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Bioequivalence is going mainstream.
Ever since the FDA’s Pharmaceutical Science and Clinical Pharmacology Advisory Committee concluded in April of 2010 (in an 11-2 vote) that current bioequivalence standards are not sufficient for narrow therapeutic index (NTI) drugs, there’s been a growing focus and understanding on the fact that less variability equals better predictability.
(Narrow therapeutic index, per the FDA, means that, “small changes in blood concentration have the potential to result in serious therapeutic failures and/or serious adverse drug reactions.”)
Currently, the “sameness” of a brand product and a generic version is evaluated based on a two-treatment crossover study to prove bioequivalence, the aim being to show that the 90 percent confidence intervals of the geometric mean test/reference ratios for both maximum plasma concentration and the area under the plasma concentration-time curve fall within a range of 80 percent to 125 percent.
(“Equivalent” doesn’t mean the same thing as “identical.”)
“All men are created equivalent” just doesn’t have the same ring, does it?
This is an urgent public health issue – and it’s got momentum.
It’s too simplistic to call these “quality” problems. There’s a range from sub-standard Active Pharmaceutical Ingredient (API) and manufacturing issues, to excipient changes (excipients are the substances other than the pharmacologically active drug contained in a pill) and, most importantly, bioequivalence and bioavailability standards.
“We are losing control over what people are swallowing,” said Dr. Harry Lever, a cardiologist at the Cleveland Clinic who is trying to raise awareness of the matter among U.S. lawmakers. “Now, when a patient comes in who is not doing well, the first thing I do is look at their drugs and find out who makes it.”
Bioequivalence does not always equal therapeutic equivalence – and that’s especially true for Toprol XL. Recently two large Indian manufacturers, Wockhardt and Dr. Reddy’s Laboratories, have announced recalls over the last two months totaling more than 100,000 bottles of Toprol XL because their products were not dissolving properly — therefore probably not working as they should. The drug is a beta blocker that treats high blood pressure and heart ailments.
The issue of bioequivalence and therapeutic substitution will be at or near the top of the budget agenda in state capitols across the United States. NTI generic drugs, biosimilars and non-biologic complex drugs (NBCDs) are a medical option, but as every state in the union attempts to tighten its budget, requiring patients to use these follow-on products is an enticing, but incorrect and dangerous policy option. Placing short-term budgetary considerations before long-term patient well-being is pennywise and pound foolish, and is deleterious to both the public purse and public health. As an article in the Journal of Infection so aptly stated, “Nothing is more expensive than treatment failure.”
FDA’s recent draft guidances on bioequivalence for both generic and innovator products, as well as the move towards independent labeling for generic products are additional steps the agency has recently taken to address the issue of drug quality beyond safety and efficacy. And the implications for NTI generics, biosimilars and NBCDs is obvious.
(Something else to consider is for the FDA to report bioequivalence data in labels.)
The bioequivalence issue is clearly rising up the list of FDA priorities. Consider the agency’s action last week when it informed Mallinckrodt its methylphenidate hydrochloride tablets might not be therapeutically equivalent to Concerta, which is made by Johnson & Johnson ’s Janssen Pharmaceuticals Inc.
The FDA, in a statement, said the drug produced by Mallinckrodt may deliver the drug at a slower rate than another generic version of Concerta. As a result of its analysis, the FDA said the Mallinckrodt products are still approved and are eligible to be prescribed, but it no longer recommends them as an automatic substitution for Concerta.
But there’s a serious process issue that cannot be ignored. Mallinckrodt said the FDA informed the company that the change was based on new draft guidance for determining equivalency between the drugs that was published on November 6th – but the guidance has an open comment period that runs through January 5th, 2015. The FDA said this change was based on the application of its new Draft Guidance for determining bioequivalence of methylphenidate hydrochloride products just published on November 6, 2014. Although the Draft Guidance has an open comment period through January 5, 2015, the agency nevertheless confirmed that this change would be reflected on November 13, 2014 in the on-line Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations.
That may or may not be the proper public health decision – but it certainly doesn’t seem fair relative to thoughtful public comment. Not surprisingly, Mallinckrodt is suing the U.S. Food and Drug Administration for “unlawful” reclassification.
This is not a trivial issue. Regulatory predictability is at the foundation of the problem – and is the keystone of the solution. Minus sound and timely guidance, companies will think twice about whether or not to proceed with generic copies of medicines with a narrower therapeutic index. And that equates to less competition – which results in higher prices. This is as true for NTI medicines as it is for biosimilars. The good news is that guidances exist. The same is not true (at least not yet) for NBCDs. That should be next on the agenda – especially as it relates to A/B ratings. After all, if there are going to four categories of biosimilars, each with its significant impact on therapeutic interchangability, shouldn’t there be a commensurate finesse for similarly complex non-biologics approved under the Hatch-Waxman generic approval process?
As my friend and colleague, Dr. Scott Gottlieb has written:
The complex drugs fall in a regulatory gap. FDA has tried to retrofit the “Hatch Waxman” generic drug law and policies that govern approval of small molecule drugs to these complex drugs, with sometimes troubling results. Regardless of the decision FDA makes with Copaxone, it remains clear that Congress and FDA alike need to re-examine the regulatory process when it comes to these intricate drugs.
The problem is that FDA has refused to define these complex drugs as distinct from normal, small molecule medicines. That has forced the agency to rely on less information in approving these complex copies than it probably would like. The agency’s desire to try and squeeze these complex drugs through its existing generic law approval pathway may have as much to do with political expediency as with good science. FDA is probably well aware that getting Congress to define a distinct category for these medicines, and give FDA proper tools, could be a heavy political lift. So FDA is doing what it often does: trying to massage its existing authorities and regulatory practices to fit novel challenges. But at what cost?
The good news is that the FDA recognizes the need for more specific, regular, and predictable standards. That’s precisely why the agency has asked industry to identify drug products that require explicit bioequivalence testing guidances.
Robert Lionberger, head of the FDA’s Office of Research and Standards, said the agency’s objective is to develop a product-specific BE guidance before a manufacturer files an ANDA for the drug in question.
That bad news, per a report in Drug Industry Daily, is that the agency has more than 1,200 product-specific guidances posted to aid ANDAs, leaving hundreds of potential generic targets without an FDA-sanctioned roadmap for development. Their absence has complicated the process of submitting successful ANDAs.
Is the NBCD pathway, for example, something that should be considered as part of the pending 21st Century Cures legislation?
We are increasingly living in an n-of-1 world. Small is the new Big. We must think differently about bioequivalence on the front end and pharmacovigilance on the back-end. While we must continue to capture adverse event data, we must also strive to capture Substandard Pharmaceutical Events (SPEs). SPEs occur when a product does not perform as expected—perhaps because of API or excipient issues – or too broad of a bioequivalence range and issues relating to therapeutic interchangeability.
When it comes to 21st-century pharmacovigilance, we have to both broaden and narrow our views about bioequivalence to the patient level. Outcomes is so much more than a value-based reimbursement issue.
There is a growing awareness that science of attacking cancer is reaching a critical mass and is producing a truly transformational approach to treatment: one that re-engineers our natural immune responses to do the job of not just killing cancer cells but teaches the remaining ones to start become healthy.
There is a growing awareness that the way insurers have shifted cost to patients is discriminatory and that the claim that it’s a reaction to high prices is bogus.
There is a growing recognition that the value new medicines yield must be measured in terms of every month of every life gained. More people are alive today because each era of treatments keeps people alive longer for the next generation of therapies that improve and lengthen life even more.
And there is a growing recognition that the pace of progress is too damn slow, too dependent on outdate scientific methods that require people dying of disease to be randomized to different treatments or different combinations of treatments in ways that have little to do with their unique and increasingly accessible biological differences.
There is an increasing emphasis on improving the quality of life and the fact being treated for cancer does not mean being treated like a victim.
And finally, people are increasingly aware that by sharing information more quickly about the real world experience with medicines is the most scientific and efficient way to cure cancer.
I am honored to be part of this courageous community of advocates, patients, scientists and biopharmaceutical companies that express their awareness with growing discontent with the status quo. As Thomas Edison said: “Discontent is the first necessity of progress.”
At the same time that regulators in France, Germany, Belgium and Luxembourg are suspending the marketing approval of 25 generic drugs due to concerns over the quality of data from clinical trials conducted by India's GVK Biosciences, another Indian firm, Zydus Cadila, has launched a biosimilar of Adalimumab (an anti-TNF-α monoclonal antibody, which is approved in many countries for the treatment of inflammatory diseases, including rheumatoid arthritis, plaque psoriasis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease and ulcerative colitis.)
Bad timing and, perhaps, bad science.
The quality of Indian pharmaceuticals has come under fire this year, with regulators in Europe and the United States citing problems ranging from data manipulation to sanitation and banning the import of certain products from several firms. And, it should be noted, these violations are for generic drugs, not biosimilars.
French and German regulators are investigating drug approvals based on clinical trials meant to show that these generic drugs were equivalent to the original branded versions conducted by GVK Bio between 2008 and 2014.
A Zydus Cadila spokesman commented that, “This therapy will offer a new lease of life to millions in India who have not had access to this therapy so far.” But the reality is that their product is more likely to be aggressively marketed for export.
Most importantly is the question of quality – or lack thereof. As company’s ranging from biotech innovator Amgen to multinational generics manufacturer Sandoz struggle to fulfill the clinical requirements for an Adalimumab biosimilar, two obvious questions arise -- (1) What does Zydus Cadila know that large multinational manufacturers don’t; and (2) What do Indian regulators know that their counterparts in the US and the EU are struggling to understand?
To not aggressively ask these questions is to bury one’s head in the sand.
And here’s an even tougher question -- In order to boost pharmaceutical exports, are Indian regulators willing to license substandard products?
According to a May 2012 article in The Lancet,
“To say that India's drug regulatory authority, the Central Drugs Standard Control Organisation (CDSCO)-whose remit includes new drug approval, licensing of manufacturing facilities, and regulation of drug trials-is not fit for purpose seems a gross understatement.”
“If I have to follow U.S. standards in inspecting facilities supplying to the Indian market,” G. N. Singh, India’s top drug regulator, said in an interview with an Indian newspaper, “we will have to shut almost all of those.”
Does that mean US standards are too high or that Indian ones are too low? Well, where you stand depends on where you sit. And if you’re sober and sitting up straight, the answer is obvious.
According to Dilip Shah, Secretary General of the Indian Pharmaceutical Alliance, some Indian manufacturers “doctor their data.” The solution? “Regulators should have regular liaison with manufacturers in India and China to explain to them how GMP works and that they don’t have to cheat.”
Feel better now?
The bad news is that Missouri is the only state that does not have a prescription drug monitoring program.
According to the New York Times, Missouri is the only state in America that has declined to keep a prescription drug database — the primary tool the other 49 states use to identify people who acquire excess prescriptions for addictive painkillers and tranquilizers, as well as the physicians who overprescribe them … Not having the database has not only hampered Missouri’s ability to combat prescription drug abuse, but also attracted people from neighboring states looking to stockpile pills and bring them home to take themselves or sell to others, according to law enforcement officials, legislators and data compiled by a prescription drug processing firm.
“Welcome to Missouri — America’s Drugstore,” said Dr. Douglas Char, an emergency room physician in St. Louis. “We aren’t just allowing abuse, we’ve created a business model for dealers.”
The good news is that Republican State Representative Holly Rehder is drafting a bill to change that.
The prescription drug-monitoring program (PDMP) is a database that collects information to let doctors and pharmacists lets doctors and pharmacists know a patient's prescription history. The program is used to reduce the amount of medications that are sold on the street and to reduce the risk of doctor shopping and abusing painkillers for nonmedical reasons.
One of the reasons the Show Me State has remained the Don't Show me State are unfounded concerns over privacy and Big Brotherism. Rehder’s proposed program would allow for only doctors and pharmacists to obtain the information and police officers would have to obtain a warrant to access the information.
Bob Twillman from the American Academy of Pain Management said the program helps identify not only if people are abusing drugs, but identifying their addiction so they can get professional help.
The bill previously passed in the House but has run into some roadblocks in the Senate, including St. Joseph Senator Rob Schaaf, who said the database would violate the privacy of citizens. After successfully sinking a 2012 version of the bill, Mr. Schaaf said of drug abusers, “If they overdose and kill themselves, it just removes them from the gene pool.”
Really?
Rehder said she is willing to work with Schaaf and others in order to get the bill passed.
Holly – don’t go lightly.
ACA should allow prescription drugs
President Barack Obama is fully vested in the claim that his Affordable Care Act is a success.
During a recent news conference, he pointed to the supposedly salutary effect the ACA has had on mitigating rising health care costs. "Health care inflation has gone down every single year since the law passed, so that we now have the lowest increase in health care costs in 50 years," Obama said.
Obama is right that health care inflation has slowed. The Centers for Medicare and Medicaid Services have reported exactly that for the past several years. But his praise is misplaced. Thanks is not due to the ACA but rather to increased access to prescription drugs, which help folks manage illnesses and stay out of the hospital. The ACA actually threatens to increase health care spending by keeping these vital prescription drugs out of reach for many Americans.
If policymakers are serious about slowing runaway health care costs, they need to ensure that sick people have good access to prescription medicines that will make them better.
Consider the example of Medicare Part D. In 2006, Medicare Part D expanded access and reduced the costs of prescription drugs for millions of Americans. The following year, prescriptions filled by Medicare beneficiaries jumped by 14 percent, and, as a result, the annual growth in spending per beneficiary dropped by almost half.
A new National Bureau of Economic Research study credited Part D coverage with an 8 percent drop in hospital admissions for seniors and around $1.5 billion in reduced hospital spending.
The Congressional Budget Office reached a similar conclusion in 2012, finding that spending on medical services dropped by 0.2 percent for every 1 percent increase in prescriptions filled.
In fact, failure to regularly take prescribed medications puts considerable strain on the health care system. A study from the Annals of Internal Medicine estimates that non-adherence already costs the health care system $100 billion to $289 billion a year. That includes avoidable hospitalizations, nursing home admissions and premature deaths.
Given the power of prescription drugs, the Obama administration should be pushing to increase their accessibility. Instead, the administration is actively working against them.
Since Medicare Part D began, the government has required insurers to cover drugs in six treatment areas. The Obama administration, however, proposed early this year to limit coverage of immunosuppressants, antidepressants and antipsychotic medicines for diseases like schizophrenia. The proposal caused an outcry from patients, health care providers and members of both political parties, and the administration scrapped the plan.
But now the Obama administration is doing damage elsewhere — by limiting prescription drugs through the health care exchanges created by the ACA.
Plans available through the exchanges often charge patients significant out-of-pocket fees to access needed prescription drugs. For moderate to low-income patients, these high costs may force them to miss prescriptions.
Insurance companies decide how to share costs with patients by using a tiered system. A patient who needs a drug in the lowest tier might have to pay only a $15 copay. But for those drugs in the highest tier, patients can pay as much as 40 percent of the actual cost of the drug, which can run up to tens of thousands of dollars.
Too many key medications on too many plans are now listed in the highest tier. A recent study from Avalere Health found that more than a fifth of all "Silver" Plans — the most popular coverage — require patients to pay 40 percent of the costs associated with seven classes of drugs. And 60 percent of Silver Plans placed all drugs for multiple sclerosis and rheumatoid arthritis on the highest cost-sharing level.
Just as expanded access to drugs reduces overall health care spending, restricting access drives up costs. Patients who can't readily afford to spend thousands of dollars on, say, their AIDS medication, will probably end up skipping doses. This non-adherence will increase hospitalization rates and overall health care spending.
If the Obama administration wants to put a brake on health care spending, it must preserve robust access to prescription drugs. The White House's attempts to limit prescription drug access in Medicare Part D are incredibly shortsighted. Instead, the administration should be doing all it can to ensure that more Americans have access to these vital drugs.
Peter J. Pitts, a former Food and Drug Administration associate commissioner, is president of the Center for Medicine in the Public Interest.
Here's a snapshot of what the impact HIV would have today on hospitalization, hospital costs and hospital deaths if we had listened to the naysayers. Data for chart below is from Agency for Healthcare Research and Quality (AHRQ), based on data collected by individual States and provided to AHRQ by the States for the Clinical Classification Code for HIV
Eleven of the 12 cancer drugs the Food and Drug Administration approved for fighting cancer in 2012 were priced at more than $100,000 per year, double the average annual household income, according to a report by the Journal of National Cancer Institute.
Those claims are inaccurate at best and lies at worst.
First, as a Milliman study showss, the average cost of chemotherapy is about $25000. A far cry from the $120K Kantarjian and Bacn assert.
And while most of the new targeted cancer drugs are expensive, the average price -- including a standard discount and not counting any patient assistance -- is $5000 a month.
The fact is, cancer drugs, as a percentage of what people spend, of cancer care and total health care spending is small.
An HHS study shows that prescription drugs, on average, cost people with cancer about $800 a year.
Kantarjian and others claim cancer drug prices cause bankruptcy. Also misleading. Cancer patients filing for bankruptcy comprise 2.2 percent of total filings. That's about 36,000 people a year. The vast majority are low income and are unemployed. That is a financially crushing combination for many more cancer patients beyond those who file for bankruptcy. But drug prices are not to blame.
It is true that many more people are paying thousdands for cancer drugs but as my next blog reveals the Kantarjians and Bachs of the world deliberately ignore the role insurance comapne play in turning life saving drugs into a finanially sickening challenges. More on that in my next post.
This Sunday, the Boston Globe asked, “Has health care improved with reclassification of hydrocodone?”
Here’s the response of the dynamic Cindy Steinberg, policy chair for the Massachusetts Pain Initiative and national director of policy and advocacy for the US Pain Foundation:
No.
Severely restricting access to the most commonly used and highly effective pain medication is unjustly punishing the millions of law-abiding citizens who struggle to live with pain every day while doing little to solve the problem of abuse and addiction.
Hydrocodone combination products are effective for both acute and chronic pain and are useful and appropriate for a wide range of painful conditions and diseases. They have relatively few side effects and have been shown to have lower abuse potential than single entity opioids. In 2011, approximately 47 million Americans used hydrocodone analgesics for pain relief.
The number of Americans now living with pain is staggering. The Institute of Medicine has documented that there are more than 100 million living with chronic pain in this country. Ten million Americans live with chronic pain so severe that it has disabled them, and this number is expected to increase as the population ages.
When prescribed to individuals with pain severe enough to require these medications, the incidence of abuse and addiction is extremely low. For many with chronic pain, these medications mean the difference between a life worth living or not.
The new rules took effect Oct. 6. They require patients to obtain an original hard copy prescription for every 30 days of their medication — necessitating many more doctor visits — and then hand-delivering the script to their pharmacy. Doctors can no longer call in, fax, or electronically submit these prescriptions. Refills are prohibited.
According to Rebecca Fortelka, who suffers from cerebral palsy and several other chronic pain conditions writing in the Nov. 18 National Pain Report, hydrocodone combinations are one of the only pain medications she can tolerate. Soon after the new rules went into effect, she contacted her doctor’s office as she was running out of her medicine and needed a renewal. “My pain was spiraling out of control as I was rationing meds to prevent being out of them,” she wrote. It took her doctor’s office four weeks to get the hard copy prescription ready, leaving her to suffer.
Cutting off the supply of pain medication will not solve abuse and addiction. Those who are predisposed to the disease of addiction will turn to other medications or illicit substances, leaving those with the disease of chronic pain with fewer options. People with addiction disorders need better treatment for the disease of addiction, coordinated follow-up, and continuing support.
Recent critics of cancer drug prices claim that the new higher priced medications drive up total health care spending.
In fact, the opposite is the case. The evidence is overwhelming. In fact, the addition of new medicines under Medicare's drug plan (Part D) has led to an absoute reduction in what's been spent on Medicare overall, $380 billion less to be exact. A recent Health Affairs blog notes: "Much attention in particular has focused on the remarkable slowdown in Medicare spending over the past few years, and rightfully so: Spending per beneficiary actually shrank (!) by one percent this year (or grew only one percent if one removes the effects of temporary policy changes).
Yet the disproportionate role played by prescription drug spending (or Part D) has seemingly escaped notice. Despite constituting barely more than 10 percent of Medicare spending, our analysis shows that Part D has accounted for over 60 percent of the slowdown in Medicare benefits since 2011 (beyond the sequestration contained in the 2011 Budget Control Act)."
Critics will respond that the decline in Medicare spending was a function of the recession. Not true. "The recession and its aftermath appear to have had little effect on Medicare Part A and Part B spending; senior’s incomes are less influenced by economic downturns and the large majority of beneficiaries have supplemental coverage that shields them from most Part A and Part B cost-sharing. The primary analysis on the topic from CBO, in fact, found that only one-eighth of the slowdown in Parts A and B from 2007-2010 could be explained by factors related to the economy – and not through the usual channel of utilization impacts that take place in the private market."
Finally, some argue that the decline in spending was due to increased use of generic drugs on the part of Medicare consumers. In fact, most of the increase in Part D spending is the result of the use of new medicines for cancer, MS, diabetes and other drugs for the most expensive conditions Medicare patients deal with. This is in line with studies conducted by Frank Lichtenberg and others showing that each dollar spent on new medicines reduces what would be spent on hospitals, doctors, etc. by $6.
Looking at the price of a new medicine or what we spend on biopharmaceuticals in isolation is misleading. Use of innovative medicines should be looked at in terms of the impact it has on other medical spending and the lives of patients.
Source: World Health Organization National Health Account database (see http://apps.who.int/nha/database/DataExplorerRegime.aspx for the most recent updates).
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
