org355: Alzheimer’s Drug

From the New York Times

I'll start with a quote from the end of the article: “They have a Solomonic decision to make, with one study that demonstrated very promising effects and the other study that didn’t demonstrate an effect,” he said. “I think it’s a challenging decision, because everybody wants to do what’s best for patients and families.”

1. What sort of evidence would you want to have, to determine that this drug can cause a delay in cognitive decline?

2. What are the pros and cons of approving this drug?

Re: Alzheimer’s Drug

by | HANY IBRAHIM KHALIFA MAHMOUD - Saturday, 7 November 2020, 5:13 PM

Hi Sujit,

Thank you for sharing this interesting article.

First question: I would say that following Bradford Hill Criteria, I can see this molecule didn't fulfill these criteria:

Consistency - This drug didn't show consistency in the association between drug and delay in cognitive decline. Having 2 studies with contradicting results didn't reflect a consistent evidence.

So, the required evidence should fulfill Bardford criteria.

Second question:

If this drug was approved with no sufficient evidence of its efficacy, and may be after additional future evidence it will be proven that the drug is not effective which means patients were exposed to a drug that may cause additional side effects or additional burden considering it administered through IV; also the healthcare system already paid for an additional drug which was finally proved as not effective, which wasting of resources that could have been used for other healthcare services.

However, approving the drug could provide significant benefit to patients who currently doesn't have any other option (If the drug efficacy and safety were confirmed).

What do you think?

Re: Alzheimer’s Drug

by | FATHIMA MINISHA - Sunday, 8 November 2020, 5:09 AM

Hello everybody...
Another great read! and a disease that truly baffles researchers all over the world and is still such a huge challenge for the medical field.

1) Since we are trying to prove the efficacy of a drug, we would need more Phase III trials to show if the drug actually has a benefit. So far there are only 2 trials reported and with conflicted results- one of the trials show a potential benefit and the other does not. Its not clear if both studies are comparable (and that we are not comparing apples vs oranges)... maybe the first study that showed a benefit was done in patients with mild-moderate cognitive impairment and the second study maybe was done in severe cases. In such a case, it would not be fair to claim conflicting results. Even then, its not enough evidence.

2) Pros- the most important thing is the hope it gives to patients and families. As mentioned in the article, for a very long time there has not been any major breakthrough in Alzheimer's. So, just the presence of an option would be of immense help mentally to the patients and care givers. If the drug is actually effective, it could delay the progress of the disease, especially if started early on in the disease- hence reduce the burden on society and on precious care-givers. Patients would get many more years of independence which is ultimately the aim behind any treatment option for Alzheimer's.

Cons- If the drug is approved without sufficient evidence, the problem would be that patients would be exposed to the drug and get no benefit. Phases 2 and 3 only give a limited and short term evidence of safety. Phase 4 trials focus on the long term safety of medications. So, if there is no efficacy, we would be exposing patients without actually being aware of long term side effects or problems with drug. That would be a major problem.

What do you all think?
Thank you Hany for talking about the Bradford Hill Criteria- I looked it up because you mentioned it and now I know...:-)

Fathima

Re: Alzheimer’s Drug

by | NADA BASSAM JUMAH RABIE - Sunday, 8 November 2020, 10:13 AM

Thank you for brining this inserting issue to highlight

1. That is an interesting question regarding what sort of evidence would we accept. First, it's worthwhile to mention that usually we do't build our practice on one ( or few) trials and we need to look on how this trial was conducted, validity , applicability and so on

we need to know that after a given period of time, how did the rate ratio differ between the treatment and placebo group. How much was the improvement in the cognitive function or at least for how long did it stabilize? How much was the sample size? where other important confounding factors considered in this article?
A better evidence can be taken from a meta-analysis/systematic review and will help us make a better informed decision .

2. Pros: offering a potential benefit to people with AD

CONs: if the therapeutic efficacy is not true, we are exposing the patients unnecessarily with potential side effect ( even though safety profile is said to be favorable, but long term follow up is needed). Also the drug is costly and issuing bodies will have to strategize its use compared to other proven interventions.

Bringing up Bradford-Hill criteria is interning. From my understand, it has its importance in studying the relation between an exposure and effect, however, when applying it practically it will be have multiple flaws.
Let's take for example consistency that was mentioned. It's not uncommon in area of medical research to have some conflicting results especially at the beginning. At more studies come ( and hopefully a meta-analysis/systematic review comes) a better decision can be made. So results from what I know are often not consistent.

Would like to hear what others think about that ?

Re: Alzheimer’s Drug

by | HANY IBRAHIM KHALIFA MAHMOUD - Sunday, 8 November 2020, 5:19 PM

Hello Nada,

Thank you for sharing your thoughts.

Regarding the meta-analysis / systematic review; I am not aware of the available evidence or all ongoing clinical trials on this new molecule however considering the current stage where this molecule still under investigation for its main and first indication, I am not sure if there are enough published trials to conduct a meta-analysis or systematic review that can provide an evidence for efficacy and safety.

Regarding the Bradford hill criteria, when I referred to them I was just referring to the general mindset for assessment of causality, however I agree with you; when assessing clinical trials positive or negative we need to ask questions and assess why it is positive or negative and to what extent it is relevant to clinical practice.

Re: Alzheimer’s Drug

by | Sujit Rathod - Monday, 9 November 2020, 3:42 PM

Hi Hany - kudos for highlighting Bradford-Hill!

A brilliant professor of mine would always interject "Bradford Hill guidelines, not criteria" whenever one of us mentioned them. And so I shall do the same!

This is to say, you should absolutely use Bradford Hill as a way to consider the question of causation, but it is not necessary to meet everything to be causal. Temporality is the one one that is essential.

Re: Alzheimer’s Drug

by | CATIA PROENCA - Tuesday, 10 November 2020, 9:00 AM

Great read and not an easy decision those advisors have in their hands.
1. An RCT is the type of evidence needed for a drug approval (most of the times). I would say that if even in the controlled environment of an RCT the drug was shown to work once but not twice, the likelihood of the drug working in the real world is scarce. If we are pragmatic this alone would be enough to reject the approval. But for me what was more meaningful was reading that the effects observed in the positive trial were very small, which may not me clinically meaningful. That should also be considered. I am unsure that it would be ethical to run a third trial unless they discovered that the drug is effective in a particular subgroup and they need to design a study targeting that subgroup, with enough power. I didn’t see this mentioned in the article thus I’m assuming it’s not the case.

2. The cons: exposing patients to an ineffective drug, increased safety issues to patients, waste of resources, preventing other drugs from being tested... Pros: a small sub-population of patients may benefit from the drug which would improve the patients and caregivers quality of life, costs averted from other treatments.