Fortunately, most of us feel comfortable taking drugs available by prescription, knowing that they have been approved by the US Food and Drug Administration (FDA). This perception has been somewhat altered recently when the agency approved Biogen’s new drug. 

Aduhelm, the trade name, is a monoclonal antibody designed to treat Alzheimer’s disease. The controversy stems from the use of surrogate endpoints as the basis for approval. Surrogate endpoints are laboratory measurements, radiographic images, physical signs or other measurements thought to predict clinical benefits but is not itself a measure of clinical benefit.

Surrogate endpoints stand in contrast to a direct measure of a patient outcome, often referred to a clinical endpoint. This could include living longer, symptom relief or an improved quality of life. In the case of Biogen, the company focused on a reduction of brain amyloid plaques and not actual clinical trial evidence of treatment success or patient benefit. FDA approved the drug despite an advisory panel’s almost unanimous rejection. (Panel approval is part of the regulatory process.)

The contested approval of the drug has been a concern and few physicians are prescribing  Aduhelm.

Because nongeneric drug prices are extremely costly, it behooves each of us to become acquainted with  the evidence for approval. You can request this information from your doctor or seek the information on the internet. Moreover, more and more people are taking them, and that applies to more than 131 million Americans. 

Utilization is particularly high for older people and those with chronic conditions. (My wife takes at least seven different drugs and eye drops and I take five, sometimes more.)

The statistics on medication usage among elderly patients in the U.S. are eye-opening: More than one-third of prescriptions drugs used in the US are taken by elderly patients; the ambulatory elderly fill between nine and 13 prescriptions a year (including new prescriptions and refills).  In light of such wide spread usage and their perceived value and cost,  consumers may wish to understand the means by which drugs are approved.  Here are the requirements as stated in the federal regulations:

 To approve a drug in the United States, the following process must be followed:

•    Analysis of the target condition and available treatments — FDA reviewers analyze the condition or illness for which the drug is intended and evaluate the current treatment landscape, which provide the context for weighing the drug’s risks and benefits. For example, a drug intended to treat patients with a life-threatening disease for which no other therapy exists may be considered to have benefits that outweigh the risks even if those risks would be considered unacceptable for a condition that is not life threatening.

•    Assessment of benefits and risks from clinical data — FDA reviewers evaluate clinical benefit and risk information submitted by the drug maker, taking into account any uncertainties that may result from imperfect or incomplete data. Generally, the agency expects that the drug maker will submit results from two well-designed clinical trials, to be sure that the findings from the first trial are not the result of chance or bias. In certain cases, especially if the disease is rare and multiple trials may not be feasible, convincing evidence from one clinical trial may be enough. Evidence that the drug will benefit the target population should outweigh any risks and uncertainties.

There is also a provision for accelerated approval in special cases as follows:

Accelerated Approval

In some cases, the approval of a new drug is expedited.

Accelerated approval can be applied to promising therapies that treat a serious or life-threatening condition and provide therapeutic benefit over available therapies. This approach allows for the approval of a drug that demonstrates an effect on a “surrogate endpoint” that is reasonably likely to predict clinical benefit, or on a clinical endpoint that occurs earlier but may not be as robust as the standard endpoint used for approval. This approval pathway is especially useful when the drug is meant to treat a disease whose course is long, and an extended period of time is needed to measure its effect. After the drug enters the market, the drug maker is required to conduct post-marketing clinical trials to verify and describe the drug’s benefit. If further trials fail to verify the predicted clinical benefit, FDA may withdraw approval.

History

From 1992 to 2020, accelerated approval has been used for more than 253 drugs, of which 125 (49.4%) have been granted full approval and 16 (6.3%) have been withdrawn.  Most of the drugs granted accelerated approval have been for cancer and all require continued confirmation studies (post-market clinical trials to prove efficacy.

Final Thoughts

The Biogen case has elicited calls for a review of the accelerated approval pathway.  According to a recent viewpoint in the Journal of the American Medical Association, accelerated approval is often not accompanied by confirmatory studies. Moreover, it can be difficult to remove some drugs from the market if studies do not demonstrate or substantiate long term benefit.

Max Sherman is a medical writer and pharmacist retired from the medical device industry.  His new book “Science Snippets” is available from Amazon and other book sellers. It contains a number of previously published columns.  He can be reached by email at  maxsherman339@gmail.com.