Risk Communication inNDA (New Drug Application)

Massie Ikeda MD, PhD

Chief Medical Reviewer

Pharmaceuticals and Medical Devices Agency

Standard Disclaimer

• This is not an official PMDA/MHLW guidance or policy statement.

• No official support of endorsement by PMDA/MHLW is intended or should be inferred.

Today’s TopicsWhy do we need:

1. Clinical trials ?

2. Regulatory body ?

3. Risk communication ?

“New Drug” reminds you of・・・

• Newspaper Articles

• Tough Diseases: HIV, Cancer

• High-Techs in Medicine

• Severe Adverse Effects

• Mega Pharma Companies

• Clinical Trials

Why do we need clinical trials ?

• Is it OK with animal data only ?

• Let safe drugs only go into the market？• Are clinical trials dangerous？• Let us leave to the doctors？• Why do we need placebo ?

We humans needour own human data.

You never want dog or cat food on your dinner menu.

The same with your drug.

Are you happy withalternative medicine only?

You probably need drugs whose data have been scientifically

reviewed.

Human Experiment Era

Today’s TopicsWhy do we need:

1. Clinical trials ?

2. Regulatory body ?

3. Risk communication ?

Benchmarking of Drugs: Who does it ?

Independent BodyRegulatory Authority

•PMDA

•FDA

•EMEAIn your home country?

MHLW JPMA

FDA

PhRMA

EMEA

EFPIA

ICH

ICHInternational Conference on Harmonisation of Technical Requirements for Registrat

ion of Pharmaceuticals for Human Use

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

• Japan, USA, EU• To make common regulations and share data

on clinical trials• It is not an academic conference• Working on drugs but not on devices

各種分科会があるTuesday, 8 June 2004Time Code Topic8:00 am - 9:00 am CTD-CG CTD Implementation Coordination Group

9:00 am - 5:00 pmICG Industry Coordination Group9:00 am - 5:00 pmRegulators Regulators Meeting

9:00 am - 5:00 pmM1P MedDRA PtCWG9:00 am - 5:00 pmM2 Electronic Standards for Transfer of Information (eCTD)9:00 am - 5:00 pmE2B EWG Electronic Submission in Individual Case Safety Reports9:00 am -10:30 amS7B/ E14 Safety Pharmocology Qt Prolongation/ Clinical Qt Prolongation10:30 am - 5:00 pmS7B Safety Pharmocology Qt Prolongation9:00 am - 5:00 pmS8 Immunotoxicology10:30 am - 5:00 pmE14 Clinical Qt Prolongation12:00 pm - 5:00 pmQ4 Pharmacopoeial Harmonization9:00 am - 5:00 pmQ5E Comparability of Biotechnological/ Biological Products9:00 am -10:30 amQ8/ Q9/ QSGMP Plenary10:30 am - 5:00 pmQ8 Pharmaceutical Development10:30 am - 5:00 pmQ9 Risk Management9:00 am - 5:00 pmQS Quality Systems12:00 pm - 5:00 pmPDG Pharmacopoeial Discussion Group9:00 am- 12:00 pmPDG/ Q4 Pharmacopoeial Discussion Group/ Pharmacopoeial Harmonization9:00 am - 5:00 pmGT Gene therapy

QE5分科会参加者名簿

What is ICH E5 for?

• For providing good drugs faster to everybody in the world, especially ICH resions.

• It is not intended to bypass important domestic clinical studies.

Importance of ethnic differences

• Intrinsic

PK/PD, genetic analysis (in future), etc.

• Extrinsic

differences in clinical practice, etc.

Ethnic Difference in Alcohol Dehydrogenase

Alcohol Welcome Acceptable HateADH Active Partial DeficientJapanese 56 40 4Whites 100 0 0

Warfarin for NVAF

Japan

US

Coagulation factor mutation

SARS & HLA typing

An example of difference among Asians

SARS & HLA typing

HLAB46Jpn 4.4Krn 4.4Vtnm 13.2Sngp 15.1Kanton 15.4

Importance of ethnic differences

• Intrinsic

PK/PD, genetic analysis (in future), etc.

• Extrinsic

differences in clinical practice, etc.

Japan USA

MHLW approval

Universal health insurance coverage国民皆保険

FDA approval

Health insurance system C

Health insurance system B

Health insurance system A

CTD(Common Technical Document)

as CV of the Drug

Our common ground to analyse the benefits and risks of the drug

CTD as a CV of the new drug

Disclosure & accountability is essential.

CURRICULUM VITAE FORMATFORTENURE AND PROMOTION DOSSIERS

NAME: ___________________________________________________________ (Last)(First)(Initial)EDUCATION: UNDERGRADUATE: ________________________________________ GRADUATE: _______________________________________________POST DOCTORAL: _________________________________________

ACADEMIC APPOINTMENTS (inclusive dates):

OTHER APPOINTMENTS AND PROFESSIONAL CONSULTANTSHIPS (including other remunerated employment):

LICENSURE AND CERTIFICATION:

CTD as CV of the Drug

•Disclosure & Accountability•It is not a brochure or propaganda•Disclosure of not only the benefit•Explain why

•The drug is indicated to the target•The drug overcomes the rivals

CTD is

CV of the drug applicationCommon ground of

communicationKey for disclosure and

accountability

Time to approval  PMDEC/MHLW　 NDA FDA (CDER)

　　 Standard NDAapproved year

approvals

median months to approval

approvals

median months to approval

1997 40 33.6 101 15.01998 58 36.6 65 12.01999 71 30.6 55 13.82000 84 18.8 78 12.02001 57 15.5 56 14.02002

   

67 15.352 15.8

Today’s TopicsWhy do we need:

1. Clinical trials ?

2. Regulatory body ?

3. Risk communication ?

Our Mission

BenefitRisk

No bad news is bad news

when people are not aware of its shadow.

Why not share the bad news ?

because it comes out sooner or later.

Difficulties in risk communication

LiabilityConflicts of interestsUncertainty & Variety

Adverse events: Drug-related on notOne understands A causes B but others do notChanges as time goes by

But we have to share bad news because:

It will come out, anyway.Early intervention before disasterStay calm & avoid panicTo correct the system effectivelyTo make no scapegoat

Common Flaws in NDA

• Focus only on efficacy instead of safety

• Insisting on safety:– No significant difference compared with the

placebo– No causal relationship– Very low frequency– No similar case in PMS outside Japan

Our Common Aim-Regulatory Authority & Pharma Co-

Good Drugs for People

Not conflict but Cooperation

The sooner, the better ?The lessons from Rofecoxib ( Viox

x)• Cox2 Inhibitor

– Stomach-friendly super aspirin– FDA approved in May 1999

• Voluntary withdrawal in September 2004

• Due to an increased risk of cardiovascular events (including heart attack and stroke)

Stop Confrontation

Drug Co.

Citizens

Government

Media

Future Issues

• Synthesizing data on safety– Pharmacovigilance system– Harmonization on safety data

• Safety and order-made medicine, e.g. SNP

• Media Relation– Risk Communication with lay press & people