Are clinical trial data shared sufficiently today? Yes

Clinical trials are essential for the successful development of new medicines that save and improve lives and provide hope for millions of patients. Biopharmaceutical companies are committed to the continuous improvement of clinical trials to bring innovative medicines to the patients who need them. This includes protecting the safety of study participants, overcoming barriers to greater participation, and fostering new medical discoveries.

The biopharmaceutical industry is firmly committed to enhancing public health through responsible reporting and publication of clinical research and safety information. In the process of drug development, companies routinely publish their research, collaborate with academic researchers, and disclose clinical trial information at the time of patient registration, drug approval, and for medicines whose research programs have been discontinued. In addition, PhRMA has set out voluntary principles to fortify biopharmaceutical companies’ commitment to the highest standards for ethics and transparency in the conduct of clinical trials. PhRMA’s Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results1 are designed to help ensure that clinical research conducted by biopharmaceutical research companies continues to protect patients and provide meaningful medical research results to healthcare professionals and patients.

The biopharmaceutical sector may provide more information about its research and products than any other industry. As expected by the healthcare professionals that prescribe innovative medicines, the current biomedical research system includes wide sharing of trial results with government regulators, academic and medical communities, and physicians through submissions to the US Food and Drug Administration (FDA) and other international regulatory bodies, presentations at medical conferences, and publication in peer reviewed journals.

Information on clinical trials for potential new medicines is already required by US law to be posted on, the publicly accessible clearing house maintained by the National Institutes of Health (NIH). As of May 2013, has information on 146 213 studies in all 50 states and in 185 countries. NIH reported last year that “receives more than 95 million page views per month and 60 000 unique visitors daily.”2

While these efforts are working, the biopharmaceutical industry is engaged in a dynamic ongoing process to improve on all aspects of clinical trials and is committed to taking part in a multi-stakeholder dialogue to advance responsible data sharing that protects patient privacy, maintains the integrity of the regulatory review process, and preserves incentives for biomedical research. We are reaching out to groups such as the Institute of Medicine, the Harvard Multi-Regional Clinical Trial Center, Project Data Sphere of the CEO Roundtable on Cancer, and the European Alliance for Personalized Medicine.

Processes for data sharing or disclosure must take account of patients’ informed consent and the reality that re-identification of patients based on anonymized information is possible.3 Threats to patient privacy will jeopardize patient willingness to participate in clinical trials, which would delay the availability of new therapies.

Dumping millions of pages of clinical trial information into the public domain without providing appropriate scientific and clinical context or guidelines for meta-analysis could lead to second guessing of the expert decisions of national regulators worldwide, undermining patient trust and confidence in the safety and effectiveness of approved medicines.

Mandatory public disclosure of intellectual property, confidential commercial information, and proprietary scientific methods found in clinical trials could stifle discovery and open the possibility of competitors or unscrupulous actors using the information for their own products in other markets or countries. Without appropriate protection for intellectual property to incentivize the enormous investment risk involved, biopharmaceutical companies will be discouraged from investing in the next generation of new medicines, leading to patients and physicians being deprived of innovative therapies to tackle the serious and life threatening diseases of the 21st century.

The modern clinical trial system and associated sharing of information led to more than 340 new medicines approved by the FDA over the past decade, with 39 new medicines in 2012 alone. It contributed to over 30 new medicines approved for HIV in the past three decades—based on the work of 2400 completed trials—turning what was once a death sentence into a treatable, chronic condition.

Since 2000, PhRMA member companies have invested about $550bn (£330bn; €390bn) in research and development, including clinical trials, in the search for new treatments and cures. No government or academic institution has the resources or multidisciplinary expertise to conduct the clinical trials needed to develop the new medicines patients need. Only the biopharmaceutical industry can take on this considerable risk at such a scale, and only a carefully balanced regulatory and competitive environment can foster the future investments in this research necessary to produce new treatments to benefit current and future patients.


Pharmaceutical Research and Manufacturers of America. Principles on conduct of clinical trials and communication of clinical trial results. 2011.

US National Institutes of Health.

Gymrek M, McGuire AL, Golan D, Halperin E, Erlich Y. Identifying personal genomes by surname inference. Science2013;339:321-4.

Abstract/FREE Full Text

Source: BMJ




Does adding routine antibiotics to animal feed pose a serious risk to human health?

As fears rise over resistance, some countries have banned routine use of antibiotics in animal feed. David Wallinga says a ban is possible without damaging food productivity, but David G S Burch argues that the drugs used in agriculture are not those causing problems with resistance in humans

Yes—David Wallinga

You cannot dispute the warning of England’s chief medical officer, Sally Davies, that antibiotic resistance is one of modern health’s greatest threats. Also beyond dispute is her analysis of its causes—the lack of new drugs combined with massive overuse of existing antibiotics. What physicians and policy makers generally overlook, however, is the critical role played by the ongoing overuse of antibiotics in livestock and poultry production. Enforceable measures to reduce this overuse must be core to any effort to avert the coming catastrophe. Because meat production is global in nature, these measures must be implemented nationally and supranationally.

Cost of resistance

Resistant infections generally cause more morbidity, mortality, and longer periods in hospital. In the United States alone, associated treatment costs add as much as $26bn (£17bn; €20bn) to the nation’s annual hospital bill; in 2012 dollars, the figure could be nearly $35bn, closer to $70bn if lost work and other societal costs are included.1 2

It will get worse. Ten times more cases of meticillin resistant Staphylococcus aureusoccurred in US children’s hospitals in 2008 than a decade earlier.3 From 2000 to 2009, admissions to hospital associated with Clostridium difficile doubled to 336 000,4 while deaths have tripled. Infections by deadly extended spectrum β-lactamase producing Enterobacteriaceae (especially Escherichia coli) are on the rise, in hospital and in communities.5 The World Health Organization states that bacteria – including antimicrobial resistant bacteria—commonly transferring from food animals to people comprise Salmonella, Campylobacter, E coli, and Enterococcus species. Emerging evidence shows that S aureas, including MRSA and C difficile, “also occur in food animals [those we eat] and can later be found in food products and environments shared with humans.”6

Interest in creating a pipeline of new antibiotics is understandable. But we cannot be sure that drug companies will succeed, regardless of the size of the financial incentives extended to them. Even if they do, some bacteria are likely to acquire resistance to the new drugs in a fraction of the time spent developing them. Meanwhile, how affordable will these new patented drugs be?

Ecological challenge

An ecological approach frames the problem of antibiotic resistance differently. Like Darwin, an ecologist asks what characteristics of the microbial ecosystem drive bacteria to evolve, acquire, and then expend the fitness cost to retain resistance genes in the first place. The answer is the selection pressure provided by our enormous use of antibiotics. This use creates environmental reservoirs of resistance genes (other genetic “determinants” of resistance, like plasmids) and resistant bacteria. These reservoirs now exist throughout the bacterial ecosystem: in the gut flora of human and food animals; in sewage plants, rivers, and farms; as well as in households and hospitals. By itself the development and use of new antibiotics will only add to this selection pressure. To decrease that pressure, overall reductions in antibiotic use—which is unpopular with drug companies—should come first.

That is where antibiotic overuse in animal agriculture becomes relevant. Data for drugs sold in the US in 2009-11, collected by the US Food and Drug Administration, show that antimicrobials added to animal feed or drinking water comprise 72% of all US sales of antimicrobials, over 13 000 tonnes a year.7 Most, though not all, antimicrobials routinely fed to US animals are medically important, including penicillins, tetracyclines, aminoglycosides, streptogramins, macrolides, and sulfas.

These are not single injections for sick animals. They are additives in feed given routinely, without a prescription, at lower than therapeutic concentrations, for purposes such as growth promotion and controlling disease in otherwise healthy animals being raised in crowded and often unhygienic conditions that can promote disease.

The US is not exceptional. Frank Aarestrup, head of the World Health Organization’s collaborating centre for antimicrobial resistance in foodborne pathogens and of Denmark’s National Food Institute, found that before Denmark phased out antibiotics for growth promotion, which it completed in 2000, about two thirds of antimicrobial use in pork and 90% in poultry production was for promoting growth and most of these were human antibiotics.8

Selection for resistant bacteria can occur at antibiotic concentrations hundreds of times lower than those previously thought9; the lower concentrations of antibiotics put into animal feed compared with injections for sick animals therefore offer little basis for complacency. New research also indicates that antibiotics in feed can spur the spread of resistance by promoting new genetic mutations10 as well as by promoting the transfer among gut bacteria of resistance genes (including, potentially, antibiotic resistance genes) through phages.11 Transfer of resistance between pathogenic and commensal bacteria, Gram negative and Gram positive bacteria species, and between bacteria in farm and human settings have all been observed, not surprisingly. All inhabit the same microbial ecosystem.

An essential and typically overlooked point is that antibiotic resistance, often including resistance to a dozen or more antimicrobials of different classes, is often physically linked on single strands of DNA. The physical linkage means that cross selection can and does occur. In other words, exposure to just one of the antimicrobial agents represented on that genetic “cassette” can provide the selection pressure for a previously susceptible bacteria to acquire resistance to all the antimicrobials physically linked on that cassette. The fact of cross selection means that regulatory agencies’ typical approach of assessing the risk of single bug-drug combinations is at odds with the actual threat of resistance that exists in the microbial ecosystem.

Routine antibiotics are not necessary

Contrary to claims by some in the livestock and drug industries, routine antibiotics are not necessary for animal health. Pasture based production was the norm before antibiotics. Industrial style meat production, in which animals are confined in close quarters and fattened on soy and maize based feeds, also is possible without routine antibiotics, as Denmark has shown. Writing last year in Nature, Aarestrup compared Denmark, where antibiotic use is now 50 mg/kg of meat produced, with the US, where it is 300 mg/kg.8 Denmark has reduced antimicrobial use in livestock production by 60% while increasing pork production by half since 1994.

Almost every European and North American public health authority agrees: routine antibiotic use in animal food production likely worsens the epidemic of resistance. Hundreds of studies, recently summarised, comprise the ever growing body of evidence.12 Less certain is the political will to act on that information.

No—David G S Burch

When antibiotics are used, whether in humans or animals, there is a risk of selection for resistance. This applies not only to the target bacteria but also to commensal bacteria such as Escherichia coli and Enterococcus species that exist in the gut and may also be exposed to the antibiotic. Resistant infections have become increasingly problematic in hospitals and care homes, hence the concern about the extent of antibiotic use. However, adding antimicrobial products to the feed of animals in the European Union is unlikely to affect development of critical drug resistance in humans and pose a serious risk to human health.

How resistance develops

Treatment with oral antibiotics exposes the gut microflora to the drug and even some injectable products are excreted through bile into the gut. The drugs may kill susceptible bacteria and leave resistant ones, or resistant mutants may develop through a natural competitive response, with genes for resistance then passed from one bacterium to another, often by plasmids. Resistant strains are therefore just as likely to occur from human treatment as from adding an antimicrobial substance to the feed of an animal.

Veterinary medicine often involves treating large numbers of animals. Medicated feed is a common approach in the United Kingdom and other countries such as the US, especially in pigs, but less so in poultry where water medication is often preferred. More than half of antimicrobial use in the UK is in feed.13 Some countries want to reduce antibiotic use in animals because of fears about resistance, and the Netherlands has stopped the routine use of these drugs in feed. The main concerns in the Netherlands were an increase in meticillin resistant Staphylococcus aureus (MRSA), which had spread throughout the European Union pig herd, but not in the UK; increasing identification of extended spectrum β-lactamase producing bacteria, especially in poultry; and increasing fluoroquinolone resistance in E coli, again, especially in poultry.14

Different antibiotics

So was use of antibiotics in feed associated with this increased resistance? It was not. No meticillin or related products (which directly select for MRSA), third or fourth generation cephalosporins (which select for extended spectrum β-lactamase producing bacteria), or fluoroquinolones are approved for use in feed in the EU. In the UK the antibiotics licensed for use in feed under veterinary prescription only are mainly older classes such as tetracyclines, macrolides (tylosin, tilmicosin, and tylvalosin), lincosamides (lincomycin), pleuromutilins (tiamulin, valnemulin), diaminopyrimidine-sulfonamide combinations (trimethoprim-sulfadiazine), β-lactams (penicillin V, amoxicillin), aminoglycoside-aminocyclitols (neomycin, apramycin, and spectinomycin), and amphenicols (florfenicol).

Since the complete ban of antibiotic growth promoters in the EU, completed in 2006, the glycopeptide, avoparcin (human use: vancomycin, teicoplanin) and the streptogramin, virginiamycin (human use: quinupristin, dalfopristin) are no longer used in feed, although virginiamycin is still used in the US. Oxazolidinones (linezolid), carbapenems (meropenem, imipenem), and glycylcyclines (tigecycline) are not used at all in feed or licensed for veterinary use. A current controversy is colistin, which is approved for use in feed in some EU countries but not in the UK and is being considered for use in humans as a last resort, despite its toxicity.

Low risk of transmission to humans

How bacteria that might carry resistance genes are transmitted to humans must be considered. Farmers and workers in close contact with animals are likely to be exposed to infections from animals. The transmission of MRSA from infected pigs to farmers is common,15 but transmission to the general public is rare, reported at 0.003% of the population in Denmark.16

The main potential route of transmission to the public is through contaminated food products. Zoonotic infections, such as Salmonella enterica Enteritidis has been shown to be transmitted through eggs and poultry meat. The reported incidence of S Enteritidis infection in the EU fell by 41% between 2006 and 2009 because of the vaccination of laying and breeder flocks.17 Campylobacter is still a major contaminant of chicken carcasses, and the EU needs to tackle this. Pig meat and beef seem to be very low campylobacter carriers in comparison, but they are associated with S Typhimurium, with reported cases affecting 0.0045% of the UK human population.18 It is difficult to quantify Escherichia coli and enterococci carriage and spread by food to humans, but if campylobacter and salmonella are used as models, their contamination rate and survival after consumption are also likely to be relatively low. If the meat is cooked properly and there is good hygiene in the kitchen, the risk is extremely low—almost zero.

Environmental transmission is another possible route, through faecal and slurry spreading on fields, but normal mains water processing seems to be highly effective in managing this risk. Regulatory authorities assess the environmental risk of manure and the safety of antimicrobial residues in edible tissues before use is approved, unlike in human medicine.

Given that the critical antimicrobials in human medicine are not used in animal feed, that regulatory authorities conduct thorough assessments of the risk of resistance from use of antimicrobial substances, and that the environmental effect and the effects of residues in edible tissues are also assessed, it is highly unlikely that adding antibiotics to feed poses a serious risk to humans, especially compared with the extensive use of antibiotics directly in humans.

Source: BMJ


Fertility treatment and risk of childhood and adolescent mental disorders: register based cohort study.


Objective To assess the mental health of children born after fertility treatment by comparing their risk of mental disorders with that of spontaneously conceived children.

Design Prospective register based cohort study.

Setting Nationwide register based information from Danish National Health Registers cross linked by a unique personal identification number assigned to all citizens in Denmark.

Participants All children born in Denmark in 1995-2003 with follow-up in 2012 when the children were aged 8-17; 33 139 children were conceived after fertility treatment and 555 828 children were born after spontaneous conception.

Main outcome measures Absolute risks and hazard ratios for overall and specific mental disorders estimated with adjustment for potential confounding variables. Estimated association between the risk of mental disorders and subtypes of procedures, hormone treatments, gamete types, and cause of infertility.

Results The risk of mental disorders in children born after in vitro fertilisation or intracytoplasmic sperm injection was low, and was no higher than in spontaneously conceived children, except for a borderline significant increased risk of tic disorders (hazard ratio 1.40, 95% confidence interval 1.01 to 1.95; absolute risk 0.3%). In contrast, children born after ovulation induction with or without insemination had low but significantly increased risks of any mental disorder (1.20, 1.11 to 1.31; absolute risk 4.1%), autism spectrum disorders (1.20, 1.05 to 1.37; 1.5%), hyperkinetic disorders (1.23, 1.08 to 1.40; 1.7%), conduct, emotional, or social disorder (1.21, 1.02 to 1.45; 0.8%), and tic disorders (1.51, 1.16 to 1.96; 0.4%). There was no risk systematically related to any specific type of hormone drug treatment.

Conclusions There was a small increase in the incidence of mental disorders in children born after ovulation induction/intrauterine insemination. Children born after in vitro fertilisation/intracytoplasmic sperm injection were found to have overall risk comparable with children conceived spontaneously.


In this large long term follow-up of an unselected cohort of children conceived after fertility treatment, we found a systematically small increased risk of mental disorders in children born after induced ovulation/intrauterine insemination compared with spontaneously conceived children. When we considered the diagnoses in categories of mental disorders, there was a significant increased risk of autistic spectrum disorders, hyperkinetic disorders, tic disorders, and conduct, emotional, or social disorders. In contrast, beside a borderline significantly increased risk of tic disorders, we found no association between conception after IVF/ICSI and risk of mental disorders in childhood or adolescence. There were no systematic associations between cryopreserved embryos or gametes, types of hormones, or cause of infertility and risk of mental disorders.

What is known on this topic

  • Children born after fertility treatment have an increased risk of some perinatal outcomes such as low birth weight, shorter gestational age, and congenital malformations
  • The risk of malformations is related to the subfertility rather than the procedures or treatments
  • Long term development is sparsely investigated and few have studied children born after induced ovulation
  • The overall long term development of children born after IVF/ICSI is comparable with that of children conceived spontaneously
  • Children born after induced ovulation seem to have a small increased risk of autism, hyperkinetic disorders, conduct, emotional or social disorder, and tic disorders, but the absolute risks are low
  • Source: BMJ

What this study adds


Mediators of the association between pre-eclampsia and cerebral palsy: population based cohort study.


Objective To test the hypothesis that pre-eclampsia is a risk factor for cerebral palsy mediated through preterm birth and being born small for gestational age.

Design Population based cohort study.

Setting Clinical data from the Norwegian Cerebral Palsy Registry were linked with perinatal data prospectively recorded by the Medical Birth Registry of Norway.

Participants All singleton babies who survived the neonatal period during 1996-2006 (849 children with cerebral palsy and 616 658 control children).

Main outcome measures Cerebral palsy and cerebral palsy subtypes.

Results Children exposed to pre-eclampsia had an excess risk of cerebral palsy (unadjusted odds ratio 2.5, 95% confidence interval 2.0 to 3.2) compared with unexposed children. Among children born at term (≥37 weeks), exposure to pre-eclampsia was not associated with an excess risk of cerebral palsy in babies not born small for gestational age (1.2, 0.7 to 2.0), whereas children exposed to pre-eclampsia and born small for gestational age had a significantly increased risk of cerebral palsy (3.2, 1.5 to 6.7). Non-small for gestational age babies born very preterm (<32 weeks) and exposed to pre-eclampsia had a reduced risk of cerebral palsy compared with unexposed children born at the same gestational age (0.5, 0.3 to 0.8), although the risk was not statistically significantly reduced among children exposed to pre-eclampsia and born small for gestational age (0.7, 0.4 to 1.3). Exposure to pre-eclampsia was not associated with a specific cerebral palsy subtype.

Conclusions Exposure to pre-eclampsia was associated with an increased risk of cerebral palsy, and this association was mediated through the children being born preterm or small for gestational age, or both. Among children born at term, pre-eclampsia was a risk factor for cerebral palsy only when the children were small for gestational age.


In this study we found that pre-eclampsia was associated with an increased risk of cerebral palsy and that the excess risk was mainly mediated through preterm birth, but also through being born small for gestational age. Exposed children born at term as non-small for gestational age did not have an excess risk of cerebral palsy and we did not find that a specific cerebral palsy subtype was more common in children exposed to pre-eclampsia than not exposed. Thus we were not able to find evidence for a direct effect of pre-eclampsia on the risk of cerebral palsy.

What is already known on this topic

  • Pre-eclampsia is a frequent cause of preterm birth and being born small for gestational age, both of which are known risk factors for cerebral palsy
  • Observational studies have shown conflicting results with respect to whether pre-eclampsia is a risk factor for cerebral palsy
  • Pre-eclampsia is a risk factor for cerebral palsy mainly mediated through preterm birth and being small for gestational age
  • Among term born children exposed to pre-eclampsia only those born small for gestational age had an excess risk of cerebral palsy
  • Pre-eclampsia was not associated with specific subtypes of cerebral palsy

What this study adds


Source: BMJ


Gene Patenting — The Supreme Court Finally Speaks.

Are human genes patentable? On June 13, the Supreme Court gave its long-awaited answer — a unanimous “no.” The case, Association for Molecular Pathology v. Myriad Genetics, 1 has generated enormous interest among medical institutions, industry organizations, patient advocacy groups, and scientists. “ Life’s instructions,” James Watson asserted in one of 49 amicus curiae briefs, “ought not be controlled by legal monopolies created at the whim of Congress or the courts.” For some, the gene patents were symbols of a shrinking public domain and an overreaching patent system that traded too much monopolistic power for too little innovation. For others, the challenge to the patented genes amounted to an attack on the intellectual-property protections that fuel private investment in biomedical discovery.

Although ethical and policy arguments were a major feature of the debate surrounding the case, the decision focused squarely on the definitions of two codes: the genetic code and the patent code. All nine Justices of the Court agreed that the segments of DNA that make up human genes are not patentable subject matter under section 101 of the Patent Act2 because they are products of nature. However, the Court held, molecules that are reverse-transcribed from messenger RNA (mRNA) to eliminate intron sequences — so-called complementary DNA (cDNA) — are eligible for patents. The decisive sentence of Justice Clarence Thomas’s ruling crisply stated that, “a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but that cDNA is patent eligible because it is not naturally occurring.”

The decision joins a suite of recent Supreme Court cases that are reshaping patent law, with important implications for innovation in the life sciences. Here we review the Myriad Genetics case and the reasoning of the Court and discuss the implications for health care and the biotechnology industry. Patient advocates and industry groups alike can find something to celebrate in this Supreme Court decision: although it will open up competition in the genetic testing arena and drive down prices, it leaves undisturbed most of the intellectual-property rights on which the biotechnology industry depends.


The human genes at issue in the Myriad Genetics case are BRCA1 and BRCA2. In federally funded research dating back to the 1980s, Mary-Claire King and others identified a region of chromosome 17 that must contain a gene mutated in families with many cases of breast cancer. That gene became known as BRCA1, and it turned out to also predispose women to ovarian cancer.

King’s 1990 report of genetic linkage for a “breast-cancer gene”3 set off an intense race to clone and sequence it. A team led by Mark Skolnick of the University of Utah won that race4; Skolnick was also a cofounder of Myriad Genetics. In 1994, Michael Stratton and others mapped another locus in chromosome 13,5 which precipitated another furious race to identify and clone what became known as BRCA2. That race ended in a near tie,6 with the Stratton group publishing in Nature 7 just a day after Myriad filed a patent application,8-10 having gotten wind of the Stratton work.11

Myriad sought patent protection for methods of detecting and comparing DNA sequence variations and for the isolated DNA molecules. The claims on DNA molecules included cDNA and genomic DNA, sometimes both in the same claim. The Supreme Court parsed these elements in its decision .Types of Patents Issued to Myriad Genetics Relating toBRCA.). Applications by Myriad for BRCA1 and BRCA2 were broken into separate patents, covering different aspects of the work. These patents undergirded the commercialization of its BRACAnalysis test for predisposition to breast cancer, which Myriad first made available in 1996. Myriad filed subsequent patents and acquired rights to other BRCA patents by out-of-court settlements and now states that it has 24 patents containing over 500 claims relating to this field.12

The American Civil Liberties Union (ACLU) and the Public Patent Foundation, representing more than 20 plaintiffs, filed suit against Myriad in May 2009 in federal court for the southern district of New York. The litigation arose in large part because, in the intervening decade, a steady drumbeat of criticism had grown against the business practices of Myriad and against patents on genes in general. Objections raised by public health advocates included the restriction set by Myriad on certain uses of its genes in the context of research, its refusal to allow independent confirmatory testing of ambiguous initial results,13 and the high price of its genetic test (up to $4,000).14Advances in sequencing technology had made it possible for patients to have dozens of genes sequenced for less than what Myriad charged for BRCA1 and BRCA2 testing.15 Fueling advocates’ arguments were surveys showing that gene patents reduced access to testing16,17 and research showing that legal restrictions on gene sequences reduced product development by up to 20 to 30%, as compared with diagnostic products arising from freely available sequences.18

Inventors must satisfy several statutory criteria in the Patent Act to obtain patent protection, but theMyriad case focused on just one: whether the claimed inventions met the basic definition of patentable subject matter. That is, did they constitute inventions at all? The Patent Act defines the scope of patentable subject matter as “any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof.”2 The Supreme Court has previously established that “Anything under the sun that is made by man” is eligible for a patent19but has read into the patent statute an important implicit caveat that laws of nature, natural phenomena, and abstract ideas belong in the public domain.

In March 2010, Judge Robert Sweet of the southern district of New York issued a summary judgment order in the Myriad case, invoking long-standing Supreme Court doctrines to conclude that this caveat excluded DNA from patentability.20 He invalidated all 15 claims challenged in seven of the Myriad patents. The next year, a divided panel of the Court of Appeals for the Federal Circuit tempered the district court holding. The three-judge panel unanimously affirmed Judge Sweet’s determination that Myriad could not patent its method of testing for cancer risk by comparing a patient’s isolated BRCA1 and BRCA2 sequences to the reference sequences. By contrast, the panel upheld the method claim for the use of BRCA1 and BRCA2 in screening potential therapeutic agents against cancer and held that cDNA could be patented.

Most controversially, the Federal Circuit split 2 to 1 on whether DNA molecules corresponding to sequences found in cells were patentable because they were described in the patent claim as “isolated.”21 The two judges in the majority reached their conclusion that isolated DNA is eligible for patents in different ways. Judge Alan Lourie reasoned that the act of severing covalent bonds in the process of isolating the DNA created a new molecule, and Judge Kimberly Moore argued that not only fragmentation but also the demonstrable utility of isolated DNA sequences, as compared with native DNA, was the basis for patent eligibility.22 Judge William Bryson wrote a vigorous dissent arguing that isolated molecules were not eligible for patents because they were not different enough from their natural counterparts.

The Supreme Court reviewed the decision of the Federal Circuit court in 2011 but sent the case back for reconsideration in light of a newly issued Supreme Court decision invalidating a patent on a method of diagnostic testing.23 The Federal Circuit court judges did not substantively change their opinions in 2012, reiterating the same logic and coming to the same 2-to-1 split.24 On November 30, 2012, the Supreme Court agreed to hear arguments on one question only: Are human genes patentable?


To answer this question, the Supreme Court returned to the opaque and oft-contested boundary line between human inventions and discoveries of naturally occurring phenomena. Writing for a unanimous Court, Justice Thomas cited the long history of the Court of drawing a distinction between compositions of matter that are made by humans and those that are naturally occurring.Major Supreme Court Decisions Defining the Boundary between Inventions and Products of Nature.). The relevant doctrine, however, has been “vague and malleable,” in the words of Justice Felix Frankfurter in a seminal 1948 case.25 Cases have lacked clarity and consistency during the past hundred years, with the criterion that inventions must involve the application of human ingenuity seemingly established in different ways.

In considering patents on DNA sequences, Justice Thomas struck a balance between the long-standing principle that discoveries of natural phenomena are not patentable and the competing notion that “all inventions at some level . . . apply laws of nature, natural phenomena, or abstract ideas” by drawing a line between genomic DNA and cDNA. The isolated DNA sequences were not the proper subject of patents, he wrote, because they were not markedly different from the sequences found in nature. Indeed, they derived their diagnostic usefulness from having the identical sequence. Justice Thomas distinguished between the claims of Myriad and those at issue in the landmark 1980 case of Diamond v. Chakrabarty, which ushered in the modern explosion in biotechnology patents. In that case, a bacterium was genetically engineered to contain four naturally occurring plasmids, each of which was useful in breaking down oil. The inventor inserted the plasmids into the DNA of the microbe, giving rise to an organism not found in nature. No similar transformation of a product of nature was present in the claims of Myriad covering the isolated DNA sequences.

The cDNA claims, the Court held, were another matter. Because cDNA is reverse-engineered by scientists from mRNA to include only the protein-coding exons, it is different from any naturally occurring genetic material. It thus falls on the invention side of the line between discovery and invention. To then earn a patent, a sequence of cDNA would have to meet the remainder of the criteria required in the Patent Act of all inventions, including novelty, utility, and nonobviousness, although these considerations were not at issue in the Myriad case.

The parties challenging the cDNA patent claims argued that cDNA is a product of nature because it represents the naturally determined stretch of nucleotides that codes for the mRNA. Its information is what matters, they asserted, and that is the same as naturally occurring DNA. However, the Court focused on the human ingenuity involved in reverse-transcribing the sequence as a separate nucleotide array. The fact that some DNA sequences mimicking cDNA may occur by chance in nature was deemed insufficient to undercut its patentability.

Myriad represents the third in a series of decisions since 2010 in which the Supreme Court has redefined the boundaries of its three main exclusions from patentability — laws of nature, natural phenomena, and abstract ideas. In each of these categories, the Supreme Court has ultimately shown a more restrictive stance on patent eligibility than the Patent and Trademark Office.

The first case, Bilski v. Kappos, involved an abstract idea. In striking down a patent on an investment strategy, the Court announced that it supported a “high enough bar” on patenting abstract ideas that would not “put a chill on creative endeavor and dynamic change.”26 The patent was invalidated because it “would preempt use of this approach in all fields,” over a vigorous dissent from Justice John Paul Stevens, who agreed with the outcome but wanted to set down an even more formal rule excluding business methods from patent eligibility.

Next in 2012 came Mayo v. Prometheus, in which the Court unanimously invalidated patent claims on a method of adjusting the dose of thiopurine antiinflammatory drugs on the basis of metabolite levels.23 In that decision, the Court expressed concern “that patent law not inhibit further discovery by improperly tying up the future use of laws of nature,” which in that case was the correlation between doses of a drug and its physiological effects.27

Myriad extends this judicial anxiety to the context of DNA molecule claims. In concluding that “[g]roundbreaking, innovative, or even brilliant” discoveries of such natural phenomena are not patentable, the Court stressed the social cost: it “would `tie up’ the use of such tools and thereby `inhibit future innovation premised upon them.’”


Advocacy groups have heralded the Myriad decision as a huge win for patients. “VICTORY!,” the ACLU declared, “Our genes belong to us!”28 The invalidation of genomic DNA claims — and the earlier refusal by the appellate court to allow patents on methods of detecting BRCA1 and BRCA 2mutations — permits other companies to market their own genetic tests. Indeed, within days of theMyriad ruling, at least five competitors had announced that they would enter the market.29,30

Myriad has responded to this new competition with further infringement litigation.31 Patent claims by Myriad covering other methods and other “synthetic” DNA sequences such as primers and probes have not been challenged, and the Supreme Court specifically noted that they might indeed cover patentable subject matter. With the prospects for such infringement claims uncertain, however, Myriad may also seek to capitalize on its proprietary library of BRCA mutations, which provides a competitive advantage in interpreting rare mutations. The last deposit of data on BRCA variations by Myriad into the federal Breast Cancer Information Core database occurred in 2004, and a group of coauthors, including some from Myriad, published a manuscript listing 118 additional mutations in 2006.32 Since then, Myriad has not made public other BRCA variations that it received while holding its monopoly on testing. Recently, a physician-led grassroots effort has been organized to obtain data on rare variants directly from patients and their providers and publicly disseminate it, which could undermine this competitive advantage.33,34

Ultimately, the end of the Myriad monopoly should improve access to genetic testing and rapid turnaround of results by driving down the price — DNA Traits, for example, will charge less than $1,000 — and expanding capacity for analyzing samples. When the case was brought, one crucial concern was whether the claims in question blocked analysis by means of whole-genome sequencing. Myriad argued that its patents on isolated DNA involved sequestering BRCA sequences from others in the genome and that whole-genome sequencing would not infringe such patents. The ACLU pointed out, however, that the plain meaning of the claims would indeed cover molecules created during whole-genome sequencing. Given the outcome of the case (and in light of the oral arguments presented by Myriad before the Court), institutions offering whole-genome sequencing should no longer fear lawsuits from parties holding patents on isolated DNA.35

Although the Myriad decision places in jeopardy thousands of patent claims, its effects on biotechnology companies and innovation will probably be modest. A recent analysis estimated that as many as 3535 unexpired patents on naturally occurring, human gene sequences may be affected,36 although the applicability of the decision will depend on the specifics of each individual patent claim. Furthermore, because nothing about the reasoning of the Supreme Court would prevent its holding from being applied to nonhuman genes, several thousand patent claims relating to other organisms may also be affected, with implications for a range of applications outside human medicine. However, the same study showed that patent claims on merely isolated DNA were already on the decline. Since 2005, companies have sought to patent naturally occurring gene sequences much less frequently than they did in the past, perhaps because the Patent and Trademark Office raised the bar for meeting another requirement for patenting an invention — showing that it has practical utility. Some companies also found it more difficult than expected to profit from these DNA sequences and abandoned their patents.35,37,38 As a result, after Myriad, we expect that companies developing DNA-based therapeutic agents will need to more clearly distinguish their inventions from the genome itself and specify the claimed uses so as to avoid questions about covering the naturally occurring sequences.

Claims on DNA that has been engineered, in contrast, have been on the rise — in both frequency and scientific importance36 — and will continue to enjoy protection after Myriad.35 Patents on synthetic DNA include those on vectors and engineered molecules that could be useful as therapeutic agents themselves (e.g., in gene transfer) or in the process of making therapeutic proteins for so-called biologic drugs. Since these technologies remain squarely within the bounds of patentability outlined by the Supreme Court, the effects on innovation emerging from these areas should be minimal.

The impact of the Myriad decision on innovation will also be muted by the fact that the holding itself was clearly limited by Justice Thomas to isolated DNA corresponding to sequences found in nature. However, it may affect patent applications on DNA-based therapeutic agents, such as (still experimental) DNA vaccines, which will now have to clarify how the active sequence is not merely isolated but has been transformed and has a specific utility. It could also spill over into other areas of medical research, such as the development of diagnostic testing for microbes, which have genomes lacking introns altogether.

Finally, Myriad is important as an expression of strident judicial opposition to patents on methods of making medical diagnoses. The method claims for detecting genetic sequence alterations were struck down unanimously by the Federal Circuit court, and the Supreme Court declined to take up the question on appeal. It will therefore be impossible for companies to mimic a business model of identifying a gene sequence and attempting to control the production of diagnostic tests from it. The combination of the Myriad and Mayo decisions greatly diminishes the prospects of Myriad or any other company claiming monopolies on genetic diagnostic tests alone, without a direct linkage to therapeutic agents or other molecular transformations. For example, companies seeking to develop multigene diagnostic or prognostic tests will have to try to claim some combination of methods of diagnosis and modification of the DNA molecules, rather than relying simply on patents covering the underlying isolated DNA. Whether this will reduce private investment in genetic diagnostic testing and necessitate supplemental public research funding remains to be seen.


The Myriad decision will be an important symbol for those who seek to foster scientific discovery by protecting and expanding the public domain. It also has symbolic resonance with the ideal that our common humanity cannot be owned. The Universal Declaration on the Human Genome and Human Rights declares the human genome to be “the heritage of humanity” and that “the human genome in its natural state shall not give rise to financial gains.”39 The Supreme Court quietly came to a similar conclusion, though with attention to preserving the incentives important for biomedical innovation.

It is interesting that although the Supreme Court decision concerns human genes, humanness had no bearing on the decision. Nor does the law allow courts to consider whether patenting human genes — or anything else — should be disallowed on grounds of morality. There is a disconnect, then, between the reasons the Supreme Court articulated for its decision and the rich set of ethical and policy concerns that have animated much of the public interest in the case.

Those powerful ideas may or may not have swayed the Court as it considered a vague and open-ended legal doctrine. If the questions raised during oral argument are any indication, however, the justices were primarily interested in innovation — both in preserving patent incentives for investing in research and in the blocking effects that patent rights can have on upstream discovery. Viewed in this light, the decision represents a careful balancing act.

Source: NEJM




U.S. Hospitalizations for Pneumonia after a Decade of Pneumococcal Vaccination.


The introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into the U.S. childhood immunization schedule in 2000 has substantially reduced the incidence of vaccine-serotype invasive pneumococcal disease in young children and in unvaccinated older children and adults. By 2004, hospitalizations associated with pneumonia from any cause had also declined markedly among young children. Because of concerns about increases in disease caused by nonvaccine serotypes, we wanted to determine whether the reduction in pneumonia-related hospitalizations among young children had been sustained through 2009 and whether such hospitalizations in older age groups had also declined.


We estimated annual rates of hospitalization for pneumonia from any cause using the Nationwide Inpatient Sample database. The reason for hospitalization was classified as pneumonia if pneumonia was the first listed diagnosis or if it was listed after a first diagnosis of sepsis, meningitis, or empyema. Average annual rates of pneumonia-related hospitalizations from 1997 through 1999 (before the introduction of PCV7) and from 2007 through 2009 (well after its introduction) were used to estimate annual declines in hospitalizations due to pneumonia.


The annual rate of hospitalization for pneumonia among children younger than 2 years of age declined by 551.1 per 100,000 children (95% confidence interval [CI], 445.1 to 657.1), which translates to 47,000 fewer hospitalizations annually than expected on the basis of the rates before PCV7 was introduced. The rate for adults 85 years of age or older declined by 1300.8 per 100,000 (95% CI, 984.0 to 1617.6), which translates to 73,000 fewer hospitalizations annually. For the three age groups of 18 to 39 years, 65 to 74 years, and 75 to 84 years, the annual rate of hospitalization for pneumonia declined by 8.4 per 100,000 (95% CI, 0.6 to 16.2), 85.3 per 100,000 (95% CI, 7.0 to 163.6), and 359.8 per 100,000 (95% CI, 199.6 to 520.0), respectively. Overall, we estimated an age-adjusted annual reduction of 54.8 per 100,000 (95% CI, 41.0 to 68.5), or 168,000 fewer hospitalizations for pneumonia annually.


Declines in hospitalizations for childhood pneumonia were sustained during the decade after the introduction of PCV7. Substantial reductions in hospitalizations for pneumonia among adults were also observed.

Source: NEJM


What You Should Know about Palliative Care.

Palliative care is often misunderstood. People may associate it with end-of-life care or “giving up” – especially when facing a serious health challenge like cancer. But palliative care may not be what you think, and you shouldn’t be afraid to ask for it. Here’s a closer look at what palliative care is – and isn’t.

Palliative care doesn’t automatically mean end-of-life. The word palliative means “relieving pain” or “alleviating a problem,” and that’s exactly what this type of care is intended to do: be an extra layer of support that helps reduce the symptoms, anxiety, and stress often associated with a serious illness. A palliative care specialist addresses symptoms such as nausea, loss of appetite, fatigue, or weight loss.

“Although many people think all we do is take care of the dying, in fact we help patients with many different outlooks and diagnoses, at varying stages of illness,” says Janet Abrahm, MD, chief of adult palliative care at Dana-Farber/Brigham and Women’s Cancer Center.

It puts you in control. Palliative care is helpful throughout your cancer experience. Early on, it can help make treatments easier to tolerate. At later stages, it can reduce suffering, help you carry on with daily life, and assist in planning for future medical care.

“Patients and families may assume that cancer comes with pain and suffering,” says Abrahm. “And some patients are afraid they won’t know whether the cancer is getting better if they take medications  to reduce pain. We have other measures to monitor whether the cancer is getting better, so please let’s treat the pain.”

It offers benefits at any age. While palliative care is often associated with adult care, children can also benefit from it. For example, the Pediatric Advanced Care Team at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center helps ease pain in young patients.

It can spark important conversations. Palliative care involves helping patients and their loved ones discuss their priorities and wishes. This may be as simple as making sure the family has had a conversation about naming a health care proxy, or weighing the benefits and burdens of a treatment. But it can also involve discussions about a patient’s desires in extreme medical situations – such as needing a ventilator to stay alive.

“Opening this dialogue can help patients become more empowered in their care decisions,” Abrahm says. “And just talking about these difficult topics can be incredibly freeing for family members.”

So what’s the best time to ask your health care team about palliative care? Abrahm says it’s OK to ask about it right from the start – any time you face a diagnosis of a serious or life-limiting illness.




New two-drug combination shows activity in ovarian cancer.

A novel pairing of two cancer drug types showed promising activity and had manageable toxicities, according to a first-of-its-kind clinical trial led by scientists at Dana-Farber Cancer Institute

The combination of a PARP inhibitor and an anti-angiogenesis drug, tested for the first time in advanced ovarian and triple-negative breast cancers, achieved a 61 percent clinical benefit rate in the ovarian cancer patients, said the researchers, led by Joyce Liu, MD, MPH, and Ursula Matulonis, MD, of Dana-Farber. The drug combination was less active in the small number of advanced breast cancer patients.

The report was posted online by the European Journal of Cancer.

“This study shows that the combination of a PARP inhibitor and an angiogenesis inhibitor is feasible with toxicities, and had definite clinical activity in ovarian cancer patients,” said Liu, a gynecological oncologist with the Susan F. Smith Center for Women’s Cancers at Dana-Farber/Brigham and Women’s Cancer Center.

Clinical benefit rate” refers to the percentage of patients with advanced cancer that have experienced a complete response (cancer no longer visible on imaging), a partial response (the burden of cancer has decreased by at least 30 percent), or whose disease has remained stable for at least six months.

One of the ovarian cancer patients had a complete response and seven had partial responses – a 44 percent response rate – and three additional patients had stable disease for at least 24 weeks. The drugs didn’t achieve clinical responses in the breast cancer patients, though two patients had stable disease for 24 weeks or more.

“The trial began in April 2010, and some patients have done very well, with a few still on treatment after over two years on trial,” Liu said. The study was designed to evaluate the toxicity profile of various doses of the drug, and to look for signs of clinical activity, but overall survival wasn’t measured.

The patients experienced significant toxicities, including fatigue, high blood pressure, and diarrhea; Liu said these symptoms were controlled with medications and reducing doses when necessary. “The side effects were very representative of what you’d expect to see with either of the drugs alone,” she added.

The Phase 1 trial included 20 patients with ovarian cancer and eight with triple-negative breast cancer, meaning the tumors lack receptors for estrogen, progesterone, and HER2/neu. Patients took the two drugs daily in pill form: Olaparib, a PARP inhibitor, and cediranib, an angiogenesis inhibitor. PARP inhibitors block the activity of a repair protein in cancer cells, causing them to self-destruct. Cediranib blocks a protein, VEGF, that enables tumors to grow new blood vessels to feed their rapid growth. Angiogenesis inhibitors are designed to prevent new vessels from developing.

PARP inhibitors also have some anti-angiogenic effects, suggesting that the two types of drugs might have synergistic effects in cancer. The current trial was the first designed to test this idea specifically in breast and ovarian cancers. The next stage of this two-part trial is a Phase 2 study that will examine whether the two-drug combination is better than olaparib alone in recurrent ovarian cancer.

“We do need to ask if this combination is superior to a PARP inhibitor alone, and we are hoping to determine this in our ongoing Phase 2 trial,” said Liu.


In vivo cardiac reprogramming contributes to zebrafish heart regeneration.

Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the developed world due to the limited capacity of adult mammalian ventricular cardiomyocytes to divide and replace ventricular myocardium lost from ischaemia-induced infarct1,2. Hence there is great interest to identify potential cellular sources and strategies to generate new ventricular myocardium3. Past studies have shown that fish and amphibians and early postnatal mammalian ventricular cardiomyocytes can proliferate to help regenerate injured ventricles456; however, recent studies have suggested that additional endogenous cellular sources may contribute to this overall ventricular regeneration3. Here we have developed, in the zebrafish (Danio rerio), a combination of fluorescent reporter transgenes, genetic fate-mapping strategies and a ventricle-specific genetic ablation system to discover that differentiated atrial cardiomyocytes can transdifferentiate into ventricular cardiomyocytes to contribute to zebrafish cardiac ventricular regeneration. Using in vivo time-lapse and confocal imaging, we monitored the dynamic cellular events during atrial-to-ventricular cardiomyocyte transdifferentiation to define intermediate cardiac reprogramming stages. We observed that Notch signalling becomes activated in the atrial endocardium following ventricular ablation, and discovered that inhibiting Notch signalling blocked the atrial-to-ventricular transdifferentiation and cardiac regeneration. Overall, these studies not only provide evidence for the plasticity of cardiac lineages during myocardial injury, but more importantly reveal an abundant new potential cardiac resident cellular source for cardiac ventricular regeneration.

Source: Nature



New tools automatically match patients with clinical trials.

The majority of Americans—72%—say they would take part in a clinical trial recommended by their doctor, according to a survey released last month by the Alexandria, Virginia-based science advocacy group Research!America. Despite that enthusiasm, though, there’s a shortage of enrollment. According to US government estimates, only about 3% of patients with advanced cancer enroll in phase 1 trials. Part of the problem, experts believe, comes down to a lack of awareness: the general public doesn’t know about investigational trials, and few physicians discuss the option with their patients.


New tools unveiled this year that automatically prescreen patients for trials based on their electronic medical records and email matches to doctors could help solve the problem. “We’ve needed these kinds of tools for a long time,” says Eric Topol, a cardiologist and director of the Scripps Translational Science Institute in La Jolla, California. “Physicians are really busy, and there are so many clinical trials that no human could track them all.”

The US federal registry,, currently lists more than 145,000 trials in all 50 states, as well as 184 foreign countries. Wading through those listings is a daunting task for individuals interested in signing up for a study, assuming that they know of the resource to begin with. Ultimately, problems with patient recruitment delay clinical trials by 4.6 months, on average, according to the Center for Information and Study on Clinical Trial Research Participation, a nonprofit organization in Boston. That holdup means it takes longer for treatments to reach the market.

To increase enrollment, some patient-advocacy groups have started playing matchmaker. A year ago, the Michael J. Fox Foundation for Parkinson’s Research launched the Fox Trial Finder, a web portal designed to help pair people with Parkinson’s with clinical studies (see Nat. Med. 18, 837,2012). The Alzheimer’s Association’s TrialMatch, meanwhile, has been up and running since 2010. Anyone can register online or by phone and see if he or she—or a patient or loved one—is a good fit for any of the 153 trials in 621 locations. To date, there have been 11,166 referrals, says Heather Snyder, the Chicago-based association’s director of medical and scientific operations.

In addition to the Fox Trial Finder and TrialMatch, for-profit companies have unveiled web portals to link people with studies. New York’s EmergingMed helps connect individuals with cancer trials, and in late May, Michigan-based CureLauncher unveiled a clinical-trial-matching service for a range of disorders. But tools such as these rely on the gumption of patients and doctors to wade through web listings. A new wave is emerging of automated tools that do away with the need for patients or physicians to manually enter information.

On alerts

Earlier this year, the Virginia Commonwealth University’s Massey Cancer Center in Richmond unveiled two new tools that work with its Clinical Trials Eligibility Database, which stores information about patients and clinical trials at the center. Since February, its MD Alert Notification System has automatically prescreened the list of scheduled patients each morning and emailed physicians when it finds that one of those individuals is eligible for one or more of 75 open trials at the center.

“If the patient is interested, one click by the physician refers them to the research nurse associated with that trial,” says Lynne Penberthy, director of the Massey Cancer Center’s informatics core who oversees the tracking and matching tools. Another new computer application there, the Automated Matching Tool, has been available since January. It screens all patients in the system on a scheduled basis, not just those coming in for a visit.

An algorithm known as Trial Prospector offers even greater automation for clinical trial enrollment. In a pilot study presented at last month’s American Society of Clinical Oncology meeting in Chicago, the program reached into the medical records of 60 people with gastrointestinal cancer who had scheduled appointments at the University Hospitals Seidman Cancer Center of the Case Comprehensive Cancer Center in Cleveland, Ohio. It pulled out 15 pieces of information—including age, diagnosis and blood count—that it compared to eligibility criteria of the 300-plus trials in Cases’s database. It then emailed doctors lists of any matches, and it also shows the studies for which the patient didn’t qualify and explains why; for example, some factors, such as low red blood cell count, might be easily fixed with a transfusion. The algorithm was 100% accurate, and 11% of the patients ended up enrolling in a trial suggested to the doctor by the algorithm.

“In theory this could be readily adapted anywhere, but we’ve still got a long way to go,” says Neal Meropol, associate director for clinical research at the Case Comprehensive Cancer Center. His team plans to refine Trial Prospector over the next 6 to 12 months, expand it to other cancers, and test it in a community-practice setting, where physicians aren’t highly specialized and may not have as much knowledge of open trials.

Penberthy similarly sees automated trial matching tools as a way to reach a more diverse set of participants. “We’re hoping that this is going help increase the equity,” she says. “It may help to increase minority patients enrolled in clinical trials,” an underrepresented population.

Topol, who isn’t involved with the programs, says that although automated matching programs are in their infancy, “eventually they could build something that’s extraordinary.”

Source: Nature