Thursday, September 20, 2007

The Product Pipeline and Clinical Trials: Bringing a Drug to Market - Full Version!

 

I. Pre-clinical Steps in the Product Pipeline: How does a drug candidate (recombinant or otherwise) get through the federal regulatory processes and finally make it to market?

 

1. Discovery Research: (~$155-225 M), ~ 5.5 years!!!

• Lead compound screening: Promising target or lead molecules are identified and tested as candidates for drug development.($15M - $35M)
  
  
• Discovery testing: Effect on tissue culture cells - Human/animal ($20M - $40M)
  
  
• Scale-Up: Can drug be manufactured safely & economically (ongoing) ($82M - $100M)
  
  
• Stability and Formulation: Is drug adequately stable in chemical, light, moisture, and during formulation into tablets and capsules. Does the compound's solubility allow it to be absorbed in therapeutic concentrations in the body (ongoing). ($38M - $50M)

2. Pre-clinical: ($65M - $90M) ~ 4 years!!

• ADME/Tox: "In vitro (cell cultures) and in vivo (animals) before human testing:
• Absorption - how does the drug enter the body - reach the plasma/ bloodstream
• Distribution - where the drug goes in the body after it has been absorbed = plasma
• Metabolism - how the drug is changed by the body - e.g. in the liver CytP450s
• Elimination - or "clearance" - the route by which the drug or metabolites leave the body
• Note: 30% of all drug candidates in the pipeline CRASH AND BURN at this step due to toxicity profiles and side effects" Lots more interesting ADME info

• FDA will require in IND 3 components of toxicity: "(a) a pharmacological profile of the drug in living cells/animals; (b) drug toxicity studies in at least two species of animals, and (c) short-term toxicity studies ranging from 2 weeks to 3 months."
  
  
• File for patent protection: (PS. This is a good little article!) If things look promising at this point, the company will file a US Patent Application (to protect their drug candidate from use / commercialization by others), and possibly international patent applications.
  
  
  • Note: In the US, the "First to Invent" gets the patent; in almost all other countries, the "First to File" gets the patent. People in industry MUST keep up-to-date, signed lab notebooks! More about this when we talk about patents!
    
  • The 20-year patent protection clock starts ticking when and if the patent is granted (~ within 2 years or so?), even though the product will NOT be to market for another 6-8 years!!! The Hatch-Waxman act can 'give back' some of that time by extending the patent for 1/2 of the years the drug was under development and testing. More on this later.

3. File an IND to the FDA: To pursue human studies, must first submit an Investigational New Drug application to the FDA for approval. The FDA's Center for Drug Evaluation and Research (CDER) reviews the IND, and The Center for Biologics Evaluation and Research (CBER) regulates biological products.

• The IND is "the result of a Successful Pre-clinical Trial" AND the only way to advance to human clinical trials.
• The IND must provide pre-clinical data in 3 areas to justify the testing of the drug in humans:
  • Animal Pharmacology and Toxicology Studies (ADME/Tox) (see a-c above)
  • Manufacturing Information - can the company produce the product as a medicine?
  • Clinical Protocols and Investigator Information - VERY detailed!
• The IND review process and all the steps that have to be completed before clinical trials can begin - yikes!
• 30 days after receipt by the FDA, the IND is given either a "safety acceptable to proceed" OR a "clinical hold decision".
• The IND must be filed annually until the clinical testing is over.
• About 85% of all IND applications move on to begin clinical trials.
• More later on ' Treatment IND's / 'Emergency use IND's (ie: Compassionate access)

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II: Clinical Trials -Testing experimental drugs in humans:

Refer to Dr. Michael Turik's lovely powerpoint presentation.

 

An addition about Inclusion/exclusion criteria: Who can participate in a clinical trial (inclusion and exclusion criteria)? (information from link)

• "Before you join a clinical trial, you must qualify for the study.
• Guidelines are based on such factors as age, type of disease, medical history, and current medical condition.
• Some research studies seek volunteers with illnesses or conditions to be studied in the clinical trial, while others need healthy volunteers. .
• The factors that allow you to participate in a clinical trial are called inclusion criteria and the factors that keep you from participating are called exclusion criteria. It is important to note that inclusion and exclusion criteria are used to identify appropriate participants and keep them safe.
• The criteria help ensure that researchers will be able to answer the questions they plan to study."

A review of NDAs:

File an NDA with the FDA: The FDA reviews all drugs and clears them for marketing, mandated by the Prescription Drug User Fee Act (PDUFA, 1992), that allows the FDA to charge drug companies a fee for reviewing their NDA / BLA. Previously, taxpayers alone paid through Congressional budget approval.

• New Drug Applications (NDAs) typically contain 120,000 pages of data and take the FDA a median of 12 months to review.
• Biologics License Application (BLAs) are similar, and are used for biologics (most biotechnology drugs!) drugs derived from living sources.
• The FDA either approves the drug, denies approval, or sends the dreaded "Refuse-to-file" (RTF) letter that sends the company back to redo portions of its clinical trials before ruling: provide more data, answer difficult questions, defend product labeling statements; can set a company back for months or years ! (Better than having an unsafe product on the market, though!)
• Biotech stock prices* hang in the balance during this time -- between phase III clinical studies and the NDA decisions [*as well as HUMAN LIVES of course...]
• We won't go here, but if you want to read the story about the FDA's Refuse-to-File letter to Imclone (the sad tale of "Insider pessimism" involving Martha Stewart - formerly inmate Stewart, Samuel Waksal - now inmate Waksal and others), see Securities and Exchange Commission v. Martha Stewart and Peter Bacanovic.
  
  

Examples of Clinical Trials - published:

The OTC trial: Pre-clinical and Phase I: James Wilson, patient Jesse Gelsinger Snif.

Phase II Efficacy: Endostatin Aug 2006: Back to the drawing board!
Phase II Efficacy: J Clin. Oncology, 2001 [PDF] Phase II Study of Rituximab Vose et. al . - a much better outcome and a great paper!

Phase III: December 4, 2006 End of Drug Trial Is a Big Loss for Pfizer

Phase III: Good news! Docetaxel (D) versus docetaxel plus gemcitabine (DG) as front-line treatment of patients with advanced non-small cell lung cancer: A randomized, multicenter phase III trial.

Phase III: Erbitux increases overall survival in Phase III lung cancer study and related NY Times Story posted to our website: ImClone Claims Positive Erbitux Results on Lung Cancer: ImClone Systems Inc. and Bristol-Myers Squibb Co. claimed Tuesday that the drug Erbitux improved the survival rate of patients with the most common type of lung cancer in a late-stage study. Shares of ImClone climbed $6.97, or 18 percent, to $44.90 Tuesday. The stock reached a 52-week high of $47.22 earlier in the trading session.)

 

After the NDA is filed:
Phase IV trials: Additional approval after the drug or treatment has been marketed...

• Measure the drug's impact on patient sub-groups / population (especially children, the elderly, pregnant women)
• Supply information on as-yet undetected adverse outcomes, especially in sub-group populations.
• Provide additional information on the drug's long-term morbidity and mortality profile.
• Phase IV trials can be conducted voluntarily OR at the request of the FDA. The FDA has the right to make Phase IV studies a condition of market approval.
• While phase IV trials are conducted, the company can begin to market its product.

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III: Drug Delivery Options

 

There are 3 main routes to get a drug into the bloodstream / plasma:

 

	Advantages	Disadvantages
Parenteral (IV, IM, SubQ)	1. Professionally administered 2. Compliance 3. 100% bioavailability	1. Fear of needles 2. Sterile conditions required 3. Invasive / infection
Oral (Enteral)	1. Inexpensive formulation 2. Easy to take, flexible options: 3. Pills, tablets, enteric-coated, liquids,	1. First pass metabolism 2. Compliance 3. Poor solubility
Pulmonary	1. Quick entry into bloodstream (and lungs) 2. Large surface area 3. Non-invasive	1. Lung inflammation 2. Poor dosage control

 

What other ways can you think of to get medicines into the blood plasma?

Sublingual, intranasal, epidural, topical...

 

Way Cool Drug Delivery: Alza

Founded in 1968 by Dr. Alejandro Zaffaroni

6 other Drug Delivery options:

 

1. OROS Oral Delivery: 13 drugs!

• Each of the 3 has a "Push" compartment that swells with water and slowly releases drug.
• OK for liquids or for 2 different drugs / concentrations
• Procardia XL - extended the patent AND the indications!, Glucotrol XL, Sudafed 24 Hour, Concerta for 12 h ADHD control- Pfizer's first $1B drug...!

2. D-Trans (transdermal)

• Patch: backing layer, drug reservoir, rate-controlling film and an adhesive.
• Transderm Scõp, Estraderm HRT, Nicoderm and Nicoderm CQ, Duragesic® (fentanyl) CII, Testoderm, Transderm Nitro

3. STEALTH Liposomes - Pegylated!

• Liposomes are recognized by the immune system and often destroyed before significant amounts of drug can reach the intended disease site.
• STEALTH liposomes evade immune system by PEGylation
• Doxil (Adriamycin)

4. DUROS Implants

• Titanium implant placed under the skin of a patient’s upper arm with an osmotic engine / piston
• Viadur: For prostate cancer. Releases leuprolide acetate, which reduces the amount of testosterone produced by the testicles to treat the symptoms of advanced prostate cancer. Viadur releases leuprolide acetate for 12 months

5. E-Trans (transdermal +!)

• Electrotransport technology = Low-level electrical energy to actively transport drugs through intact skin
• Patient-controlled transdermal delivery =self-administer up to six times per hour.
• E-TRANS Fentanyl

6. Macroflux - Microneedle array

• Oct 06: spun out into its own company with J&J: its own company: macroflux.com
• Nice clinical trial results, but no products on the market yet~!

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IV: Beyond Clinical Trials...Some variations on the basic theme...

 

1. Speeding things up: Since 1997, the FDA has been approving drugs at almost twice its usual rate (6 months rather than 10 months), thanks in part to money provided by the drug industry to speed the drug review process.

Fast Track Review: (since 1997) Investigators work closely with the FDA; can submit individual parts of the NDA to the FDA one at a time to speed approval.

Priority Review: (since 1997, up for renewal Oct 2007!) The following letter codes describe the review priority of the drug:

• S - Standard review for drugs similar to currently available drugs - offer only minor improvement (or none) over drugs already on the market.
  • The FDA has 60 days to accept or reject the NDA for review,
  • FDA action at ~10 months
    
    
• P - Priority Review for drugs that represent potential major advances in health care - reserved for products that address unmet medical needs
  
  
  • The FDA has 45 days to accept or reject the NDA for review
  • FDA action not later than 6 months.
  • [PDF from the FDA about PDUFA] :) See more below
    
• Biotech 101: The Road to FDA Approval: "The "PDUFA clock" starts on the day the NDA is filed with the FDA. Biotech firms typically issue press releases when drugs are filed, so it's relatively easy for investors to count forward six months from that day to find the date by which the FDA must issue its decision, often referred to as the "PDUFA date."
• On March 7, 2006: FDA Grants Priority Review For Bristol-Myers Squibb's Investigational Oncology Treatment Dasatinib
  • NDA submission date: December 28, 2005.
  • PDUFA date: June 28, 2006.
  • Did it happen? PRINCETON, NJ -- June 29, 2006 FDA Approves SPRYCEL™ (dasatinib) With Two Indications (CML, ALL)
• This semester - Fall 2007: Neurocrine Biosciences, Inc. (NBIX) Announces PDUFA Action Date of December 12, 2007 for Indiplon Capsules
• An Investor's Guide to the New PDUFA
  

Accelerated Review / Approval : (Since 1992) For serious or life-threatening illnesses, or for illnesses for which no therapy exists or a significant advantage over existing drugs.

• Puting the drug up for early review after establishing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, rather than the primary endpoint originally proposed in the study.
• Approval is granted even though there may be some "uncertainty as to the relation of that endpoint to clinical benefit... BUT the sponsor MUST agree to conduct post approval studies and to accept expedited procedures to remove drugs when the further studies failed to confirm effectiveness.
• TWO Key features: (review!)
• 1. Surrogate endpoint that reasonably predict that a drug provides clinical benefit (ie: approving drugs to prevent strokes (primary endpoint) on the basis of evidence that they lower blood pressure, OR a drug to extend survival of breast cancer patients (primary endpoint) if clinical trials reveal that the drug has an ability to shrink tumors dramatically, within 4 weeks of receiving the drug.
• 2. Continuation of Phase III/IV testing after market approval to demonstrate benefit (if not confirmed, the FDA can withdraw the product).

2. Compassionate Use: An alternative to clinical trials for desperately ill patients.

• Access to experimental medications before the drug has approval, to save the life of a critically ill patient.
• Procedure: M.D. applies to the pharmaceutical company and FDA via a Treatment IND; approval considered on a case-by-case basis. Criteria:
  
  
  • Advanced / Serious / life-threatening disease
  • No approved treatment options / undergone all standard treatments without success.
  • No appropriate clinical trial options (or patient does not substantially satisfy entry criteria).

• However, if designed well, a compassionate access program can produce enough data to help the drug win FDA approval.
• The company usually has valid reasons for refusing compassionate access - giving an experimental drug to a few people before it is proved wastes resources, time, and money (and the drug itself) that could be spent on determining whether the drug works.

3. The Orphan Drug Act of 1983,

• Encourages development of new drugs for the treatment of rare diseases, such as Huntington's disease, ALS (Lou Gehrig's disease), Tourette syndrome, and muscular dystrophy, Gaucher's disease.
• Afflict so few patients (<200,000) - not economically feasible for pharmaceutical companies to compete in these markets.
  
  
• The ODA provides 4 financial incentives

  1.) Tax Credits for the cost of clinical research.
  2.) Government grant funding.
  3.) Assistance for clinical research.
  4.) Seven years of exclusive marketing for the first sponsor that passed through the FDA!

• The FDA has approved ~260 orphan drugs since 1983, with 1,400 under development. [Image]
• Cerezyme - that's some orphan drug!! "Cerezyme is Genzyme's (GENZ) treatment for Gaucher's disease, a rare genetic condition marked by an enlarged liver and spleen, low red blood cell counts, and thinning of bones. Genzyme charges roughly $170,000 to $600,000 per patient per year!!! Even though Genzyme's patent protection for this drug expired years ago, 60 percent of the estimated worldwide market of ~4,000 patients still take Cerezyme. See the link - Who Pays?

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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V: Timeline!

FromThe Drug Development and Approval Process : It takes 15 years on average for an experimental drug to travel from the lab to U.S. patients. Only five in 5,000 compounds that enter preclinical testing make it to human testing. One of these five tested in people is approved.

	Early Research /Preclinical Testing	File IND at FDA	Clinical Trials			File NDA at FDA	FDA		Phase IV
			Phase I	Phase II	Phase III
Years	6.5		1.5	2	3.5		1.5	15 Total	Additional post- marketing testing required by FDA
Test Population	Laboratory and animal studies		20 to 80 healthy volunteers	100 to 300 patient volunteers	1000 to 3000 patient volunteers		Review processs/ approval
Purpose	Assess Safety and biological activity		Determine safety and dosage	Evaluate effectiveness, look for side effects	Confirm effectiveness, monitor adverse reactions from long-term use
Success Rate	5,000 compounds evaluated		5 enter trials				1 approved

 

 

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Not on exam! but explore if you are interested

What about generics? ANDA "Abbreviated New Drug Approval - is used by generics manufacturers of a previously approved drug. Once approved as bioequivalent ('comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use'), an applicant may manufacture and market the generic drug product." Under Hatch-Waxman, generic manufacturers seek FDA approval before the expiration of the patent so they are ready to roll the day the innovator drug goes off patent!!!

What about herbal supplements? Passage of the Dietary Supplement Health and Education Act in 1994 restricted the Food and Drug Administration's control over dietary supplements, leading to enormous growth in their promotion.

 

For more information, see An FDA Guide to Dietary Supplements - very readable, with a section (but not a very reassuring one...) on 'Monitoring for Safety'. "Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), the dietary supplement manufacturer is responsible for ensuring that a dietary supplement is safe before it is marketed. FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market. Generally, manufacturers do not need to register their products with FDA nor get FDA approval before producing or selling dietary supplements. Manufacturers must make sure that product label information is truthful and not misleading." YIKES!

 

What about BTC 'behind the counter' designations?
Some Cold Medicines Move Behind Counter: Well, wave the flag against illigal drug trafficking:

'Under the Patriot Act signed by President Bush on March 9, 2006, all drug products that contain the ingredient pseudoephedrine must be kept behind the pharmacy counter and must be sold in limited quantities to consumers after they show identification and sign a logbook.' (Sad article in US Pharmacist about the Meth Crisis, ca. 2006)

 

Good article: Pharmacy Times, January 2007:
A Third Category? Medicines Go Behind the Counter
Handled case-by-case for now; would take an act of Congress to make BTC an official designation.

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Objectives for Clinical Trials: (posted Thurs 9/20)
TWO lectures: September 18 (Dr. Michael Turik) and Sept 20, 2007 (kmarrs)
Study powerpoint slides carefully and compare to our web notes!

1. Describe the acronym ADME/Tox and how these 4 criteria influence the drug level and pharmacological activity of a drug candidate
2. Explain the purpose of an IND and what pre-clinical data must be presented to the FDA to justify the testing of the drug in humans (look in both our web notes and Dr. Turek's slides, especially slides 25-27, 39). When must the FDA make their deteminiation after the IND is submitted, and what are two alternate outcomes of the FDA decision?
3. Compare and contrast Phase I, II, III, and IV clinical trials (look in both our web notes and Dr. Turek's slides, especially slides 28-32). For each stage, be sure to have a rough idea of how many years, how much $$, and how many patients (where applicable) would be involved at each stage.
4. Distinguish between inclusion and exclusion criteria for a clinical trial.
5. Compare the 3 main routes to get a drug into the bloodstream (parenteral, enteral, and pulmonary) - advantages and disadvantages.
6. Explain the 6 'way cool' drug delivery options manufactured by Alza: OROS (ex: Concerta), D-trans (ex: Nicoderm, Estroderm, Fentanyl), Stealth Lisposimes (ex: Doxil), DUROS (ex: Viadur), E-Trans (ex: E-Trans Fentanyl), Macroflux (no products yet!)
7. Important: Compare and contrast the three process that can speed up NDA consideration and FDA approval:
   • Fast Track
   • P- (priority) Designation (and PDUFA Date calculation, vs. S-Designation)
   • Accelerated Approval (surrogate vs. primary endpoint, continuation of clinical trials).
8. Describe Compassionate access and criteria for Treatment IND consideration
9. Explain the Orphan Drug Act, why it was implemented, how it provides an incentive to pharmaceutical companies, and describe a few Orphans!