Those who have taken an interest in Clinuvel will have learned with joy that, on Monday February 6^th, the company announced its first official filing for SCENESSE® (afamelanotide) with the European Medicines Agency. It has taken our teams around six years to arrive at this point. Benchmarked against peer companies, it is a relatively swift development path for a first-in-class drug; we first publicly announced our erythropoietic protoporphyria (EPP) program in September 2006. It is an opportune moment to reflect briefly on how we reached this milestone and then discuss the steps that must be taken from here.

Clinuvel announced its first encouraging results from the EPP program in February 2007, following the completion of an open-label Phase II study (CUV010) of five patients in Switzerland. These results, published in the New England Journal of Medicine and Photochemistry and Photobiology, confirmed what had already been reported to the physicians involved throughout the study: afamelanotide enabled patients to expose parts of their skin to sunlight and monochromatic light – for the first time – without incurring phototoxic reactions. These reactions can range from swelling and burns to long lasting lesions, accompanied by intense pain for which no analgesic seems to work. These patients have been literally scarred for life.

These first results gave reason for optimism for the second larger trial, CUV017. In this multicenter trial, conducted in Europe and Australia, the physicians in charge learned that patients received a clinical benefit from the drug enabling them to lead an unrestricted outdoor life during the spring and summer. This was the first breakthrough in EPP we had seen under conditions of use. The drug’s reported safety profile was excellent, and with dialogue and guidance from the EMA, two new trials were initiated. The challenge for these studies was to capture data relevant to quality of life and outdoors exposure. In November and December 2011, we reported the positive outcomes of these studies – Phase II US (CUV030) and Phase III EU (CUV029) – which formed the final elements of the EMA submission. Being aware that regulatory agencies wish to see mid and long term safety data and clinically meaningful results, the other indications for which SCENESSE® was tested by Clinuvel have been included in our submission, providing essential supporting data from approximately 650 patients treated with SCENESSE®. Foremost, the results of all four EPP studies demonstrated SCENSSE® was a viable prophylactic treatment for EPP, and one which was well tolerated by those patients during the clinical program.

Running parallel to the clinical program, afamelanotide obtained orphan drug designations from the FDA, EMA and Swissmedic in 2008, and Australia’s TGA in 2010 for the treatment of EPP. This formal regulatory status entitles the company to certain incentives for its program. More than 20 individual regulatory approvals and consent from ethics committees for each trial site helped us to better understand the regulatory needs and ensured we conformed to the expected international standards. I expect there are many who follow the company and who don’t quite understand and appreciate the effort required to secure these approvals, but each one was a significant step toward our final goal and cause for confidence and celebration for our teams.

In May 2010 we received one of the biggest boosts to the program’s standing and further proof that we were on track to deliver this drug for patients for whom there is no therapy. At the completion of our first European Phase III study, the Italian regulatory authorities made SCENESSE® available for prescription prior to its formal EU approval, resulting in the company obtaining its first reimbursement for drug supply, known formally as an AIFA 648/96 listing. While maintaining our focus and yet with reasonable modesty, it indicated an important positive review in Europe. To our knowledge this special dispensation had never been given for a novel medical therapy in dermatology. Today, the Italian patients continue to benefit from SCENESSE®; their anecdotes of life on drug are most gratifying and make us realise how difficult life must be for those condemned to an indoors existence.

Over the course of the EPP program we collected more than half a million data points from patients, recording their experiences which differentiated between active and placebo treatment. More than a million physician report forms were written up and reviewed by the clinical study investigators and their teams. Without the dedication of the academic centers and their willingness to participate in the trials, we would not have reached our first filing. From this position, I thank both physicians and patients for their continued effort, time and belief in the drug and our teams.

Moving forward from the positive news and landmark event of submitting a first dossier to the EMA, new challenges lie ahead. The regulatory review period is an active process which will require more work and time from our teams over the coming months. The EMA’s task is to challenge our dossier and pose questions on all aspects of the drug’s development. Those who are familiar with drug development know that this process will take time, but we are confident that we have optimised the European dossier in anticipation of a rigorous review. Audits, inspections and reviews have been conducted and passed, but undoubtedly more will follow. Although the EMA review process is confidential, we hope to be able to give updates when appropriate. Looking further afield, we now await feedback from the FDA on the direction of our US program; another step which is entirely dictated by the FDA review and timelines and which will likely set new challenges for Clinuvel’s EPP program in 2012.

If there is one learning that I take away from the past six years, it’s that the CUV team embraces the numerous challenges along the journey and will continue to meet them. Health, persistence from our teams and safety of SCENESSE® are the requisites for further success.

A protoporphyrin IX molecule

Over recent months I have written several times of the need for Clinuvel to prove clinical relevance in our trials with the use of SCENESSE® (afamelanotide) in erythropoietic protoporphyria (EPP). In orphan populations the need to demonstrate how a novel drug assists in their daily activities and improve their lives is at the forefront of the regulators’ minds. And so it should be, after all the objective of the pharmaceutical industry is to develop drugs which address either disease or symptoms adequately and safely. The results the company released yesterday from our Phase II US study of the drug in EPP (CUV030) have given us important data towards demonstrating clinically relevant improvement of patients’ lives.

In EPP we identified a patient population who are absolute intolerant of light and UV. Since childhood they have come to accept the causality between minimal amounts of light exposure and the price to pay for this. Once EPP patients expose themselves, they start feeling strange and subtle sensations of their skin, tingling, tickling and persistent stimulation. If they do not heed to these pre-warning signs, they literally burn their skin within minutes with irreversible damage. The pain described by the many patients suffering from this genetic disease is hardly describable, the scars are not only on their skin, they are literally condemned to an indoors and isolated life.

Each patient we have spoken to has vivid memories of burns and skin reactions – being forced into an isolated life at school, missing out on social occasions, having to wear protective clothing, having to explain their ‘invisble’ disease to family and friends and partners, most of all missing out on their children’s outdoors lives.

I see it as Clinuvel’s task to offer these patients a ‘normal’ existence: an ability to go outdoors and live with the anxiety of the consequences of light exposure. If the administration of SCENESSE® would enable these patients to lead a normal life during spring and summer, free of anxiety and to actively seek outdoors exposure, we would have succeeded in our mission.

The challenge has always been and continue to be for patients to overcome their lifelong anxiety, trust in the drug and slowly alter their behavior. In analysing the data of the latest trial (CUV030) we have identified how the patients on drug were seeking minutes and hours outdoors without suffering the painful episodes typically reported when suffering from this disease.

In the pharmaceutical sector, we all become aware of the scarcity of resources and need to demonstrate efficacy in life-threatening diseases, improvement of symptoms in severe diseases and better quality of life for patients. Mankind is entitled to an improved quality of life; efforts to better one’s existence should be the principal motive in developing drugs. This task has been quite challenging for Clinuvel’s teams over the years, but we have now witnessed and learned from US patients who received SCENESSE® how the treatment changed their spring and summer existence.

The many letters we received from the broader EPP community have been appreciated and at times have been endearing. The impact and degree of suffering EPP patients (and their families) have gone through is only realised when reading these letters. An existence in the dark for the majority of one’s life is hard to imagine.

I empathise with all of the porphyria community and express the hope that we can continue to assist all these patients who have endured their ordeal. It is a privilege to serve you.

Since 2006 Clinuvel has trialed SCENESSE® in a truly unique group of individuals: patients living with erythropoietic protoporphyria (EPP), a rare genetic blood disorder which causes an absolute intolerance to light.

EPP prevents patients from leading ‘normal’ lives, especially outdoors. It is one of the few diseases that manifest clinically with initially invisible symptoms which cause severe dermal pain for several days. This not only presents a challenge for diagnosis and treatment, but also for generating meaningful clinical trial results – those which are measurable numerically and are used by regulatory authorities to evaluate the efficacy of a drug in a patient population. Here, real life patient experiences during a trial can play an important role in providing clinical relevance and analysing hard data.

I had never seen a case of EPP clinically prior to the commencement of our program with SCENESSE® (this is, I expect, the case for the majority of physicians, and even dermatologists). Yet, I’ve since spent many hours talking to EPP patients and their physicians, reading their correspondence and discussing this contact with the Clinuvel team to try to better understand EPP and how we may measure and evaluate the effects of our drug clinically and in a ‘lived’ experience.

Understanding EPP in practical terms is difficult for someone who has never had this first-hand experience. An EPP burn, patients tell us, is not like sunburn or a scald. The pain is an intense deep burning sensation without relief, yet is largely invisible (at least for the initial reaction).In the following days skin can be painful and swollen or develop into blisters, a rash, scabs or crusts. During this period, many EPP patients report an inability to focus on anything other than their reaction, seeking the dark and relying on high-dose pain killers or sleeping medication for distraction. A 1987 patient survey conducted by E Rufener of the Brain Research Institute at the University of Zürich – one of the first to recognise the social and psychological distress EPP causes – suggested that personality changes and suicidal thoughts were common following a reaction.

Seemingly trivial day-to-day tasks can cause a reaction or must simply be avoided due to the anxiety of provoking an EPP reaction. To provide context, most EPP patients will incur one or two ‘severe’ reactions to sunlight (i.e. those requiring hospitalisation and prolonged use of analgesics) in their lifetime; following this experience there is a – well justified – fear of incurring such burns and pain again and so subsequent exposure is avoided. Work and other activities are left to the twilight hours or are endured with an extreme risk of severe pain or the serious discomfort of bulky ‘sun gear’ (and the unwanted attention it can bring). Thus, following diagnosis of EPP, the standard advice given to patients to date is that they should avoid sun and light exposure and hence avoid the pain it can cause.

Yet, to suggest someone should simply ‘avoid sun’ fails to account for the practical realities of such an endeavor or the devastating effect it can have on work life, social interaction (particularly during the crucial development years of childhood) and physical and mental well-being. Many of these individuals are forced to live a nocturnal life or with the constant fear of sunlight exposure, knowing that even accidental exposure may cause debilitating pain and force them indoors for several days. It is unsurprising that EPP patients report much higher levels of mental illness and unemployment compared to the general populace.

Adults with EPP are forced to learn their limits. They change their whole way of life and adopt behaviours to avoid reactions and the consequential pain. In childhood, however, a lack of diagnosis (the ‘average’ age of diagnosis is 8 years old) and understanding of EPP can lead to horrific, painful reactions. Many children with EPP, desperate not to appear different to their peers, will participate in outdoor activities and endure the pain of an EPP reaction until it reaches a critical, intolerable level and they recieve severe burns. Hospitalisation and/or heavy sedation at this point are not uncommon. This is a burden no child or their parent should have to endure at these times.

It is Clinuvel’s goal to make a therapy available to this patient group – initially as adults, but with a longer term view to all with EPP – to reduce the mental and physical burden of EPP and help patients live a daily routine with exposure to light, something that many of us take for granted. The questions the team is seeking to answer now (with clinical results from two late stage EPP studies) are intended to help us reach this goal. In short, we need to know how the treatment of EPP with SCENESSE® can be evaluated statistically and, just as importantly, with an understanding of the impact of EPP on their daily lives (i.e. clinical relevance).

More than 250 individuals with EPP have been involved in our clinical program to date across three continents. Following the completion of our studies a large percentage of these have corresponded with the company – either directly or through their treating physician – to provide feedback or support for the program. Here, real-life feedback from patients who are returning to work, taking part in social activities outdoors for the first time or being able to conduct daily tasks without pain or fear of a reaction, all make for powerful ‘data’, particularly when contextualised with the severe physical and social impact of EPP prior to therapy.

The personal nature of this correspondence and willingness to share has struck me and continues to be a humbling experience. Yet, what many of these individuals probably haven’t realised is the true impact of their words on helping to further our EPP program. Over the years patient correspondence has not only helped reinforce the value of the program to the team but provided us with invaluable insight well beyond what we see in statistics or numbers. As we now approach the release of final analysis from our two studies, personal reminders that the therapy has dramatically altered an individual’s life for the better and allowed him or her to ‘live normally’, means we appear to be achieving the goals we have for our patients. In terms of how we review results, approach numbers and conduct our discussions with physicians, these powerful patient experiences are never far from our minds.

Reference

Rufener, EA 1987, ‘Erythropoietic protoporphyria: a study of its psychosocial aspects’, British Journal of Dermatology, 116:703-708.

Earlier this month Sanofi, the world’s fourth largest pharmaceutical company by revenues, announced that it would go on a cost-cutting spree, trimming its expenditure by $US2.9billion annually and cutting many thousands of jobs in the process. Amidst the upheaval, Sanofi stated its key goal for 2012 onwards was ‘generating sustainable growth’ for shareholders (the complete presentation can be viewed here). One of the key targets for its cuts was R&D costs, both in terms of overall spend and employee headcount.

Sanofi isn’t alone in its belt-tightening operations. Along with many others, the three biggest pharmaceutical companies – Pfizer, Novartis and Merck – have all announced reductions, layoffs and restructures in the past 12 months. On each occasion, R&D departments have borne the brunt of the cutbacks, with the development of upcoming, in-house drugs coming to a standstill. Although this trend is not new to the pharmaceutical sector, the questions now are whether the US and EU can maintain their leading roles in medical development globally and who, if anyone, will win from cost-cutting?

There are several elements at play here, but the recent reductions have made one thing clear: drug development is evolving and it’s doing so rapidly. What’s less clear is whether the industry will continue to deliver innovative therapies to patients. After all, isn’t this the essence of pharmaceutical advancement?

For the ‘big pharma’ mentioned above, rationalisation and consolidation dictate the Board rooms. Driven by market conditions, initial spend and job cuts are a necessary element of an overall organisational change in strategy. Sanofi’s recent acquisition of orphan drug specialist Genzyme and Pfizer’s 2009 purchase of Wyeth saw both companies seek to minimise overlapping functions, streamline administrative or marketing divisions and reduce ‘waste’. While it is an unpleasant exercise for any organisation, these measures are necessary in order to facilitate the effective amalgamation of two organisations. Without preempting the outcome of any of these mergers, the success rate of M&A doesn’t hold much promise; perhaps success in this context needs redefining.

Beyond mergers and acquisitions, and often contributing to them, are several influential factors changing the playing field for drug developers. Featuring prominently in post-cutting analysis for many companies is a looming ‘patent cliff’. Here, a number of high-revenue, high profit-margin, large patient population drugs are coming to the end of their exclusive ‘life’ and big pharma lacks new products to fill the gaps.

Analysis by the Wall Street Journal reveals that nine patented drugs with total US sales of US$35bn will lose their exclusivity by the end of 2013; including Pfizer’s Lipitor, which generates annual sales of approximately $US7.5bn in the US alone. Increased competition by generic manufacturers who move in after patents lapse will quickly eat away at these markets, yet companies have few new drugs to replenish their pipelines; most of which aren’t expected to earn a fraction of these sales. In addition, we’ve recently seen the failure of several high profile Phase III studies, leading to the abandonment of prospective development programs and a subsequent narrowing of pharma pipelines.

Against this backdrop, and in the face of the recent global financial turmoil, insurance companies and health maintenance organisations that help patients meet drug expenses are similarly looking to reduce their costs. These payers are pressing for cheaper ‘branded’ drugs and are immediately switching to lower cost generics once they become available. For many industry watchers, we are nearing the end of an era when pharmaceutical companies had been able to produce drugs for mass markets and enjoy ‘blockbuster’ status (in excess of US$1bn annual sales).

The increased market pressure has forced companies to re-think their strategies, with resource allocation being one of the first areas to come under review when striving to sustain growth. As I’ve written before, the industry’s focus on rare indications is one such approach, but in the coming years it is likely that we’ll see a range of R&D tactics employed by big pharma to help grow its revenue and further its product reach. Unfortunately, this will see some drug programs slashed before their time, much to the detriment of patients.

On a more positive note, a scarcity of resources tends to fuel creativity, so, amid this pharma revolution, success will most likely originate from motivated teams who can maximise their proof of concept. Further ahead, innovative approaches, such as patient-driven partnerships and targeted therapies, may result in faster drug development, a greater number of drugs for specific groups and, ultimately, a better outcome for patients. Some also believe that the centre of the pharma industry may move to continents where the production costs are lower, resulting in a loss of global leadership for Europe and the US, but regional success elsewhere. Only time will tell how the pharma story will unfold, in the interim however, it is likely that innovative cost-cutting will remain the industry’s mantra.

Further reading & references

Merck To Cut Another 12,000 To 13,000 Jobs, Pharmalot, July 29, 2011

The Top 20 Pharmaceutical Companies, Contract Pharma, July 14, 2011

Pfizer Plans Deeper Cost Cuts, WSJ, June 8 2011

The XX Percent Solution: Pfizer To Cut More Jobs, Pharmalot, November 12, 2010

Image reference

‘IMG_1014’ uploaded to Flickr.com by Sue Waters on 22 November 2008, <http://www.flickr.com/photos/suewaters/3181424529/in/photostream/>

As we recently discussed, a number pharmaceutical companies have been fined for promoting off-label uses of their drugs. These practices are difficult to control and the monetary penalties seem to have had little effect on manufacturers, as the number of off-label breaches being reported continues to grow.

In the world of contemporary medicine, off-label prescribing plays a fundamental role in providing the best available standard of care for several health problems. In some areas of practice, including oncology, pediatrics and obstetrics, off-label prescribing provides some of the best known interventions for patients. Yet, off-label prescriptions can also threaten the safety of the patients if they are not supported by legitimate scientific evidence. Hence, promoting such uses of drugs is not encouraged by the regulatory authorities with a view to safeguard the health of patients (a key regulatory role).

It is imperative, when discussing the issue of off-label marketing, that we take into account the regulators’ perspective and consider the measures taken to control the phenomenon of off-label marketing and to work with the industry to expand ‘on-label’ uses for specific drugs.

The Food and Drug Administration (FDA) and other regulatory authorities around the world have laid a framework to govern the promotional activities of the pharmaceutical companies. Recently, new guidelines were finalised for the dissemination of information on unapproved uses of drugs by the FDA in the US.  This document, called the ‘Good Reprint Practices’, is designed to provide an outline for drug makers to engage in legitimate off-label marketing. As per the guidelines, journal articles or other reference material drawn on to support the off-label use of a drug must be published by an organisation whose editorial panel consists of independent, unbiased experts. These reference articles are able to be distributed to healthcare professionals, medical or health organisations, drug formulary committees and hospitals. Similar rules apply for companies in the European Union under the Community code Directive 2001/83/EC.

The guidelines have not brought about any significant decline in the number of illegal marketing cases and drug manufacturers continue to go against the law in search of greater financial benefits. The number of off-label prescriptions, especially for pediatric patients, provides some drug manufacturers with an impetus to market unapproved uses of drugs more aggressively. In 2006, Gazarian et al. revealed that 90% of the drugs prescribed to children are off-label, which indicates the commonality and legality of the issue and also raises the question as to why so many drugs are prescribed off-label for children. An article by pediatrician Alexander Cvetkovich-Muntañola, in the February issue of Foresight, suggested that the limited number of drugs tested in children often forces pediatricians to resort to off-label use.

According to a 2009 FDA report, there are a variety of reasons for the limited number of drugs tested in children. The most important being the perception amongst pharmaceutical companies that the pediatrics market will not be able to provide good returns on their investments.  It is also much more difficult to conduct clinical studies in children as there are additional factors which need to be taken into consideration which are unnecessary in the study of adult patients (i.e. the need for a child-friendly study environment and administration techniques, age appropriate equipment and the employment of pediatric specialists). Ethical issues and recruitment difficulties compound these problems.

For these reasons, the studies are not only difficult, but also expensive. Large investment risk for potential minimal return is not a sound business strategy in an increasingly competitive pharmaceutical landscape. This lack of commercial incentive is another factor contributing to the small number of drugs approved for children.

In an attempt to combat these issues, regulatory authorities have begun providing incentives to the pharmaceutical industry to encourage pediatric studies and registration. Under the Best Pharmaceuticals for Children Act (BPCA) and the Pediatrics Research Equity Act (PREA), which were issued in 2002 and 2003, respectively, pharmaceutical companies in the US are eligible for an additional six months of market exclusivity for a drug if they conduct studies in children as per FDA guidelines. The corresponding European authority, the EMA (European Medicines Agency), have made similar provisions for pediatric drugs in Europe. To ensure that the studies done on pediatric drugs are legitimate, the EMA has introduced a new development plan, called the Paediatric Investigation Plan (PIP), which verifies the relevance of the data obtained from studies conducted in children before a drug can be authorised for use in this group.

The success of these incentives indicates that the introduction of new, similar programs may encourage more valid research by pharmaceutical companies. This will not only help bring more drugs to market but also increase the on-label uses of existing drugs. If conducted legitimately, off-label marketing is capable of opening up new areas of research to benefit multiple patient groups.

References

Cvetkovich-Muntañola, A 2011, ‘Pediatric Clinical Trials: One Size Doesn’t Fit All’, Foresight, vol. 4, no. 2, retrieved 15 August 2011, <http://www.incresearch.com/Resource/Foresight/Foresight_201102-V4-Issue2.pdf>.

Covington & Burling LLP 2009, Food & Drug E-ALERT: FDA Issues Final Guidance on “Good Reprint Practices”, Covington & Burling LLP, retrieved 20 August 2011, <http://www.cov.com/files/Publication/3d62ff1e-19f0-4636-9363-d3c5b5e7e996/Presentation/PublicationAttachment/5126d07c-225b-46b7-81b7-de3ca1e60924/FDA%20Issues%20Final%20Guidance%20on%20%E2%80%9CGood%20Reprint%20Practices%E2%80%9D.pdf>.

Drakulich, A 2008, ‘FDA to Allow Off-Label Information, Draft Guidance May Be Too Soon, Too Simple’, retrieved 15 August 2011, <http://pharmtech.findpharma.com/pharmtech/article/articleDetail.jsp?id=492953>.

European Medicines Agency n.d., ‘Paediatric investigation plans, waivers and modifications’, European Medicines Agency, retrieved 15 August 2011, <http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000293.jsp&jsenabled=true>.

European Medicines Agency n.d., Directive 2001/83/EC of the European Parliament and of the council of 6 November 2001 on the Community Code relating to medicinal products for human use, European Medicines Agency, retrieved 15 August 2011, <http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004481.pdf>.

Food and Drug Administration 2011, ‘Drug Research and Children’, retrieved 15 August 2011, <http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143565.htm>.

Food and Drug Administration 2009, ‘Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices’, retrieved 15 August 2011, <http://www.fda.gov/RegulatoryInformation/Guidances/ucm125126.htm>.

Field, RI 2008, ‘The FDA’s New Guidance for Off-Label Promotion Is Only a Start’, Pharmacy and Therapeutics, 33(4):220-249, retrieved 15 August 2011, <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730097/>.

Gazarian, M, Kelly, M, McPhee, JR, Graudins, LV, Ward, RL, Campbell, TJ 2006, ‘Off-label use of medicines: consensus recommendations for evaluating appropriateness’, The Medical Journal of Australia, 185(10): 544-548, retrieved 15 July 2011, <http://www.mja.com.au/public/issues/185_10_201106/gaz10250_fm.html#0_CHDIHHCF>.

Hathaway, C, Manthei, J & Scherer, C 2009, ‘Exclusivity Strategies in the United States and the European Union’, Update, (3): 34-39,retrieved 16 August 2011, <http://www.lw.com/upload/pubContent/_pdf/pub2655_1.pdf>.

Image reference

‘Law gavel’, uploaded to Wikimedia Commons on 6 June 2011 by Nodar Kherkheulidze <http://commons.wikimedia.org/wiki/File:Law_gavel.jpg>

The marketing model for US prescription pharmaceuticals is often debated for its direct-to-consumer (DTC) advertising as the United States is one of the few jurisdictions globally which allows this type of marketing. Yet equally debated is promotion directly to physicians, key decision makers in the prescription process. Physician promotion comes in many forms, ranging from one on one visits with sales representatives to educational sponsorship to the ubiquitous branded pen.

The model has both its supporters and critics; the former argue that advertising plays an important role in physician education and the dissemination of vital product information. The latter see product promotion as being too influential on prescribing habits, with the potential to undermine patient health, lead to overprescribing and/or inflate healthcare costs. In the midst of this argument is the FDA’s Division of Drug Marketing, Advertising, and Communications (DDMAC), responsible for enforcing Federal Regulations on the advertising of prescription meds.

There is a growing body of research devoted to reviewing, analysing and critiquing the US pharmaceutical marketing model, with a recent paper likely to fuel further discussion on the merits and pitfalls of one common form of pharmaceutical promotion: medical journal advertising.

A team led from New York’s Mt Sinai School of Medicine analysed 12 printed biomedical journals dating from November 2008. They sought to determine the pharmaceutical industry’s adherence to FDA advertising guidelines, with a focus on safe prescribing. Of the 12 journals reviewed, nine contained a total of 89 unique advertisements for 82 products. Eighty-three of these were deemed to be ‘full’ advertisements and were subsequently analysed according to the Mt Sinai team’s methodology.

The researchers determined that only 15 (18%) of the 83 ads fully adhered to the FDA’s regulations for prescription advertising. A further 27 (33%) were categorised as “possibly non-adherent” as they presented incomplete information, often described as unsupported claims of peer reviewed literature support or study efficacy. The remaining 41 advertisements (49%) were regarded as not adhering to FDA regulation on at least one count. In analysing safety claims, the authors found that 48 (57.8%) of the advertisements did not “quantify serious risks” of the products they promoted. In short, the team “found low rates of adherence to FDA guidelines among physician directed pharmaceutical advertisements and inadequate information for safe prescribing.”

While the authors acknowledged the limitations of their review and the lack of validation to their methodology, they also asserted that their “findings have important policy implications”. The group is calling on the FDA to make changes to its “Bad Ad Program”, designed to help physicians report potential breaches in marketing and, subsequently, improve prescribing practices.

Editor’s note: the study has already encountered some reactions from within the pharmaceutical industry. For one perspective, see this post by John Mack, publisher and editor of Pharma Marketing News.

Reference

Korenstein D, Keyhani S, Mendelson A, Ross JS. 2011, ‘Adherence of pharmaceutical advertisements in medical journals to FDA guidelines and content for safe prescribing’, PLoS One, 6(8):e23336. Epub 2011 Aug 17. Available online at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0023336.

Image reference

‘back cover, Japanese dream book’, posted to Flickr.com by bunky’s pickle on January 20, 2009 < http://www.flickr.com/photos/verylastexcitingmoment/3214854006/>

Development of novel drugs is truly like no other business: one attempts to address questions that may have never been previously posed – let alone answered – in the pursuit of improving the lives and quality of life of patients. As I eluded to in my recent letter to shareholders, the team is now well into the analysis of results from our erythropoietic protoporphyria (EPP) program; two studies from the US and Europe. This is a complex and time consuming task that requires one to collate and make sense of thousands of data points to answer a seemingly straight forward question: does this trial show that the drug is safe and effective?

Obtaining an answer needs to be understood from the concept of clinical relevance. Put simply, results don’t just need to show that a treatment or intervention has an effect on a disease. Rather, they need to indicate that that effect is relevant to the current clinical understanding, treatment and care for the disease or indication. They need to show that the drug’s effect is having a positive, meaningful impact upon a patient’s prognosis and care. This is a crucial point to consider in the development of protocols and in the careful analysis of results, as it is how regulators will review the results.

Later this year, pending clinical results, we intend to file SCENESSE® (afamelanotide) with the European Medicines Agency (EMA) for marketing authorisation approval (MAA). If successful, this will allow us to make the drug available across Europe. The team’s current work is focused on building a dossier of information which will allow the EMA to objectively review all data on the drug’s safety and efficacy as a prophylactic treatment for EPP.

In analysis, however, numbers are only half the work. One must employ lateral thinking to determine the relevant outcome of a study, followed by a discussion with the relevant medical community to challenge and validate the study results.

Rare diseases are often poorly understood, even in the medical community, and very seldom seen outside of specialist centres. Here clinical relevance is of even greater value as traditional study endpoints are generally of little value and unique, disease specific, endpoints must be developed, quantified and employed. Looking back at when we commenced our EPP program in 2006, we had to first work with the community of patients, physicians and regulators to develop and validate these endpoints before embarking on an expanded clinical program.

In short, the quantitative objective of our EPP studies is to determine whether the drug can prevent or reduce the incidence and severity of reactions in EPP, caused predominantly by light around 408nm in wavelength (blue spectrum). From a clinical relevance perspective, however, we also aim to be able to show whether the drug improves the patients’ quality of life, allows them to expose their skin to sunlight for extended periods of time or alters the UV/light avoidance behaviour ingrained in them since childhood (including so-called ‘shadow jumping’). The addition of objective clinical measurements – such as phototesting – provides further numerical support.

These factors will form the basis of our understanding of whether SCENESSE® provides a benefit to our patients and has a positive and measurable impact on their lives. In the coming weeks we will learn the results from this program and ideally be able to confirm the clinical relevance of the first prophylactic treatment in EPP.

Use of drugs in patient populations for purposes which are not approved by the regulatory authorities is termed ‘off-label’ use. As the regulatory authorities do not have specific power over doctors’ prescribing habits (provided that the doctor assumes the medical risk), it is a common practice to prescribe drugs for purposes which have not been authorised by the regulators. While it is legal for doctors to prescribe off-label drugs, it is illegal for companies to market the use of these drugs.

The regulatory authorities (EMA/FDA etc), before allowing the marketing of a drug for its approved uses, review data from pre-clinical and clinical trials for safety and efficacy of the drug. On the other hand, off-label uses of a drug do not undergo tests and review as per the standards required by the regulatory authorities and therefore cannot be guaranteed for safety and efficacy. Therefore, promoting off-label uses of a drug is deemed illegal for pharmaceutical companies as patients are exposed to possible adverse effects and the efficacy of the drug is unproven.

The marketing authorisation process of the regulatory authorities has stringent parameters according to which drugs need to be tested. During this process, the drugs are given a ‘label’, which provides information regarding the use of the drug, i.e. exact diseases and dosage (Kesselheim, Mello, Studdert, 2011). Often, the reasons cited for pharmaceutical companies to engage in off-label marketing practices are to increase the sales revenue of the drug or to minimise competition from generic drugs. In a US study, Kesselheim, Mello and Studdert suggested that there are three goals for the off-label marketing strategies of the companies which are not mutually exclusive. The most common goal was to expand the use of a drug to treat unapproved diseases (85% of the cases). The others were to alter (usually increase) the dosage of a drug or to expand the use of a drug in unapproved patient groups, such as children.

According to Gazarian et al. 2006, approximately 40% of the drugs prescribed to adult patients and 90% of the drugs prescribed to pediatric patients are off-label. A 1998 article published in the British Medical Journal, suggested that doctors in the US and UK have shown quite some interest in using off-label drugs for pediatric patients. Off-label drugs used in these cases are usually established drugs, like morphine and paracetamol. They are often used in violation of the terms of product license, generally giving higher dosages than recommended. A number of cancer patients are also put on off-label medication as many of the cancer drugs have multiple uses. Radley, Finkelstein and Stafford conducted a study in 2001 which took into account 160 commonly prescribed drugs in the US. Their study revealed that, of 150 million off-label prescriptions that were written for the drugs that year, 73% had limited or no scientific support. This increased concerns for the safety of the patients being prescribed these medications.

In recent years, it has come to light that many of the big pharmaceutical companies have been fined for promoting off-label drugs.  Bloomberg released an article in 2009 discussing Pfizer’s billion dollar fines for off-label drug promotion. The company had already paid a hefty sum of US $430 million in the form of fines for promoting unapproved uses of an epilepsy drug, Neurotin, in 2004. Again, in 2009, Pfizer was asked to pay a huge amount to settle cases regarding the promotion of off-label uses of Bextra. The Financial Times reported the settlement amount to be US $2.3 billion, which was the largest criminal fine ever paid in US history. Bextra had been approved for pain relief only in cases of menstrual pain and arthritis, but according to Bloomberg, the company executives at Pfizer were pushing salespeople to promote Bextra as a general analgesic. Among other companies, Bristol Myers Squib Co. and Eli Lilly Co. have also paid large amounts in fines for off-label marketing.

Cases involving off-label promotions by drug manufacturers continue to make the news, despite the monetary penalties and the safety concerns about the patients.  Although illegal, off-label promotion seems to be a profitable business strategy. The annual sales figures that are achieved by the companies with this strategy seem to dwarf the fines they have to pay for using it. This has become a serious problem for the regulatory authorities and the people who are being treated with these drugs. In future blogs, we will look at the measures that are being taken to address this problem from a regulatory perspective.

References

Craft, GS, Jr 2008, ‘Promoting Off Label in Pursuit of Profit: An Examination of Fraudulent Business Model’, Houston Journal of Health Law & Policy, vol. 8, pp. 103-131, retrieved on 15^th July 2011, http://www.law.uh.edu/hjhlp/Issues/Vol_81/Craft.pdf

Evans, D 2009, ‘Pfizer Broke the Law by Promoting Drugs for Unapproved Uses’, Bloomberg, 9 November, retrieved on 15^th July 2011, http://www.bloomberg.com/apps/news?pid=newsarchive&sid=a4yV1nYxCGoA

Fugh-Berman A, Melnick D 2008, ‘Off-Label Promotion, On-Target Sales’, PLoS Medicine, vol 5, no 10, retrieved on 15^th July 2011, http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0050210

Gazarian, M, Kelly, M, McPhee, JR, Graudins, LV, Ward, RL, Campbell, TJ 2006, ‘Off-label use of medicines: consensus recommendations for evaluating appropriateness’, The Medical Journal of Australia, vol 185, no 10, pp. 544-548, retrieved on 15^th July 2011, http://www.mja.com.au/public/issues/185_10_201106/gaz10250_fm.html#0_CHDIHHCF

Horen, B, Montastruc, JL, Lapeyre-mestre, M 2002, ‘Adverse drug reactions and off-label drug use in paediatric outpatients’, Br J Clin Pharmacol, vol 54, no 6, pp. 665-670, retrieved on 15^th July 2011, PubMed Central Database.

Jack, A 2009, ‘Pfizer to pay a record fine for off label promotion practice’, Financial Times, 28 January, retrieved on 15^th July 2011, http://www.ft.com/intl/cms/s/0/d58caf5e-ecdc-11dd-a534-0000779fd2ac.html#axzz1S2QBn7OM

Kesselheim AS, Mello MM, Studdert DM, 2011, ‘Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints’, PLoS Medicine, vol 8, no. 4, retrieved on 15^th July 2011, http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000431

Radley, DC, Finkelstein, SN, Stafford, RS, 2006, ‘Off-label Prescribing Among Office-Based Physicians’, Archives of Internal Medicine, vol 166, no. 9, retrieved on 15^th July 2011, http://archinte.ama-assn.org/cgi/content/full/166/9/1021

Turner, S, Longworth A, Nunn, AJ, Choonara, I 1998, ‘Unlicensed and off label drug use in paediatric wards: prospective study’, British Medical Journal, vol 316, pp. 343-435, retrieved on 15^th July 2011, http://www.bmj.com/content/316/7128/343.full.pdf

Image reference

‘Medicine Drugs’ uploaded to Wikimedia Commons on 22 December 2009 by Mizunoryu

< http://commons.wikimedia.org/wiki/File:Medicine_Drugs.svg>

Stem cells are immature, unspecialised cells which have the ability to develop into other adult cells with a specific function, i.e. skin cells, red blood cells, nerve cells (neurons), etc.

Stem cells have two important properties:

1. They are capable of renewing themselves indefinitely, i.e. they can divide many times to produce lots of other stem cells.
2. They have the ability to differentiate. This means that they can grow and mature into a specialised cell. Differentiation may involve changes in the cell’s size, shape, interaction with their surrounding environment and activity/function. This process requires external stimulation from chemical factors, or other cells, to activate and regulate the development of stem cells into specialised cells when they are needed.

There are two main types of stem cells; embryonic stem cells and adult stem cells (also known as ‘tissue specific’ or ‘somatic’ stem cells). Embryonic stem cells exist in an embryo at approximately 5-7 days and are ‘pluripotent’; they have the potential to become any type of body cell, given the correct stimulation. In contrast, adult stem cells inhabit a particular area within adult tissues (i.e. muscle tissue, fat tissue, connective tissue) and can only differentiate into cells of that tissue, termed ‘multipotent’. So while still immature and undifferentiated, to a certain extent, their fate is predetermined.

A small number of tissue-specific, adult stem cells are positioned in different parts of the body, in regions called niches, early on in development. Adult stem cells can remain dormant, or quiescent (non-dividing), in the niche for many years. They serve as a continual source and origin of new cells to maintain and repair body tissues throughout one’s lifetime.

Much recent scientific energy (and indeed media coverage) has focused on the potential of stem cells to regenerate or replace lost and damaged cells in the body. The use of stem cells in this way, to prevent, treat or cure various medical conditions and diseases, is called ‘cell-based therapy’.

Much controversy has arisen over the use of embryonic stem cells, which are often derived from excess embryos donated by IVF participants. By comparison, adult stem cells – which can often be sourced from different tissues –  tend to be less contentious, with their use in the regenerative process proving most exciting and worthy of significant resource investment.

This piece is an abstract from Clinuvel’s latest Technology Update: Stem Cells and Repigmentation in Vitiligo.

Image reference

“Cells” uploaded to Flickr.com on August 11, 2010 by RembergMediaImages <http://www.flickr.com/photos/rmgimages/4881836093/>

Scarcely a day goes by that the Clinuvel team is not contacted regarding the latest conference: everything from monitoring to manufacturing to marketing is analysed, discussed and disputed across the globe in conference form. It’s impossible – and unwise – for small companies to try to attend all these forums, but it is equally impossible to work in the space without looking outside the office door: there is much to be learned from what others have done or not done to succeed in an industry fraught with failure.

And indeed there was much to take on at the recent World Orphan Drug Summit, held in Frankfurt last week.

As highlighted late last month in a CEO Blog post, ‘orphan’ drugs – those for rare diseases – are gaining more and more of the pharmaceutical spotlight as big companies move in. Indeed, many of these organisations were represented in Frankfurt and presented interesting case studies, yet it was recurring themes from those working around the industry – in regulation, reimbursement and research – which reinforced the challenges faced by orphan drug developers.

The raw stats behind the orphan drug program are interesting, but don’t tell the full story. It’s estimated that 6,0000-8,000 rare diseases exist, affecting 27-36 million individuals across Europe. Since the introduction of orphan legislation in Europe in 2000, 850 orphan drug designations (ODDs) have been granted by the EMA with 63 orphan products approved for marketing up to 2010¹. Prices for these products vary, but some genetic therapies for life threatening disorders can cost in excess of €100,000 annually per patient (pricing itself being one of the most contentious issues in the space).

None of these products’ stories could be considered identical, but it was clear that those working in the orphan drug space face similar challenges in getting their drug to market.

The frameworks for drug development were one of the key issues. In short, regulatory and payer frameworks have been developed for indications or diseases which have larger patient populations and/or better understood symptoms or causes. Drugs are evaluated to ensure they are safe and effective for a given patient population. For most ‘mainstream’ drugs this evaluation is able to rely on wide-ranging data or existing medical literature which can help determine the impact of symptoms either in isolation or in comparison with other diseases. Often there are even existing measures for specific diseases or disease categories which can help determine the efficacy of a treatment or comparative treatments.

These factors allow regulators and others to effectively and objectively review the merits of a treatment and recommend on its approval for use. Yet, for orphan indications little, if any, of this information exists or can be easily generated throughout the life of a program. As a result orphan developers must better understand their target indication(s), work more closely with their patients and work harder to educate regulators on the impact of both disease and drug. Framework doesn’t really exist to evaluate whether a drug is safe and effective in an indication when much of this information is lacking, making the development process and regulatory question even harder. The rarer the disease, the more difficult the process.

Fortunately, there are programs underway which help expand upon the orphan drug legislation to improve both evaluation and eventual patient access. Unfortunately, there is yet to be any true consensus at an international level on how best to approach many of these issues with evidence that national interest may sometimes stand in the way of improved international access, even once the regulators give an approval. What was clear from those who have overcome these issues, however, is that no two orphan developers are the same and a flexible, unique and collaborative approach to rigid drug evaluation framework is essential to success in the orphan drug space.

¹ Note that some ODDs may be for multiple diseases for a single product, or multiple products for a single disease

Image reference

“Green leaf of a bio plant in nature” posted to Flickr.com on August 31 2008 by epSos.de <http://www.flickr.com/photos/epsos/3384297473/>