Saturday, 17 December 2011

Developing Drugs

You Wrote "Dr. Timothy Coetzee et al have a vision for MS research that is unlike anything I've come across in MS investigation. I'm a huge supporter of the 'FastForward' programme but remain disappointed by how little it has delivered in real terms".

FastForward aim to help bridge the funding gap in Innovation and whilst you are entitled to your opinion about delivery, I think you may have an unrealistic expectation of what they can achieve in the few years that this initative has been in existence.

It draw you attention to a post that was done over the summer. Some of the new readers may not have looked at, if you remember it stop now and save yourself a few minutes.

This is a way of getting across the amount of time that it takes to get a drug to market. Even if drug studies were being funded at the the Phase III study level it would take 3-5 years to get some success which is as long as fastforward has been around. However, many projects are not so advanced and are in the first bit of the board and it will be a few more years for them to go forward and things will fail along the line.

CoI: We have been fortunate to have been supported by FastForward

Drug-The Game-Part I

Each day we hear about drug-treatment this and drug-treatment that, but why aren't you doing something and giving me a drug that will work for MS?

The MS community is trying!. Drugs are appearing with increasing frequency, but progress is painfully slow!. Why is this the case?

The answer is in Drug - the boar
d game.

"I think the perception, or at least the Hope, of develop
ing drugs for MS is abit like:"
You have an idea !...You test it out!...Drug is ready for treatment of MSers!....It's a Sprint to the Finish

However the Reality it is... it's a Long-Distance Race...or Marathon
You meet scientists, see the TV, read an article or talk to MSers in the stands..The Idea is born.....You start running! .....but, You have to get more energy for your idea to keep you going...so,
You have to write a grant to a charitiy to get funds to do the research. With each lap of the track (taking 6months -1 year), your Idea gets stronger.This idea gets sufficiently mature, so that you feel that you can reach the end! You think that you can make a drug to hopefully treat MS.

However, you are not at the finish..........,You are at the Beginning!
You now have your Piece to Start........Drug


A game of chance..where the winner takes all and the loser really looses..big time!!

Drug The Game Part II

Why Does it take So Long to Develop a Drug For MSers
Find Out! Play.......Drug

You now have your Piece to Start........Drug

Basic Rules
File Patent to Start (Throw a six pay £100,000). The patent gives you legal protection to develop your drug for a number of years before competitors can do anything similar. There are no Short Cuts (Throw 3 or above to move one space forward). Each Space Forward Costs You Money. The Further You Go the More it CostsYou need Money in Hand to Move to the Next Stage of Paper Work.First to Get Across the Finish Line Wins.. Get $1billion
There are many Tasks to complete to get round to the winning post


Optimize the Drug so you do Chemistry (Chem) and Laboratory Work.....You show that it is probably safe and that it works in models of MS. You test the Drug in Animals to show that it is safe and shows no Toxicity..... You get Ethical (E) Approval to perform studies in humans then.....You test the Drug in a few healthy people, so it's Safe for human use. Phase I Trial....then you test the Drug on MSers to see that it's Safe and maybe works. Phase II Trial. An Independent Panel, do an interim analysis (IA) to check for Safety Issues. Then You test the Drug in alot of MSers to show that it Works (Phase III Trial. Then you get Regulatory Approaval (from FDA, EMA) to Sell the Drug to MSers.

You win the Game (or do you?)

Whilst you are spending your millions, supporting the development of another drug you...
Do the paper work such that you hopefully gets approval by NICE
Convince Government to prescribed the drug to MSers. The Drug Company checks to ensure that drug continues to be safe. Phase IV

However back to the Game. You can't do all this without money, so we need a Financial Zone


This contains Charties, Philantrophist, Government, Venture Capitalist and Drug Companies. Stay in Financial Zone and take as many turns as necessary to get enough funds to proceed

Each Move in the Financial Zone is the throw of the Dice..........
This can mean it takes time to go back to charities at each stage of development
Therefore it helps if you have the Support of a Drug Company

At each set of Paper Work, Turn a Card (See next installment for details) to See your Fate!

Remember...there are a lot more Snakes than there are Ladders,
Many of them will Send you back to Start!

"Recently you have seen that Lacquinimod failed to reach the target in a phase III study. The company either has to do the trial again or go back to the start! A few months ago Movecto (Cladribine) reached the stage of Regulatory Approval and was withdrawn.
Gilenya turned down by NICE twice for being too expensive".


Drug-the Game Part III

So you all know the Rules, How much is it Going to Cost?
Alot


Whats on the Cards?


Financial Zone (FZ)
Charity Funding
Grant Funded-Role Dice For Amount
Grant Needs Rewriting-Try Again Next Turn
Grant Rejected
-Miss a Turn and Try Again
Grant Rejected-Return to Start
Not Enough Funds-Miss a Turn
Project funded byPhilantropists-Role Dice For Amount
Project funded byVenture Capitalist-Role Dice For Amount
Charity changes Priorities- Return to Start

Company Funding
(a)
Project Funded-Role Dice For Amount
Company Change Priorities. Drug Project Dropped. Go back to Charity Route
Company Merged. Drug Project Dropped. Go back to Charity Route
Company Merged. Drug Project Fast-Tracked: Role Dice for amount + Gain £2,000,000
Funded by Bad Profits Forcast-Role the Dice For Amount and Half-it.


Chemistry (Chem) Results
Drug has not Detectable Issues that Prevent Development--Proceed to Toxicology
Drug causes Degradation of Other Drugs-Drug Fails.Back to Start
Drug causes Degradation of Other Drugs-Need More Chemistry-Go Back to Microscope
Drug causes Mutations in cells.Drug Fails.Back to Start
Drug causes Mutations in cells-Need More Chemistry-Go Back to Microscope
Drug doesn't work in EAE.Drug Fails.Back to Start
Drug doesn't work in EAE.Need More Chemistry-Go Back to Microscope
Drug may cause tumour growth-Drug Fails.Back to Start
Drug may cause heart problem-Drug Fails.Back to Start
Drug may cause heart problem--Need More Chemistry-Go Back to Microscope
Drug can not be delivered using a Pill,-Use Injectable-Miss a turn & Proceed to Toxicology
Drug can not be delivered using a Pill, Drug Fails-Go Back to Start
Drug can not be delivered using a Pill, Need More Chemistry-Go Back to Microscope
Drug is rapidly Degraded. Drug Fails-Go Back to Start
Drug is rapidly Degraded. Need More Chemistry-Go Back to Microscope
Drug is rapidly Degraded. Need More Chemistry and EAE study-Go Back to Microscope/Mouse
Drug can't get into Brain. Drug Fails-Go Back to Start
Drug can't get into Brain. Need More Chemistry-Go Back to Microscope
Lawyers Did Not File Patent at Start. Competitor has Patent.Project Fails-Go Back to Start
Lawyers Did Not File Patent at Start. Now Filed. Extra £20 million at Completion
Patent Validity is Challenged. Win case Lose £100,000 and Proceed to Toxicology
Patent Validity is Challenged. Lose £100,000 and Go back to Start
Pharmaceutical company buys the drug-Use Company FZ
Pharmaceutical company buys the drug-Get £1,000,000 & Use Company FZ
Pharmaceutical company buys the drug-Get £3,000,000 & Use Company FZ

Toxicology (Tox) Results

Before being used in humans currrently drugs must be tested on animals (one small mammal species and one large animal species) for the length of time that human trials will take
Animals All Healthy-Proceed to Ethics

Problem with Large Animal Study, Repeat-Back to Rabbit.
Animal Death, Maybe Technical reason, Repeat-Back to Rat.
Animals Death, Project Fails-Go back Start
Animals Death, Repeat Chemistry of Drug-Go back to Microscope
Damage in Tissues, Maybe Technical reason, Repeat-Back to Rat.
Damage in Tissues, Project Fails-Go back Start
Damage in Tissues, Repeat Chemistry of Drug-Go back to Microscope
Animals All Healthy, but need to check higher Drug Dose-Back to Rat
Pharmaceutical company buys the drug-Use Company FZ
Pharmaceutical company buys the drug-Get £2,000,000 & Use Company FZ
Pharmaceutical company buys the drug to stop development. Miss 4 turns + loose £100,000
Lawyers Did Not File Patent at Start. Competitor has Patent.Project Fails-Back to Start
Lawyers Did Not File Patent at Start. Now Filed. Extra £50 million at Completion-Go to Ethics
Patent Validity is Challenged. Win case Lose £100,000 and Proceed to Toxicology
Patent Validity is Challenged. Lose £100,000 and Go back to Start

Ethical (E) Review
All procedures in humans must be approved by an Independent Ethical Review board. People on trial must give informed consent such that they agree to participate and understand the risks of doing so.
Ethically Sound-Proceed to Phase I

Paperwork Not in Order,Resubmit-Miss a turn
Ethical Case Not Made,Resubmit- Miss a turn


Phase I Results
No Adverse Effects-Proceed to Phase II
Drug gets broken down quickly-Reformulate-Go back to chemistry.
Drug induced side-effect. Start again at Chemistry
Drug induced Side-Effect. Start again.
Pharmaceutical company buys the drug-Use Company FZ. Proceed
Pharmaceutical company buys the drug-Get £2,000,000 & Use Company FZ
Pharmaceutical company buys the drug to stop development. Miss 4 turns + loose £100,000
Phase II Interim Analysis (IA)
A independent panel of Doctors ass the the results half way through the study to check if there are safety issues that warrant stopping the trial.
No Health Issues Identified. Continue Trial
Health Issue Identified. Trial Stopped. Go back to Start
Drug is Working So Well. Not Ethical to Continue with Placebo Group. Trial Stopped-Go to Phase III
Placebo Group not Progressing so Positive Results Not Possible. Repeat Trial. Go back to Phase II

Phase II Results (IIR)
No Adverse Effects-Proceed to Phase II
No Adverse Effects and seems to be working-Proceed to Phase II
Drug induced side-effect. Start again at Chemistry
Drug induced Side-Effect. Start again.
Drug causes Cancer. Start again.
Drug causes Infection. Decide How to Mnitor and Treat. Miss Two Turns
Pharmaceutical company buys the drug-Use Company FZ. Proceed

Phase III Results (IIR)
You have to state what the main outcome will be before the trial starts. If that main effect is not found, its a failure even if it has an affect on a other outcomes.
No Adverse Effects and Treats MS-Proceed to Regulatory Approval
No Adverse Effects but Does No. Return to Start
Drug fails to Change One symptom, but treats other symptoms. Repeat Trial
Drug induced side-effect. Start again at Chemistry
Drug induced Side-Effect. Start again.
Drug causes Cancer. Start again.
Drug causes Infection. Decide How to Mnitor and Treat. Miss Two Turns
Pharmaceutical company buys the drug-Use Company FZ. Proceed

Regulatory Approval (FDA/EMA)
To market/sell a drug comes approval is needed from the FDA (Food and Drug Administration, USA) and EMA (European Medicines Ageny, Europe).

Drug Appoved-Throw a Six to Cross Finishing Line and Start Selling the Drug
Paperwork Not in Order-Miss Two Turns and Try Again
Regulators want more Safety Data-Repeat Phase III Trial
Regulators want more Safety Data-Company Pull Out. Back to Start
Regulators want more Safety Data-Company Pull Out, Repeat Phase III Trial with Charity
Regulators want more Efficacy Data-Repeat Phase III Trial
Regulators want more Efficacy Data-Repeat Phase III Trial. Back to Start
Regulators want more Efficacy Data-Company Pull Out Repeat Phase III Trial with Charity

I think you can seee that it is not easy to win and it may take along time to get round the board

Drug-The Game Part IV

Can we speed up the Process of Discovery for MS
You know how long it takes to get road the board to win.......Drug



Find Pathway that may be a useful Drug Target
If the pathway of disease that is present in both MS and Cancer/Epilepsy.

Start with a drug that has won the game for another disease such as in Cancer/Epilepsy. As this Drug has passed all the safety issues, you just need to show it works in MS. Therefore Start with Phase III studies in MS.

This Saves Years

This approach is being used to help find drugs that maybe useful for Progressive MS

Drug-The game-Back Again!

You said " Actual game? Who'll play a game you can almost never win "

Well first thing to say is ask the San Marino Football Team!

However we can increase the odds of completion by increasing the number of "proceed cards" within the "Decks of risk". Secondly if I were to offer a real wad of cash to people who completed the game in the minimum number of moves, or say to the player who wins with the least number of moves within one year, then I am sure some of you would play!. The more the cash prize the more players.

The fastest you can get round is about 50 turns, just think of incentives, the darts player with the nine dart finish or the 147 break in snooker or the hole in one form the golfer. Likwise there is an incentive for the pharmaceutical industry to get round the board and they get a cash prize, with a limited amount of time to spend it.

Education. Drug-The Game. Time lines

You asked for Time Lines about how long for useful drugs.

It is not possible to predict, because each drug is different and the problems they encounter will be different. However "If I came up with the idea for the cure for MS tomorrow how long would it take?".

Well if you start with an Idea at 12, it'll be about 3 before you even start Drug-the Game. Even after you show that the drug is active in animal models of MS, it takes time to get your drug ready for testing in humans and about a year to do the early safety studies in humans. You are now at 6. The trials in MSers (Phase II) take 2-3 years for a drug that effects relapses so we are at 8. For symptom control drugs this will be shorter maybe about a year. For progressive MSers I am sorry to say that we are not yet totally sure (as we need to get an active drug) but hopefully should be no longer than for relapsing MS.
The trials in MSers to show the drug really works (phase III) will take a year or more longer than the earlier studies as it involves alot more MSers than the phase II studies. Therefore it takes more time to recruit enough people for the study So we are now at 11. It takes about another year sorting out the paper work and then getting the regulatory bodies to approve a drug (so we are a 12). Then maybe another year whilst NICE make up their mind about the value of the drug. So we are at 13 and this is "Year" watch. Tysbri took about 14 years to go round the board. I am sorry it is painfully slow..but this is the process that every drug no matter what disase is being examined, must take. The aim is to find drugs that work and are safe. This is set by the regulators. When some drugs were fast-tracked to save time, in some instances safety issues appeared suggesting that a more cautious approach was best. It's all about safety.

As mentioned in Part IV one may start with a drug known to be safe in humans and speed the process up.

There are also drugs at every stage of the game as we speak, and yes there are drugs aimed for progressive MSers in development.

3 comments:

  1. It's amazing that any new drug gets to market. Do you think putting into trials for MS other already proven drugs has speeded up though? I mean, I think the first trials of alemtuzumab on MS were in the early 90's and it's still not approved

    ReplyDelete
  2. I think the two A's from Cambridge
    would have done things differently with hindsight.

    As they would tell you, the road from CAMPATH in about 1983 to Lemtrada in 201?......has been a twisty road and shows some of the difficulties in academics trying to develop their ideas.

    Rule Number 1, would be to find a commercial partner that actually wants to develop your drug for the condition you want it tried in, rather than have is sat on a shelf some where. This what happen to Alemtuzumab a few times.

    However, full marks to the two A's
    for persistence.

    Wonder if company developing the drug will develop competitor drugs that they have sat on the shelf?

    ReplyDelete
  3. I think if we looked in the 1990s we didn't know how to do trials for relapsing remitting MS, people know alot more now, however it still takes a lot of resource and energy to get any drug to market and it is a slow process.

    In terms of trying to use established drugs from other diseases in MS, some of those trials have already been started and others are planned. This is particularly a plan for progressive MS, as it will speed the process as you avoid two sides of the board game.

    The interesting thing will be what happens when one or more of these drugs is actually shown to work. If you don't have pharma behind it, it will be a slow tedious process as academics don't have the skill sets needed for this.

    If alemtuzumab was not a biological but a chemical drug......they would have been
    too slow and would have fallen by the wayside

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.