Minggu, 11 Desember 2011

[Koran-Digital] NEJM: Drug Shortages — A Critical Challenge for the Generic-Drug Market

 Perspective
Drug Shortages — A Critical Challenge for the Generic-Drug Market

Bruce A. Chabner, M.D.

N Engl J Med 2011; 365:2147-2149December 8, 2011

Comments open through December 14, 2011

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    While the oncology community has been focusing much of its attention on the remarkable activity and enviable science related to the discovery of targeted drugs, the importance of standard cytotoxic therapeutics has suddenly become apparent, owing to shortages of the common workhorses of cancer treatment — methotrexate, leucovorin, 5-fluorouracil, cytosine arabinoside, vincristine, etoposide, the anthracyclines, paclitaxel, cisplatin, and others. The list of generic drugs in short supply across all medical specialties is astounding and includes antibiotics, anesthetic agents, antihypertensive medications, and common electrolyte solutions and vitamins.1 These shortages, which primarily affect injectable generic drugs, have forced physicians to prioritize patients, improvise standard regimens (substituting capecitabine for 5-fluorouracil, for example, in adjuvant therapy for colorectal cancer), and at times, choose unproven treatment options for patients with curable disease. The National Cancer Institute has watched with increasing concern as common drugs have disappeared from the shelves of cancer-center pharmacies, threatening the completion of research protocols.

    The gravity of the problem has provoked a response from oncologists and from governmental agencies. In November 2010, the American Society of Clinical Oncology convened a summit on drug shortages. The Food and Drug Administration (FDA) has set up a special office for collecting information on drug shortages, stepped up its inspection of facilities shut down because of production problems, and loosened requirements for drug importation. Congress has held hearings, and Senators Amy Klobuchar (D-MN) and Robert Casey (D-PA) have proposed legislation requiring early warning of impending shortages from companies anticipating problems with drug supply. On October 21 of this year, the Life Sciences Consortium of the CEO Roundtable on Cancer convened a meeting of interested parties at the Institute of Medicine to consider solutions. Despite all this discussion, no simple answer is in sight, and the number of drugs in short supply grows daily.

    The origins of drug shortages are multifactorial, but simply stated, the problem for cancer treatment stems from a confluence of factors: consolidation of generic-drug production in the hands of a few manufacturers (Teva, Bedford, APP Pharmaceuticals, Hospira), who in turn have experienced both increased demand for drugs and production "problems." In general, generic drugs are sold for very limited profit, as fixed by Medicare legislation, and therefore are produced as inexpensively as possible, using older and less efficient production facilities, and with limited inventories to reduce carrying costs for the company. Contamination of commercial drug vials with particulate or biologic matter has led to the closure of several key plants (Bedford and Hospira).2

    These plants are being upgraded to comply with FDA standards. The FDA has taken additional measures to expand the drug supply. It has hastened its inspection and approval of new or refurbished facilities and has stated its intent to expedite approval of alternative manufacturers from the United States and abroad. However, the list of drugs in short supply continues to grow. In the face of these production difficulties, there has been suspected stockpiling of scarce drugs by hospitals and by "gray-market" (unofficial, though not necessarily illegal) wholesalers that are out to profit from the sudden unfulfilled demand. To add to these problems, the worldwide demand for oncology drugs is growing rapidly, as Asian, South American, and even African countries expand access to cancer treatment. This trend is likely to exacerbate the shortage and divert supplies abroad.

    Are there alternative sources of drugs? There is an extensive untapped capacity to produce generics in Europe and Asia. Major pharmaceutical companies, such as Pfizer and Sanofi, have generic products, many of which are sold exclusively overseas. In recent months, Pfizer has begun to market in the United States two drugs, irinotecan and doxorubicin, that it formerly produced on patent in this country. Sanofi has offered to make its extensive list of common generics available in the United States but has not yet been encouraged to do so by the FDA. Major pharmaceutical companies could re-enter the market for off-patent products, but they need the incentives of a reasonable profit and an expedited route to marketing approval.

    A number of long-term remedies, both legislative and regulatory, have been suggested. Although manufacturers cannot be required to produce drugs to meet market demand, congressional hearings have led to calls for requirements for early warning about shortages. Others, including me, have suggested basic changes in the Hatch–Waxman Act of 1984, which set standards for the generic-drug category. We propose that, as a part of a new license application, manufacturers should be required to present projections for product demand and plans for meeting those demands. Legislation could require that a company establish redundancy in its production capacity for generics, just as it does for patented drugs, and could allow the FDA to revoke marketing licenses for companies that fail to meet minimal production goals. Holders of Abbreviated New Drug Application (ANDA) licenses who have effectively met market demand and maintained production should be afforded priority review in the competition for future generic licenses, while the track record of those that fail should be a strong negative factor in consideration of approvals for new applications. Even exclusivity in licensing generic products could be considered. In assessing the growing urgency of the situation, we must keep in mind that some of the current leading patented drugs used in oncology, including granulocyte colony-stimulating factor (G-CSF) and erythropoietin products, will be coming off patent in the next few years, and the problem of providing life-sparing generics will only get worse.

    Finally, a greater financial incentive for manufacture of generics would very likely improve industry's track record. Currently, Medicare legislation resets reimbursement for injectable generics at no more than 6% above the average sales price (ASP) paid during the preceding quarter for any given agent.3 These limits affect price and reimbursement for all purchasers and providers, result in little profit for the manufacturer and the provider in the U.S. market, and greatly limit the ability of generic-drug manufacturers to increase their prices. Meanwhile, generic drugs manufactured in the United States can be sold abroad for a greater profit. This differential will promote the "leakage" of U.S. drugs to overseas markets.4 Although the United States can ill afford higher prices for drugs, raising the price of generics, which currently account for less than 2% of the cost of cancer drugs, would have minimal effect on the total cost of cancer care.

    On October 31, 2011, in response to the shortages, President Barack Obama issued an executive order in which he broadened reporting requirements for potential shortages and instructed the FDA to accelerate reviews of new applications for marketing of generics and to provide information to the Justice Department about possible collusion or price gouging related to the shortages. This action represents a step forward in addressing this issue. The specific manner in which these orders will be implemented and the degree to which they will ameliorate the drug shortages are unclear. The executive order does not improve reimbursement for generic drugs or address the need for redundant production facilities or incentives such as rewarding past performance in the approval of new generics applications.

    It will be up to the community of cancer doctors, patients, and concerned citizens to demand further action at the federal level and by the private sector to ensure access to lifesaving and life-extending drugs. A license to market lifesaving products should entail a public obligation to meet demand. After all, if we can afford to spend billions of dollars on medical research, we should, as a society, enjoy the fruits of that investment by assuring the manufacture of generic drugs.

    Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

    This article (10.1056/NEJMp1112633) was published on October 31, 2011, at NEJM.org.
    Source Information

    From the Massachusetts General Hospital Cancer Center, Boston.
http://www.nejm.org/doi/full/10.1056/NEJMp1112633

comments :

NANCY DOW, MD | Physician | Disclosure: None
SILVER SPRING MD
November 05, 2011

Drug Shortages

Why not just admit that the principles of Behavioral Economics 101 have proven once again to be fulfilled?

"Price controls on any product will create shortages of that product" no matter how well intended they are. Businesses that want to stay competitive will divert their resources to other products. That opens the door to black markets and complete loss of control of the quality of the price-controlled product. Exactly what we're seeing now.

I would contend that the solution is actually easy... though probably impossible due to its political incorrectness. Congress needs to fix the incentives. They need to remove the reimbursement limit for injectables that was included in the Medicare legislation of 2003. Attempts to defy the reality of supply and demand will be tremendously expensive and will inevitably prove to be futile.

GERARD VENTURA, MD | Physician - Oncology | Disclosure: None
NACOGDOCHES TX
November 04, 2011

Political Will? -The Duck Wins

The economic incentives that cause this are not part of an overall strategy but nonetheless reflect the refusal of Congress over the last 30 years - one whole generation - to lead and govern responsibly, for fear of not being re-elected (sound familiar?). The remuneration for go-along/get-along after a stay in DC (consulting and board chairs) also plays a role.
It reminds me of the Ronald Reagan joke.
How do you tell the Italian at the cock fight? He's the one who brings a duck.
How do you know the Mafia's involved? The duck wins.


Bola Akinlade | Physician | Disclosure: None
November 01, 2011

Drug Shortages — A Critical Challenge for the Generic-Drug Market

Dr. Chabner's perspective on the shortage of essential drugs in the US is most welcome and provides a valuable insight from a physician's view, adding to the recent spate of news on this most important topic. As he points out, the solutions are not easy. However, it does appear that economic incentives should surely persuade manufacturers to fill these shortages. His comment of "even African countries..." in the context of describing regions that have a demand for these drugs seemed somewhat condescending and unnecessarily gratuitous. I am inclined to believe that Dr. Chabner did not intend this. Nevertheless, the issue of drug shortages should not just be a US-centered problem, but should be looked upon as a global issue, with all stakeholders putting heads together to address this very challenging problem. I am aware that given the existing economic realities, many US-based pharmaceutical companies are shifting their sales and marketing focus to emerging markes such as India and Brazil.

JOSEPH WILDMAN, MD | Physician | Disclosure: None
SHORT HILLS NJ
November 01, 2011

Drug shortages

Bravo, Dr.Chabner! This pressing issue has heretofore been approached with incredible timidity and passivity. "A license to market lifesaving products should entail a public obligation to meet demand." Why should we not add that "a license to manufacture absurdly expensive and profitable new products should entail an obligation to meet the OVERALL pharmaceutical needs of the community?" The next Rituxan, for example,should not be approved without a requirement that the manufacturer guarantee sufficient supplies of the cyclophosphamide and doxorubicin which are so often given with it; the next Oxaliplatin without guarantees for 5FU and leucovorin.

GORDON HUTCHINSON, MD | Physician | Disclosure: None
NEW HAVEN CT
October 31, 2011

Drug shortages

I like Dr. Chabner's point of view! The "license to market lifesaving products should entail a public obligation to meet demand." Enforcement of this ethical obligation would rely on tough standards for production and supply, but ensure an easier path to licencing the next generic for responsible manufacturers and a pathway out of business for those who are not. I do not think that procuring drugs from foreign sources is currently a viable solution to this crisis given the FDA's known inability to effectively monitor drug or pharmaceutical constituent production outside the US.




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