"You may be interested in learning more about generic drug concerns. Would you like a copy of the Sankar and Glauser paper?" The attractive drug rep smiled. Who could quarrel with "no substitutions should be made for people with epilepsy without the knowledge and approval of the prescribing physician"? Generic drugs account for more than 50% of drugs sold, even in China. Are we being cheated?
Which companies can we trust?
BP has repeatedly chosen dangerous policies that increase profits. Their Texas City, TX refinery exploded in 2005, killing 15 workers. BP was fined but still behaves irresponsibly. They released toxic gases in April 2010, rather than shut down the refinery, saving money but probably harming neighbors.
What about generic drugs? My hospital, a safety net hospital with many uninsured patients, has big budget problems. One major drug is the anticonvulsant levetiracetam (brand name Keppra). We call it LEV. Twenty-six generic forms of LEV are licensed. Our pharmacy buys a batch of whatever is cheapest, every 6 weeks or so. My patients say, look, now I’ve got orange pills, triangular pills, etc. I say don’t stop taking it.
Pundits condemn simplistic quick-fix voters. I’ve got good news, bad news, and sobering news.
Corporations in the news- first BP:
• The Texas City refinery was built in the 1930s and had many owners before BP took it over in 1998 after merging with Amoco. Amoco had already been cited for failure to upgrade the refinery. BP took over the refinery and cut their budget, cutting inspectors and maintenance workers (saved just over $1 million), eliminating safety calendars, reducing purchases of safety shoes for employees ($50,000 in savings), and eliminating safety awards: $75,000 in savings.
• By 2004, Texas City was BP's most profitable refinery, earning more than $900 million yearly. However, London executives demanded further reductions in the plant's $300 million operating budget ($65 million or 21.7%). Manager Don Parus resisted. He sent corporate bosses pictures of workers who had died at the plant and told them that there was "a huge cultural issue at TXC on safety," according to internal BP data.
• As the plant's profits continued climbing, reaching nearly $100 million in January 2005 alone, Parus emailed his staff saying that "2004 was not a positive year for Texas City Safety," citing three "avoidable" deaths and a major fire. He called for a two-day leadership meeting that "can, and must, be a turning point for the Safety Performance of this site."
• That same month, a Telos Group report outlined multiple safety hazards. These auditors concluded that plant employees lived with an "exceptional degree of fear", and that "blindness" across the entire corporation kept important safety information from the top levels of BP management.
• The March 23 explosion that killed 15 workers was caused by human error, overfilling a cracking tower. Investigations showed that some alarms failed to sound, some alarms sounded and were ignored, BP had disabled some safety warnings and didn't install a flare to burn off excess gas from overflows. This had been recommended by safety engineers. Manager Walt Wundrow advised against this expenditure: "My counsel is avoid any pre-investment against uncertain future requirements," because capital expenditure "is very tight. Bank 150k savings now." another BP employee agreed. "Bank the savings in 99.999% of the cases" he wrote. Making almost $100M monthly in profits, they wouldn't spend $150K on safety. Later the Baker commission, chaired by petro-friendly James Baker, concluded "BP appears to have had a corporate blind spot relating to process safety."
• The refinery, the third largest in the United States, had another fire in the summer of 2005. BP agreed this year to pay $50 million more in fines and is still haggling with OSHA over additional fines. The mayor of Texas City and some other local politicians say "Don’t kill the goose that laid the golden eggs, don’t be too hard on BP". Sound familiar?
• You might read this propublica article about BP's continuing mismanagement, toxic corporation releases toxic gas. Too many are saying, "go easy on BP, we don't want them to bankrupt them and lose jobs".
DeCoster eggs, Salmonella and cheap food
Iowa's Wright County Eggs were contaminated with Salmonella. That farm had huge piles of feces and had not been inspected. Owner Jack DeCoster started in Maine, and expanded into Ohio and Iowa. DeCoster cut corners and had problems with the authorities. He wasn't daunted by small fines, because he could sell eggs for less. Abbott laboratories knows how to make Similac. They cut corners and beetles got into the formula. Too much guvmint regulation? NOT ENOUGH INSPECTION. For more about DeCoster factory farms, see habitual offender, dangerous to workers and the public
Ajkai Timfoldygar owns and operates the Hungarian aluminum plant whose sludge reservoir broke and released a toxic red sludge of extremely high pH that killed and injured many humans and did great damage to rivers and agriculture. I direct you to the excellent Kos diary, disastrous releases close to home about an even more damaging toxic release in the US that was mostly ignored by government regulators.
My personal experience
Over half of my patients are children with epilepsy. I use a lot of LEV. It stopped the seizures of David Axelrod’s daughter, Lauren, after almost 20 years of uncontrolled epilepsy, but it doesn’t work for all patients, and isn’t our best drug. I chose it for this diary because it has more generic forms than any other drug that I use. Our pharmacy seems to select generic drugs by price for almost all generics. That is not the policy used by most retail pharmacies. Most US pharmacies are chain pharmacies. They often push particular brands of generics, some made by subsidiaries of the same company. When you go to a new pharmacy, you may get a different generic.
A bit more about generic drugs
The basic ideas are simple. Two drug formulations are assumed equivalent if they produce similar blood levels over a defined time period. Company A produces a new drug and gets exclusive rights to sell that drug for a period of time. After that, company B can sell the same product as a generic drug if a sample of people given the new generic have similar blood levels.
How this works:
The company does the testing, using healthy 'volunteers' who take the proposed new generic med. Blood is drawn frequently from an indwelling line over 36-72 hours. The FDA reviews the data: they generally accept 30-35 or so volunteers and assume that the company is honest. They don't ask for volunteers of different ages or sick people who might metabolize the drug differently. They want both the peak blood level or the area-under-curve to be between 80-125% of the brand or 'innovator' drug (the FDA's term) value on average in all the volunteers. These two statistics are generally correlated- they are shown in the figure. a typical graph of blood level over time
Cmax is the maximal blood level attained, which varies between people. AUC or area under the curve refers to the shaded area- usually Cmax and AUC are closely correlated for any particular drug. This approach is mostly valid, but it must be modified if there are important "active metabolites" (Google that) such as in the case of clopidogrel (PlavixR) and fluoxetine (ProzacR). It assumes that there are no contaminants in the medicine that might alter binding of the drug to transporters, receptors, enzymes, etc. All medicines, whether liquid, capsule or tablet contain multiple chemicals- binders, buffers, lubricants, etc. Many drugs contain magnesium stearate as an "excipient" (Google that), you'll also find it in salad dressings.
A few people are allergic to it. It's a fatty acid found in our bodies- in excessive amounts it may alter the protein binding of many drugs, which might or might not alter the blood level curve. In rare cases, people can tolerate generic but not brand name form of a drug or vice versa, often because of allergy to various components of the drug, including "natural colors". Those components usually differ between generics and brand name drugs, the active drug itself does not. Many chemicals are much less stable in solution than in powder form; solutions often contain stabilizing agents not found in the powders. I try to avoid using liquid medicines as much as possible- many of the drugs that I use are stable in solution for only a few days. However, some parents report that the pharmacist said, "Oh, your doctor must not know about children and how they love liquids"- I tell them that I know about children AND drugs and that there are many reasons to minimize the use of liquids. That has little to do with generics. Abbott didn't plan for beetles in its Similac; likewise drug manufacturers don't want crap in their drugs. But they may cut corners and the FDA has very few people allocated to inspecting drug manufacturers, especially foreign ones. The FDA is doing fewer inspections: 2682 in 2005 and down to 2221 in 2008, the last year that we have data for.
Dubious FDA policies
- They don’t always require the minimal blood level testing that I’ve mentioned. For very water-soluble chemicals and "non-critical drugs" the FDA accepts data from in vitro studies of tablet dissolution. These cheap tests offer no protection against contaminants, too much excipient, etc. Even worse, the FDA won’t disclose which drugs it has approved solely on the basis of these "biowaivers". secret deals
- The FDA sees its main job as getting as many generic drug applications processed as rapidly as possible. They don’t want to waste time on inspections or ordering testing of a larger number of "volunteers". I don’t have to tell you that the metabolism of almost all drugs, including caffeine, ethanol and cannabis extracts is different in the sick and elderly. Those are the main recipients of prescription drugs.
- The FDA makes no effort to limit switching from one generic to another, or even to compel pharmacies to tell us if we are switched to a new formulation. A thoughtful patient may assume that he or she got the wrong pills when they find that the new pills look different. The FDA does not require drug labeling by country of manufacture. We had serious problems with Chinese made heparin; I think that drugs made in the US, Canada or Mexico are safer than those from the lowest wage countries.
- FDA regulation of drugs, although problematic, is much better than their regulations of new devices, new forms of radiation therapy, etc. FDA policies overall are similar to those of the European Medicines Agency (EMA) and Health Canada.
What’s the argument against generic drugs?
Most neurologists have been totally gulled by drug reps. Here’s their story: Mr. E was prescribed a generic antiepileptic drug. Now I hear that he landed in the hospital after a convulsion. He’s angry and I never approved his generic. There are such cases. Neurologists can truthfully say, "Substitution of brand-name AEDs (antiepileptic drugs) with generic AEDs can and does lead to breakthrough seizures". However, if we study the data carefully, a much more complex picture emerges. Suppose that a generic is ineffective for seizure control. The longer that you take it, the greater the chance of a seizure breakthrough. So, what is the evidence?
Gagne and coworkers studied medication refills and breakthrough seizures in British Columbia. Their paper is Refilling and Switching of Antiepileptic Drugs and Seizure-Related Events. They reviewed refills with the same drug and switches, whether from brand to generic or one generic to another. Here’s what they found- most seizures came right away in the first few days after getting a refill. First, their figure 2, p348 seizures linked to refills
Seizures are most frequent at the right hand side of the figure- soon after patients get refills or switch drugs. One day before the seizure, 9 patients (maximum of any day) got refills of the same drug and none got switched. Something about refills is a problem. I found the Gagne data bit hard to follow. I asked them for the raw numbers, which they sent and I expressed in this Excel chart. My presentation of Gagne's data in 5 day packets
My chart shows zero days on the left; I grouped the data into five-day periods. Notice the consistent large difference between refills and switches, which are much less frequent. The more recent your refill, the more seizures.
What’s happening? Why are refills a problem? I got some data on intervals between refills in my patients from one cooperative pharmacy. These patients all had prescriptions that authorized refills. The only reasons to delay refills past 30 days (the pharmacy gives only a 1 month supply) are 1. Forgetting 2. The cost of co-pays 3. Inconvenience, that you must get to the pharmacy before it closes. The average period between refills was 35 days and 20% of patients went beyond 40 days, so they missed many doses of medication. I have some personal experience: I take Lisinopril for hypertension. Until this year, when I switched to Kaiser, I could only get a 30-day supply. Working fulltime, I often got home after 7 PM and my local pharmacy closes at 8 PM; I often missed 1-2 days of medication at the end of the month, even though I accept the goal of controlling my blood pressure completely. Kaiser gives me a 100 day supply and mail refills, so my problem is solved, no more running out.
What’s my conclusion?
Drugs that I use are equally effective as generics or brand name. We used brand name Keppra until this year, now we use generic LEV and the pharmacy keeps switching between different generics. I wish that they wouldn’t do that, since it makes patients uneasy about their medicine and the cost savings from this constant switching are small. Failure to take your medicine (nonadherence or noncompliance) is our number one problem - we had it with the brand name drugs, it may be more common today, but there isn’t one of my patients that did well on brand name Keppra that I’ve had to switch. Now, I know that the Internet is full of complaints about generic drugs, including generic LEV. I’m telling you that this hasn’t been valid in my experience.
Does this apply to every generic?
No. Delayed release medications pose special problems. I worry about delayed release generics- the FDA should require much more extensive data before accepting them, likewise for complex drugs (many of which produce no blood level) like therapeutic proteins including insulin and monoclonal antibodies, low molecular weight heparin, glatiramoids, iron-carbohydrate complexes etc. I agree with the opinions of Schellekens et al. I don’t say that all generics are OK; I’m very dubious about generic companies in faraway lands that are never inspected. The FDA should not approve any generic unless it will inspect the plant within the next 18 months and without warning.
What about patients who want brand name drugs?
I have a few patients with insurance that can get brand name drug for a higher copay. If they want it I put on the prescription, Patient requests brand name form. I don’t say brand name medically indicated because that has not been true with any of the antiepileptic drugs that I use. Pharmacies go along, they get more money. It is certainly possible that bad batches of both generic and brand name drugs may appear, just like the Similac batch with beetles in it.
A few of my medical friends are rigidly in favor of generics because "they are modern and they save money". However, 80% of the doctors I know have closed minds and oppose generics with varying intensity. I say, why don’t you evaluate the drug in question- don’t make sweeping conclusions for or against all generics. Have I tested all 26 LEV generics? No, but I can tell you that blood levels have been fine in my patients taking generic LEV. I have seen one patient who tolerated generic carbamazepine and not brand name TegretolR, but I’ve seen no examples of that phenomenon with the other antiepileptic drugs. I know that some but not all forms of generic LEV contain magnesium stearate. There’s room for lots of improvement and a much wiser approach to medical treatment and approval of new treatments, drugs or otherwise.
You may want to check the Propublica web site "Dollars for docs" and its list of doctors that have gotten recent payments from Big PhRMA. This is part of the problem Propublica investigates docs who speak for PhRMA. However, I know that some of those getting paid to talk up the risks of generic drugs are true believers and some docs are just suspicious. I plan to write another shorter diary about how to get the most out of generic drugs for patients after the election, just focusing on practical issues.
The good news: Generic forms of all the drugs I use have been fine, as long as the patients didn't stop taking them - in a few cases, I've increased or decreased the dose based on what I saw (Patient sleepy for example, so reduce the dose). Not a single controlled trial of generic vs brand name drug has shown the brand name to be superior, but the trials have been too small to settle the issue.
The bad news- Too many American docs too quickly accept drug company propaganda
The sobering news- The FDA has a simplistic and naive view of generic issues and worries more about drug company advertising than quality control.
References
- Gagne, JJ et al, Refilling and Switching of Antiepileptic Drugs and Seizure-Related Events. Clin Pharmacol Ther 88: 347, 2010.
- Moore, N et al, Are generic drugs really inferior medicines? Clin Pharmacol Ther 88:302, 2010.
- Schellekens, H et al, The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol. 2010 released on line, not yet in print
- Munger, MA, et al, Medication Nonadherence: An Unrecognized Cardiovascular Risk Factor. MedGenMed. 9: 58., 2007.
- Steinman, MA, Hanlon, JT. Managing Medications in Clinically Complex Elders "There’s Got to Be a Happy Medium". JAMA 304:1592, 2010.
References 4 & 5 discuss many problems of overmedication, medication nonadherence, etc. These problems often worsen if constantly changing generics are used.