In the 12 months ended September 2009, global prescription sales growth of generic drugs climbed by 7.7%, up from 3.6% in 2008, according to US-based health care information and consulting company IMS Health. This compares with the 5.7% growth seen within the overall global pharmaceutical universe last year, says Doug Long, vice-president, industry relations at IMS Health.

During that 12-month period, global generic products generated $83bn (€59.8bn) in audited sales, according to IMS. US market data provider BCC Research estimates that the global market was worth $84bn in 2009.

The global industry virtually had 10 years in a row of good growth – not only in prescriptions but also in sales. All the dynamics of the generics industry were strong and it seems to have even prospered more during the economic slowdown. Generics now account for 72% of the total US pharmaceutical market volume, reaching an all-time high in 2009, he adds. However, they still only account for 17% of total sales, despite generics sales having more than tripled since 2000. In the 12 months ended November 2009, the US generics market was valued by IMS at $31bn. BCC Research estimates the US market in 2009 at $34bn.

The demand for generics is increasing steadily because of pressure to control health care costs. But at the same time, fierce price competition is resulting in slashed profit margins for participating companies. A major growth driver for the generics sector is that several blockbuster pharmaceutical brands are coming off patent and therefore open to generic competition.

Israel-based Teva Pharmaceutical Industries’ (18% global market share), Switzerland-headquartered Novartis’s US generics business, Sandoz (10%), and both US-based Mylan (6%), and Watson (6%) are leading generics manufacturers, already occupying 40% of the global market. IMS estimates that sales from the top 10 US generic players grew at an average of 13.2% last year.

AT THE TOP

The top four global generics manufacturers – Teva, Sandoz, Mylan and Watson – also accounted for 47% of the US market as of 2009, according to IMS. The top 10, which also includes Canada’s Apotex, Pfizer’s US-based generics business Greenstone, Qualitest Products, Mallinckrodt and Actavis US, all US, and Lupin Pharmaceuticals, the US subsidiary of India-based Lupin, accounted for 66% of the market.

This means there are still many players out there that are pretty small and would be ripe for acquisitions or mergers. Everybody expects that there will be consolidation within the generic drugs industry as smaller producers are experiencing significant margin pressure in this environment.

At the same time, large companies are consolidating their operations in established markets and/or expanding into emerging ones through local acquisitions or partnerships.

In May 2009, Sandoz acquired the specialty generics business of Austria-based Ebewe Pharma, while Teva closed its acquisition of US-based Barr Pharmaceuticals in December 2008.

In December, Teva’s Japanese joint venture, Teva-Kowa Pharma, acquired a 66% stake in generics firm Taisho Pharmaceutical Industries.

In Teva’s 2010-2015 growth strategy announced in early January, the company says it will continue to acquire companies that will boost its market share in attractive geographies as well as enhance its branded business with niche specialty products.

“Only those who are agile and strong will survive in this business,” according to Teva president and CEO Shlomo Yanai during the company’s investor meeting last month in Jerusalem. “About 15% of our business will come from acquisitions. We are taking the necessary steps and building our infrastructure by getting assets and know-how either internally, through acquisition or partnerships.” Teva estimates its 2009 global sales at $13.9bn, of which 70% are from generic products. Yanai is targeting $31bn in sales by 2015, of which 70% will still come from generics.

“There is still room to grow in generics,” says Yanai. “Almost $150bn of branded drugs are going to be off patent in the next five years. This does not include the expiration of biologics, which is an additional $50bn potential.” Teva projects that the global generics market will reach between $135bn and $150bn by 2015. BCC estimates the global market to reach $129.3bn by 2014, representing a 9% annual growth rate.

BOOMING MARKETS

While generics firms are eagerly awaiting the ticking patent expiration of several branded blockbuster drugs, manufacturers are also monitoring the increasing emergence of government health care reforms worldwide.

In almost any given country in the world, you may see different kinds of initiatives or reforms on their own health care systems or even regulating their own pharmaceutical industry. This will increase the pace of generic drug penetration, especially in countries that are asking for better health care.

International markets are especially ripe for generics. In the $59bn global generics market in developed countries, Japan only accounts for 6%, while the US holds 42%, and five major European national markets account for 23%.

China, India, Eastern European countries and Brazil are rising centers of generics activity in emerging markets, Evers adds.

Big pharmaceutical companies are even buying generics firms to get into these emerging markets.As an example France-based Sanofi Aventis’s acquisitions last year of Brazil’s Medley and Mexico’s Kendrick, and in 2008 of Czech Republic-based Zentiva. UK-based GlaxoSmithKline (GSK) acquired Aspen of South Africa in July 2008, while at the same time, Japan’s Daiichi Sankyo acquired India’s Ranbaxy.

US-based Pfizer is now also reportedly in a bidding war against Teva for the acquisition of Germany’s Ratiopharm. In 2009, Ratiopharm holds 3% of the global generics market.

Pfizer started increasing its activities in generics last year with an expanded relationship with Indian firm Aurobindo in March and a commercialization deal with Indian injectable generics specialist Claris Lifesciences. Last month, Pfizer announced a deal with US-based Strides Arcolab to commercialize off-patent sterile injectable and oral products.

At this point, it looks like Pfizer is really geared up towards expanding more into the generics market. Still, not everything is expected to be rosy for the generics market, especially after 2013, when patent expiries will be significantly lower.

The slowing growth in branded blockbusters being developed by research and development-based manufacturers will ultimately lead to fewer opportunities for generics companies.They are now looking ahead and trying to compete in a less crowded and less competitive market such as in biosimilars.

Biosimilars are generic versions of biotechnology-based drugs.

REGULATORS CLOSE IN ON PAY-FOR-DELAY DEALS

Generic and branded pharmaceutical companies are not always at each other’s throats. Both the US Federal Trade Commission (FTC) and the European Commission announced their closer scrutiny of the so-called “pay-for-delay” deals, where branded drug companies pay generics firms to delay the market launch of their generic drugs for a certain period of time.

Last month, the Commission asked companies including AstraZeneca, GlaxoSmithKline and Niche Generics, all of the UK, Gemany’s Boehringer Ingelheim, Novartis and Roche, both Swiss, and France’s Sanofi-Aventis to provide information pertaining to generics settlement agreements in Europe between July 2008 and December 2009.

From now on, the Commission also plans to gather this data on an annual basis in the same way as the FTC, which produces annual reports detailing the type and frequency of settlement agreements undertaken by US pharmaceutical companies.

The FTC released a report in January that claimed that the number of pay-for-delay deals in the US increased from zero in 2004 to a record 19 in 2009. The deals are said to cost consumers $35bn (€25bn) over 10 years. The Commission, meanwhile, estimates that these kinds of deals could have cost European consumers €3bn ($4bn) between 2000 and 2007.

The nation currently spends $275 billion a year on prescription medicines. But over the next five years, analysts forecast a golden era for generic drugs, as patents begin to expire on brand-name medications with more than $60 billion in combined annual sales. That will open the door to copycats that may be 30 percent to 80 percent cheaper.

“There’s a tidal wave of generic drugs, and we are just in the beginning of the tidal wave,” said Laizer Kornwasser, an executive for Medco Health Solutions, which manages prescription drug plans. The rise of generics has helped slow spending increases for prescription medications over all, even though an aging population is consuming more drugs and even as new medicines enter the market — including cancer drugs costing tens of thousands of dollars.

Ronny Gal, an analyst for Sanford C. Bernstein who follows generic companies like Teva Pharmaceutical Industries, Barr Pharmaceuticals and Mylan Laboratories, predicts 10 to 13 percent annual profit growth in the industry by 2010. He describes the generic trend as “good for everybody but the branded pharmaceutical companies.” Last week, the big drug maker Johnson & Johnson announced it would eliminate up to 4,800 jobs as it braced for generic competition to its drugs, Risperdal for schizophrenia and Topamax for seizures and migraine headaches.

In the previous year, combined United States sales of the drugs were $4 billion. Shortly after the Johnson & Johnson statement, Sanofi-Aventis announced that it had already been hard hit by low-cost alternatives to its sleeping pill, Ambien, which became available in generic form in April.

As frequently happens when generics appear, sales of the name-brand Ambien plunged — to $91 million in the second quarter, from $420 million in the same period last year. Generics already account for 60 percent of prescriptions in this country. And that portion is expected to rise, as cheaper substitutes arrive to treat many chronic conditions. Already consumers have flocked to new generic versions of five major drugs, including Ambien and discount alternatives to Norvasc for high blood pressure.

Soon generic competition is expected to hit Fosamax, a $2 billion drug in this country that slows bone loss and is often used by postmenopausal women. In 2009, the heartburn and ulcer medication Prevacid, a $3.5 billion product in this country, is expected to become available as a generic product. And by 2011, a generic substitute is expected for what has been the world’s single best-selling medicine, the cholesterol drug Lipitor, a drug with annual United States sales exceeding $5 billion. Several experts predict that generic drugs will keep drug price inflation in the single digits for the next several years.

“It’s much better than it was in the ’90s, before these drugs started going generic,” said Dr. Steven B. Miller, chief medical officer for Express Scripts, another company that manages drug benefit plans. “The drug trend was always double digit.” As recently as 2002, he said, the annual drug inflation rate was 18.5 percent.

Companies like Express Scripts are promoting the use of generics by setting lower co-payments for them, reducing the amount patients must pay out of pocket. Also helping to propel the copycat drug trend is the success of generic manufacturers in challenging patents held by brand-name companies. But another reason is that many patents are simply expiring on drugs that were introduced during the late 1980s and early 1990s, an unusually productive era of research and development for the pharmaceutical industry.

Patents provide 20-year protection from generic competition. But because companies often apply for patents in early stages of drug development, before drugs are approved, pharmaceuticals may have fewer years of what is called effective patent protection. And now, as nearly every big drug maker watches its best sellers fade away, there are fewer potential blockbuster drugs waiting to take their place.

“At the end of the day, it’s basically a failure of innovation,” said Richard T. Evans, a consultant with the firm Avos Life Sciences, a research and consulting firm for the drug industry. Mr. Evans said it was hard to know whether the drug industry was merely in a cyclical lull or whether it suffered from a systemic decline in productivity.

But the Pharmaceutical Research and Manufacturers of America, the trade group for brand-name companies, said that company research and development budgets are increasing each year, even as generic competition cuts into profits.

“I don’t think we would support the contention that there’s a lull,” said Caroline Loew, the industry group’s senior vice president for scientific and regulatory affairs. Citing diseases like Alzheimer’s, Parkinson’s and cancer, she said, “The companies are tackling diseases that are extremely complex. The biological mechanisms are very poorly understood. By definition, that sort of science, which is very much emerging science, is going to take longer.”

One way the pharmaceutical industry is working to counter the generic trend is through its own generic subsidiaries and contracts for the production of company authorized generics. Such drugs currently account for 9 percent of prescriptions dispensed in this country, according to data from IMS Health.

For example, the generic unit of Pfizer, Greenstone, last year began marketing its own version of the Pfizer antidepressant Zoloft. The Food and Drug Administration approves generic drugs that contain the same active ingredients as brand-name pharmaceuticals, and the agency says that generic drugs meet the same quality standards as brand-name drugs.

Yet in a study conducted in 2002 by AARP, 22 percent of those surveyed indicated they thought that generic drugs might be less effective or of poorer quality than brand-name drugs.

Mr. Gal, the Sanford Bernstein analyst, said that the generic drug industry was still working to overcome such suspicions. The F.D.A. estimates that consumers can save an average of 50 percent when they switch from name brands.

The actual financial benefit to individuals, though, depends largely on their health plans.

Corporate drug plan managers like Medco Health Solutions and Express Scripts work aggressively on behalf of employers to encourage the use of generic drugs. One way is by setting lower co-payments for them. That may mean an out-of-pocket expense of $20 less for generics than name-brand medication. The savings can add up quickly for consumers who need multiple drugs. Medicare is also using incentives to encourage the use of generics in its Part D drug plan.

James and Rosemarie Cola, a retired couple in Queens, take 16 medications between them. Over the last few years, out-of-pocket costs for several of their drugs have fallen, as generics have become available.

Mr. Cola, 82, a retired hairdresser and makeup artist who earned an Emmy for his work in daytime television, recently paid only $9 for a 90-day supply of cilostazol, a substitute for the branded drug Pletal for leg pains. The drug became available as a generic in 2004.

Mrs. Cola, 74, is expecting to see several of her medications become generic within the next few years, including Zyrtec for allergies, Lipitor for cholesterol, and Coreg for heart problems.

“We’re living on pills,” said Mrs. Cola, a retired substance abuse counselor and social worker.

Whatever the cost savings, Mrs. Cola says she must think twice before switching from one formulation to another whenever one of her drugs becomes generic.

“I don’t like to change drugs,” Mrs. Cola said.

People go to medicine cabinets to find relief. Medicines, on the other hand, go to medicine cabinets to die a slow and undignified death. There’s the penicillin from 1997, the eyedrops with the label worn off, the reddish goop that may have once been cough syrup. And amid all these sputtering bottles and vials, you can’t find one measly Band-Aid.

Is it time to give your medical supplies a checkup? Apart from your prescriptions, all you want are the tools to treat minor cuts and burns, headaches, fevers, coughs, itching, allergies, or a runny nose. (The key word here is minor. For severe symptoms, bypass the cabinet and go directly to your doctor.) Here’s what you really need to keep your cabinet as healthy as you prefer to be.

For Pain, Headaches, Fever

No need to buy both the regular- and extra-strength versions of these products. Anyone who needs a bigger dose can take an extra pill (and you’ll save space).

Aspirin: Still a favorite painkiller and fever reducer, though some find it too irritating to the stomach. Also, it can interfere with blood clotting, so people who take blood thinners or are about to have surgery must not take it. Children and teenagers should avoid aspirin as well, because it has been linked in young people to Reye’s syndrome, a rare condition involving swelling of the brain and liver.

Acetaminophen: May be a better choice for anyone who wants or needs to avoid aspirin. Pediatric doses are also available. Adults taking acetaminophen pills (Tylenol is one brand) must avoid other products that also contain the drug, such as many combination cough-and-cold remedies, as overdoses can harm the liver.

Ibuprofen or naproxen sodium: Ibuprofen (Advil and Motrin) and naproxen sodium (Aleve and Naprosyn) are effective painkillers for adults and children 12 and over. (Motrin also has a children’s formula.) Like aspirin, they may irritate the stomach.

Warning: All these painkillers can cause problems if mixed with too much alcohol. People who have three or more drinks a day should consult a doctor about using them.

For Congestion From Colds

Decongestants: Two popular kinds are pseudoephedrine (in Sudafed and Sinarest) or phenylephrine (in Dristan Cold Multi-Symptom and Rynatan). Note: Federal law requires that products containing pseudoephedrine be located behind the counter; you’ll have to show identification to buy them, and sign a logbook.

Warning: Many cold remedies contain antihistamines, which cause drowsiness and are best reserved for allergies.

For Coughs

Cough medicine: For a dry, hacking cough, look for one that contains the cough suppressant dextromethorphan. Big-name brands include Robitussin Maximum Strength Cough and Pertussin. If the cough is producing mucus, use something with guaifenesin, an expectorant, to loosen secretions. These include Robitussin PE and Benylin Expectorant Formula.

Warning: A cough that lasts more than a week or is accompanied by a fever may be a sign of bronchitis or pneumonia and should be treated by a doctor.

For Allergies

Antihistamines: Diphenhydramine (in Benadryl), chlorpheniramine (in Chlor-Trimeton), and clemastine (in Tavist Allergy 12 Hour Relief) all work to relieve sneezing and a runny nose, but each causes sleepiness. Loratadine (in Claritin) is nonsedating.

Eyedrops: Drops that contain an antihistamine and a decongestant, like Naphcon A and Opcon-A, can soothe itchy eyes.

For Digestive Problems

Calcium carbonate tablets: Tums and Rolaids both relieve heartburn, which occurs when stomach acid backs up and irritates the esophagus. They temporarily neutralize the acid and also provide calcium, which is deficient in many people’s diets.

Maalox or Mylanta: Both products give longer-lasting relief.

Tagamet, Prilosec, Pepcid, or Prevacid: Not crucial, but you might want to keep one of these products, which decrease acid secretion, on hand. But anyone suffering from chronic heartburn should see a doctor to find out what is causing it, whether dietary changes can help, and which type of drug is best.

Warning: Be wary of treatments for constipation and diarrhea. Although drugstore shelves are lined with remedies for constipation, doctors discourage their use more than once in a great while because the body can become dependent on them. (Fiber-based products like Metamucil are least likely to be habit-forming.) Chronic constipation may be caused by a diet deficient in fiber or a more serious health problem. Occasional attacks of diarrhea can be relieved by Pepto-Bismol, Kaopectate, or Imodium. But letting the illness run its course may get rid of the offending germs faster. Parents should keep Pedialyte on hand to prevent dehydration in small children suffering from diarrhea or vomiting.

For Itchy Rashes, Bug Bites, and Other Skin Problems

Calamine lotion: This old-fashioned pink liquid soothes itching from rashes and bites and dries up weepy rashes like the kind you get from poison ivy.

Antihistamine cream: Use one (like Benadryl Itch Stopping Cream) to relieve intense itching. Or try one that combines calamine and an antihistamine, like Ivarest.

Cortisone: A 1-percent cream or ointment may relieve a persistent itch that’s not cured by the medications above.

You May Also Want:

Benzoyl peroxide or salicylic acid: Acne sufferers can benefit from masks, washes, and spot treatments with these ingredients.

Antifungal cream: More effective in curing athlete’s foot than powders and sprays. Top brands include Lamisil, Micatin, and Lotrimin, all of which can also be used to treat jock itch.

Yeast-infection medicine: Monistat, Gyne-Lotrimin, and other antifungals work well. But they will not fight vaginal infections that sometimes mimic yeast infections. If your drug does not work within a few days, see a doctor.
Bladder-infection medicine: Phenazopyridine (Uristat and Prodium) can relieve the burning and the urge to urinate. But it does not treat the infection, which may require antibiotics.

For Cuts and Burns

Bandages and gauze pads: A box of adhesive strips in assorted sizes and a box of gauze pads (the large size, four by four inches, which can be cut down) will be adequate to dress most cuts, scrapes, and burns.

Medical tape: This will hold gauze in place. People with sensitive skin need paper tape marked “hypoallergenic.” If the gauze is applied to fingers, an arm, or a leg, it can be wrapped instead of taped with the kind of nonglue cloth wrap that sticks only to itself. Johnson & Johnson sells a product called Hurt Free Tape in two widths.

You May Also Want:

Hydrogen peroxide: When used to clean wounds, it stings less than alcohol.
Antibiotic ointment: It can protect and moisten a closed wound or a minor burn. Antibiotic Band-Aids are also an option.

Liquid bandage: Paint on one (like New-Skin) to seal off a small, uninfected cut, taking the place of a more cumbersome bandage.

Butterfly bandages: By pulling together the edges of a cut, these bandages help it heal with minimal scarring. They’re worth considering if you have extra space in your medicine chest.

Tools

Thermometer: The electronic kind is usually accurate and sturdy, and a good choice for those who are wary of the mercury in traditional thermometers. For babies, rectal thermometers are most accurate.

You May Also Want:

Magnifying glass and tweezers: To remove splinters.

Pill cutter: Comes in handy if you need to cut a dose in half. (But always ask your doctor or pharmacist first whether cutting the pill will change the rate at which it dissolves, and whether that matters.)

Eyeglass repair kit

For Tooth Care

Toothpaste, Floss, and a New Spare Toothbrush

You May Also Want:

Rub-on painkiller: Anbesol, Orajel, and Zilactin work on toothaches, gum pain, teething pain, canker sores, and cold sores.

Dental-repair kit: Such kits as Temparin and Dentemp contain dental cement for temporarily replacing a lost filling or crown―good if you have had a lot of dental work done.

]]> https://genglob.com/genglobmag/2009/10/must_have_generic_medicine_at_home/feed/ 0 https://genglob.com/genglobmag/2009/10/novel_agents_erlotinib_erlocip_treatment_nslc/ https://genglob.com/genglobmag/2009/10/novel_agents_erlotinib_erlocip_treatment_nslc/#comments Tue, 13 Oct 2009 22:40:04 +0000 admin https://genglob.com/genglobmag/?p=29 Integration of Novel Agents Into Treatment Regimens for Patients With Advanced Non-Small-Cell Lung Cancer

Treatment options in non-small-cell lung cancer (NSCLC) have expanded recently due to the demonstration of efficacy of targeted agents alone or in combination with existing cytotoxic chemotherapies. Research with these approaches is ongoing, and the 2006 American Society of Clinical Oncology meeting featured presentations from studies of epidermal growth factor (EGFR) inhibitors and antiangiogenic agents, as well as on the use of other novel compounds.

EGFR Inhibitors

The 2 major classes of EGFR inhibitors in clinical use are, based on their mechanisms of action, tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. The former group is exemplified by gefitinib and erlotinib while the latter includes cetuximab and panitumumab.

Phase 3 trials employing the EGFR TKIs in first-line metastatic disease yielded negative results when these agents were administered concurrently with chemotherapy. Subsequent preclinical evidence suggested that sequencing chemotherapy with EGFR inhibitors may be more efficacious. Therefore, the Southwest Oncology Group performed a randomized phase 2 trial (SWOG 0342)[1] comparing concurrent chemotherapy plus cetuximab vs sequential chemotherapy followed by cetuximab in metastatic NSCLC. The plan was to select the arm with superior overall survival and subsequently compare it with chemotherapy alone in a phase 3 trial. However, the trial, which enrolled 242 patients, revealed virtually identical median progression-free (4 months in both arms) and overall (10 months in concurrent arm, 9 months in sequential arm) survival.

Based on the notion that cancer is a disease with multiple alterations, several agents are being developed that target different pathways at once. Thus, a randomized phase 2 trial evaluated a multikinase inhibitor known as ZD6474, or vanitinib, that targets both the EGFR and vascular endothelial growth factor (VEGF) receptor. This study enrolled patients who had failed platinum-containing first-line chemotherapy and compared docetaxel plus or minus ZD6474 at either 100 mg or 300 mg daily. Progression-free survival, the primary trial end point, was higher in both experimental arms (18.7 weeks in the 100-mg arm and 17 weeks in the 300-mg arm vs 12 weeks in the docetaxel-alone arm), suggesting that the addition of ZD6474 to second-line chemotherapy is efficacious. Currently, a phase 3 trial comparing docetaxel with docetaxel plus ZD6474 100 mg daily as second-line treatment for NSCLC is being conducted.

Another trial in a similar group of patients compared ZD6474 300 mg with gefitinib 250 mg in a randomized, crossover design. Progression-free survival was significantly better in the ZD6474 arm (11 vs 8.1 weeks, P = .025), meeting the trial’s primary end point. Of the 66 patients who crossed over to the alternate arm, there was 1 objective response in a patient who switched from ZD6474 to gefitinib.

In a randomized phase 2 trial, single-agent erlotinib was compared with carboplatin/paclitaxel chemotherapy in poor performance status (PS 2) patients with treatment-naive, advanced NSCLC. The primary end point was progression-free survival. Outcome measures, including response rate (12% vs 2%), progression-free survival (3.5 vs 1.9 months), and overall survival (9.7 vs 6.7 months), favored the chemotherapy arm. Overall, quality of life was equivalent between the 2 groups — compelling the authors to conclude that chemotherapy should remain the standard of care for unselected patients.

Several groups reported on attempts to select patients for EGFR TKI therapy. From prospective trials, it appears that specific mutations in EGFR exons 19 and 21 convey an exquisite sensitivity to these agents, with response rates between 60% and 95%. Of note, tumors with exon 19 mutations appear to be more sensitive compared with those that have mutations on other loci. Moreover, 1-year survival of patients harboring EGFR mutations and receiving TKI therapy appears to be over 80%. These findings were also observed in patients with bronchioloalveolar cell carcinoma, in that those with evidence of somatic EGFR mutations had an 83% observed response rate and a 22-month median overall survival.

In a similar prospective study, investigators examined the effects of gefitinib in NSCLC with respect to EGFR gene copy number, EGFR protein expression by immunohistochemistry, and activation of an EGFR downstream protein, AKT. Subjects were required to be never smokers and/or test positive for increased EGFR gene copy number or AKT activation. The overall response rate in the 42 patients enrolled thus far was 48%, with a 1-year survival of 69%. Increased EGFR gene copy number or exon 19/21 mutations were strongly associated with a positive response.

Conversely, evidence now exists to identify patients who may not derive benefit from treatment with an EGFR TKI. A subset analysis[8] of tissue samples from patients participating in the BR.21 trial comparing erlotinib with placebo in second- or third-line metastatic NSCLC indicated that those harboring a K-ras mutation have a poorer survival (hazard ratio 1.63, P = .03 in multivariate analysis) when treated with the EGFR TKI. These findings must still be viewed as preliminary, keeping in mind the retrospective nature of the analysis and the relatively small number of patient samples available for study. Nevertheless, this report, coupled with the investigators’ prior findings of lack of benefit in EGFR-negative tumors by immunohistochemistry, suggest that patients with K-ras mutations who do not express the EGFR protein are unlikely to benefit from EGFR TKI therapy.

Antiangiogenic Agents

Following the positive results of ECOG 4599, which added bevacizumab, a monoclonal antibody directed against VEGF, to doublet chemotherapy in first-line metastatic disease, a number of antiangiogenic agents have been under investigation in NSCLC. In addition, the combination of bevacizumab and erlotinib was reported to have activity in second-line metastatic NSCLC, prompting a randomized phase 2 trial evaluating bevacizumab in combination with either chemotherapy (docetaxel or pemetrexed) or erlotinib compared with chemotherapy alone in patients whose disease was refractory to first-line chemotherapy. Consistent with the first-line therapy results, the addition of bevacizumab to either erlotinib or chemotherapy was superior with respect to response rate, progression-free survival, and overall survival. The 6-month overall survival was 72.1% for bevacizumab plus chemotherapy and 78.3% for bevacizumab plus erlotinib, compared with 62.4% for chemotherapy alone. The bevacizumab/erlotinib arm was the best tolerated.

The administration of multikinase inhibitors with predominant in vitro activity against VEGF receptors is also being investigated in NSCLC. Clinical trials with 2 similar agents — sunitinib and sorafenib — were reported in patients with disease refractory to chemotherapy. Both studies allowed prior therapy with an EGFR inhibitor. Sunitinib was administered at 50 mg daily on a 4-weeks-on/2-weeks-off schedule to 63 patients enrolled in the United States and Europe. The objective response and disease control rates (responses plus stable disease) were 10% and 53%, respectively. Toxicity with sunitinib was similar to that seen in other settings, with asthenia, myalgia, and nausea being most common. In addition, 3 subjects experienced serious hemorrhages and 5 subjects (8%) experienced grade 3 hypertension.

A phase 2 trial of single-agent sorafenib, 400 mg twice a day, in a similar cohort of patients was also reported. This study enrolled 52 subjects with no objective responses reported but a disease control rate of 59%. Adverse events were typical of the agent in other diseases and included diarrhea, palmar-plantar erythrodysesthesia, and asthenia. Grade 3 hypertension occurred in 4% of subjects, and 1 patient suffered a fatal pulmonary hemorrhage. A regimen of sorafenib plus chemotherapy is currently being investigated in a randomized phase 3 trial in first-line metastatic NSCLC.

The rare but serious incidence of pulmonary hemorrhage associated with bevacizumab was investigated in a retrospective review of patient risk factors from ECOG 4599. Although only 6 cases met the criteria for early-onset hemorrhage related to bevacizumab, there appeared to be an association between these events and the presence of cavitation on pretreatment radiographs. Whether this association is real and whether it applies to all antiangiogenic agents is unknown. Nevertheless, caution should be used when these agents are considered for patients with cavitation.

Other Novel Agents

Several other novel agents have also been tested recently in NSCLC. Two randomized trials employed agents targeting the eicosanoid pathway. This pathway is implicated in several processes, including cell differentiation, and is a key mediator of inflammation. Modulation of this pathway at several points by LY293111, including inhibition of cyclooxygenase (COX)-2 and stimulation of peroxisome proliferators-activated receptor gamma, yielded promising preclinical data; thus, a randomized phase 2 trial  of the agent in combination with cisplatin/gemcitabine was undertaken in chemotherapy-naive patients with advanced NSCLC. This 3-arm trial, which administered LY293111 at 200 mg twice a day or 600 mg twice a day vs placebo, used progression-free survival as its primary end point. After enrolling 201 patients, it appeared that LY293111 was associated with a greater degree of diarrhea, especially at the 600-mg dose, but did not improve efficacy.

The Cancer and Leukemia Group B took a similar approach to inhibition of the eicosanoid pathways by administering a COX-2 inhibitor (celecoxib), a 5-lipoxygenase inhibitor (zileuton), or both in combination with carboplatin and gemcitabine in a randomized phase 2 trial. The primary end point was the rate of failure-free survival at 9 months. The agents appeared well-tolerated in combination with chemotherapy, and, although there was no difference in the primary end point, a trend toward benefit was observed in the arm administering both inhibitors. Moreover, subjects who expressed high levels of COX-2 and received celecoxib appeared to benefit compared with their low expressing counterparts.

A clinical trial administering bortezomib, a proteasome inhibitor currently approved for use in multiple myeloma patients, in combination with gemcitabine and carboplatin was reported by the Southwest Oncology Group. This phase 2 nonrandomized trial enrolled 121 patients and reported a 21% response rate, a median progression-free survival of 5 months, and a median overall survival of 11 months. Although the median survival was encouraging, the other outcome measures suggested that the addition of bortezomib is unlikely to improve efficacy in this setting.

In a phase 3 trial, investigators compared whole brain radiation alone with a combination of motexafin gadolinium and whole brain radiation therapy in 554 NSCLC patients with brain metastases. Time to neurologic progression was the primary end point. Motexafin gadolinium did not interfere with the ability to administer whole brain radiotherapy and was generally well tolerated. Time to neurologic progression trended in favor of the experimental arm (15.4 vs 10 months) but did not reach statistical significance (P = .12). Of note, it appeared that patients who began therapy within 4 weeks of diagnosis derived the greatest benefit from motexafin gadolinium; subset analysis of this group favored the experimental arm.

Conclusion

NSCLC continues to pose a treatment challenge, especially in advanced and metastatic disease. For the first time ever, targeted agents have been shown to have demonstrated efficacy in the treatment of this disease and at least one, erlotinib, is currently approved for use. It is very likely that the next few years will witness a dramatic increase in the number of novel therapies available. Two classes of agents will dominate in the near future — EGFR inhibitors and antiangiogenic agents. However, with increasing understanding of the molecular biology driving NSCLC, a greater number of agents with varied mechanisms of action will become part of individual patient management.

]]> https://genglob.com/genglobmag/2009/10/novel_agents_erlotinib_erlocip_treatment_nslc/feed/ 0 https://genglob.com/genglobmag/2009/10/universal-access-to-cancer-drugs/ https://genglob.com/genglobmag/2009/10/universal-access-to-cancer-drugs/#comments Mon, 12 Oct 2009 09:03:34 +0000 admin https://genglob.com/genglobmag/?p=27 In 2005 more than 11 million new cases of cancer were diagnosed and more than 7 million people died (accounting for approximately 13% of global deaths) from this devastating disease – over 70% of whom live in low- and middle-income countries. In 2020, if current trends continue, new cancer cases will increase to 16 million per year and more than 10 million people will die; between 2005 and 2015, it is projected that 84 million people will die of cancer.  The absolute number of cases of cancer in persons younger than 50 years old is not predicted to increase in the next 50 years, but the absolute number of cases in persons aged 65 years and older is expected to double between 2000 and 2030.

Cancer is mostly treated using a combination of surgery, radiotherapy and systemic treatment, including cytotoxic drugs, hormonal therapy, or targeted treatment approaches. The latter include monoclonal antibodies or “small molecule” drugs that bind to more or less tumour-specific molecules (i.e., particular molecules present in or on the tumour cells and (ideally) not present, on normal cells) and in doing so, block the processes of carcinogenesis, tumour growth or spread. Because of their specificity for cancer cells, particularly if directed towards the molecular lesions that give rise to cancer (which are not present in normal cells), such molecules will have large benefits in terms of reduced toxicity compared to non-specific cytotoxic drugs. Drugs, a word applied here to all such systemic therapies, have for long played a central role in the treatment of some cancers, such as leukemias, lymphomas, testicular cancers and childhood cancers, and in recent years have played an increasingly important role in the management of many other cancers, usually in conjunction with surgery and/or radiation therapy, albeit, their value varies greatly from one cancer to another. Unfortunately, many patients worldwide do not have access to the drugs they need. This is part of a broader problem of access to optimal cancer care, which remains a significant challenge in many parts of the world.

Cancer drugs: the facts

• In 2006, global pharmaceutical sales across all disease areas grew 7% to $643 billion – 87% of sales were in North America, Europe and Japan. It is estimated that the global pharmaceutical market will more than double in value to $1.3 trillion by 2020.
• Sales of cancer drugs reached $34.6 billion in 2006, which represents a 20.5% increase in sales over the previous year; cancer drug sales are now ranked second, after lipid regulators, . Expenditure on cancer drugs account for between 10-20% of spending on cancer care and about 5% of total drugs expenditure.
• Worldwide, industry sales are projected to continue to grow strongly at 7 per cent per annum over the next five years. Espicom Business Intelligence estimate that the annual sales of pharmaceuticals will reach US$892.6 billion in 2008 and project that it will reach US$1,247.7 billion in 2013. The markets driving this change will be:
  • Central/Eastern Europe, with 9.5 per cent growth per annum;
  • The Americas, with 8.4 per cent growth per annum;
  • Middle East and Africa, with 6.4 per cent growth per annum;
  • Asia/Pacific, with 5.5 per cent growth per annum; and
  • Western Europe, with 5.0 per cent growth per annum.:
• Sales of generic drugs are increasing – last year sale of these drugs represented over half of the drugs sold in 7 of the leading pharmaceutical markets worldwide. Generic versions of a number of commonly used cancer drugs are widely available. A number of cancer drugs are set to lose their patents in the near future, and it is likely therefore that over the coming years sales of generic cancer drugs will increase.
• Innovative cancer drugs are developed as a result of both public and private investment in cancer research. It has been estimated that the pharmaceutical industry spends between $6.5 – 8 billion per year on cancer research. Public investment (ie. Governmental and charitable) in the development of cancer drugs is much lower and therefore, drug development is mainly driven by commercial considerations rather than public health priorities. This means that there is less investment in the development of drugs to treat rarer cancers with few or no available treatment options, or in rare cancers, such as childhood cancers. This is likely to change to some degree as drug development is increasingly focused on targeted therapies, since most targets are confined to one or a small number of cancers. It is inevitable, however, that the very large difference in incident cases in various cancers, for example, breast or lung cancer versus retinoblastoma or specific sarcomas, will continue to influence decisions with respect to product development.
• Currently over 380 compounds are in development for cancer, and half of those in the late stages development are targeted therapies. While the more limited toxicity of such molecules should eventually reduce the total cost of cancer treatment, the price of the targeted therapies (all patented) that have made it to the market to date has been set very high and prices continue to increase dramatically. The industry claims that their pricing policy reflects the cost and risk involved in research particularly in the development of new drugs, many of which never make it to the market. However, some of these so called innovative drugs are “me too” products (i.e. only slightly modified compounds in comparison to established precursor drugs) and often (although there are exceptions) have small benefits – measured, for example, in terms of a few months increase in survival, such that the high prices set for them are generally not justifiable. For these and other reasons, the pharmaceutical industry has been accused of lacking transparency in its approach to pricing of innovative drugs.
• Other factors may greatly influence price – for example, some targeted therapies may need to be administered over long periods in order to maintain cancers in a quiescent stage, which will have a significant effect on the cost of treatment. It is clear that while still under patent protection, targeted drugs will increase the overall cost of cancer care will increase significantly and most targeted therapies will be unaffordable for low and middle income countries, and even create major financial problems in the highest income countries. At the present time, however, the overall contribution from targeted therapies to cancer control remains small. Moreover, patients in low and middle income countries currently have difficulty in affording even traditional cytotoxic drugs, particularly in diseases where treatment may last for years (such as in acute lymphoblastic leukemia and breast cancer treated with anti-hormonal therapies).  Finally, targeted drugs require demonstration of the presence of the target in or on the tumour cells, requiring high quality laboratory services, which are not always available in developing countries, or not affordable by patients. Thus, targeted therapies, in countries with limited resources are presently a controversial health priority.

Access to cancer drugs

Worldwide access to cancer drugs is extremely unbalanced: whereas it is usually covered by health care systems in developed countries, in low and middle income countries only a small fraction of the population has insurance; the remainder must pay out of pocket and, if they cannot afford it, may not receive treatment at all.

Cancer drugs can improve outcomes when they are available, affordable, of assured quality and properly used. However, the World Health Organization (WHO) estimates that nearly one third of the world’s population does not have access to full and effective treatment with the medicines they need – this rises to over 50% in the poorest parts of the world. Even in highly developed countries access to some drugs and to the best available therapy is not guaranteed for everyone. There are a number of reasons for this, including:

1. Drug costs – even standard cytotoxic drugs as listed, for example, in the WHO list of Essential Cytotoxic Drugs are out of reach of the poorest patients, while the high price of patent-protected cancer drugs makes them unaffordable for many countries. Patent enforcement by pharmaceutical companies in low and middle income countries, therefore, can totally inhibit access.
2. Insufficient public funding of health – governments in many countries do not provide reimbursement for essential cancer drugs.
3. Restrictive regulations – the cost of importing drugs, including duties, taxes, fees and distribution costs may grossly inflate the prices of standard drugs.
4. Poor infrastructure – many countries lack the facilities necessary to enable complex cancer drug regimens to be administered safely and effectively
5. Irrational use of cancer drugs – There is a dearth of adequately trained health professionals who are competent to prescribe and administer cancer drugs. In addition, many countries lack national evidence-based treatment guidelines from which a national Essential Drugs List would logically follow. Guidelines developed in the USA and Europe, for example, may not be suitable in low resource settings for reasons of cost, drug availability, limitations in supportive and nursing care, etc., but many oncologists in low and middle income countries use such guidelines, at least in modified form, even when they contain drugs that provide minimal if any benefit at a substantially higher cost. Paradoxically, this may result in more expensive analogues with little or no advantage being purchased, while more affordable and often equally effective drugs in a developing country setting (although there are few comparisons of this type in the literature) are unavailable.
6. Bureaucratic policies – In many countries worldwide national opiate policies are too restrictive, which limits availability to morphine and other pain-relieving drugs. Frequently doctors are afraid to prescribe opioids, have misconceptions about their use or do not employ the principle of prevention of symptoms in the practice of palliative.  It is estimated that 80% of cancer patients who suffer severe pain have no access to opiates and many more have limited or inadequate access.
7. Counterfeit medicines – The global market in fake drugs that range from those containing harmful toxic substances to those with inactive, useless ingredients or those which contain only a fraction of the stated quantity of the active ingredient is increasing at a rapid pace. Counterfeiting is greatest in those regions where regulatory and legal oversight is weakest. In developed countries sales of counterfeit drugs represent less than 1% of the pharmaceutical market. This rises to 10-30% in parts of Asia and Latin America and up to 70% in some African countries. Some pharmaceutical companies have established drug donation programmes to address access problems in low-income countries. Although useful in the short-term these programmes are not a long-term solution to cancer drug access.

WHO has developed a list of essential cancer medicines, which is updated and revised biennially. This list provides a foundation for the development of national essential drug lists based on the prevailing pattern of cancer in the country as well as economic considerations. However, while most countries can afford to purchase these drugs, poor procurement practices may result in intermittent availability (or availability, when out of stock in a public hospital, via the private sector at greatly increased cost). Patients may not be able to afford the drugs when they must pay out of pocket.

Large pharmaceutical companies can grant voluntary licenses to governments in low-income countries to facilitate the production of of generic versions of innovative cancer drugs. This would not affect the bottom line of large companies, as their primary market is developed world for such drugs. This would also bring in the necessary competition and price within the reach of common people in such countries.

Japan promises to be one of the most lucrative generic markets in the world. Between 2005 and 2008, the Japanese generics market grew at a CAGR of around 7.5% to register ¥ 333 Billion (US$ 3.5 Billion) in revenue, according to “Japanese Generic Market Forecast to 2013”, a new research report by RNCOS – an industry research firm. Currently, generics accounts for just 5 per cent of the Japanese drug market but the market size is likely to grow many folds. The government officials with a view to bring down healthcare costs are encouraging doctors to prescribe generics to the patients.

Other factors such as a large number of patent expiries and the largely un-penetrated nature of the market are also contributing towards the market growth. Japan’s per capita expenditure on healthcare is comparable to that of many western countries. Moreover, the country’s share of total health expenditure dedicated to drugs is very high. The government therefore has come up with reform measures and programmes to support the generics sales and investments made by the global giants in this sector, the report said.

The Japanese Ministry of Health, for example, announced a programme two years ago to increase generic drugs market share from 17% to more than 30% by 2012. Besides, the government introduced a generic substitution system in which pharmacists are allowed to substitute generic drugs if doctors do not specify that a brand name drug is to be dispensed.

Despite this huge opportunity, the generics are facing a number of other challenges. Generic drugs are still regarded as cheap, low quality alternatives of branded drugs in Japan. Both physicians and patients are skeptical about their safety and efficacy. A number of awareness and educational programmes, however, are expected to increase the awareness of generic drugs in the future. At present, the generics market in Japan is dominated by domestic manufacturers. The top six manufacturers accounting for 56% of the total market in 2007. But opening up of the market and introduction of a number of generic-friendly reforms is attracting a number of foreign players in the market.

Ranbaxy Laboratories, now a subsidiary of Daiichi Sankyo, was among the first Indian company to foray into Japan. Ranbaxy set up a 50:50 joint venture with a local company, Nippon Chemiphar, in 2005. Ranbaxy has launched five products in the Japanese market, led by voglibose, clarithromycin and amlodipine, in therapeutic segments such as diabetes, anti-infectives, anti-allergics, anti-fungals and hypotensives. Of this, voglibose and clarithromycin are among the top-selling generic brands in Japan. In 2007, Ranbaxy earned nearly $30 million revenue from the Japanese market. But following its acquisition by Daiichi, Ranbaxy stopped the JV with Nippon, in 2008.

Lupin is another Indian player that has been keen get into the generic space in Japan. In October 2007, Lupin acquired Kyowa Pharmaceuticals to enter Japan. Sales of Kyowa have grown over 21 per cent during the past year and it ranks as the eighth-largest generic player in Japan, according to Lupin.

The Ahmedabad-based Zydus Cadila entered the Japanese market in 2006 with the acquisition of Nippon Universal Pharmaceutical. Nippon has a network of more than 4,000 hospitals and clinics across the country. Zydus plans to launch at least five to six products every year in Japan.

Similarly, Dishman Pharmaceuticals and Chemicals, another Ahmedabad-based company, entered Japan through a joint venture, Dishman Japan, in association with Azzurro Corporation, a 30-year-old marketing firm.

Several other Indian generic players including Biocon and Dr Reddy’s have set their eyes on this high-value market.

So, the generic makers see a huge opportunity to make investments into the country as the global financial crisis is not reaping enough margins to the generic manufacturers in the European countries. Generic companies can set high prices and reap high margins in less intense competition and the unexploited nature of the Japanese generics market.

When Big Pharma invents a new drug, it’s like a cash machine. With patents protecting new discoveries from competition, drug developers like Pfizer, GlaxoSmithKline, and AstraZeneca can charge whatever they want for their little miracles. Until, that is, the patent expires. Then it’s goodbye profits, and hello generics! Behind every new drug is a generic copycat — like Teva, Mylan, or K-V — ready to start selling a nearly exact yet much cheaper version virtually the day patent protection ends.

This year, according to Standard & Poor’s research, branded drug sales are set to decline for the first time. That’s partly due to the economy, but also due to increasing competition from generics. IMS Health, the industry’s clearinghouse for drug sales data, says that $24 billion worth of branded drugs this year will get generic competitors, up from $18 billion last year. The figure will hit $30 billion by 2012.

That’s why, even though drug companies are some of the most profitable businesses in the world, investors are sour on them unless they’ve got a lot of new discoveries in the pipeline. Drug stocks hit a record low price-to-earnings ratio of 10x in June, according to S&P.

Investors know the generic onslaught will only continue. In the coming years, patents for blockbuster drugs like Lipitor, Viagra, and Plavix will expire. That’s in addition to familiar drugs like Wellbutrin and Zithromax that already have generic competitors.

Here, based on data from IMS, are the best-selling generic drugs of last year:

Fentanyl
Launched: January 2005
2008 sales: $900 million
Branded equivalent: Duragesic, by Janssen, 2008 sales of $1.1 billion

Mylan’s copy of Janssen’s Duragesic patch was the top-selling generic drug last year, raking in about $500 million for the Canonsberg, Pa.-based company. The patch treats pain related to cancer by delivering a steady release of fentanyl, a super-strong painkiller, to the nervous system over a 72-hour period. Though several other generics makers — including Watson Pharmaceuticals (WPI), Lavipharm S.A., Actavis Group, and Teva Pharmaceutical Industries (TEVA) — produce similar products, Mylan (MYL, Fortune 500) secured the first legal approval in November 2003 and represents just over half of the $900 million market for fentanyl-based drugs.

Amlodipine besylate and benazepril hydrochloride
Launched: July 2007
2008 sales: $779 million
Branded equivalent: Norvasc, by Pfizer (PFE, Fortune 500), 2008 sales of $2.2 billion

Pfizer’s Norvasc, which treats high blood pressure and chronic chest pain, had annual sales of $2.4 billion in 2008. But its generic counterpart, amlodipine, is gaining quickly, with revenues of $779 million last year. The biggest producer and distributor of amlodipine is Israel-based Teva, whose approval to produce it was approved by the FDA in May 2007. Teva set a generic industry record with $2.38 billion in sales in the second quarter of 2007, thanks in large part to the successful launch of amlodipine.

Metoprolol succinate
Launched: May 2008
2008 sales: $675 million
Branded equivalent: Toprol, by AstraZeneca (AZN), 2008 sales $807 million

The generic equivalent of AstraZeneca’s Toprol, made by St. Louis-based K-V Pharmaceutical Company (KVA), treats high blood pressure. K-V first started making the drug six years ago, but it took five years to settle patent-infringement lawsuits with AstraZeneca. The generic version hit the market in May 2008. Since then, K-V’s competitors Sandoz (the generics arm of global giant Novartis (NVS)) and Andrx Pharmaceuticals (the generic arm of Watson) have been working to develop their own versions of Toprol.

Lamotrigine
Launched: February 2005
2008 sales: $671 million
Branded equivalent: Lamictal, by GlaxoSmithKline (GSK), 2008 sales $1.6 billion

It took a long time for Teva to secure approval from the FDA for their generic copy of GlaxoSmithKline’s bipolar and epilepsy drug Lamictal. Lamictal is one of the top-selling branded drugs in the United States, with around $2.2 billion in annual sales. After three years of legal wrangling, Teva won the battle in 2005 — though Teva also lost a suit last year trying to bar GSK from producing a branded non-chewable version of Lamictal, saying that it violated the previous agreement. Even so, lamotrigine sales brought in $671 million for Teva and other generic drugmakers in 2008.

Risperidone
Launched: September 2008
2008 sales: $610 million
Branded equivalent: Risperdal, by Janssen, 2008 sales $2.1 billion

As with top-seller fentanyl, Mylan also took on Janssen– founded by the eponymous Dutch scientist who invented antipsychotic drug Haldol — in mental-illness drugs. Mylan released a generic version of Janssen’s Risperdal Oral Solution, which treats schizophrenia and mania associated with bipolar disorder. Though the generic drug was approved for sale in September 2008, voiding an exclusivity agreement held by Teva, Mylan and co-developer Dr. Reddy’s Labs (RDY) plan to ship it soon. Expect risperidone to move up the best-seller ladder.

Omeprazole
Launched: July 2008
2008 sales: $609.8 million
Branded equivalent: Prilosec, by AstraZeneca, 2008 sales $1.1 billion

Prilosec, AstraZeneca’s juggernaut small-intenstine cancer treatment, received its first generic challenge from Andrx, which developed a generic version in 1998. (Andrx is now a division of Watson, which acquired it in March 2006 for $1.9 billion.) However, AstraZeneca sued to stop the release of the drug and won, forcing Andrx to wait until AZ’s patent expired. Once it did, in 2001, several generic drug producers secured FDA approval for their own versions of omeprazole, launching it into the ranks of the top sellers.

Azithromycin
Launched: November 2005
2008 sales: $599 million
Branded equivalent: Zithromax, by Pfizer, 2008 sales $429 million

Generic drug companies aren’t just persistent — they’re fast, too. When Pfizer’s patent on Zithromax expired on November 1, 2005, Teva and Sandoz wasted no time in launching their generic equivalent, azithromycin. They both received FDA approval two weeks later and launched their products for sale the same day. Zithromax was the single most prescribed antibiotic at the time, but after its patent expired, Pfizer shifted its promotional focus away from the drug and towards Zmax, a similar antibiotic taken in just one dose instead of several times a day.

Budeprion
Launched: December 2006
2008 sales: $521 million
Branded equivalent: Wellbutrin, by Biovail (BVF), 2008 sales $579 million

Where there are generic drugs, there are lawyers. Biovail tried to avoid the coming generic onslaught for its antidepressant Wellbutrin by launching an extended-release version of the drug, called Wellbutrin XL, in August 2003. However, Taiwan-based Anchen filed a generic patent for the XL version, too. Biovail succeeded in suing to delay the release for 30 months, but a judge ruled in 2006 that Anchen could proceed. So Biovail took its case to the FDA — but the FDA also approved Anchen’s generic version. Anchen signed an agreement with generic competitors IMPAX Laboratories (IPXL) and Teva to jointly produce the drug. Now they’re embroiled in a lawsuit alleging that the generic version doesn’t work as well as branded Wellbutrin XL

“The global generics market has posted double-digit gains in recent years. But in 2008, despite robust volume increases, we are seeing the first significant decline in sales growth as manufacturers increasingly compete in fierce price battles within most of the world’s major markets,” said Murray Aitken, senior vice president, Healthcare Insight, IMS. “This trend is very apparent in markets like the U.S. and U.K. as generics companies contend with aggressive competition and cost-containment measures enforced by both private and government payers.”

The top eight global markets – the U.S., Germany, France, the U.K., Canada, Italy, Spain and Japan – today account for 84 percent of total generics sales. The U.S., the world’s largest generics market with 42 percent of global sales, has experienced a 2.7 percent sales decline in the twelve months ending September 2008 while volume increased 5.4 percent during the same period. Generics products now account for 63.7 percent of the total U.S. pharmaceutical market volume. The U.S. generics market is currently valued at $33 billion, compared with $34 billion last year, reflecting declining prices and fewer blockbusters losing patent protection in 2008. However, generics sales rose 10.2 percent in Japan, 16.9 percent in France, 12.5 percent in Italy and 10.5 percent in Spain in the twelve months through September.

The top 10 generics companies currently hold a 47 percent share of the generics market worldwide. The three leading generics manufacturers are Teva with 11 percent market share, Sandoz with 9 percent, and Mylan with 8 percent.

“Through this decade and next, we expect the distinction between R&D-based pharmaceutical manufacturers and generics companies to blur,” noted Alan Sheppard, director, Generics, IMS. “Many of the largest R&D companies have stated their intention to expand their generics businesses to compensate for slower growth in the branded sector. At the same time, large generics manufacturers are looking to capitalize on their development expertise and technology to produce new chemical entities and establish their own R&D businesses. This will give leading generics companies an advantage in building market share over many smaller local manufacturers”.

The IMS 2008 Global Generics Perspective report identifies the following key market dynamics:

• Consolidation and expansion. Smaller generics producers are experiencing significant margin pressure in this environment. At the same time, large companies are consolidating their operations in established markets or expanding into emerging ones through local acquisitions or partnerships. As a result, the generics industry is becoming more divided between large, high-performing companies extending their global footprint and smaller, local producers.
• Dependence on branded blockbusters. Generics companies will benefit as products generating $139 billion in branded sales in the top eight world markets lose their patent protection through 2012. However, in the longer term, the slowing growth in large branded blockbusters being developed by R&D-based manufacturers ultimately will lead to fewer opportunities for generics companies.
• Vertical integration in distribution. Wholesalers are extending their reach into new markets and expanding their role in supplying generics products. This is especially the case in Europe, where wholesalers increasingly are sourcing generics products for private-label supply, and expanding their ownership of pharmacies as governments liberalize pharmacy ownership rules.
• New distribution models. The direct-to-pharmacy distribution strategies used by major pharmaceutical companies in Europe potentially could restrict wholesaler business opportunities, which ultimately may lead to wholesalers charging a fee for service for generics drugs shipped to retail pharmacies. That, in turn, could reduce the incentive for pharmacies to promote the use of generics, shifting the economics of distributing and selling these products.
• Centralized contracting and the increasing role of payers. A trend toward centralized contracting will benefit those generics manufacturers with a broad portfolio and low-cost manufacturing base. Companies with the breadth and scale to fulfill high-volume contracts by payers are most likely to succeed in this environment. Payers are turning to contracting as a way to encourage price competition. For example, in Germany, 68 percent of generics sales are now covered by payer contracts. The Netherlands has adopted a similar system that has led to steep discounts for generics, ranging from 55 to 93 percent. In Canada, Ontario also is considering adoption of a contracting model.
• Emerging competition from biosimilars. As biotech products lose their patent exclusivity, they will more likely face competition from biosimilars, lower-cost versions of brand-name biotech drugs. Germany is at the forefront of the evolving biosimilars market, where there is growing acceptance of these products. In the U.S., the regulatory approval process for biosimilars still remains subject to legislative action and implementation by the Food and Drug Administration, but resolution is expected in the near-term.

“The global generics industry is about to embark on a decade of seismic change, and the impact to both patients and healthcare systems cannot be overstated,” Aitken added. “Over time, scientific innovation flows from the originator to generics manufacturers, increasing patient access to low-cost, effective therapies following the loss of patent exclusivity of branded products. This advances the quality of life for consumers – particularly those with chronic diseases – and also enables healthcare systems to reallocate funds for investments in the next generation of innovative products.”