	While debt from medical school loans is inevitable for most oncology and hematology fellows, there are strategies they can consider to lessen that burden. Moreover, recent announcements from the Obama administration would cut loan debt for some medical school borrowers.

	Nevertheless, many fellows and young physicians still face substantial debt when they complete their schooling. Matthew Shick, senior legislative analyst for the Association of American Medical Colleges (AAMC), told Oncology Fellows , “Medical school tuition and fees continue to rise. The amount medical students borrow to pay for medical school has averaged around $160,000 for the past 3 years (as reported by medical students graduating in 2009, 2010, and 2011).”

	Similarly, the American Medical Association (AMA) estimated the average educational debt of indebted graduates of the class of 2010 at $157,944.

	However, some good news has emerged to brighten the financial outlook for borrowing students. The Obama administration announced in late October that it will reduce the maximum required payment on student loans from 15% of discretionary income annually to 10%. Obama said the plan would go into effect in 2012, instead of 2014. In addition, the White House says the remaining debt would be forgiven after 20 years, instead of 25. The proposal is expected to affect some 1.6 million borrowers starting in 2012.

	In other good news, AAMC’s Shick said that recent statistics indicate that “Since 2008 we’ve started to see a recent trend of medical education debt leveling off.”

	Finally, the economic stimulus bill that President Obama got through Congress includes an additional $300 million for students who agree to take public service jobs, including those in medicine.

	Still, many observers of healthcare trends contend that the spiraling debt burden has serious consequences for American medicine. For example, Catherine Spina, MD, a PhD candidate at Boston University School of Medicine, and immediate past chair of the Organization of Student Representatives (OSR) of the AAMC, wrote in a newsletter in February 2011: “The grim financial outlook of state-funded schools has translated to an increased burden on the learner. As a result, many matriculating medical students arrive with more debt from their undergraduate educations and are forced into deeper debt as they shoulder the expense of soaring medical school tuition.”

	One possible consequence of the crushing weight of debt, according to some observers, is to steer young physicians into the higher-earning specialties rather than lower-paying primary care medicine. S. Ryan Greysen, MD, assistant clinical professor of medicine for the Division of Hospital Medicine at University of California San Francisco, who has written on the subject for The New York Times , said that “My sense is that the rising cost of medical education may be part of a cultural shift where the practice of medicine is more of an investment than a calling. I make the argument in my [New York Times ] article that medical education is seen now as a personal investment and I hear colleagues refer to their debt as a ‘mortgage,’” especially since “obtaining medical education in the United States has become a loandependent, individual investment.”

	Greysen is quick to point out that the data on how school loans affect the kind of medicine young physicians choose to take up are ambiguous, with some studies showing that it has minimal effect.

	“The studies here are often conflicting—some show that students with higher debt are less likely to practice primary care or work with underserved populations but others show there is no relationship with debt,” Greysen said. “Several recent studies have shown correlations between debt and stress or burnout&mdash;and these may affect students’ decisions about which specialty they enter,” he added.

	Shick said of this issue: “In the 2011 AAMC Graduate Questionnaire, students reported personality fit, specialty content, work/life balance, role model influence, future family plans, fellowship training options, income expectations, length of residency, competitiveness of specialty, and expectations of family as having a higher influence on specialty choice than student debt.”

	However, he added: “That being said, the cost of medical education weighs more heavily on certain cohorts of students. With the high price tag and expected debt burden, the decision to attend medical school can be daunting for socioeconomically disadvantaged and minority students who are typically more averse to taking out high loan volumes.”

	Nonetheless, oncology and hematology fellows do have choices that can substantially reduce their debt.

	One of those choices is public service medicine that makes young physicians eligible to receive loan repayment programs (LRPs). Applicants for these programs must agree to commit to practicing for a specified time in a medically underserved region of the United States or in research at an approved institution.

	The National Institutes of Health (NIH) is the largest provider of LRPs, recruiting physicians to practice in areas designated by the US Health Resources and Services Administration either as a Health Professional Shortage Area or a Medically Underserved Area. To qualify for this program, applicants must be willing to work full-time serving patients in the designated areas.

	For example, the American Society of Clinical Oncology LRP, funded by Susan G. Komen for the Cure, provides repayment of qualifying educational debt to oncologists or oncology fellows who, after completing their training, commit to practicing oncology in a medically underserved region of the United States. The LRP will repay up to $35,000 per year for 2 years (up to $70,000 total) of qualifying education loans. For questions, contact grants@ asco.org or call 571-483-1662. [

 For more on loan repayment programs, see Finance for Fellows in the October 2011 issue of Oncology Fellows .]

Increased Funding for Public Service Medicine.

	The LRPs get funding through the National Health Service Corps (NHSC), which has been given a financial boost from Congress and the Obama Administration. The American Recovery and Reinvestment Act of 2009 (the so-called stimulus package) provides an additional $300 million in funding for NHSC, including $168 million for LRPs, to increase the physician workforce in medically underserved areas.

	According to AAMC’s Shick, the expanded funding means that NHSC practice locations will increase significantly, to include urban and rural areas not previously designated as health professional shortage areas. He predicted that the program, which is already strong, is going to be even stronger, providing many more opportunities in urban areas than there were in the past.

	An option for oncology and hematology fellows is military service. The Armed Forces, through the Health Professionals Loan Repayment Program (HPLRP), offer up to $40,000 per year to physicians who commit either to active duty service or to service in the National Guard or Reserves, or to the Veterans Health Administration. [

 For more on HPLRP, see Finance for Fellows in the October 2011 issue of Oncology Fellows .]

 The AAMC, Shick said, has advocated strongly for the following proposals:

			Reduce the amount of interest paid on federal Stafford loans through the Department of Education. At the current 6.8% rate for graduate and professional students, medical students can expect to repay between $300,000 and $450,000 on the average $160,000 medical education debt (between $140,000 and $290,000 in interest).		

			Increase funding for the NHSC, the federal program that provides scholarships and loan forgiveness in exchange for primary care practice in underserved areas. Additionally, Shick said, the AAMC sponsors Financial Information Resources Services and Tools (FIRST) for medical education. He said this program “offers a full range of resources for medical school applicants, students, and residents to help expand their financial literacy, make smart decisions about student loans, and manage their student debt wisely.” Students and fellows can learn more about this program online at www.aamc.org/first.		

 1. Spina C. Viewpoint: Drowning in debt: innovate or else. AAMC Reporter. https://www.aamc.org/newsroom/reporter/ feb11/174772/viewpoint.html. February 2011. Accessed November 30, 2011. 

Articles

While debt from medical school loans is inevitable for most oncology and hematology fellows, there are strategies they can consider to lessen that burden.

What Oncology and Hematology Fellows Can Do to Reduce Their Loan Debt

Oncology and hematology fellows are eligible for loan repayment programs (LRPs) for their medical education debts, but usually there’s a catch. The catch is that the applicant fellow must agree to commit to practicing for a specified time in a medically underserved region of the United States, in research at an approved institution (usually a medical school), or in the military.

	Most LRPs are sponsored by national, state, and local governments, but a handful are offered by private organizations. Typically, after completing a residency, physicians can apply to practice in areas designated by the US Health Resources and Services Administration either as a Health Professional Shortage Area or a Medically Underserved Area. To qualify for this program, applicants are not required to come from any particular ethnic or racial background, but they must be willing to work full time serving patients in the designated areas.

	The largest provider of LRPs is the National Institutes of Health (NIH). The NIH says that it is committed to encouraging outstanding health professionals to pursue careers in biomedical, behavioral, social, and clinical research. One of the objectives of the NIH Loan Repayment Program is to provide financial help to fellows who choose to stay in academic medicine by relieving some of their student loan debt. The NIH recognizes that salaries in academia usually do not match those in private practice, so the LRP seeks to help qualified fellows continue their careers in academic medicine.

	If a fellow commits to at least 2 years of conducting qualified research funded by a domestic nonprofit organization or a US federal, state, or local government entity, NIH may repay up to $35,000 of qualified student loan debt per year, including most undergraduate, graduate, and medical school loans. Loan repayment benefits are received in addition to the institutional salary that fellows might earn for their research.

	If a fellow is or will be conducting qualified research at a domestic nonprofit institution outside NIH, he or she may be eligible for an LRP in one of the 5 LRP categories.

	An example of a nonprofit program is the one administered by the American Society of Clinical Oncology (ASCO). It offers LRPs to a number of fellows each year. Applicants must be an associate or active ASCO member or submit a membership application with the award application. The program will repay up to $35,000 per year for 2 years (up to $70,000 total) of qualifying education debt. For application forms and complete application criteria, visit the ASCO Cancer Foundation Website at www.conquercancerfoundation.org/foundation and click on “Cancer Professionals” and then click on “Grants & Awards.”

	Loan repayment programs are offered through the NIH at numerous medical institutions, including a pediatric oncology position at Johns Hopkins University in Baltimore, the Children’s Hospital of Philadelphia, Memorial Sloan-Kettering Hospital in New York, and the University of Texas Southwestern Medical Center in Dallas. Benefits vary, but on average participants are required to provide service for 2 to 4 years. Fellows can contact the financial aid office of medical schools for more information.

	The US armed forces are another major source of LRPs, through the Health Professionals Loan Repayment Program (HPLRP). Participants can receive up to $40,000 per year for 3 years. Fully trained clinicians are eligible for loan repayment in exchange for service in an eligible assignment. Financial grants are available for fellows who commit to active duty service and for those who choose to serve in the National Guard or Reserves.

	For just about every specialty or field within the US Army Medical Department, the National Guard offers fellows a bonus and/or an LRP. With a 3-year service agreement, physicians can receive special pay for health professionals of up to $75,000, paid at $25,000 per year over 3 years. And with another 3-year commitment, the bonus may be renewable. The National Guard is seeking physicians, residents, fellows, and medical students in a variety of specialties, including medical oncology/hematology.

Combining 2 Careers: The Guard and the VA

	Fellows can combine 2 paths into 1 career that fulfills a military service requirement as well as the medical needs of military patients. Selected fellows can work full time for the Veterans Health Administration and serve part time in the National Guard. By combining National Guard service and VA employment, applicants are eligible for education loan repayment assistance from both organizations. While the National Guard offers the HPLRP to qualifying members, VA medical professionals can benefit from the Education Debt Reduction Program (EDRP), which can eliminate up to $38,000 of your outstanding loans. For more information about EDRP, fellows can contact a local National Guard recruiter. The program also provides $2500 each year for continuing medical education (CME) credit.

	Physicians who agree to serve in Reserve units, as in the National Guard, are eligible to receive the special pay for health professionals of $75,000, paid in yearly increments of $25,000 for 3 years. They are also eligible for medical school loan repayment of up to $50,000 over 3 years.

	In addition to NIH, military services, and state LRPs, some private institutions provide grants to cover medical education loan debts, such as the Janet and Ray Scherr Fellowship Fund. The loan amount for this program is a maximum of $10,000 per individual. For every year after graduation that the trainee stays in academic pediatrics, one-half of 1 year’s repayment will be forgiven if the individual remains in a full-time academic pediatric position. For every year after graduation that the individual remains on the faculty at Mattel Children’s Hospital UCLA, a full year’s repayment will be forgiven.

	If you are interested in learning more about loan repayment programs, you can contact the NIH office that handles the programs (www.lrp.nih.gov), your local armed forces recruiter, your medical school outplacement office, or your employer’s human relations office. In addition, the American Association of Medical Colleges (AAMC) maintains a database of state and other loan repayment programs for medical school students.

Matthew T. Corso is a veteran editor and writer who has worked in medical publishing for more than 25 years.

Itâ€™s no surprise that you acquire significant debt during your medical training. Here are some ways to get those loans paid off.

Loan Repayment Programs for Oncology/Hematology Fellows

Both industry and clinical sources agree that cancer vaccine research—despite numerous stumbles in the past 15 years&mdash;is finally on the right track to achieve major advances in treatment. As one senior CEO of a company hoping to launch a new vaccine within the next several years said: “We’re beginning to figure out how to do this.”

	That optimistic assessment is echoed by other clinical researchers and market analysts. For example, GlobalData, an international industry analysis specialist that tracks pharmaceutical development, confidently proclaimed: “The present pipeline for cancer vaccines seems to be very promising, with numerous molecules present in the phase II and III stages. From the market perspective, there are going to be multiple launches of vaccines between 2010 and 2013-14, which would substantially increase the market size and growth.”

	This bright outlook is shared by one of America’s foremost researchers in cancer immunotherapy, James P. Allison, PhD, director of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center in New York City.

		Table: Promising Cancer Vaccines in Advanced Clinical Trials

	“The story is encouraging,” said Allison of the variety of vaccine formulations being investigated. (See “Types of Cancer Vaccines Being Investigated.”) Allison is one of the discoverers of the role that T cells and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) play in spurring the human immune system to attack cancer cells.

	Because of this renewed optimism, the cancer vaccine industry appears to be going full speed in trying to find effective treatments. An estimated 130 potential cancer vaccines are now being studied, many in advanced clinical trials 

	But that optimism is tempered by past failures of once high-flying investigational cancer vaccines and by the steep cost of the few cancer vaccines that have recently been approved and entered the market.

	Researchers and investors have been encouraged by the recent FDA approval of 2 vaccines: sipuleucel-T (Provenge), for the treatment of prostate cancer, and ipilimumab (Yervoy), for the treatment of metastatic melanoma. Provenge, which is manufactured by Dendreon, a company based in Seattle, Washington, was approved in April 2010 and uses a patient’s dendritic cells and cultures them with genetically engineered antigens. Yervoy was approved in March 2011 and is a human monoclonal antibody manufactured by Bristol-Myers Squibb. Allison, at Memorial Sloan-Kettering, was one of the founders of the cellular process on which ipilimumab is based.

	Robert L. Kirkman, MD, president and CEO of Oncothyreon, which is based in Seattle, said that the START (Stimulating Targeted Antigenic Responses To NSCLC) study is a multicenter, randomized, double-blind, placebo-controlled trial that is evaluating patients with documented, unresectable stage IIIA or IIIB NSCLC. The START study will involve more than 1300 patients in some 30 countries.

	At the same time, the companies are sponsoring the Stimuvax INSPIRE (In Asian Patients: Stimulating Immune Response) trial, also a phase III study testing the vaccine in Asian patients with advanced NSCLC. The trial is enrolling approximately 420 patients in China, Hong Kong, South Korea, Singapore, and Taiwan. INSPIRE is similar in design to START and will evaluate the efficacy, safety, and tolerability of Stimuvax in patients with unresectable stage III NSCLC. The primary endpoint is overall patient survival.

	The START study is “pretty far along,” said Kirkman. He said the company was encouraged by the “very strong data from the phase II study,” which “showed a very significant 17-month improvement in median survival.” The 3-year survival data from the study, presented in 2007 at the International Association for the Study of Lung Cancer Congress in Seoul, South Korea, showed that patients given Stimuvax had a median survival of 30.6 months, compared to 13.3 months in patients not exposed to the vaccine.

	"Cancer vaccines take a while to get started and you must follow patients for some time for reasonable expectations to result."

	An effective and life-prolonging treatment for NSCLC is a critical unmet need in medicine. The company said that the condition, which accounts for 85% of all lung cancers (about 1.6 million new cases are diagnosed worldwide each year), is rarely diagnosed at its earliest and most potentially curable stage when it is subject to surgical resection. Most patients are diagnosed when the tumor has already advanced to stage III, when the cancer has invaded the chest tissues or mediastinal lymph nodes and is inoperable, or to stage IV, when the cancer has spread to other organs.

		Types of Cancer Vaccines Being Investigated

 boost the immune system by using only one or a few antigens, rather than whole tumor cells that contain many thousands of antigens. The antigens are usually proteins called peptides. Antigen vaccines may be specific for a certain type of cancer, but they are not made for a unique patient like autologous cell vaccines are.

		Scientists can produce many antigens in the laboratory and can change antigens to make them more easily recognized by the immune system. This new technology means that large amounts of specific antigens can now be given to many patients.

 Dendritic cells are antigen-presenting cells that help the immune system recognize cancer cells. They break down cancer cells into smaller pieces (including antigens), making it easier for T cells to recognize and attack them.

		Dendritic cell vaccines are autologous vaccines and must be made individually for each patient, a complex and expensive process. Physicians remove some of the cells and treat them in the laboratory to make them multiply. This creates many more dendritic cells than if they just used cells taken from the patient. These dendritic cells are then exposed to cancer cells or cancer antigens. The dendritic cells are then reinjected into the patient. Sipuleucel-T (Provenge) is an example of a dendritic cell vaccine.

 Antibodies are made when the immune system responds to antigens. The unique part of each type of antibody is called an idiotype. But the immune system also makes some antibodies that treat other antibodies like antigens (ie, sometimes the body makes antibodies against other antibodies).

		Antibodies and antigens can work together as a team. So an antibody to a particular idiotype of another antibody (an anti-idiotype) will usually look like the antigen that triggered cells to make the antibody in the first place. The anti-idiotype antibodies look like the antigen and appear foreign, so injecting them into the body causes the immune system to attack the anti-idiotypes, as well as the antigens themselves. Therefore, they can trigger an immune response against that specific cancer.

 When tumor cells or antigens are injected into the body as a vaccine, they can initially cause the intended immune response, but their effectiveness may weaken over time. Unless there is further stimulation, the immune system will often return to its normal (prevaccine) state. To circumvent this, scientists have searched for a way to provide a steady supply of antigens to sustain the immune response.

		One way to sustain the immune response is through DNA, the nucleic acid that contains the genetic instructions used in all living organisms. Cells can be modified with parts of DNA that code for target antigens, signaling cells to keep making more antigens. These types of therapies are called DNA vaccines.

		Researchers have been able to use this process to remove some of a patient’s cells, treat them with DNA that codes for a target antigen, and then return them to the patient. The altered cells would then make the antigen continuously to keep the immune response strong.

 Vectors are delivery systems that can get antigens or DNA into the body. Vectors may include viruses, bacteria, yeast cells, or other structures. Vectors may be used to deliver more than one cancer antigen at a time, which may make the body’s immune system more likely to mount a response. Also, viruses and bacteria vectors may trigger their own immune responses from the body, which may help make the overall immune response even stronger.

Definitions are adapted from the American Cancer Society and National Institute of Cancer of the National Institutes of Health (NIH).

	The target of the Stimuvax vaccine, Kirkman said, is the mucin-1 (MUC-1) glycoprotein, a tumor-associated antigen that is greatly overexpressed on tumors in lung, pancreatic, breast, and prostate cancers. Consequently, Kirkman said, if Stimuvax proves effective and safe, it might be useful “in a broad range of cancers.”

	Kirkman is aware of the large number of investigational cancer vaccines that have fallen by the wayside after disappointing trials. Consequently, he said, vaccine developers must have the patience and resources to commit to extended clinical trials. “Cancer vaccines take a while to get started and you must follow patients for some time for reasonable expectations to result,” he said.

	Nevertheless, he said, the current research has buoyed the hopes of all cancer vaccine investigators. “We’re beginning to figure out how to do this,” he said of the various processes being tested to attack malignant cells (see “Basic Categories of Cancer Vaccines”). “Now we have 2 vaccines (Provenge and Yervoy) and these have gone a long way to encourage people that the approach works,” Kirkman said.

	An advantage of vaccines such as Stimuvax is that they are allogeneic, also known as “off-theshelf” (ie, peptide-based products that can be injected in any qualifying lung cancer patient). “Our vaccine is not patient-specific,” Kirkman said, contrasting Stimuvax with patient-specific (autologous), whole-cell vaccines that must be taken from a patient’s own tumors.

	While Kirkman and his group are looking forward to the completion of their vaccine’s phase III trial, projected sometime next year, Edward G. Shaw, MD, is part of a team just beginning a phase I trial for another cancer vaccine—this one for brain cancer. Shaw, a professor of radiation oncology at the Wake Forest University Baptist Medical Center in Winston-Salem, North Carolina, is testing the vaccine in patients with low-grade gliomas. In fact, the patients in his trial will be the first humans tested for these kinds of slow-growing brain tumors.

	“The vaccine is similar to many vaccines used to prevent infectious diseases in that it’s a process of passive immunity,” Shaw explained. The study will determine whether patients who receive the vaccine (antigen peptides in combination with poly-ICLC) can develop an immune response, thereby spurring cytotoxic T lymphocytes (CLTs) against the glioma cells. The study (Effects of Vaccinations With HLA-A2-Restricted Glioma for Adults With High-Risk WHO Grade II Astrocytomas and Oligo-Astrocytomas) is being undertaken in collaboration with the immunologist Hideho Okada, MD, PhD, and his research group at the University of Pittsburgh in Pennsylvania.

	Shaw, who has worked in cancer research for more than 25 years, said he is “cautiously optimistic that this is the way to go.” The target date for the completion of the low-grade glioma trial is the end of this year, Shaw said.

	In addition to proving efficacy, other challenges that cancer vaccine developers face are safety and cost, according to Clifford S. Goodman, PhD, senior vice president of the Lewin Group, a healthcare policy and management consulting firm based in Falls Church, Virginia.

	“Like other cutting-edge technologies, cancer vaccines will be subject to higher evidence requirements for demonstrating safety and effectiveness,” said Goodman, who has led nationally recognized studies in such areas as organ transplantation. He serves as chair of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) for the Centers for Medicare & Medicaid Services (CMS). The MEDCAC provides independent guidance and expert advice to CMS and reviews and evaluates clinical data on the effectiveness of drugs and services either covered under Medicare or that may be eligible for coverage under Medicare. The MEDCAC judges the strength of the available evidence and makes unbiased recommendations to CMS based on that evidence.

	"The FDA does not consider cost effectiveness in making coverage decisions, but that ‘smart companies [that] are doing their homework’ need to be aware of ‘the financial environment...tempered by regulatory and payment requirements that will mediate access’ to new drugs."

	Goodman, who has testified to Congress on issues pertaining to Medicare coverage of healthcare technology, said the FDA does not consider cost effectiveness in making coverage decisions, but that “smart companies [that] are doing their homework” need to be aware of “the financial environment...tempered by regulatory and payment requirements that will mediate access” to new drugs. In expanding on this theme, Goodman stated, “The cost of these (new vaccines) may pose a barrier to access, depending on patient cost-sharing arrangements” such as patient copay and insurance coverage.

	The issue of cost is sensitive because the industry-set price tags for Provenge and Yervoy—$93,000 and $120,000, respectively&mdash; have certainly raised eyebrows among healthcare specialists and regulators.

		Autologous vaccines are made from killed tumor cells that are surgically taken from the patient in whom they will later be used. The cells are treated and then injected back into the patient. Autologous tumor cell vaccines have potential drawbacks: the expense can be prohibitive in creating a new, unique vaccine for each patient; and cancer cells tend to mutate over time, so an autologous tumor vaccine might become less effective later if the cancer cells in the body change.

		Allogeneic vaccines use the cells of a particular cancer type that come from someone other than the patient being treated. These vaccines are not geared for just one person and are often called off-the-shelf vaccines because they are intended for many patients. Once these cells are treated they are usually injected with one or more adjuvant substances to stimulate the immune system.

		Cancer preventive vaccines are designed to prevent cancer from developing.

		The FDA has approved 2 types of cancer preventive vaccines: vaccines against the hepatitis B virus, which can cause liver cancer, and vaccines to prevent human papillomavirus (HPV), which can cause cervical cancer.

		The vaccines available for hepatitis B include Engerix-B (GlaxoSmithKline) and Recombivax HB (Merck). There is also a combination vaccine for hepatitis A and B available for adults, Twinrix (GlaxoSmithKline). These vaccines are given intramuscularly.

		The approved vaccines against human papillomavirus types 16 and 18 are Gardasil (Merck) and Cervarix (GlaxoSmithKline), both of which are HPV quadrivalent vaccines. The types of HPV that these vaccines prevent are responsible for about 70% of cervical cancer cases.

		Cancer treatment vaccines are intended to treat existing cancers. So far, the FDA has approved 2 vaccines to treat cancer that has already occurred. Sipuleucel-T (Provenge) is a dendritic cell vaccine for the treatment of metastatic castration-resistant prostate cancer. Ipilimumab (Yervoy) is a human monoclonal antibody approved for the treatment of advanced melanoma.

	Aside from cost, the FDA has sounded a sobering warning against excessive euphoria about the current state of cancer vaccine research. Peter F. Bross, MD, the medical review officer in the FDA’s Office of Cellular, Tissue, and Gene Therapy, reminded everyone that “there is no well-established roadmap for clinical development of cancer vaccines, and the clinical development paradigms for more traditional chemotherapeutic agents may not apply to cancer vaccines.” For example, Bross said, “Unlike traditional chemotherapeutic agents, a cancer vaccine may improve survival without causing the tumor to shrink. A cancer vaccine may require substantial time after administration to produce the immune response necessary for effectiveness. Assays to measure this immune response tend to be difficult to standardize, and the assay results may not be reliable.”

	Moreover, Bross said: “In the absence of tumor shrinkage or a reliable assay, it can be difficult to detect clinical activity, select the most promising dose and regimen, or determine whether the product is promising enough to deserve further study. Therefore, cancer vaccine development programs often rely on singlearm studies with historical comparisons which may not be reliable predictors of the activity of the product. In the absence of an established surrogate, such as tumor shrinkage, for clinical benefit, development of cancer vaccines will likely require long-term studies with survival endpoints that take years to reach.”

	In addition to the several dozen cancer vaccines in advanced trials, many more are being tested in animal studies. An example is Oncothyreon’s other investigational cancer vaccine, ONT-10, which also targets the MUC-1 glycoprotein. Kirkman said the vaccine is now in animal studies and is designed to trigger a T-cell response to cancer cells.

	Allison said the research is convincing that all cancer vaccines need a co-stimulatory signal teaming with the main treatment molecule to successfully halt the cellular proliferation in cancer—a necessary “one-two punch,” if you will.

	One of the key lessons that cancer vaccine researchers are learning, Allison said, is that immunotherapy should concentrate on “treating the immune system, not the tumor.”

Both industry and clinical sources agree that cancer vaccine research is finally on the right track to achieve major advances in treatment.

Emerging Cancer Vaccines Appear to Be on Track for Major Advances

The shortage, which began in 2009, accelerated in 2010, and has shown no signs of abatement so far in 2011, according to Erin R. Fox, PharmD, manager of the Drug Information Service at University of Utah Health Care, which provides data for the American Society of Health-System Pharmacists (ASHP) Drug Shortage Resource Center. Dr Fox has led the drug shortages project since 2001.

	“Through December 2010 we’ve tracked 211 new shortages, and that’s the most ever,” Fox said. This compares with 149 new shortages in 2008 and 166 in 2009 (Figure), according to the Drug Information Service’s data.

	While the shortages include a variety of drugs, such as antimicrobials and anesthetic agents, the FDA reports that about 75% involve chemotherapy sterile injectables for cancer patients.

	“Already in 2011 we have seen recalls due to quality issues and have seen new shortages occur as a result,” said Captain Valerie Jensen, RPh, the FDA’s Associate Director of the Drug Shortage Program.

	In explaining one of the key reasons for the shortage, Fox, who is also associate professor (adjunct) in the Department of Pharmacotherapy at the University of Utah College of Pharmacy in Salt Lake City, added, “What makes chemotherapy drugs so different to deal with is basically there are no alternatives and they’re not easy to substitute. It’s a disaster.”

	The shortages of chemotherapy agents (Table) are “definitely affecting patient care,” according to Bona E. Benjamin, BS Pharm, Director of the Medication-Use Quality Improvement for the practice development division of the ASHP.

	“Regarding oncology drug shortages, we’ve gotten anecdotal reports that some patients are not getting drugs when they should be, that they’re not getting all of the drugs they need, or are not getting any drugs at all for a time,” Benjamin said. “And that means patients are not getting the best outcome that they should.”

	Her contentions about patient care are corroborated by Ali McBride, PharmD, MS, a clinical pharmacy specialist at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital, in St. Louis, Missouri. “We’re seeing a lot of shortages,” McBride said. His unit has delayed patients starting chemotherapy until they were able to get an emergency supply of a drug. In some cases, he said, autologous transplants also have been delayed.

	One example he gave concerns the shortage of intravenous (IV) etoposide, a chemotherapeutic agent used in a variety of cancers, including lung cancer. In response to the shortage, some physicians have been switching from an IV to an oral formulation. “This increases the risk of dosage errors because patients usually have to double up on the oral medication,” McBride said. “This is truly a crisis, when patients can’t get the treatment regimen that they need,” he said.

	In an attempt to find solutions for the shortages, ASHP, the Institute for Safe Medication Practices (ISMP), the American Society of Anesthesiologists, and the American Society of Clinical Oncology convened a Drug Shortages Summit in Bethesda, Maryland, in November 2010.

	The summit found that a major cause of the shortages is that fewer manufacturers are producing the sterile injectables, most of which are generic, thereby limiting contributors to the supply chain. Consequently, manufacturing and production-line problems result in stunted supply. The problem of few suppliers came sharply to light when two of the largest sterile injectable manufacturers, Teva Pharmaceuticals and Hospira Inc., had to shut down some production lines in 2010 because of difficulty in meeting required quality control standards.

	“Not many people are manufacturing (the target drugs) these days. There’s just not enough resiliency in the supply chain,” Fox said.

	Benjamin concurred. “It’s very complex to produce sterile injectables, especially if you’re talking about cytotoxic drugs such as chemotherapy agents,” she said.

Asked to comment on the FDA’s understanding of the shortages, Captain Jensen said:

	“In general, the older sterile injectable drugs are being made by fewer and fewer manufacturers each year. The firms continuing to make these older injectables have limited capacity and only so many products can be made on the existing manufacturing lines. The firms often discontinue these older drugs in favor of newer, more profitable drugs. Unfortunately, when a quality problem develops at one manufacturer or there is any delay or a discontinuation by a manufacturer, a shortage usually develops due to the limited ability of the remaining firms to meet the shortfall. The recent shortages have mainly been caused by a large number of quality issues, as well as delays and discontinuations.”

	An FDA survey concluded that 43% of the shortages of sterile injectables in 2010 was attributable to product quality issues, such as particulate and microbial contamination, newly identified impurities, and chemical stability changes. Another 18% of the shortages was caused by manufacturers simply discontinuing production of a drug and 9% was due to raw material issues.

	The point about raw materials is cogent when one considers that an estimated 80% of the raw materials used in the production of pharmaceuticals comes from outside the US, according to an ASHP report published in 2009. The reliance on foreign raw materials, the report said, can result in supply problems at home when war or political upheaval disrupts trade, when disease-causing microbes contaminate the extraction process, or when climatic or environmental conditions retard growth of plants used to make the raw materials.

	The summit report says that suppliers’ struggles to comply with good manufacturing practices have been exacerbated by increased FDA inspections of injectable products. The FDA has increased the inspections, the report noted, “based on the higher likelihood of harm” to patients if the manufacturing processes are inconsistent with stated quality standards.

	In addition to fewer suppliers, more stringent production standards, and harder-toget raw materials, rising worldwide demand for injectable chemotherapeutic drugs is also putting pressure on the system.

	“We now have the globalization of drugs,” McBride said. “The demand from around the world has increased, limiting the supply of these products. It’s really scary.”

	In addition to patient care, drug shortages have also derailed clinical trials meant to test the effectiveness of various chemotherapy regimens, several clinicians complained. “These shortages are also linked to ongoing or planned clinical studies because the drugs are not there for the testing,” McBride said. “So you wind up with haphazard studies and that’s very frustrating,” he said.

	Also contributing to the problem is the traditional policy of manufacturers and healthcare centers to adopt “just-in-time” inventory management, intended to reduce the cost of inventory and optimize cash flow, the ASHP said in its 2009 report. While generally recognized as sound business policy for all stakeholders, during times of scarcity “this practice results in little or no inventory cushion to address short-term shortages,” the ASHP said. In a related consequence, some medical centers have begun stockpiling drug products when they get them, a strategy that “can exacerbate the shortage and divert unneeded supplies away from other health systems with patients in need,” according to the ASHP.

	Another factor contributing to the shortages, according to the summit report and other industry leaders, is that manufacturers are not required by law to alert the FDA when a manufacturer discontinues a product or when the production process is interrupted. This often leaves medical centers off-guard, bewildered, and frustrated, and they frantically search for new sources of the drug. The FDA cannot force a manufacturer to produce a product, and there is no penalty for a company that does not notify the FDA when production of a drug is discontinued.

	An FDA survey found that 85% of respondents had no information about why a shortage of a particular drug was occurring and no advanced warning when they discovered the shortage. This has placed an anxiety-filled burden on treatment centers to spend time searching for possible supplies of the drug from nonroutine sources or trying to find suitable alternative agents.

	The lack of requirement for notification of truncated drug supply is receiving attention from Congress. US Senator Amy Klobuchar (D-Minnesota) has written to the FDA, urging the agency to step up its monitoring of the problem of shortages. “Physicians, pharmacists, and patients are currently among the last to know when an essential drug will no longer be available,” said Klobuchar. “That’s not right. There needs to be better coordination between the pharmaceutical industry, the FDA, and healthcare providers so patients don’t lose access to the medications they depend on,” the senator said.

	Klobuchar said she plans to introduce legislation that would give the FDA the authority to require early notification from pharmaceutical companies when they decide to limit or discontinue production of prescription drugs.

	The summit report recommends that the FDA be given the statutory authority to require manufacturers to notify the FDA when there is a single production source or when there is an interruption in the supply of raw materials, in the manufacturing process, or in active pharmaceutical ingredients.

	Fox endorsed that kind of legislation, saying that one of the best things that can happen is increased transparency of the entire supply process.

	Some medical centers have successfully scrambled to prevent the shortage of sterile injectables from affecting patient care. “We have definitely felt the effects [of the shortage], but so far we’ve been able to manage by borrowing and trading,” said Timothy Cox, MD, an oncologist affiliated with the St. Joseph Mercy Port Huron Health System in Michigan. That has meant that medical personnel are spending a lot of valuable time trying to find enough product, according to Cox.

	He also said that the shortage has presented real problems for oncologists who prescribe combination chemotherapy regimens that require agents that are now in short supply. An example, Cox said, is the regimen he uses for patients with testicular cancer, which is cycles of BEP (bleomycin, etoposide, and cisplatin). All three of those drugs are in short supply. “And there are not a lot of options for alternatives,” he said.

	Some manufacturers of sterile injectables have been able to sustain supply in their chemotherapy product lines and avoid shortages. For example, Amgen has not experienced any interruption in production, according to Mary Klem, a spokeswoman for the company’s Research and Development/ Manufacturing Division. Amgen makes a number of oncology injectables, including denosumab, filgrastim, and panitumumab.

	“Our long-standing history in biotechnology manufacturing has enabled us to apply the know-how to meet the demand for oncology drugs,” Klem said. While acknowledging that shortages of product can happen to any company for a variety of reasons, Klem states that Amgen has multiple strategies in place to ensure uninterrupted production schedules.

	But one of the largest manufacturers of generic sterile injectables, Teva, has confirmed problems that have led to disrupted production. Denise Bradley, senior director of corporate communications at Teva, said in a statement: “Our facility in Irvine, California, which makes our injectable products, has been on a voluntary production hold since April 2010. We anticipate beginning production at this facility again in March. We will be bringing up one manufacturing line at a time—with the focus being on those oncology products that are on the drug shortage list.”

	However, she said the company would not identify the drugs for which production will be resumed. “We are not releasing the names of the drugs we’re starting production on at this time,” she said. Teva manufactures many of the most commonly used sterile injectable chemotherapy agents, including bleomycin, cisplatin, desmopressin, doxorubicin, etoposide, and leucovorin.

	The welcome news that Teva was stepping up production is in line with the FDA’s forecast that manufacturers are close to reviving production output. In fact, the FDA’s Captain Jensen said, “Many of the shortages of chemotherapy drugs that occurred in 2010 are being resolved by the manufacturers; however, the leucovorin and cytarabine shortages continue to be severe. We are continuing to work on all of the shortages that have occurred and are continuing to offer assistance to all of the manufacturers on anything that will help meet patient needs.”

	When asked if the FDA was confident that manufacturers can meet current demands, Jensen responded by providing a status report on the production expectations for the chemotherapy drugs. “For cisplatin, the two firms have increased supplies and report they are currently able to meet all demand. Doxorubicin is now being released by all three manufacturers, and they are all working to meet all demand. The shortage is anticipated to continue to improve based on what the manufacturers are reporting,” she said.

	Furthermore, Jensen said, “Bleomycin is now being released by one firm (Teva), and two of the other manufacturers plan on releases in March—so again, based on manufacturers’ plans, this shortage is anticipated to continue to improve as well. Leucovorin has been in shortage due to one firm having manufacturing issues and the remaining firm has not been able to meet demand. A new generic firm has recently launched its leucovorin injection and it is working to increase supplies. Cytarabine has been in shortage due to delays and manufacturing problems at the three manufacturers. One of the firms is planning additional supplies to be released soon.”

	Pharmaceutical companies’ plans to recharge production efforts “give us hope that they will be doing the right things for the long term,” Fox said.

	What steps has the FDA taken to help manufacturers refill the supply chain of these drugs? “When there is a quality problem causing the shortage, the FDA works with the affected firm to address the issue, Captain Jensen said. “We’re also working with the remaining firms on anything that they can do to increase their production. Sometimes they will need an additional manufacturing line or an additional site or supplier qualified to help increase capacity, and (we) are glad to help with these issues to address a shortage. For leucovorin, cytarabine, and the others, FDA continues to offer assistance to all of the manufacturers and is exploring all possible options to help with supplies.”

	Regarding FDA’s oversight of this problem, the summit panel recommended that the agency be given the authority to require manufacturers to provide notification 9 to 12 months before a drug is pulled off the market and to require them to have more than one production site for a sole, essential drug. “This would give the FDA the chance to help mitigate or avert the kinds of shortages we’re having now,” Benjamin said.

The shortage, which began in 2009, accelerated in 2010, and has shown no signs of abatement so far in 2011, according to Erin R. Fox, PharmD, manager of the Drug Information Service at University of Utah Health Care

Matthew T. Corso

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