Everyone in the health care industry is going to be affected, one way or another, by the major shake-up being planned by the European Union (EU) for rules on drug marketing. The proposals, which indicate clearly the direction in which the European Commission in Brussels is moving, are also in due course likely to be applied to the Medical Device Directives. They range widely from marketing authorizations to intellectual property rights, from advertising to generic competition. They cover health protection, completion of the EU internal market, boosting industry competitiveness and meeting the challenges of globalization and of taking on new member states during the coming decade.
The commission will be publishing and pushing through a package of three new proposals over the next year or so:
A draft regulation on marketing authorizations and the functioning of the European Agency for the Evaluation of Medicinal Products (EMEA; London).
A draft directive on medicinal products for human use.
A draft directive on veterinary medicinal products.
Innovative products are likely to benefit particularly, with new marketing authorization options becoming available for products showing significant therapeutic, scientific or technical innovation, or where authorization is demonstrably beneficial to EU patients. Applicants will be able to request an accelerated assessment procedure in which the normal 210-day period for processing is reduced to 150 days. There will also be conditional authorizations, valid for one year at a time, for innovative products for which data are still being gathered. In addition, the new rules will allow marketing of medicines for compassionate reasons, even before authorization.
Under the new regulations, the EMEA will be able to offer a wider range of advice to companies, especially regarding the development of new therapies, and covering the conduct of trials and tests to demonstrate quality, safety and efficacy, particularly with regard to GMP compliance. It will be able to help companies submitting applications for products with only a limited market, by taking responsibility for some translations, for instance. Additionally, each EMEA committee will have to set up a standing working party with the sole remit of providing scientific advice to companies.
The processing of marketing applications will be sped up in a number of ways. For example, once the commission has reached a draft decision on an application through the centralized procedure, member states will only have 15 days to submit written observations, instead of 28 days today. Where there is a disagreement between the commission and the EMEA regarding a marketing authorization, it must be resolved in 30 days, as compared to three months at present. Companies will no longer have to renew their authorizations every five years; they will remain valid indefinitely. There are also numerous ways in which the mutual recognition system is to be tightened up, with shorter time limits in almost every case.
Although companies will receive a standard 10 years of data protection after product authorization, they can get an 11th year of protection if they gain approval for a new application. On the other hand, conducting necessary tests and trials for a generic medicinal product will not be regarded as an infringement of patent-related rights or of supplementary protection certificates for the products being copied, so that generic suppliers will be able to prepare their copies for launch immediately on patent expiry of the original.
Almost everything has a flip side too, so the commission's proposals also include some new constraints on industry. The EMEA will be able to require companies to provide "all information" on sales or prescription volumes and to inform the EMEA of the dates of actual marketing of the product and of withdrawal from the market in the event it ceases to be sold. The commission will, for the first time, be able to impose financial penalties if companies fail to observe obligations listed in marketing authorizations. When a product previously authorized is no longer actually marketed for two years, the market authorization will automatically lapse.
The role of the EMEA is to be expanded to include supervision and pharmacovigilance. Companies will have to record and report all suspected serious adverse reactions no later than 15 days from receipt of information, and the EMEA is to make adverse reaction information available via a permanently accessible database to all member states, alongside appropriate pharmacovigilance information to the public. Interim precautionary decisions can be taken immediately by the EU (instead of within two weeks) where there are doubts regarding product quality or safety. A final decision must be taken within six months.
Information on certain product groups for chronic diseases – including AIDS, asthma and chronic bronchopulmonary disorders, as well as diabetes – can be made available direct to the public, but under strict conditions and to respond to expectations expressed by patient groups. This will probably require the setting-up of self-regulatory procedures by the pharmaceutical industry at member state level.
Debate on these proposed regulations and directives will move from European level (European Commission and European Parliament) to national level and back again, and some of the technical details associated with them are likely to be changed. Health care technology marketing will undoubtedly change in Europe as a result.
Men may get the Pill too
Hormonal oral contraceptives for men are now undergoing clinical trials. If those trials produce satisfactory results, a Pill for men should then become available for those who want it. Two European drug companies, Organon (Oss, the Netherlands) and Schering (Berlin, Germany), are developing this male contraceptive pill.
It has taken years of research to balance the twin basic requirements of switching off sperm generation while at the same time maintaining libido. Richard Anderson and his group at the Human Reproductive Sciences Unit (Edinburgh, Scotland) have been running a small-scale clinical trial on 66 men in Edinburgh and Shanghai, China, using a male pill taken once a day together with a balancing injection once every three months. The pill contains a synthetic hormonal gestogen which shuts off production in the brain of molecules which stimulate the gonads. To counterbalance the resultant fall in testosterone levels, the participants receive an injection of a slow-release testerone derivative.
First results are impressive. All volunteers stopped producing sperm within four months of starting the trial and there were no pregnancies among their partners. Their sperm counts returned to normal within four months of stopping the treatment. Short-term side effects included acne, mood swings and weight gain and were experienced by a number of the volunteers. Organon is taking Anderson's trial results forward with a 120-man trial currently under way, with results expected next spring.
Schering is collaborating with Eberhard Nieschlag's group at the Institute of Reproductive Medicine at the University of Munster (Munster, Germany) and has already started clinical trials using injectable hormones. Both the Scottish and German researchers are aiming to refine their approaches using better testosterone derivatives and new alternatives to the gestogens with all their side effects. There are even rumors that the two companies may decide to cooperate on the project. Although male tolerance of complications like three-monthly injections or side effects seems likely to make a male hormonal contraceptive a hard sell, surveys of 5,000 people in Scotland, China and South Africa suggest that over half of the men polled would use a male oral contraceptive, and just as important, only 2% of the women questioned would not trust their partners to take it.
A number of other laboratories are studying more sophisticated methods of suppressing male fertility than just flooding the body with hormones. Trevor Cooper at the University of M nster is focusing on whether a drug can be developed which will prevent sperm traveling down the epididymis, a long tube leading from the testes, while David Clapham and his group at the Harvard Medical School (Boston, Massachusetts) are working to develop a drug to block the action of a protein called CatSper. Absence of this protein, which is only found in sperm, results in sperm moving only sluggishly so that they are unable to pierce the zona pellucida in order to fertilize the egg.
Vaccines are also being investigated by several groups, with John Herr and his team at the University of Virginia (Charlottesville, Virginia) scanning the human genome to locate suitable gene sites. They have already located more than a dozen genes and their associated proteins that are active in the latter stages of sperm or egg life. Herr is ready to begin human trials of a vaccine against LDHC4, a protein found in sperm. In female baboons, this reduced fertility by 70%. By combining LDHC4 with other newly isolated sex-cell proteins, the group hopes to develop a vaccine that will improve this rate to near 100% when used in women.
European Forum for Cancer Research
In early summer, Research Commissioner Philippe Busquin of the European Commission in Brussels, Belgium, held a meeting at which leading cancer researchers, clinicians and research managers from 27 countries discussed how to improve coordination of European cancer research and surveillance. A result of the meeting has been the creation of a Europe Forum for Cancer Research under the auspices of the European Commission.
A number of promising innovations are arising from EU-funded projects including markers for screening and noninvasive diagnosis, and anticancer gene therapy.
Biomed 2 is a project that aimed to improve breast biopsy by combining a minimally invasive technique called percutaneous breast biopsy with highly sensitive detection of small non-palpable breast lesions using magnetic resonance imaging. Siemens Medical Solutions (Erlangen, Germany) was a major contributor to the project, which also developed as an offshoot a new method of reducing the risk of cancer cell dissemination to surrounding tissues during biopsy.
Photocure (Oslo, Norway) has obtained Swedish marketing approval for its Metvix PDT aminolevulinic acid derivative-based photodynamic therapy in the treatment of actinic keratosis (AK) and basal cell carcinoma (BCC). Therapy consists of an application of Metvix cream which is absorbed into the cancer cells, followed by photoactivation of the drug by Curelight, Photocure's light source. There are an estimated 2 million new cases of BCC globally each year, as well as 20 million cases of AK. Metvix is currently under review in the rest of the European Union, Iceland, Norway and Australia.
Cervical cancer screening is failing to control disease in many developing countries, according to a study just published in the Bulletin of the World Health Organization (Geneva, Switzerland). Cervical cancer incidence and mortality has fallen substantially in recent years in most industrialized countries, arguably as a result of efficient screening programs involving a cervical smear test. But at least 7 to 10 per 100,000 at-risk women die each year in developing countries, according to the study.
Many screening programs in "middle-income" countries have the "unrealistic notion" of very frequently repeated screening tests – once a year – that target a wide age range (e.g., 20-65 years) of women, the study says. "It is more realistic and effective to target high-risk women (e.g., 35-49 or 30-50 years) with a good quality and highly sensitive test once or twice in their lifetime." Even a once-in-a-lifetime test can yield a reduction of 25% to 30% in incidence, said Dr. Rengaswany Sankaranarayanan at the International Agency for Research on Cancer (Lyon, France).
KS Biomedix (Guildford, England) reported that the FDA has granted fast-track status to the company's lead oncology product, TransMID-107R, for the treatment of adult recurrent inoperable high-grade gliomas. Based on the transferrin-mediated delivery of a diptheria toxin that is capable of selectively killing tumor cells, TrnsMID-107R has already produced positive results in Phase I and II trials. A pivotal Phase III clinical trial is slated to commence this year.
Stephen Powell, CEO of KS Biomedix, said, "We are delighted that the FDA has decided to grant fast-track status to TransMID-107R ... the positive response by the FDA underscores the value of TransMID-107R for the treatment of this highly aggressive form of brain cancer."
Mental/neurological disorders affect 450M
In a new report titled "New Understanding, New Hope," the World Health Organization (WHO) aims to help people with mental disorders around the world. "Mental illness is not a personal failure. In fact, if there is failure, it is to be found in the way we have responded to people with mental and brain disorders," said Gro Harlem Bruntland, WHO Director-General. "I hope this report will dispel long-held doubts and dogma and mark the beginning of a new public health era in the field of mental health."
Depressive disorders are already the fourth-leading cause of the global disease burden. They are expected to rank second by 2020, behind ischemic heart disease but ahead of all other diseases.
WHO estimates that one in four people will suffer from a mental or neurological disorder at some point during their lifetime. Some 120 million globally suffer from depression and 50 million from epilepsy. Each year, 10 million to 20 million people attempt suicide and 1 million are successful. The report said that most mental and behavioral disorders can be successfully treated, and much of this prevention, cure and treatment is an affordable alternative to large custodial mentalhospitals.
Although endoscopy has revolutionized the diagnosis and treatment of gastrointestinal disease, visualization of the investigational site is limited to surface mucosa. Detecting lesions with no superficial content or those with infiltration other than at the biopsy site is still a problem. Endoscopy with concomitant magnetic resonance imaging (MRI) can overcome these difficulties.
The resulting need to design an endoscope that can be used with an MRI system has been solved by Endoscan (London) in collaboration with the Robert Steiner Magnetic Resonance Unit at Imperial College (London). Achieving compatibility between instruments and the MRI system involved total redesign using a completely new set of materials. In fact, the concept became so novel that it was patented in May.
Additionally, a "sleeve" coil design has been developed so that coils can rapidly be changed for specific field strengths. The prototype MRI-compatible endoscope is currently undergoing clinical trials at Hammersmith Hospital (London), with preliminary results showing the technique to be useful particularly in the examination of small esophageal tumors when deciding whether to operate or not.
Crucell to develop Type 2 diabetes therapies
University Medical Center Utrecht (UMC; Utrecht, the Netherlands) discovered that the self-aggregation of a protein called human islet amyloid polypeptide (hiAPP) is associated with the destruction of insulin-producing cells and hence, the onset and progression of Type 2 diabetes. Preventing the formation of these hiAPP aggregates or encouraging their elimination may be an innovative treatment for the disease.
Under an agreement signed in May between UMC and Crucell (Leiden, the Netherlands), the intellectual property on this work is assigned to Crucell, which will be responsible for the commercialization of the discovery.