Summary: Earlier this month, an FDA committee voted on whether it should tighten the rules for generics to make certain that they are exactly the same as brand-name drugs. Medical research says that they are equivalent in all of the important ways. But critics have been raising questions, stirring controversy in the media. HealthBeat’s Naomi Freundlich took a look at the problem in January. Recently, Merrill Goozner, who is a member of the FDA committee, reported on its decision. Why did the committee decide not to jack up the requirements for generics? What is it doing to ensure that generic manufacturers are meeting safety standards? Why is the FDA’s decision politically important at this point in time? A final question : Is the generic version of the anti-depressant Wellbutrin really as effective for all patients?

Imagine that you are taking a medication that works well for you. But the monthly co-pay is $75.  This is more than you can afford. A generic is available, and the co-pay is only $10. The FDA says that it is just as good. But when you take it, you’re not sure. It sometimes seems that the pain is worse—or that you are more tired, or more depressed than you were when you were taking the brand-name drug. How can you be certain? When you try to think about how you feel, you realize that your mind is trying to diagnose your mind.  It’s a standoff that leaves you totally flummoxed.

The debate over generic vs. brand-name drugs cannot be easily resolved. Human beings are suggestible creatures, and if we are told that a drug is less expensive, we are inclined to think it might not be as effective.

That said, today most Americans trust generics. This suggests that most patients haven’t felt a difference. As Merrill Goozner of GoozNews fame points out in the April 22 issue of Fiscal Times:  “generic manufacturers’ share of the market surged last year to 75 percent of all prescriptions, up from 57 percent in 2004. Cost-conscious patients increased their purchase of generic prescriptions by 5.9 percent in 2009, while prescriptions for brand name drugs fell 7.6 percent, according to IMS Health.”

Nevertheless, over the past three years, the FDA’s Office of Generic Drugs has been receiving what Goozner describes as “a steady trickle of reports from patients who suffered an adverse reaction after switching to a generic. Some in the media have seized on the story. In January, for example, The New York Times ran a piece headlined: “Not All Drugs Are the Same After All.”   Here on HealthBeat, Naomi Freundlich responded to the article. At the time, she noted that, Congress had asked the FDA to look into the controversy.

In her post, Freundlich pointed out that despite anecdotes from patients suggesting that generics are not as effective, in the overwhelming majority of cases, medical research “finds that generic drugs work just like their name-brand counterparts. The active ingredient must be identical and in the same concentration. Granted, inactive ingredients like binders and colorings can vary. But studies like this one in The Annals of Pharmacotherapy that reviewed 12 years of data from the FDA, find name-brand and generic drugs to be bioequivalent. The Annals study found that the average difference in absorption into the body between generic and name brand drugs was just 3.5%; similar to the difference found between batches of the same name brand drug.”

She argued that instead of relying on anecdotes to make policy, the government should use some of the funding that it has set aside for comparative effectiveness research to test generics against brand-name drugs. Though, as she noted, “the public—encouraged in part by drug companies, doctor’s groups and other ingrained interests—is still somewhat wary of comparative-effectiveness studies (and the related field of evidence-based medicine that uses such studies to develop treatment guidelines). To some, this approach is a thinly-veiled method for instituting health care rationing. Conservatives capitalize on this fear, raising the specter of government panels using such studies to mandate certain types of care; of the government ‘getting between you and your doctor.'”

The issue finally “came to a head” Goozner reports, earlier this month at a meeting of the FDA’s science advisory committee.” Goozner, who sits on that committee as the consumer representative, explains: “The FDA wanted its expert advisers to weigh in on whether it should adopt a slightly more restrictive standard for approving generic drugs. The stakes were pretty high. Some of the brand name pharmaceutical industry’s biggest moneymakers will be coming off patent in the next two years”. (One has to wonder whether this is why some in Congress began to press the FDA to consider tightening the standards for generics.)                         

                    Why the FDA Committee’s Decision Matters

The FDA’s ultimate decision could have an effect on whether generic firms try to compete with genetic biologics, the priciest drugs on the markets. As Goozner points out: “The recent health care reform bill included a legal path for the FDA to begin approving generic biologics. The Obama administration hopes to save $7 billion in Medicare and Medicaid costs over the next decade by purchasing generic biologics.” If the FDA jacks up standards for generic firms, this “could keep some generic firms from even trying to replicate hard-to-produce biologics.”

With the passage of health reform legislation, we are at a turning point in the history of health care in America. If we are going to hold down health care costs, while simultaneously making drugs available to everyone who needs them, we need to continue to expand our use of generics.

A more proactive FDA seems willing to help. This month it approved the first of two generic drugs used for the treatment of high blood pressure. Teva Pharmaceutical Industries (TEVA) won most of the approvals to make generic versions of Merck's (MRK) blockbusters Cozaar and Hyzaar.  The move will mark a big hit to Merck's revenue, as the two drugs together are Merck's second-highest revenue generator. In 2009, global sales of Cozaar and Hyzaar totaled $3.6 billion.

The FDA also has given Teva tentative approval to sell a generic version of Pifzer’s Viagra upon the March 2012 expiration of its primary patent. Viagra, which brought $1.9 billion in world-wide sales for Pfizer in 2009, is also covered by a patent expiring in October 2019 that covers its use in erectile dysfunction. Pfizer is suing Teva in federal court to block its version of the Viagra from being sold in the U.S. until 2019.

Large drug-makers have good reason to want to protect their monopolies over lucrative drugs; not only are many of their block-busters going off patent, the pipeline of new drugs has dried up. As regular HealthBeat readers know, in recent years, most new drugs have been “me-too” versions of older drugs.

The FDA could play an important role in opening the door to generics. At the same time, it must put patient safety first, and make sure that the less expensive drug is equivalent and poses no additional risks. Those who oppose health care reform will be only too quick to argue that the government is lowering standards in order to save money. And recently, concerns have been raised about shoddy manufacturing practices at some generic manufacturers, not only in China, but in Canada.

 Before taking a look at the FDA committee’s vote, consider two drugs at the center of the debate: Wellbutrin and bupropion.
                      

               Questions About Two Anti-Depressants

For those who question generic drugs, Teva Pharmaceutical’s bupropion, the generic equivalent of Wellbutrin, an anti-depressant made by GlaxoSmithKline, has become a popular target. In 2007, 78 patients told the FDA that their depression had returned on bupropion. The American Psychiatric Association responded by “immediately beginning to pressure the FDA to reconsider its standards for approving generic drugs,” Goozner writes.

He goes on to quote Columbia University psychiatry professor Jeffrey Lieberman who told Psychiatric News: “Many clinicians have patients who have experienced variation in response when switching from a name brand to a generic. In some cases these have been related to side effects; in other cases, it has
been a difference in efficacy.”

But, as Goozner is quick to point out, “Lieberman consults for Glaxo” as well as other antidepressant manufacturers. To my mind, this disqualifies Lieberman as an objective source on the efficacy of a product that might replace for Glaxo’s lucrative product. Lieberman may or may not be consciously or unconsciously influenced by consulting fees, but surely Psychiatric News could find a psychiatrist or psycho-pharmacologist who does not take money from the drug industry. 

Indeed, psychiatrists themselves have become increasingly concerned about how the drug industry has been tainting professional judgments. In the March 24 issue of JAMA Dr. Thomas Insel, the chief of NIMH (National Institute of Mental Health) accuses academic medicine of having become a "culture of influence," in which drug industry marketing goals have begun to engulf the practice of psychiatry. (Thanks to Dr. Daniel Carlat, of the carlatpsychiatryblog for calling my attention to this article.)  Insel concludes that industry influence has radically skewed psychiatric practice in favor of the most expensive drugs, even when evidence shows that cheaper generics work as effectively.”

Back in 2007, the FDA responded to the complaints about bupropion by taking a second look at the small differences between Wellbutrin and its generic rival and decided they “were not outside the established boundaries for equivalence nor are they different from other bupropion products known to be effective.” 

Moreover –and this is important: “The recurrent nature of major depressive disorder offers a scientifically reasonable explanation for the reports of lack of efficacy following a switch to a generic product,” the agency said in its report.  Depression often returns, even if a patient does not switch drugs.

Antidepressants drugs can also have a placebo effect, further muddying the waters. A study published in the Journal of the American Medical Association in January reports that “[t]he magnitude of benefit of antidepressant medication compared with placebo…may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with severe depression,” however, “the benefit of medication over placebo is substantial.” 

From the Patient’s Point of View

To understand just how difficult it is for a patient or a doctor to compare the effectiveness of a generic and brand-name anti-depressant consider this account of one patient’s reaction to bupropion. Writing on “Wonderment” Kelly reports:

“I’ve switched back and forth between the generic budeprioin/bupropion and the name brand Wellbutrin, as well as trying out different dosages and the one-a-day versus multiple doses a day over the last five or six years.  .  . . I had no worries about switching from the name brand to the generic because I figured they were the same (and they are, if you put quotes around same). However, a while after the switch (depression medications take an incredibly long time to work properly, 6 weeks to 6 months – the brain is an amazing thing, but easily changeable it is not), I noticed that I was more tired than I used to be. It took me quite some time to trace it back to the switch to generic, but I did.

“I was pretty certain that this wasn’t just a mind game, since I hadn’t thought there would be a difference between the two. But, doubt had crept in a bit about this. So imagine the feeling of validation I got when I read this story in the New York Times.”

Here, Kelly quotes from the New York Times article that Freundlich wrote about on HealthBeat in January headlined: “Not All Drugs are Alike:”

“After hundreds of consumers posted messages about problems with the generic drugs Budeprion XL 300 on the People’s Pharmacy website, Mr. Graedon [who runs the site] worked with an independent laboratory, Consumerlab.com, to test the drug, which in other generic versions is typically known as bupropion.

“The lab found that Budrprion XL 300 released the active drug at a different   rate than the brand name Wellbutrin XL 300.”

Kelly now feels vindicated.

“I’m not the only one! Well, of course I wasn’t, but I don’t have anyone to compare notes with. My doctor and I did figure out a decent solution (switching to the two a day [of the generic] instead of timed-release), but I have to say it’s still not as good as the name brand. Sigh. . . . However, it works well enough to not be tempted to pay the out-of-pocket price for name brand (which is… ouch! painful).

“I’m super-cool with generics on most things. I like to be cheap. (I almost wrote that I like to save money, but I don’t think that’s as accurate a statement.)  . . .

“The NYTimes article ended rather abruptly, and awkwardly,” Kelly added, “ just like this post will (most likely because in both instances, the author couldn’t figure out how to wrap things up nicely).”

Indeed, Kelly can’t quite come to a firm conclusion. She is “pretty certain” that “this wasn’t just a mind game,” because she hadn’t expected that there would be any difference. But of course she knew that he had switched to a generic; this wasn’t a blind study. So perhaps, at some subconscious level, she was worried that the generic might not be as effective?

Does the fact that the generic releases the active ingredient at a different rate explain Kelly’s exhaustion? We don’t really know. 

                             The FDA Panel Votes

When it came down to it, earlier this month, the FDA panel decided not to tighten the rules for generics. Goozner, who was present, explains: “In making the proposal for a tighter standard, Dale Conner, director of the division of bioequivalence at FDA, admitted it wouldn’t affect the vast majority of generic drug approvals. In fact, the FDA analyzed more than 2,000 generic drug applications received between 1996 and 2007 and found that just 2.6 percent of the drugs would have been rejected had the proposed tighter standard for equivalency been in place. Teva’s bupropion fell safely within the proposed new parameters.

“The goal, the FDA admitted, was to show it was doing something about a problem that didn’t really exist. Not surprisingly, the committee, which is made up mostly of academics, turned the agency down by a 12-2 vote (I voted with the majority). ‘This is more of a public relations problem than strict science,’ said Elizabeth Topp, who chaired the committee and is head of the Department of Industrial and Physical Pharmacy at Purdue University.”  (Topp was referring to the fact that the media, the pharmaceutical industry, and some who fear health care reform have been stirring up the controversy.

Goozner goes on to argue that while there are problems with generic drugs they have nothing to do with the FDA approval process. “Poor manufacturing quality controls after the generic is approved, as shown in the recent Chinese heparin scandal and Ranbaxy case, harm far more people than poorly designed generic drugs. And that problem isn’t limited to generics. Look at what just happened at Genzyme, one of the nation’s leading biotechnology fi
rms. The company had to shut down its production line after impurities were found in two of its best-selling drugs for treating rare diseases.”

But as I noted, safety problems are not limited to China or India. About two weeks ago, the FDA sent a letter to Apotex, a drug-maker that was the eighth-largest provider of generics in this country last year, citing charred particles in a diabetes drug, contamination of an antihistamine and drug cross-contamination that resulted from inadequate cleaning of manufacturing equipment. In 2009, American pharmacies filled 94 million prescriptions with Apotex medicines.

Since last August, the agency has prohibited drugs from the Etobicoke and Toronto sites from entering the United States, although Apotex has other plants it can ship from, the New York Times reports. From July 2007 to August 20009, Apotex voluntarily recalled all products associated with manufacturing concerns –about 659 batches of various drugs in the United States.

Meanwhile, under the Obama administration the FDA has been receiving additional funding, and has begun deploying inspectors abroad. “Its domestic manufacturing oversight staff is finally growing again after years of decline,” Goozner observes. (As HealthBeat has reported, the Bush administration’s approach to the FDA was “starve the beast.”)

Goozner concludes: “If the FDA wants to protect the drug-buying public (and improve its image), it should focus greater attention and resources on policing manufacturing plants, not on tinkering with bioequivalence standards that are already acceptable to the vast majority of Americans.”

Here, I partly agree. Given the evidence that revised standards would affect just 2.6 percent of generic drugs, I don’t see a reason for changing the standards. But I don’t think that government should focus only on the manufacturing problems. I would like to know more about that 2.6 percent of generics —and any other generics that a significant number of practicing physicians believe might not be equally effective for all patients. Here, I would be interested only in hearing from doctors who don’t have any financial interest in the brand-name company, whether in the form of consulting fees or stock holdings. It’s just too difficult to correct for possible conflicts of interest.

As Naomi Freundlich suggested in January, we need comparative effectiveness research—head to head comparisons of brand-name drugs and the generics that are replacing them. We should have randomized, controlled trials involving large groups of patients who don’t know whether they are taking the generic or the brand-name drug. This is work that will only be done by the government. Neither generic manufacturers nor brand-name drug-makers really want to go toe-to-toe: someone would lose and there’s too much money at risk. They are not going to fund these trials. But luckily this administration has already set aside money for comparative effectiveness research to be done by totally disinterested parties.  (This is not the job of the FDA, though I would expect that FDA committees would take an interest in the results.)

Wellbutrin and bupropion strike me as prime candidates for the research. I have no reason to believe that the generic is less effective for some patients, but we just don’t know. More importantly, I believe it is crucial to reassure patients who fear that their generic is not doing the job. We cannot leave patients who are depressed, exhausted or in pain up in the air—the anxiety alone can only add to their physical and mental problems.

Patients need complete confidence that lower-priced drugs are just as good. Medical research suggests that in the vast majority of cases, they are.  But patients should not have to try to figure this out by reading an article in the New York Times. (Or, for that matter, on HealthBeat). We know how to do comparative effectiveness research and we have the funding. Now, we just need to use it.