Are All Men Created “Equivalent”?

By Peter J Pitts

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.

Peter J. Pitts is a former FDA Associate Commissioner, and is President of the Center for Medicine in the Public Interest.

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