english.prescrire.org > Annual Prescrire Awards > The Prescrire Awards for 2010 > The 2010 Prescrire Awards: chosen in all independence by Prescrire's Editorial staff > A look back at new drugs and new indications in 2010 > New drugs and new indications in 2010: inadequate assessment; patients at risk

The Prescrire Awards for 2010

The 2010 Prescrire Awards: chosen in all independence by Prescrire's Editorial staff

A look back at new drugs and new indications in 2010
New drugs and new indications in 2010: inadequate assessment; patients at risk

In 2010, our independent analyses of 291 new drugs and indications were published in our French edition la revue Prescrire. They included: 46 new products with new brand names, 17 line extensions, and 24 copies with fancy brand names (“hidden generics”) (a).

All that glitters...
We systematically examine the therapeutic value of all new drugs, products with new brand names, line extensions, and new indications of existing products in France. In 2010, we rated 97 drugs, including 3 products that we reexamined after longer follow-up.

Half of these new products and indications – 49 to be precise – provided no advantages over existing options. Some conditions, such as cancer, diabetes and hypertension, are particularly lucrative for drug companies, but patients rarely benefit.

Lack of therapeutic advance
In 2010 we found that only 4 drugs provided a therapeutic advantage (see notes c and d of the rating table below). The only drug we rated “A real advance” was imatinib (Prescrire Int n°114), a product that had already been on the market for several years and that we re-evaluated in 2010 (see note c of the table > Prescrire's ratings over 10 years). The new data showed an overall survival time of more than 4 years with imatinib in patients with inoperable or metastatic gastrointestinal stromal tumours, compared to only 1.5 years previously.

Too few data were available to determine the role of 3 other drugs in the therapeutic arsenal (see note f of the table > Prescrire's ratings over 10 years). One of these 3 drugs was a cell therapy product (autologous chondrocytes, and coming in the May 2010 issue of Prescrire Int).

Incapable of bringing new drugs to the market that represent a real therapeutic advance, companies are recycling old drugs in the form of fixed-dose combinations or new routes of administration.

The following are a few examples in the field of cardiology, in which fixed-dose combinations continue to flood the market: amlodipine + valsartan + hydrochlorothiazide (Prescrire Int n°114), aliskiren + hydrochlorothiazide (Rev Prescrire n°315), and nebivolol + hydrochlorothiazide (Rev Prescrire n°316).

One in five new products can be avoided
In Prescrire’s at-a-glance rating system, “Not acceptable” indicates that the drug has a negative risk-benefit balance in one or more of its approved indications.

The proportion of drugs that we consider “Not acceptable” has been high for the past several years and was about 20% in 2010 (19 out of 97 ratings). Half of the products concerned are cytotoxic agents authorised for use in cancer or haematological disorders (see note e of the table  > Prescrire's ratings over 10 years).

Two generic drugs examined in 2010 have negative risk-benefit balances: nefopam in acute, especially postoperative, pain (Rev Prescrire n°324), and oxomemazine, in cough (Rev Prescrire n ° 323).

Paediatrics: inadequate assessment and little progress
Since 2007 and the implementation of the European Paediatric Regulation requiring companies to evaluate their drugs in children (unless exempted), the number of drugs authorised for paediatric use has been increasing.

In 2010, certain drugs represented a slight therapeutic advance (rated as “Possibly helpful”), but their assessment was usually minimal and sometimes wholly inadequate.

They included: 

  • darunavir (Rev Prescrire n°321) and tipranavir (Rev Prescrire n°321) for HIV-infected children;
  • losartan for hypertensive children (Prescrire Int n°108 );
  • omeprazole in heartburn and gastroesophageal reflux, and Helicobacter pylori infection (Rev Prescrire n°319);
  • the combination of peginterferon alfa-2b and ribavirin in hepatitis C (Rev Prescrire n°325);
  • botulinum toxin type A for limb spasticity (Rev Prescrire n°325).

Monoclonal antibodies: too many products, rarely helpful
The number of therapeutic monoclonal antibodies (whose international non-proprietary names (INNs) end in -mab) and their indications continue to grow, especially in oncology and rheumatology. These drugs are publicised as “targeted treatments” heralding an era of “personalised medicine”. In practice, they rarely represent a major therapeutic advance, and several expose patients to unjustified risks (see notes d and e of the table  > Prescrire's ratings over 10 years). 

Avoiding iatrogenic complications
Marketing authorisation is being granted prematurely for an increasing number of new drugs, before their efficacy and particularly, their adverse effects have been properly evaluated (Rev Prescrire n°326).

One would expect drug regulatory agencies to be more cautious and responsive following scandals such as the diethylstilbestrol (DES) disaster and, more recently, the benfluorex (ex-Mediator°) affair (Prescrire Int n°105, 107, 113 and > www.english.prescrire.org).

Market withdrawal: an effective measure, especially when timely
Drug regulatory agencies often appear reluctant to withdraw drugs with negative risk-benefit balances, allowing sales to continue unabated and needlessly exposing patients to a risk of adverse effects.

The return of topical ketoprofen to the market after initial withdrawal at the demand of the French drug agency (Afssaps) illustrates how drug companies’ financial interests are often put ahead of patient safety (Prescrire Int n°109, 112,113).

In 2010, only a small proportion of drugs with a negative risk-benefit balance were taken off the market, several years after their dangers were first identified.

They included bufexamac, a topical nonsteroidal antiinflammatory drug, because of potentially serious cutaneous disorders (eczema) (Rev Prescrire n °321, 325); carbocisteine and acetylcysteine (mucolytic agents) in infants, because of respiratory adverse effects (Rev Prescrire n ° 320,324); rosiglitazone (an antidiabetic), because of cardiovascular adverse effects (Rev Prescrire n°325, 326); and sibutramine (an appetite suppressant), also because of cardiovascular adverse effects (Prescrire Int n°107).

Refusal to grant marketing authorisation: another effective means of protecting patients
Patients were protected from exposure to unnecessary risks of certain drugs last year, after the EU Committee for Medicinal Products for Human Use (CHMP) refused to grant market approval or issued an unfavourable opinion, leading the company to withdraw its application. They included:

  • refusal of marketing authorisation for gemifloxacin, a particularly risky fluoroquinolone (Rev Prescrire n°319);
  • refusal of marketing authorisation for ixabepilone in breast cancer, because of serious and frequent neuropathies and haematological disorders (Rev Prescrire n°315);
  • refusal of extension of the indications for two psychotropics used in fibromyalgia: pregabalin and milnacipran (in depression) (Rev Prescrire n°320).

Adverse effects: insist on more openness
Because marketing authorisation is increasingly granted prematurely, the adverse effect profiles of many new drugs are not properly documented at the time of market release.

Post-marketing data on adverse effects are therefore crucial and must be made available to the public. The European Medicines Agency (EMA) issued alerts on the following products (among others) in 2010:

  • becaplermin because of infections and cancer (Prescrire Int n°108);
  • fluoxetine because of cardiac malformations in newborns exposed in early pregnancy (Rev Prescrire n°323);
  • lenalidomide because of myocardial infarction (Prescrire Int n°109);
  • olanzapine because of sudden death and urinary incontinence (Prescrire Int n°109);
  • orlistat because of interactions, pancreatitis and nephropathies (Prescrire Int n°107, 110);
  • angiotensin II receptor blockers because of a risk of cancer (Rev Prescrire n°323);
  • telbivudine because of rhabdomyolysis and neuropathies (Prescrire Int n°108);
  • tocilizumab because of intestinal perforation (Prescrire Int n°109).

Too often, information about adverse effects is still withheld or only partially released by drug agencies, preventing healthcare professionals and patients from assessing the risks associated with the drugs they use. The following are a few examples of products for which Prescrire requested information directly from regulatory agencies:

  • exenatide because of excessive weight loss (Prescrire Int n°112);
  • phloroglucinol because of serious allergic reactions (Prescrire Int n°109);
  • telithromycin because of confusion and hallucinations (Rev Prescrire n° 316).

Pharmacovigilance in Europe: the risks of subcontracting to drug companies
The European Commission’s draft text on pharmacovigilance placed patients at risk.
> Click here for Prescrire's online Dossier on Pharmacovigilance in Europe

Thanks to public mobilisation, several provisions were amended, notably clarifying the role of risk management plans (these can no longer serve to justify accelerated marketing authorisation) and by authorising direct reporting of adverse effects by patients. These reports complement those of healthcare professionals, who tend to report more serious adverse effects (Prescrire Int n°114).

In contrast, some of the measures that were adopted represent a major step backwards, such as ending member states’ public funding of pharmacovigilance, undermining its independence from drug companies. In addition, drug companies will be recording and coding adverse effects in the European database (Eudravigilance), which could lead to distortion of information.

Pharmacy patient records to limit drug risks
In France, pharmacists can set up electronic medications records ("dossier pharmaceutique") to limit drug-related risks. Pharmacy medications records improve patient safety and allow information to be shared. However, not all treatments are currently listed (Rev Prescrire n°319).

There were some welcome measures: for example, follow-up notebooks to prevent pregnancy in women treated with teratogenic drugs such as oral isotretinoin and thalidomide (Rev Prescrire n ° 316, 317). However, it was unwise of drug agencies to delegate the preparation and distribution of these notebooks to drug companies.

Inadequate "risk management" plans
“Risk management” plans and “risk minimisation” measures are frequently inadequate. They are often delegated to drug companies by drug regulatory agencies, and they mainly serve to justify premature marketing authorisation with a commitment to conduct large post-marketing trials (Rev Prescrire n°319).

Heterogeneous “umbrella” ranges: caution
In France, the self-medication market continued to grow in 2010, but most new products had little if any efficacy and did have noteworthy adverse effects. In addition, the fancy brand names and packaging concocted by manufacturers and allowed by drug agencies are unlikely to promote rational use. Pharmacists must carefully select the self-medication products they sell to their clients.

New self-medication products: amorolfine and omeprazole sometimes useful
In 2010, five drugs became available without a prescription: amorolfine (Rev Prescrire n°319), levocabastine (Rev Prescrire n°320), omeprazole (Rev Prescrire n°326), tixocortol (Rev Prescrire n ° 320) and trimebutine (Rev Prescrire n ° 326).

Some provide a small benefit:

  • amorolfine (Rev Prescrire n°321) is only applied once a week for fungal nail infections, instead of once a day as with ciclopirox;
  • omeprazole (Rev Prescrire n°326) is the standard proton pump inhibitor for gastroesophageal reflux.

In contrast, tixocortol, a steroid, should not be used for sore throat (Rev Prescrire n°320).

Fancy brand names and "umbrella" ranges: misinformation and danger
Patient safety can be improved by highlighting the INN on drug labelling or including it in the brand name, thus reducing the risk of overdose with drugs present in several self-medication products, such as paracetamol and ibuprofen. This can also help to avoid confusion between similar brand names (Rev Prescrire n°318, 325).

In practice, the INN is rarely highlighted, particularly in self-medication products. “Umbrella” ranges, in which several products with a different composition or regulatory status share a common stem as part of their brand name, are proliferating. This creates a risk of confusion between drugs belonging to the same product line. This is especially the case for products sold to treat coughs and colds. For example, the following “umbrella” ranges were extended in France in 2010: Clarix° (Rev Prescrire n°318), Codotussyl° (Rev Prescrire n°317), Dolirhume° (Rev Prescrire n°318) and Humex° (Rev Prescrire n°317).

Advertising: drug companies continue to spin their web
In late 2009, after reviewing the activities of medical sales reps, the French National Authority for Health (Haute autorité de santé, HAS) stressed the ineffectiveness of the medical sales charter, and admitted that it was incapable of regulating this activity (Prescrire Int n°109).
Although late in coming, this is a welcome realisation. In the meantime, however, drug companies continue to engage in advertising practices that put patients at risk.

Direct-to-consumer (DTC) advertising of prescription drugs: danger
The European Commission’s plans to allow companies to advertise prescription- only drugs directly to the public were once again debated by the European Parliament in late 2010 (see www.english.prescrire.org). The draft text was largely amended but still leaves the door open for some possible drug company advertising of prescription drugs to the public.

Marketing costs: nearly one-quarter of drug companies’ total spending
Patients and healthcare professionals need reliable and comparative information on illnesses and their management. Drug companies, for which each illness represents a market niche, are not in a good position to meet this need (Rev Prescrire n°324, 326). Yet marketing costs represent about 23% of drug companies’ spending, according to a survey conducted by the European Commission (Rev Prescrire n°315).

Drug promotion can take various forms, from training courses “under the influence” of the private sector (Rev Prescrire n°319), to the use of high-tech gimmickry to hide the dearth of real innovation (Rev Prescrire n°316), and advertising disguised as scientific information (Rev Prescrire n°323). Some healthcare professionals contribute indirectly to drug companies’ marketing strategies by providing information on prescriptions and sales, sometimes in return for small gifts (Rev Prescrire n°315).

Illicit advertising aimed at healthcare professionals
Doctors, pharmacists and even nurses are all targeted by drug companies seeking to increase sales of their products (Prescrire Int n°108).

Some of the advertisements banned by the French regulator (Afssaps) in 2010 are particularly informative:

  • misleading comparison and overstated results for Alimta° (pemetrexed) and Loramyc° (miconazole) (Rev Prescrire n°318);
  • minimisation of the risks of Botox° (botulinum toxin A) (Rev Prescrire n°318);
  • overstated claims concerning the indications for Calciprat vitamine D3° and Caltrate vitamine D3° (calcium + vitamin D3), Gardasil° (papillomavirus vaccine 6, 11, 16, 18), Lacteol° (Lactobacillus acidophilus) and Solacy° (vitamin A + L cystine + sulphur + yeast) (Rev Prescrire n°318; 323; 326);
  • misleading information on the indications for Inofer° (ferrous succinate) (Rev Prescrire n ° 318); Some of the advertisements banned by the French regulator (Afssaps) in 2010 are particularly informative:
  • unfounded criticism of generic versions of Omexel° (tamsulosin) (Rev Prescrire n°318);
  • overly positive presentation of Exforge° (amlodipine + valsartan) and Tareg° (valsartan) by opinion leaders (Rev Prescrire n°323).

In the United States, legal action taken against the company marking quetiapine (Seroquel°) revealed the extent to which some firms are willing to go to promote their products: off-label promotion, financial incentives for physicians to write or even simply sign articles on off-label uses. The company was forced to refund public health insurers for the costs of unwarranted prescriptions (Prescrire Int n°112).

Patients first!
In 2010, as in previous years, there was a dearth of real therapeutic advance as well as continued failings of policy makers and healthcare authorities, such as approval of poorly evaluated drugs with negative risk-benefit balances, or failure to withdraw them from the market.

Unable to rely on regulatory agencies and healthcare authorities, it is up to healthcare professionals to select drugs that truly benefit their patients and avoid needlessly exposing them to the risk of adverse effects.

©Prescrire April 2011

Note :
a- In addition: new indications, reassessments (“A second look”) for drugs already analysed in Prescrire, generics, wording changes in the labelling, miscellaneous changes, brand name changes, and market withdrawals.   

"New drugs and indications in 2010: inadequate assessment; patients at risk" Prescrire Int 2011: 20 (115): 105-110. (Pdf, free)