Generics versus Brands: Questions About Quality Control

Recent high-profile actions taken against generic drug firms have, in many people's eyes, undermined confidence in the safety of these products.

Consider the following:

April 2008 -- Some double-thickness tablets of generic digoxin produced by Actavis Totowa are discovered, prompting a nationwide all-lot recall.

May 2008 -- ETHEX Corp. begins a series of recalls of potentially oversized tablets, eventually affecting more than 200 products.

September 2008 -- The FDA blocks imports of 30 major-market generic drugs produced by Ranbaxy Laboratories, charging that the firm falsified data on its manufacturing practices.

June 2009 -- The FDA sends federal marshals to seize 33 different generic drug products at two Caraco Pharmaceutical Laboratories plants in Michigan.

August 2009 -- Barr Laboratories begins national recall of amphetamine-dextroamphetamine tablets because some tablets may have contained excess active ingredients.

Then there were revelations in July concerning Mylan Laboratories' main U.S. manufacturing plant. According to an internal company report obtained by the Pittsburgh Post-Gazette, workers had deactivated quality-control alarms on at least several occasions to keep the production line moving.

An FDA investigation found that the company handled the situation properly, and no products were recalled.

All of these problems with generics were widely publicized.

The only product-quality problem affecting a major branded drug firm to attract much attention during this period was the contamination of Baxter's heparin with melamine in early 2008 -- eventually traced to the company's bulk suppliers in China.

That generic producers are more prone to manufacturing problems "is a plausible impression to have," said Jeffrey Lieberman, MD, a psychiatrist at Columbia University. "There's a higher degree of variability of companies [and] quality control likely is variable."

This third installment in our generic versus brand series explores that issue.

A question of what 'generic' means

A superficial look at recent FDA warning letters issued to drugmakers for deviations from current good manufacturing practices, or cGMP, suggests that Lieberman is correct.

Since January 2008, the agency has sent 35 warning letters for cGMP violations related to nonbiologic drugs.

Of those, just three went to big-name branded drug companies: Procter & Gamble for potentially contaminated Sinex nasal spray; Legacy Pharmaceuticals for the Efudex brand of topical fluorouracil cream; and Noven Pharmaceuticals for its Daytrana transdermal methylphenidate patch.

But Gordon Johnston, vice president of regulatory sciences at the Generic Pharmaceutical Association (GPhA), and a former FDA official, pointed out that not all unbranded products are generic drugs per se.

He said only those covered by approved Abbreviated New Drug Applications and included in FDA's "Orange Book" are properly considered generics.

Such products as individually compounded drugs (for example, positron emission tomography tracers) and repackaged drugs are not, he said.

Nor are drugs manufactured under so-called OTC monographs -- a separate type of regulation under which over-the-counter drugs such as ibuprofen may be marketed without formal bioequivalence testing, as long as they're made with approved recipes.

Still others are raw ingredients sold to other manufacturers, rather than finished drug products.

Of the 32 warning letters sent to makers of unbranded medications, 21 appeared to be for products the GPhA does not consider to be generics, although the FDA sometimes obscures specifics in redacting the letters for public inspection.

And for three of the remaining 11, it was unclear whether the product was covered by an ANDA or not, owing to the redactions.

Even the apparent eight-to-three disparity is not what it seems, said GPhA spokesman Charles Mayr.

He pointed out that there are about 10,000 approved generic products compared with just 2,500 innovator drugs. Nearly 70% of all prescriptions in the U.S. are filled with generic medications.

"You would have to normalize for the number of units dispensed," Mayr said.

Consumer groups known for taking tough stances against defective goods also defend the generic drug industry's record.

"Overall, generic drugs appear no more likely than brand name drugs to pose risks, according to our review of available data and interviews with experts," Consumer Reports said in March.

Disinformation campaign?

In a subsequent look at generics this June, the rating group hinted that the branded drug industry is behind news articles and anecdotes that circulate about supposedly defective generic drugs.

"What we find interesting is that the subject of generic efficacy and safety rears its head every few years, and especially now as several popular branded drugs to treat epilepsy have been recently scheduled to go off-patent: Lamictal (lamotrigine), Keppra (levetiracetam) and Depakote (divalproex sodium)," Consumer Reports' health editors wrote online.

"Clearly, drugmakers have a huge financial interest in keeping their branded drugs to treat epilepsy on the market and free from competition from low-cost generics."

Peter Lurie, MD, of the advocacy group Public Citizen, agreed that many of the objections and criticisms directed at generic drugs can be traced to Big Pharma.

"The industry, for years, has been resisting generic substitution programs and supporting those who make the arguments that there is an important difference," he said. "It's a disinformation campaign about generics."

Both Consumer Reports and Public Citizen believe the cost savings offered by generic drugs make them the preferred option whenever they're available.

They have condemned Big Pharma's legal efforts to push patent extensions and limit pharmacists' ability to substitute generic for branded drugs when filling prescriptions.

Johnston at the GPhA said pharma companies have been relentless in seeking to prevent generic drugs from being approved or sold, though the tactics have changed over time.

In the 1980s, he said, they engaged in overt public bashing of generic drugs. When that didn't work, they shifted to patent litigation in the 1990s.

More recently, the branded drug industry has focused on state-level legislation and the use of federal "citizen petitions" requesting that the FDA deny specific generic drug approvals.

The latter has been relatively unsuccessful, with nearly all petitions denied, but many states now have laws restricting generic substitution without specific physician approval and new legislation is proposed every year.

Often, the lobbying efforts cite anecdotes and selected studies suggesting that generic drugs are less reliable and safe than branded innovator products, Johnston said.

"There has been a very concerted effort by the brand industry to raise these questions," he said.

Contacted for comment, the Pharmaceutical Research and Manufacturers Association, which represents branded drug firms, issued the following statement, attributed to Senior Vice President Ken Johnson:

"PhRMA has always supported patients receiving the medicines that are best for them, including both brand name medicines and generic drugs. The U.S. already has one of the highest rates of generic drug use in developed countries. According to IMS Health, seven out of every 10 prescriptions in America are now filled with a generic drug. But in the end, these are decisions that should be made between patients and their physicians, not decisions dictated by third-party payers.

"Clearly, both innovative medicines and generic drugs play a valuable role in the treatment of millions of American patients. While innovative new medicines remain a very small part of total health spending, they play a very big role in improving health and quality of life. Without today's innovative brand-name drugs to legally copy, there would be no generic drug industry. Worse yet, there would be little hope of finding new treatments and cures for a wide range of debilitating -- and often deadly -- diseases."

At least some of those raising questions about generic drugs don't believe a disinformation campaign is afoot.

Said Jeffrey Lieberman, the Columbia psychiatrist -- who reported no "personal remuneration" from pharma companies and is not a principal investigator on any pharma-sponsored research -- "There's certainly no reluctance to point a finger at generics if something goes wrong in a patient's treatment, or at the findings of a study with a generic that aren't what might be expected. I don't necessarily think there's a systematic conspiracy going on within pharma to discredit generic manufacturing."

Source : www.medpagetoday.com