined rather than to have them administered separately. The Medeva case (C-322/10) involved a vaccine comprising multiple active ingredients of which only two were the subject of a combination patent. As a consequence an SPC for this multi-component vaccine was refused, because the patent did not claim the additional active ingredients. SPC protection for a combination of the two active ingredients of the multi-component vaccine that were claimed in the patent was also refused in the United Kingdom, because the marketing authorization ("MA") was granted not for a medicinal product containing the combination of these two active ingredients only, but for the multi-component vaccine comprising other active ingredients.

The Georgetown case (C-422/10), was similar but had only one active ingredient, i.e., the basic patent claims an antigen of a vaccine, whereas the marketing authorization is for a multi-antigen vaccine, including additional antigens beyond the claimed ones. The cases were combined initially at the Court of Justice of the European Union ("CJEU") and were joined for the purposes of the oral procedure and the judgment, but the court decided that in view of the factual differences between the situations at issue in the main proceedings the cases were disjoined for the purposes of the judgment. In both cases the court felt that for a "product" covered, as a medicinal product by a MA, the essence of the SPC Regulation did not in itself rule out the possibility that the MA may cover other active ingredients contained in such a medicinal product and that in accordance with Article 4 of Regulation an SPC was intended to protect the "product" covered by the MA, not the medicinal product as such.

Thus the court's decision: Article 3(b) of Regulation (EC) No 469/2009 of the European Parliament and of the Council of 6 May 2009 concerning the SPC for medicinal products must be interpreted as meaning that, provided the other requirements laid down in Article 3 are also met, that provision does not preclude the competent industrial property office of a Member State from granting a SPC for an active ingredient specified in the wording of the claims of the basic patent relied on, where the medicinal product for which the marketing authorization is submitted in support of the SPC application contains not only that active ingredient but also other active ingredients.

by Howard E. Rosenberg, Ph.D.

The European Commission has updated its proposals with regard to the product information available to patients. Unlike in the United States, pharmaceutical companies in Europe cannot advertise their wares direct to the public, nor can they make claims about a medicine without clearance from Health Authorities and even then only in acceptable formats. The Commission's initial 2008 proposals have been updated to incorporate the European Parliament's amendments, the emphasis being on the rights and interests of patients.

The European Commission's press release explains "that patients are increasingly interested in learning more about the medicines they take and want more of a say in how they are treated. At the same time, patients are confronted with a growing volume of information from various sources and often find it difficult to identify reliable information about medicines. The increased use of the internet over recent years makes the need for clarity even more important. Online information on medicines must be accurate and reliable."

Some key elements of the amended proposals are:

1. Only certain information on prescription-only medicines will be allowed, e.g., information on label and package leaflets, prices, pre-clinical tests and clinical trials of the medicine concerned and on the instructions for correct use.
2. Only certain channels of communication will be allowed for providing information, e.g. via officially registered internet websites or through printed information provided this has been specifically requested by members of the public.

by Howard Rosenberg

The MHRA announced yesterday in a press release that the first ever children's medicine to hold a Paediatric Use Marketing Authorization (PUMA) had been granted by the European Commission.

For many years it has been recognized that medicines are generally developed and designed for adults with their use in children coming as an after thought. In an effort to get around this problem incentives have been developed in many countries for new medicines to be tested for acceptability in children either at the time of submission for regulatory approval or within certain time scales. The incentives generally increased the new product's patent life and/or added a data exclusivity period to slow down generic entry. However, for old medicines with no intellectual property cover there was a need to find some way to encourage the research and development of formulations acceptable to children and to incentivize companies to make these products available.

The MHRA has been pushing for an increase in the availability of specific children's only medicines for several years, particularly as in general many adult medicines are offered to children only as cut-down doses.

By Howard Rosenberg

Last week saw five reported cases of other manufactures' drugs being found in Nurofen Plus packets. The anti-psychotic Seroquel XL had been found in four packets of Nurofen Plus in England and Neurontin, a prescription medicine for epilepsy, had been found in one packet of Nurofen Plus bought from an independent pharmacist in Northern Ireland.

As a consequence Reckitt Benckiser (UK) has now stopped the manufacturing of Nurofen Plus and its distribution has been halted across the UK.

Reckitt Benckiser, recalled the product on Friday night and halted distribution after discovering the issue. The firm estimated 250,000 packets were in customers' hands.
Dr Aomesh Bhatt, medical director for Nurofen Plus said: "We are taking this matter extremely seriously and have decided to recall all packs of Nurofen Plus as the most prudent course of action in the current circumstances."

The UK's health authority, Medicines and Healthcare products Regulatory Agency (MHRA) has issued a class 1 drug alert to healthcare professionals, including General Practioners (GPs).